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Introdction Since their first isolation, embryonic stem (ES) cells have been regarded as the gold standard for potential use in cell-based regenerative medicine. The pluripotent nature of these cells provides them with, the ability to self-renew indefinitely in culture while retaining the capacity to differentiate into any cell type in the body1). However, the fact that ES cells can only be derived from early-stage embryos precludes the establishment of autologous cell lines for patients and immune rejection hinders the use of nonautologous ES cell lines2). The advent of mammalian somatic cell nuclear transfer (SCNT) first appeared to offer solutions for overcoming these roadblocks. SCNT is a technique whereby the DNA of an unfertilized egg is replaced by the DNA of a somatic cell. Although significant advancements toward this goal have been made, successful SCNT into human cells remains an elusive goal and is fraught with social and logistical concerns3). Alternative methods for deriving pluripotent cells, such as cell fusion and culture-induced reprogramming, have been developed, but these approaches still suffer from severe practical and technical limitations4).

cessful SCNT into human cells remains an elusive goal and is fraught with social and logistical concerns3). Alternative methods for deriving pluripotent cells, such as cell fusion and culture-induced reprogramming, have been developed, but these approaches still suffer from severe practical and technical limitations4). In 2006, Takahashi5) and Yamanaka reported the astonishing discovery that somatic cells could be reprogrammed to adopt the pluripotent stem cell state. The generation of pluripotent cells by exogenous expression of transcription factors circumvents many previous limitations because this approach is not technically demanding and does not require embryonic material or oocytes. We therefore believe that this discovery which is now known as "induced pluripotent stem cell technology" (iPS) will have a significant impact on regenerative medicine. In this article we review the current methodologies used for generating iPS cells and then discuss their potential clinical applications.

l or oocytes. We therefore believe that this discovery which is now known as "induced pluripotent stem cell technology" (iPS) will have a significant impact on regenerative medicine. In this article we review the current methodologies used for generating iPS cells and then discuss their potential clinical applications. Reprogramming somatic cells towards pluripotency by defined transcription factors5) To establish the transcription factors necessary for reprogramming of differentiated cells, mouse embryonic fibroblasts and tail-tip fibroblasts of mice were initially used. Reprogrammed somatic cells were identified by selecting for the reactivation of the Fbx-15 gene locus with a neomycin-reporter cassette whose expression is restricted to the early stage of embryonal development. Cells which are only resistant to G418 selection allowed growth of ES-cell-like colonies and cells derived by sub-culturing these ES-like colonies were designated as "induced pluripotent stem cells." It was found that of the 24 candidate genes that are implicated in the establishment and maintenance of the pluripotent state, Oct4 (Pou5f1), Sox2, c-Myc, and Klf4, were sufficient to mediate reprogramming. These iPS cells had fully demethylated Oct4 and Nanog promoters and could contribute to the formation of germline-competent chimeras upon injection of blastocysts, a characteristic which demonstrates true pluripotency.

he pluripotent state, Oct4 (Pou5f1), Sox2, c-Myc, and Klf4, were sufficient to mediate reprogramming. These iPS cells had fully demethylated Oct4 and Nanog promoters and could contribute to the formation of germline-competent chimeras upon injection of blastocysts, a characteristic which demonstrates true pluripotency. Preferred methods for preparation of iPS cells First-generation iPS cells were generated by retroviral transduction5). Since then, the technique has been optimized and reproduced in a number of different processes6). Several important variables include the choice of cell type for reprogramming, the choice of the combination of genes and small molecules used for reprogramming, as well as the gene transfer method (Fig. 1).

ransduction5). Since then, the technique has been optimized and reproduced in a number of different processes6). Several important variables include the choice of cell type for reprogramming, the choice of the combination of genes and small molecules used for reprogramming, as well as the gene transfer method (Fig. 1). For the first reprogramming attempts of both mouse and human cells, fibroblasts were used as the starting cell population5). Since the original success of fibroblast reprogramming, multiple cell types have been used for reprogramming, including keratinocytes, neural progenitor cells, hepatocytes, stomach epithelial cells, pancreatic beta cells and intestinal epithelial cells7). Several factors must therefore be considered in determining the optimal cell type for a given application: (1) the ease with which reprogramming factors can be introduced, which varies according to cell type and delivery approach; (2) the availability and ease of derivation of the given cell type; and (3) the age and source of the cells used6). An inverse correlation has been effectively demonstrated for the differentiation stage of target cells. For example, with mouse hematopoietic stem and progenitor cells being more efficiently reprogrammed than terminally differentiated B and T lymphocytes8, 9). While fibroblasts are likely to remain the choice cell type in basic research efforts, iPS cells derived for therapeutic purposes will require the donor cells to be easily attainable, less likely to contain genetic aberrations, and easy to reprogram using transient approaches6).

differentiated B and T lymphocytes8, 9). While fibroblasts are likely to remain the choice cell type in basic research efforts, iPS cells derived for therapeutic purposes will require the donor cells to be easily attainable, less likely to contain genetic aberrations, and easy to reprogram using transient approaches6). Since the first report of reprogramming, it has become evident that there is some flexibility in the factors needed to reprogram somatic cells. Of the original four transcription factor-encoding genes, c-Myc is not strictly required for the reprogramming of somatic cells and Klf4 and Sox2 have been shown to be dispensable in reprogramming strategies utilizing cell types that endogenously express them. Oct4 is the only factor that cannot be replaced by other family members and the only one that has been required in every reprogramming strategy in either mouse or human cells8).

tic cells and Klf4 and Sox2 have been shown to be dispensable in reprogramming strategies utilizing cell types that endogenously express them. Oct4 is the only factor that cannot be replaced by other family members and the only one that has been required in every reprogramming strategy in either mouse or human cells8). To aid in the production of epigenetic modifications during the reprogramming process, several studies have examined the use of small-molecule compounds. Importantly, small molecules, including DNA methyltransferase inhibitors10), the histone deacetylase inhibitor valproic acid11), and the histone methyltransferase inhibitor BIX-0 129412), have been shown to substantially improve the efficiency of reprogramming, even in cases without inclusion of exogenous Klf4 and c-Myc (for valproate) or exogenous Sox2 and c-Myc (for BIX-01294). In addition, inhibition of DNA methyltransferase activity by 5-aza-cytidine also was found to improve reprogramming efficiency13). Recently, another small molecule, transforming growth factor RI kinase inhibitor II, has also been reported to replace Sox2 by the induction of Nanog14). Of note, the effects of these small-molecule agents are not directed towards specific reprogramming events, and it remains to be determined whether full reprogramming through the exclusive use of chemicals is possible.

h factor RI kinase inhibitor II, has also been reported to replace Sox2 by the induction of Nanog14). Of note, the effects of these small-molecule agents are not directed towards specific reprogramming events, and it remains to be determined whether full reprogramming through the exclusive use of chemicals is possible. iPS cells have been generated using a number of different gene transfer methods, including retroviral, lentiviral, and adenoviral vectors and nonviral plasmids, and recently by direct recombinant protein delivery8). Initial generations of mouse and human iPS cells employed retroviral vectors5) and constitutive lentiviruses15). These viral systems, however, have been criticized because they are permanently integrated into the genome and endeavors to make iPS cells more therapeutically applicable have led to the pursuit of non-integrative approaches. A refined system which employs the Crelox system or transposases in which reprogramming factors could be delivered into the host genome and removed without any residual elements has been recently developed16). More importantly, iPS cell generation has now been achieved without genomic integration. This has been accomplished using adenoviruses17), repeated plasmid transfection18), and recombinant proteins19) and via the use of episomal vectors20) in human cells. However, the reprogramming efficiency obtained using these delivery systems tends to be dramatically lower for most cell types relative to the standard retroviral/lentiviral mediated reprogramming7). Ultimately, the logistical, financial, and practical aspects of each technique must be taken into account. It is likely that the optimal cell reprogramming method will be determined by the intended application of the reprogrammed cells. Currently, for example, the fastest and most efficient method of creating human iPS cell lines through lentiviral and retroviral transduction might represent the preferred approaches for generating iPS cells for use in large-scale drug-screening programs and disease modeling8).

ed application of the reprogrammed cells. Currently, for example, the fastest and most efficient method of creating human iPS cell lines through lentiviral and retroviral transduction might represent the preferred approaches for generating iPS cells for use in large-scale drug-screening programs and disease modeling8). Clinical relevance The recent introduction of iPS cell technology has opened a new avenue not only for cell replacement therapy but also for disease modeling and drug development21). The generation of human iPS cells from patients with a variety of genetic diseases with either Mendelian or complex inheritance including X-linked adrenoleukodystrophy (X-ALD), amyotrophic lateral sclerosis, Duchenne and Becker muscular dystrophy, Parkinson's disease, Huntington's disease, Gaucher disease type III, and Down syndrome is also possible. Such disease-specific iPS cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby enabling disease investigation, drug development and cell therapy21).

nson's disease, Huntington's disease, Gaucher disease type III, and Down syndrome is also possible. Such disease-specific iPS cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby enabling disease investigation, drug development and cell therapy21). Conclusion As a result of its tremendous potential in a wide variety of clinical and research applications, there is great interest in cellular reprogramming. The recent successes in iPS cell derivation without the use of viral vectors and genomic integration from human cells has brought the realization of the therapeutic potential of iPS cell technology closer than ever. Importantly, however, there is still much to learn about how this reprogramming process works. The key steps involved in this process consist of the choice of reprogramming factors and molecules, their delivery method, and the choice of target cell type. Given the high level of interest in iPS cells and the large number of laboratories around the world that are now studying these cells, we are hopeful that iPS cell technology will have a positive impact on therapeutic interventions. Fig. 1 Overview of the processes for inducing the derivation of pluripotent stem (iPS) cells and clinical applications.

Introduction Ureaplasma species are the most common bacteria detected in urogenital infections, including nongonococcal urethritis in men and multiple obstetrical complications in women1, 2). Since Ureaplasma spp. can be found in vaginal flora in 40% of sexually inactive and 67% sexually active women, it is known as a commensal in the female genital tract3). Although numerous clinical observational studies were conducted over a period of over 30 years, the clinical significance of these bacteria is still under debate4). These bacteria are considered to be of low virulence; however, Ureaplasma colonization has been associated with infertility5), stillbirth6), preterm delivery7, 8), histologic chorioamnionitis9), and perinatal death in neonates10). This article summarizes recent information on the role of Ureaplasma infection in diseases in preterm infants and future considerations.

Although numerous clinical observational studies were conducted over a period of over 30 years, the clinical significance of these bacteria is still under debate4). These bacteria are considered to be of low virulence; however, Ureaplasma colonization has been associated with infertility5), stillbirth6), preterm delivery7, 8), histologic chorioamnionitis9), and perinatal death in neonates10). This article summarizes recent information on the role of Ureaplasma infection in diseases in preterm infants and future considerations. Ureaplasma spp. 1. Classification and characteristics Ureaplasma spp. is a member of the Mollicutes class, which is comprised of 4 orders, 5 families, 8 genes, and nearly 200 known species, 17 of which are known to use humans as their primary host4). Another well-known member of the Mollicutes class is Mycoplasma spp., in which there are 3 species, Mycoplasma hominis, Mycoplasma genitalium, and Mycoplasma fermentans, which are known to occur in the female urogenital tract. Ureaplasma was first described by Shepard in the 1950s and were detected in the male urethritis11). Recently, Ureaplasma was subdivided into 2 separate species and 14 serovars that have been grouped according to 16S dRNA sequencing results into 2 genetically related biovars3, 4).

o occur in the female urogenital tract. Ureaplasma was first described by Shepard in the 1950s and were detected in the male urethritis11). Recently, Ureaplasma was subdivided into 2 separate species and 14 serovars that have been grouped according to 16S dRNA sequencing results into 2 genetically related biovars3, 4). U. parvum, known as biovar 1, contains serovars 1, 3, 6, and 14, and U. urealyticum (biovar 2) contains the remaining serovars (2, 4, 5, and 7-13)12). Characteristics of all serovars include lack of cell walls, limited biosynthetic abilities, small genome size, and mucosal association in the human host3). The unique characteristic of Ureaplasma is their ability to hydrolyze urea to generate metabolic energy1, 4). Some debates still occur regarding whether there is a difference in pathogenicity exists among these 14 serovars and 2 biovars. 2. Virulence factors Ureaplasma can directly activate the first component of complements and attach to host erythrocytes, neutrophils, spermatozoa, and urethral epithelial cells1). This can induce inflammation in humans and produces multiple manifestations of clinical diseases4). Since Ureaplasma spp. metabolizes urea to generate energy, it also produces secretory products such as ammonia, which may induce a local cytotoxic effect.

cytes, neutrophils, spermatozoa, and urethral epithelial cells1). This can induce inflammation in humans and produces multiple manifestations of clinical diseases4). Since Ureaplasma spp. metabolizes urea to generate energy, it also produces secretory products such as ammonia, which may induce a local cytotoxic effect. Previously reported ureaplasmal virulence factors include IgA protease, urease, phospholipases A and C, and production of hydrogen peroxide13). These factors may allow the organism to evade mucosal immune defenses by degrading IgA and injuring mucosal cells through the local generation of ammonia, membrane phospholipid degradation, prostaglandin synthesis, and membrane peroxidation3). Although phenotypic production of IgA protease and phopholipases was described several years ago, genome examination of multiple serovars has failed to reveal genes encoding these enzymes4). The multiple-banded antigen (MBA) of Ureaplasma spp. is the predominant antigen recognized during the infection process and may be involved in host inflammatory response stimulation. It undergoes a high rate of variation in vitro and exhibits variable sizes in vitro on invasive isolates, suggesting that antigen size variation may be another mechanism through which the organism evades host defenses3, 4). Ureaplasma serovars have multiple MBA genes, and some contain multiple copies of the same type of MBA gene.

s a high rate of variation in vitro and exhibits variable sizes in vitro on invasive isolates, suggesting that antigen size variation may be another mechanism through which the organism evades host defenses3, 4). Ureaplasma serovars have multiple MBA genes, and some contain multiple copies of the same type of MBA gene. 3. Vertical transmission and intrauterine infection Ureaplasmas can be isolated from endotracheal aspirations in up to 40% of newborn infants within 30 minutes to 24 hours after delivery14, 15), and from maternal and umbilical cord blood at these delivery times16). This provided evidence that vertical Ureaplasma transmission and neonatal infection may occur in newborn infants. Additionally, recovery of Ureaplasma from the chorion increased with the duration of membrane rupture, suggesting an ascending route of infection17). Those born weighing less than 1,000 g are at higher risk of infection when the mother is colonized at up to 90% of the infection rate18). The possible pathogenesis involves fetal exposure to ascending ureaplasmal intrauterine infection, passage through an infected birth canal, hematogenous dissemination through the placenta into umbilical vessels, and colonization of the skin, mucosal membranes, respiratory tract, and dissemination into the blood and central nervous system19, 20).

nvolves fetal exposure to ascending ureaplasmal intrauterine infection, passage through an infected birth canal, hematogenous dissemination through the placenta into umbilical vessels, and colonization of the skin, mucosal membranes, respiratory tract, and dissemination into the blood and central nervous system19, 20). Intrauterine infection is now believed to be a major cause of preterm birth, particularly in gestations of less than 30 weeks21). Ureaplasma spp. is the most common isolate identified in amniotic fluid. Isolated Ureaplasma spp. from the chorioamnion has been consistently associated with histologic chorioamnionitis, which is inversely related to birth weight22). Several experimental studies with intra-amniotic inoculation of U. parvum showed that it did not stimulate premature labor in mice23) or sheep24), but did stimulate progressive uterine contractions and preterm delivery in rhesus macaques25). The Rhesus macaque experimental result suggests that species differences result in differences in host response or serovar differences in virulence.

vum showed that it did not stimulate premature labor in mice23) or sheep24), but did stimulate progressive uterine contractions and preterm delivery in rhesus macaques25). The Rhesus macaque experimental result suggests that species differences result in differences in host response or serovar differences in virulence. Ureaplasma spp. infection in neonatal pathogens 1. Congenital pneumonia in preterm infants In the mid-1970s, some investigators suggested a potential role for Ureaplasma in neonatal respiratory disease after isolation of these organisms from lungs of stillborn infants with peumonitis26). Evidence that Ureaplasma spp. cause congenital pneumonia includes isolation of bacteria in pure culture from amniotic fluid, affected lungs of neonates less than 14 hours after birth in the midst of an acute inflammatory response, and chorioamnion1, 20). Other evidence includes demonstration of a specific IgM response in the neonate27), radiographic changes indicative of pneumonia in culture-positive infants28), demonstration of the bacteria in lung tissue using immunofluorescence29), and electron microscopy27).

f an acute inflammatory response, and chorioamnion1, 20). Other evidence includes demonstration of a specific IgM response in the neonate27), radiographic changes indicative of pneumonia in culture-positive infants28), demonstration of the bacteria in lung tissue using immunofluorescence29), and electron microscopy27). 2. Bacteremia and systemic infections Ureaplasma isolation from cord blood was first described in 196930) and in a recent prospective study it was shown that 23% of infants had a positive cord blood culture for this organism31). Cassell et al.32) reported that 26% of neonates culture-positive for Ureaplasma spp. in the lower respiratory tract were bacteremia with these organisms. Ureaplasma has been isolated from gastric aspirates, blood, cerebrospinal fluid (CSF), lung, and brain tissue, although this organism is most commonly isolated from respiratory secretions3). In 2 recent large prospective cohorts, Ureaplasma was detected in 17% of cord blood cultures and 23.6% of serum or CSF polymerase chain reaction (PCR) samples, with U. parvum as the predominant species detected in serum and CSF10, 31).

sue, although this organism is most commonly isolated from respiratory secretions3). In 2 recent large prospective cohorts, Ureaplasma was detected in 17% of cord blood cultures and 23.6% of serum or CSF polymerase chain reaction (PCR) samples, with U. parvum as the predominant species detected in serum and CSF10, 31). 3. Meningitis and neonatal brain injury The largest recent prospective survey of invasive infections analyzed samples from 313 very low-birth-weight (VLBW) infants with suspected sepsis/meningitis or hydrocephalus reported that the risk of severe intraventricular hemorrhage (IVH) (≥grade 3) was 2.5-fold higher in serum PCR-positive than PCR-negative infants after adjustment for gestational age, but there was no association of cranial ultrasound abnormalities with detection of Ureaplasma in CSF10). A role for Ureaplasma in neonatal brain injury is supported by recent studies in experimental animal models23). In the murine intrauterine U. parvum infection model, the brains of fetal and newborn mice showed evidence of microglial activation, deleted myelination, and disturbed neuronal development. Future studies are needed to provide additional information regarding mechanisms of Ureaplasma-mediated brain injury.

l models23). In the murine intrauterine U. parvum infection model, the brains of fetal and newborn mice showed evidence of microglial activation, deleted myelination, and disturbed neuronal development. Future studies are needed to provide additional information regarding mechanisms of Ureaplasma-mediated brain injury. 4. Role of Ureaplasma infection in lung injury and inflammation Some investigators found that Ureaplasma isolated from lower respiratory tract colonization is associated with peripheral blood leukocytosis, particularly the neutrophil component29, 33). Crouse et al.28) evaluated chest radiographs of 44 preterm infants with Ureaplasma colonization the lower respiratory tract in comparison with those who were culture-negative. They found that pneumonia was twice as common in the Ureaplasma-positive group and early radiographic emphysematous changes within 2 weeks of birth were significantly more common in the Ureaplasma-positive group. In a recent cohort study of infants less than 33 weeks gestation, Ureaplasma spp. were detected during the first week of life in tracheal aspirates or nasopharyngeal aspirates in 35% of infants10). These findings suggest an in utero onset of inflammatory responses and lung injury3).

on in the Ureaplasma-positive group. In a recent cohort study of infants less than 33 weeks gestation, Ureaplasma spp. were detected during the first week of life in tracheal aspirates or nasopharyngeal aspirates in 35% of infants10). These findings suggest an in utero onset of inflammatory responses and lung injury3). Ureaplasma infection in neonate promotes a proinflammatory cytokine cascade in the lower respiratory tract; this infection is associated with an increase in tumor necrosis factors (TNF)-α, interleukin (IL)-1β, and IL-820) and blocks expression of the regulatory cytokines IL-6 and/or IL-104). Viscardi et al.33) examined pathological specimens from Ureaplasma-infected infants and reported that Transforming growth factor (TGF)-β1 expression increased in infants with pneumonia compared with control specimens. Li and coworkers34) demonstrated that human macrophages exposed to the Ureaplasma antigen produce TNF-α and IL-6, and Ureaplasma-exposed macrophages release vascular endothelial growth factor and intracellular adhesion molecule-1. Animal models, such as mouse and primate models, have contributed substantially to the understanding of how the inflammatory potential of ureaplasmal infection induces a deregulated, proinflammatory, interstitial pneumonitis leading to a profibrotic state35, 36).

Ureaplasma infection in neonate promotes a proinflammatory cytokine cascade in the lower respiratory tract; this infection is associated with an increase in tumor necrosis factors (TNF)-α, interleukin (IL)-1β, and IL-820) and blocks expression of the regulatory cytokines IL-6 and/or IL-104). Viscardi et al.33) examined pathological specimens from Ureaplasma-infected infants and reported that Transforming growth factor (TGF)-β1 expression increased in infants with pneumonia compared with control specimens. Li and coworkers34) demonstrated that human macrophages exposed to the Ureaplasma antigen produce TNF-α and IL-6, and Ureaplasma-exposed macrophages release vascular endothelial growth factor and intracellular adhesion molecule-1. Animal models, such as mouse and primate models, have contributed substantially to the understanding of how the inflammatory potential of ureaplasmal infection induces a deregulated, proinflammatory, interstitial pneumonitis leading to a profibrotic state35, 36). 5. Association of Ureaplasma infection with development of bronchopulmonary dysplasia The classic definition of bronchopulmonary dysplasia (BPD), a supplemental oxygen requirement at 28 days of age, has been criticized since widespread antenatal corticosteroid treatment, postnatal exogenous surfactant therapy, and gentler ventilator strategies in VLBW infants, a "new" BPD, emerged. Recently, Bancalari et al.37) defined BPD as an oxygen requirement and the presence of radiographic abnormalities at 36 weeks postmenstrual age.

riticized since widespread antenatal corticosteroid treatment, postnatal exogenous surfactant therapy, and gentler ventilator strategies in VLBW infants, a "new" BPD, emerged. Recently, Bancalari et al.37) defined BPD as an oxygen requirement and the presence of radiographic abnormalities at 36 weeks postmenstrual age. Since BPD etiology is multifactorial and complex, the relationship of Ureaplasma respiratory tract colonization with the development of BPD has been debated. In 1988, 3 independent groups published results of cohort studies linking BPD development with airway colonization with Ureaplasma18, 32, 38). A meta-analysis of 17 clinical studies published before 1995 supported a significant association between Ureaplasma respiratory tract colonization and BPD development. Another recent meta-analysis conducted by Schelonka et al.39), who analyzed 36 cohort studies published between 1988 and 2004 involving approximately 3000 preterm infants, showed a significant association between Ureaplasma respiratory colonization and BPD development whether it was defined as oxygen dependence at 28 days (P<0.001) or at 36 weeks postmenstrual age (P<0.001). Other studies support the Ureaplasma respiratory colonization-BPD association, particularly in the subset of Ureaplasma-colonized infants exposed to chorioamnionitis and leukocytosis at birth3).

BPD development whether it was defined as oxygen dependence at 28 days (P<0.001) or at 36 weeks postmenstrual age (P<0.001). Other studies support the Ureaplasma respiratory colonization-BPD association, particularly in the subset of Ureaplasma-colonized infants exposed to chorioamnionitis and leukocytosis at birth3). Castro-Alcaraz et al.40) observed that persistent, but not transient, Ureaplasma respiratory complications are significantly higher in colonized infants. Mortality due to respiratory complications is significantly higher in colonized infants and the risk of a combined outcome measure of BPD or death due to lung disease was 4.2-fold higher in colonized Ureaplasma rather than in noncolonized VLBW infants14, 32). Infants with BPD have elevated proinflammatory cytokines such as IL-1, IL-6, and IL-8, with IL-8 acting as a potent neutrophil chemoattractant and, as a result, theses infants have elevated neutrophils in the lungs20). Perinatal Ureaplasma infection may promote the inflammatory cascade in the lung and impair alveolar development directly or in conjunction with oxidant and ventilator-induced lung injury3, 20). Hence, postnatal application of high oxygen concentrations and mechanical ventilation and duration of exposure may potentiate the effect of Ureaplasma-associated injury to the lungs.

ory cascade in the lung and impair alveolar development directly or in conjunction with oxidant and ventilator-induced lung injury3, 20). Hence, postnatal application of high oxygen concentrations and mechanical ventilation and duration of exposure may potentiate the effect of Ureaplasma-associated injury to the lungs. Treatment of Ureaplasma infection in preterm infants Although it is known that macrolides are the only antimicrobial agents currently available for use in the treatment of neonatal ureaplasmal infections, in the clinical field it is difficult to make decisions regarding which antibiotics should be used. Due to its toxicity, doxycycline is not an alternative unless U. urealyticum is isolated from CSF. Clindamycin has also been used to successfully treat systemic M. homin is infections in infants1). As such, making specific recommendations for treating neonatal ureaplasma infections is difficult because the spectrum of ureaplasmal disease has not been fully described and there are very few clinical studies indicating the in vivo efficacy of antibiotics1). Therefore, not only are choices between limited drug options controversial, but also the actual indications concerning conditions under which treatment should be offered, dosage, and duration of therapy is debated.

fully described and there are very few clinical studies indicating the in vivo efficacy of antibiotics1). Therefore, not only are choices between limited drug options controversial, but also the actual indications concerning conditions under which treatment should be offered, dosage, and duration of therapy is debated. Antibiotic therapy is a standard treatment modality for premature rupture of membranes (PROM). However, standard regimens failed to eradicate organisms including Ureaplasma or diminish inflammation in the amniotic cavity with PROM41). In an experimental Ureaplasma intraamniotic infection (IAI) in Rhesus monkeys, azitromycin alone or in combination with dexamethasone and indomethacin prevented fetal lung damage42). Despite the in vitro susceptibility of Ureaplasma to erythromycin, trials of erythromycin therapy in the first few weeks of life in Ureaplasma-colonized preterm infants have failed to demonstrate efficacy in preventing BPD3). Recently, Walls and colleagues43) demonstrated that azithromycin prophylaxis, but not erythromycin, improved outcomes and reduced inflammation in a murine neonatal Ureaplasma infection model. This finding suggests that azithromycin is effective if administered immediately after birth. However, there have been no published investigations of azithromycin in neonates regarding low birth weight infants. Hence, until appropriate pharmacokinetics and efficacy trials are conducted, a dosing regimen for azithromycin in neonates cannot be recommended41).

is effective if administered immediately after birth. However, there have been no published investigations of azithromycin in neonates regarding low birth weight infants. Hence, until appropriate pharmacokinetics and efficacy trials are conducted, a dosing regimen for azithromycin in neonates cannot be recommended41). Conclusions and future perspectives Recent clinical and experimental studies have shown significant evidence that Ureaplasma infection may induce inflammatory processes early in utero and, as a result it can cause intrauterine chorioamnionitis, postnatal systemic infection, and lung injury, including BPD. However, more studies are needed to determine the relationship of Ureaplasma virulence factors, host immune factors affecting pathogen susceptibility, and inflammatory variability, and interactions with environmental factors such as oxygen exposure and mechanical ventilation3). Furthermore, a study analyzing antimicrobial therapy of Ureaplasma-colonized infants should be conducted in a large, multicenter, randomized clinical trial to determine whether these antibiotics are effective in reducing BPD rate and improving neonatal outcomes.

anifestations of this disease, including microcytic anemia58) and growth impairment59). Treatment with a monoclonal antibody directed against the IL-6 receptor is associated with pronounced clinical improvement and the reestablishment of normal levels of acute-phase reactants in patients with systemic onset disease60). The clinical and pathologic manifestations of macrophage activation syndrome (MAS) are thought to result from the activation and uncontrolled proliferation of T-lymphocytes and well-differentiated macrophages, which leads to an unrestricted release of inflammatory cytokines, such as TNF-α, IL-1, and IL-6. However, the cause of the immunologic derangement associated with MAS is unknown. Recently, studies have revealed markedly decreased natural killer cell function and, in some cases, depressed perforin expression in patients with systemic onset disease; it has been suggested that these abnormalities may explain the distinctive susceptibility of these patients to developing MAS61, 62).

MAS is unknown. Recently, studies have revealed markedly decreased natural killer cell function and, in some cases, depressed perforin expression in patients with systemic onset disease; it has been suggested that these abnormalities may explain the distinctive susceptibility of these patients to developing MAS61, 62). 4. Anti-inflammatory mediators in JRA The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4. IL-10 has been shown to reverse cartilage degradation mediated by antigen-stimulated mononuclear cells in adult patients with arthritis63). In addition, a single nucleotide polymorphism connected to lower production of IL-10 is associated with a more severe type of arthritis64). IL-4 inhibits the activation of Th1 cells, which in turn decreases the production of TNF-α and IL-1 and inhibits cartilage damage65). IL-4 and IL-10 cooperate to inhibit the production of inflammatory cytokines, including IL-6 and IL-866). Higher levels of IL-4 and IL-10 mRNA within a joint are allied with a milder oligoarticular course and non-erosive disease67).

Introduction Juvenile rheumatoid arthritis (JRA) is a generic term for arthritis that has an onset before the age of 16 and persists for more than 6 weeks. The JRA nomenclature represents an exclusion diagnosis that includes all forms of chronic childhood arthritis of unknown origin. JRA is the most common chronic rheumatic illness in children and is a significant cause of both short- and long-term disabilities. The heterogeneity of this disease suggests that different factors likely contribute to its pathogenesis. The current understanding of JRA indicates that it arises in a genetically susceptible individual due to environmental factors1-3). Moreover, it has been proposed that an antigen-driven autoimmune process mediates the inflammatory pathology of some cases of arthritis (e.g., oligoarthritis, polyarthritis). In contrast, there are no signs of lymphocyte-mediated, antigen-specific immune responses in individuals with systemic onset disease. Recent investigations in the pathophysiology of systemic onset disease have indicated that this disorder is due to an uncontrolled activation of the innate immune system4). Regardless of the differences in the underlying pathogenesis of the various types of JRA, proinflammatory cytokines are consistently overproduced and are related to the clinical manifestations in all types of JRA. Modulation of these cytokines results in improvement of clinical outcome5), which strongly suggests that these cytokines play important roles in JRA.

ying pathogenesis of the various types of JRA, proinflammatory cytokines are consistently overproduced and are related to the clinical manifestations in all types of JRA. Modulation of these cytokines results in improvement of clinical outcome5), which strongly suggests that these cytokines play important roles in JRA. Currently, 3 separate classification systems are used to categorize individuals under 16 years of age with chronic arthritis. These include the American College of Rheumatology (ACR)6), the European League Against Rheumatism (EULAR)7), and the International League of Associations for Rheumatology (ILAR)8) criteria. Because none of these systems are perfect models, some JRA patients fulfill criteria for more than one subtype, whereas others are difficult to classify into any of the specific subgroups. Both the ACR and EULAR criteria are based solely on the onset type as it is manifested during the first 6 months of disease, whereas the ILAR criteria also include the course type over an unknown period of time thereafter, in order to further distinguish the group of patients with oligoarticular disease.

fic subgroups. Both the ACR and EULAR criteria are based solely on the onset type as it is manifested during the first 6 months of disease, whereas the ILAR criteria also include the course type over an unknown period of time thereafter, in order to further distinguish the group of patients with oligoarticular disease. Epidemiological studies of JRA have been hampered by a lack of standardized criteria and case ascertainment, which has resulted in wide-ranging results. For instance, the reported prevalence of JRA ranges from 0.07 to 4.01 per 1,000 children, and the annual worldwide incidence varies from 0.008 to 0.226 per 1,000 children9). However, the actual incidence and prevalence of JRA in the Asian population, including Korean children, have not been well quantified because most large epidemiologic studies performed to date have been based on populations of patients who were mainly of European ancestry. Of note, one previous study from Japan showed that JRA had a relatively low overall prevalence among the population10), suggesting lower incidence and prevalence in children of Asian origin than those of European origin. Furthermore, there are significant differences in JRA subtype distribution among the different ethnic groups as well11).

study from Japan showed that JRA had a relatively low overall prevalence among the population10), suggesting lower incidence and prevalence in children of Asian origin than those of European origin. Furthermore, there are significant differences in JRA subtype distribution among the different ethnic groups as well11). Pathogenesis 1. Associations of human leukocyte antigen (HLA) and non-HLA molecules in JRA The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 1512). To date, only 2 genetic risk factors, HLA and protein tyrosine phosphatase non-receptor 22 (PTPN22) genes, have been unequivocally confirmed as JRA susceptibility genes in multiple populations. The most well-established genetic factors for JRA are the HLA genes. Because the main function of HLA molecules is presenting antigenic peptides to T cells, HLA associations with JRA imply that this disease may be caused by an unidentified arthritogenic antigen. Many associations between subsets of JRA and the various HLA molecules have been described previously in the literature13-15). However, both the strength of these associations and the associated alleles vary between the JRA subtypes. Specifically, oligoarthritis has been consistently associated with HLA-A2, HLA-DRB1*11, and HLA-DRB1*08. Rheumatoid factor (RF)-positive polyarthritis is reportedly associated with HLA-DR4 in children, similarly to in adults. Moreover, the presence of HLA-B27 confers an increased risk of enthesitis-related arthritis. PTPN22 encodes a lymphoid-specific phosphatase (Lyp). A variant in the coding region of this gene, which is reportedly associated with a number of autoimmune diseases, has also been identified as a susceptibility locus for JRA16). The effect size of PTPN22 varies somewhat between JRA subtypes but, in general, is more consistent than that of HLA genes. A few other genes, including macrophage inhibitory factor, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α, have also been associated with JRA in different populations and subtypes17). However, these discussed genes may collectively account for only a small proportion of the total genetic contribution to disease.

ther genes, including macrophage inhibitory factor, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α, have also been associated with JRA in different populations and subtypes17). However, these discussed genes may collectively account for only a small proportion of the total genetic contribution to disease. 2. Inflammatory mediators of joint damage Synovial membranes of JRA patients contain activated T and B cells, plasma cells, and activated macrophages that are recruited via an intense neovascularization process. Host tissue cells, including activated synovial fibroblasts, chondrocytes, and osteoclasts, mediate cartilage and bone destruction. It has been established that the recruitment, activation, and effector function of each of these contributor lineages are directed principally by a network of cytokines (Fig. 1).

process. Host tissue cells, including activated synovial fibroblasts, chondrocytes, and osteoclasts, mediate cartilage and bone destruction. It has been established that the recruitment, activation, and effector function of each of these contributor lineages are directed principally by a network of cytokines (Fig. 1). Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. T-cell infiltrates are composed predominantly of T helper 1 (Th1) cells, which express an activated memory phenotype and high concentrations of chemokine receptors18, 19). Th1 cells stimulate B cells, monocytes, macrophages, and synovial fibroblasts to produce immunoglobulins and inflammatory mediators. Activated B cells produce immunoglobulins, including RF and antinuclear antibodies (ANAs). The precise pathogenic role of RF remains unknown, but it may involve the activation of complement through the formation of immune complexes. ANAs, which are mainly associated with early-onset oligoarthritis, have been reported to react against different nuclear targets, none of which are specific for JRA. Activated macrophages, lymphocytes, and fibroblasts, as well as their products including vascular endothelial growth factor (VEGF) and osteopontin, can stimulate angiogenesis. VEGF is highly expressed in synovial tissue20), whereas osteopontin is raised in synovial fluid and tissue, and correlates with new vascularisation21).

ed macrophages, lymphocytes, and fibroblasts, as well as their products including vascular endothelial growth factor (VEGF) and osteopontin, can stimulate angiogenesis. VEGF is highly expressed in synovial tissue20), whereas osteopontin is raised in synovial fluid and tissue, and correlates with new vascularisation21). TNF-α and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. These cytokines are detected in synovial fluids or tissues in a majority of JRA patients22, 23), and are known to stimulate mesenchymal cells, such as synovial fibroblasts, osteoclasts, and chondrocytes, to release tissue-destroying matrix metalloproteinases24). TNF-α and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of metalloproteinases. Collectively, these dual actions seem to lead to joint damage. Indeed, data from animal models strongly suggest TNF-α and IL-1 play roles in JRA. For instance, transgenic mice that expressed a deregulated human TNF-α gene spontaneously developed an inflammatory and destructive polyarthritis similar to JRA25). Moreover, blocking TNF-α with either a soluble TNF-receptor fusion protein or monoclonal antibodies also ameliorated disease activity in mice with type II collagen-induced arthritis26, 27). Injection of IL-1 into the knee joints of rabbits has been demonstrated to result in the degradation of cartilage28), whereas the injection of antibodies against IL-1 ameliorated collagen-induced arthritis in mice and decreased the damage to cartilage29).

activity in mice with type II collagen-induced arthritis26, 27). Injection of IL-1 into the knee joints of rabbits has been demonstrated to result in the degradation of cartilage28), whereas the injection of antibodies against IL-1 ameliorated collagen-induced arthritis in mice and decreased the damage to cartilage29). IL-6 is a multifunction cytokine that has a wide range of biological activities in various target cells and regulates immune responses, acute phase reactions, hematopoiesis, and bone metabolism30). Circulating levels of IL-6 are markedly elevated in patients with JRA, and are associated with laboratory and clinical variables of disease activity31, 32). IL-6 stimulates hepatocytes and induces the production of several acute-phase proteins, such as C-reactive protein (CRP)33). Thus, elevated levels of IL-6 in serum correlate with CRP levels in JRA patients with active disease.

th JRA, and are associated with laboratory and clinical variables of disease activity31, 32). IL-6 stimulates hepatocytes and induces the production of several acute-phase proteins, such as C-reactive protein (CRP)33). Thus, elevated levels of IL-6 in serum correlate with CRP levels in JRA patients with active disease. IL-17 is produced by Th17 cells, and induces a massive tissue reaction due to the broad distribution of the receptors to this cytokine. Recent evidence suggests that IL-17-producing Th17 cells have a crucial role in autoimmune inflammation34). In particular, IL-17 promotes a proinflammatory cytokine environment in the joint, stimulating macrophage production of TNF-α and IL-135), and synergizes with these cytokines to increase IL-6 and IL-8 production36, 37). In addition, IL-17 contributes directly to joint destruction by upregulating matrix metalloproteinases and stimulating osteoclastogenesis through receptor activation of nuclear factor-κB ligand (RANKL) induction38-40). IL-17 is increased in JRA patients with active disease compared with levels in individuals in remission41). Data from animal models also suggest IL-17 has a role in cartilage degradation. For instance, IL-17-deficient mice were demonstrated to be resistant to induction of collagen-induced arthritis42). Moreover, joint inflammation and cartilage and bone destruction were suppressed after administration of anti-IL-17 antibodies in mice with collagen-induced arthritis43).

s a role in cartilage degradation. For instance, IL-17-deficient mice were demonstrated to be resistant to induction of collagen-induced arthritis42). Moreover, joint inflammation and cartilage and bone destruction were suppressed after administration of anti-IL-17 antibodies in mice with collagen-induced arthritis43). 3. Unique inflammatory profile of systemic onset disease The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type44) and the absence of autoantibodies and autoreactive T cells45). Thus, patients with systemic onset disease do not show signs of lymphocyte-mediated antigen-specific immune responses. Instead, the typical clinical signs of systemic onset disease are associated with granulocytosis, thrombocytosis, and upregulation of acute-phase reactants, which indicate an uncontrolled activation of the innate immune system4). During both the initial manifestation and the flares of systemic onset disease, there is a perivascular infiltration of neutrophils and monocytes producing proinflammatory cytokines involved in the pathogenesis of this disease46). The predominant role of the innate immune system in systemic onset disease is also underscored by the high expression and serum concentrations of the calcium-binding proteins S100A8, S100A9, and S100A12, which are specifically secreted during activation of neutrophilic granulocytes and monocytes47). The extraordinarily high serum concentrations of these proteins are closely associated with the disease activity of systemic onset disease, and are not found in patients with other forms of inflammatory arthritis or other autoimmune or infectious diseases48, 49). S100 proteins exhibit proinflammatory effects on leukocytes and endothelial cells, and are thus likely to be directly involved in the inflammatory process of systemic onset disease50, 51).

isease, and are not found in patients with other forms of inflammatory arthritis or other autoimmune or infectious diseases48, 49). S100 proteins exhibit proinflammatory effects on leukocytes and endothelial cells, and are thus likely to be directly involved in the inflammatory process of systemic onset disease50, 51). Recent data indicate that IL-1 has a prominent role in systemic onset disease. Treatment with IL-1 receptor antagonist has been shown to reduce the clinical and laboratory features of disease activity in patients with systemic onset disease who show resistance to anti-TNF-α treatment52). In addition, activated monocytes from patients with systemic onset disease secrete significantly higher amounts of IL-1 in comparison with secreted levels from monocytes of healthy controls, whereas release of TNF-α and IL-6 is not significantly different between these groups. Another member of the IL-1 cytokine family, IL-18, was found to be extremely elevated in patients with adult-onset Still's disease compared with levels in patients with a variety of other rheumatic diseases and in healthy controls53). An equally dramatic rise in IL-18 concentration has been found in serum from children with systemic onset disease, whereas levels in children with polyarticular or oligoarticular disease were not significantly higher than levels in the healthy controls54). Moreover, IL-18 concentrations are significantly higher in patients with either serositis or hepatosplenomegaly than in patients without these manifestations.

emic onset disease, whereas levels in children with polyarticular or oligoarticular disease were not significantly higher than levels in the healthy controls54). Moreover, IL-18 concentrations are significantly higher in patients with either serositis or hepatosplenomegaly than in patients without these manifestations. The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement55, 56). In addition, IL-6 concentration is significantly higher in the synovial fluid of patients with systemic onset disease than in patients with other JRA subtypes57). The overproduction of IL-6 may explain many of the extra-articular manifestations of this disease, including microcytic anemia58) and growth impairment59). Treatment with a monoclonal antibody directed against the IL-6 receptor is associated with pronounced clinical improvement and the reestablishment of normal levels of acute-phase reactants in patients with systemic onset disease60).

ch in turn decreases the production of TNF-α and IL-1 and inhibits cartilage damage65). IL-4 and IL-10 cooperate to inhibit the production of inflammatory cytokines, including IL-6 and IL-866). Higher levels of IL-4 and IL-10 mRNA within a joint are allied with a milder oligoarticular course and non-erosive disease67). Foxp3+CD4+CD25+ regulatory T cells (Tregs) are important for controlling inflammatory processes68). In humans, an X-linked genetic defect in Foxp3 is the underlying cause of a condition that presents with multiple autoimmune conditions, which is named the immuno-dysregulation, polyendocrinopathy, enteropathy (IPEX) syndrome69). Less serious defects in Treg function have also been put forward as a cause of failed tolerance in several human autoimmune diseases. However, there is currently no evidence suggesting defects in Treg function in JRA, although the number of synovial Tregs is significantly lower in patients with extended oligoarthritis compared with the number in patients with a milder course of the disease70). Moreover, a higher number of Tregs have been found within joints of JRA patients compared with the number in peripheral blood71), which indicates an enrichment of Tregs within the inflamed joints. However, it appears that high numbers of regulatory cells in the joint fail to moderate the local inflammatory process. This finding may be related to effector T cell resistance, suppression at the site of inflammation72), or the attenuation of Treg function by local dendritic cell-derived cytokines, such as IL-673).

. However, it appears that high numbers of regulatory cells in the joint fail to moderate the local inflammatory process. This finding may be related to effector T cell resistance, suppression at the site of inflammation72), or the attenuation of Treg function by local dendritic cell-derived cytokines, such as IL-673). Clinical manifestations 1. Arthritis An arthritic joint exhibits a number of cardinal signs of inflammation, such as swelling, erythema, heat, pain, and loss of function (Fig. 2, 3). Involved joints are often warm, but are not typically erythematous. Children with arthritis may not complain of pain while at rest, but active or passive motion typically elicits pain. Joint tenderness is usually maximal at the joint line or just over the hypertrophied, inflamed synovium. Of note, bone pain or tenderness is not characteristic of JRA and may instead indicate the possibility of a malignancy involving bone. Morning stiffness and gelling following inactivity are common manifestations of joint inflammation, but young children infrequently describe these symptoms. Often, young children do not complain of pain and instead refuse to use the affected joint entirely.

stead indicate the possibility of a malignancy involving bone. Morning stiffness and gelling following inactivity are common manifestations of joint inflammation, but young children infrequently describe these symptoms. Often, young children do not complain of pain and instead refuse to use the affected joint entirely. Any joint can be affected by JRA, but large joint are more frequently involved than smaller joints74). However, small joints of the hands and feet are also affected, particularly in polyarticular onset disease75). Of note, cricoarytenoid arthritis is unusual but may be responsible for acute airway obstruction. Inflammation of the synovial joints in the middle ear has also been detected by tympanometric studies76). The temporomandibular joint and the cervical, thoracic, and lumbar spine should also be examined in the case of JRA. JRA often affects the cervical spine, and the most common changes in the upper cervical spine are anterior atlantoaxial subluxation and impaction77, 78). Subluxation of the atlantoaxial joints may also occur, rendering the affected child at risk of injury in an accident or upon attempted intubation prior to receiving general anesthesia. Scoliosis, which possibly reflects asymmetric thoracolumbar apophyseal joint inflammation, may also occur in children with JRA. Small outpouchings of symovium are not uncommon in individuals with JRA and are particularly evident at the extensor hood of the proximal interphalangeal joint and around the wrist or ankle. A synovial cyst in the antecubital area or anterior to the shoulder may be the initial or sole presentation of JRA.

ren with JRA. Small outpouchings of symovium are not uncommon in individuals with JRA and are particularly evident at the extensor hood of the proximal interphalangeal joint and around the wrist or ankle. A synovial cyst in the antecubital area or anterior to the shoulder may be the initial or sole presentation of JRA. Oligoarticular disease develops in at least 50% of children with JRA during the first 6 months of disease. This subtype is the only form of JRA without an adult equivalent. Oligoarticular disease affects up to 4 joints at presentation, with the knee joints mostly affected, followed by the ankles74). In contrast, this subtype almost never affects the hips, and rarely the smaller joints of the hands and feet. Oligoarticular disease is characterized by asymmetric arthritis, early onset (before 6 years of age), female predilection, high frequency of positive ANAs, and a high risk of iridocyclitis. The ILAR classification distinguishes 2 further categories within the oligoarthritis subtype: persistent oligoarthritis, in which the disease is confined to 4 or fewer joints, and extended oligoarthritis, in which the arthritis extends to more than 4 joints after the first 6 months of disease. Up to 50% of oligoarticular patients develop extended disease, and 30% will do so in the first 2 years after diagnosis. The risk factors for extended disease include involvement of an upper limb joint and elevated erythrocyte sedimentation rate (ESR) at onset79).

more than 4 joints after the first 6 months of disease. Up to 50% of oligoarticular patients develop extended disease, and 30% will do so in the first 2 years after diagnosis. The risk factors for extended disease include involvement of an upper limb joint and elevated erythrocyte sedimentation rate (ESR) at onset79). Polyarticular disease is defined as the presence of arthritis in 5 or more joints during the first 6 months of disease. The arthritis may be symmetrical and usually involves the large and small joints of the hands and feet, although the axial skeleton, including the cervical spine and the temporomandibular joints, may also be affected. This subtype includes children with both RF-negative and RF-positive diseases. Both types affect girls more frequently than boys. RF-negative patients often develop polyarthritis in early childhood, whereas RF-positive patients instead develop arthritis during late childhood and adolescence. Three distinct subsets of RF-negative polyarthritis have been identified. The first subset is a form that resembles early-onset oligoarticular disease, except for the number of joints affected in the first 6 months of disease. The second subset is similar to adult-onset RF-negative rheumatoid arthritis, and is characterized by overt symmetric synovitis of large and small joints, onset during school age years, increased ESR, negative ANA, and variable outcome. Finally, the third subset is a form known as dry synovitis, which shows negligible joint swelling but stiffness and flexion contractures80). RF-positive patients are primarily adolescent girls with symmetric small joint involvement and early-onset erosive synovitis. Approximately a third of these patients develop subcutaneous nodules (non-tender, firm lesions over pressure points and tendon sheaths), typically in the board of the forearm and elbow. The HLA associations in these patients are the same as in adult seropositive rheumatoid arthritis patients and likely represent the early expression of adult rheumatoid arthritis.

op subcutaneous nodules (non-tender, firm lesions over pressure points and tendon sheaths), typically in the board of the forearm and elbow. The HLA associations in these patients are the same as in adult seropositive rheumatoid arthritis patients and likely represent the early expression of adult rheumatoid arthritis. 2. Systemic extra-articular manifestations Systemic involvement may precede the development of overt arthritis by weeks, months, or rarely years. In the right clinical setting, with characteristic fever and classic rash, the diagnosis of probable systemic onset disease may be made, and confirmation of the diagnosis can follow when persistent arthritis develops81). The arthritis associated with systemic onset disease is usually polyarticular affecting both large and small joints. Asymmetric, oligoarticular arthritis is less common. The systemic pattern is prominent during the first 4-6 months of disease and rarely occurs for the first time during the later course of disease.

81). The arthritis associated with systemic onset disease is usually polyarticular affecting both large and small joints. Asymmetric, oligoarticular arthritis is less common. The systemic pattern is prominent during the first 4-6 months of disease and rarely occurs for the first time during the later course of disease. The most prominent feature of systemic involvement is a high spiking fever82). Specifically, the temperature of an individual typically rises to 39℃ or higher on a daily or twice-daily basis, followed by a rapid return to the baseline temperature or below (Fig. 4). Although this quotidian pattern is highly suggestive of systemic onset disease, patients may not present this fever pattern. Fever may occur at any time of the day, but characteristically presents in the late afternoon to evening in conjunction with the rash. Moreover, the temperature may be subnormal in the morning. During episodes of fever, an affected child commonly appears ill when chills are present, but then appears well when the fever breaks. Fever associated with systemic onset disease often responds poorly to the commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), even at high doses.

ubnormal in the morning. During episodes of fever, an affected child commonly appears ill when chills are present, but then appears well when the fever breaks. Fever associated with systemic onset disease often responds poorly to the commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), even at high doses. In the case of systemic onset disease, intermittent fever is almost always accompanied by the classic rash82). The classic rash is evanescent (usually coming and going with the fever spikes) and consists of discrete, circumscribed, salmon-pink macules (2-mm to 10-mm in size) that may be surrounded by a ring of pallor or may develop central clearing (Fig. 5). Lesions are most common on the trunk and proximal extremities, including the axilla and inguinal areas, but can also develop on the face, palms, or soles of affected individuals. The rash tends to be migratory and is strikingly evanescent: individual lesions last for up to a few hours and leave no residua. Moreover, the rash may be much more persistent in children who are systemically very ill, and may reappear with each systemic exacerbation. Such rash also occurs very rarely in children with polyarticular onset disease, and likely never occurs in those with classic oligoarthritis. Individual lesions may be elicited either by rubbing and/or scratching the skin (the so-called Koebner response), by a hot bath, or by psychological stress. The rash is occasionally pruritic but is never purpuric.

n children with polyarticular onset disease, and likely never occurs in those with classic oligoarthritis. Individual lesions may be elicited either by rubbing and/or scratching the skin (the so-called Koebner response), by a hot bath, or by psychological stress. The rash is occasionally pruritic but is never purpuric. Pericarditis and pericardial effusions are especially common in children with systemic onset disease83, 84). Pericarditis may precede the development of arthritis or may occur at any time during the course of disease, and is usually accompanied by a systemic exacerbation of disease. Pericarditis tends to occur in older children, but it is not related to sex, age at onset, or severity of joint disease. Most pericardial effusions are asymptomatic, although some children have dyspnea or precordial pain that may be transferred to the back, shoulder, or neck. In many cases, pericardial effusions develop insidiously, may not be accompanied by obvious cardiomegaly or electrocardiographic changes, and escape recognition except by echocardiography. Examination of affected patients may disclose diminished heart sounds, tachycardia, cardiomegaly, and a pericardial friction rub, usually at the left lower sternal border. Pneumonitis or pleural effusions may also occur with carditis, or may be asymptomatic and detected only as incidental findings on chest radiographs. Pulmonary rheumatoid nodules that are described in adult rheumatoid arthritis are rare in childhood.

a pericardial friction rub, usually at the left lower sternal border. Pneumonitis or pleural effusions may also occur with carditis, or may be asymptomatic and detected only as incidental findings on chest radiographs. Pulmonary rheumatoid nodules that are described in adult rheumatoid arthritis are rare in childhood. Another characteristic of systemic onset disease is enlargement of lymph nodes and spleen, either alone or in combination. Marked symmetric lymphadenopathy is particularly common in the anterior cervical, axillary, and inguinal areas, and may suggest the diagnosis of lymphoma. Mesenteric lymphadenopathy may cause abdominal pain or distention and lead to an erroneous diagnosis of an acute surgical abdomen. Splenomegaly is generally most prominent within the first years after onset of systemic onset disease. The degree of splenomegaly may be extreme, but it is uncommonly associated with Felty's syndrome (splenic neutropenia)85). Hepatomegaly is less common than splenomegaly. Furthermore, moderate to severe enlargement of the liver is often associated with only mild derangement of function and relatively nonspecific histopathologic changes86). However, massive enlargement of the liver is usually accompanied by abdominal distention and pain. Progressive hepatomegaly is characteristic of secondary amyloidosis, which refers to the tissue deposition of the fibrillar protein amyloid.

d derangement of function and relatively nonspecific histopathologic changes86). However, massive enlargement of the liver is usually accompanied by abdominal distention and pain. Progressive hepatomegaly is characteristic of secondary amyloidosis, which refers to the tissue deposition of the fibrillar protein amyloid. MAS is a rare but life-threatening complication of systemic onset disease that is characterized by demonstration of histiophagocytosis in bone marrow87). The main manifestations of MAS include fever, hepatosplenomegaly, lymphadenopathy, severe cytopenias, serious liver disease, and disseminated intravascular coagulation. The pathognomonic feature of MAS is often found in bone marrow, which includes numerous, well-differentiated macrophages phagocytosing hematopoietic elements. It has been estimated that MAS develops in at least 10% of patients with systemic onset disease, although the true incidence of MAS might be much higher since there are no validated diagnostic criteria for this syndrome and mild instances are not always recognized88). MAS bears close resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH)89). Triggers of MAS include a preceding viral illness and the addition of or a change in medications, especially including NSAIDs, intramuscular gold injections, sulfasalazine, and more recently etanercept90).

resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH)89). Triggers of MAS include a preceding viral illness and the addition of or a change in medications, especially including NSAIDs, intramuscular gold injections, sulfasalazine, and more recently etanercept90). 3. Uveitis Chronic, anterior, nongranulomatous uveitis (iridocyclitis) develops in up to 21% of patients with oligoarticular disease and 10% of patients with polyarticular disease91). However, no patients with systemic onset disease have been diagnosed as having uveitis to date92). The only known independent risk factor for developing uveitis is a positive ANA test. The onset of chronic uveitis is typically insidious and often entirely asymptomatic, although up to one half of affected children have some symptoms attributable to uveitis (e.g., pain, redness, headache, photophobia, change in vision) later in the course of their disease. Uveitis may be present at the time of diagnosis, may develop during the course of JRA, or may be an initial manifestation of JRA that is usually detected in the course of routine ophthalmologic examination. JRA patients should be screened routinely to prevent delay in diagnosis of uveitis. The earliest signs of uveitis on slit-lamp examination are the presence of inflammatory cells and increased protein concentration in the aqueous humor of the anterior chamber of the eye. In addition, deposition of inflammatory cells on the inner surface of the cornea (keratopunctate deposits) may develop later during the course of disease. Complications of uveitis include posterior synechiae, cataracts, band keratopathy, glaucoma, and visual impairment.

aqueous humor of the anterior chamber of the eye. In addition, deposition of inflammatory cells on the inner surface of the cornea (keratopunctate deposits) may develop later during the course of disease. Complications of uveitis include posterior synechiae, cataracts, band keratopathy, glaucoma, and visual impairment. Fig. 1 Cytokine signaling pathways involved in JRA. Interactions among macrophages, T cells, B cells, and non-hematopoietic cells including fibroblasts are important in the pathogenesis of JRA. These interactions are facilitated by the actions of cytokines that induce the production of other proinflammatory cytokines. Fig. 2 Swelling and flexion contracture of the right knee of a representative patient with oligoarticular disease. Fig. 3 Polyarticular disease affects the joints of the wrist and hand. The proximal and distal interphalangeal joints are erythematous. There are flexion contractures of the fingers. Fig. 4 High intermittent fever in a representative patient with systemic onset disease. Fig. 5 Typical rash in a patient with systemic onset disease.

Introduction The masticator space is defined as the separate fascial compartment containing the pterygoid, masseter and temporalis muscles and the mandible1,2). Masticator space abscess represents an advanced stage of a commonly odontogenic infection indicated by buccal pain, swelling and trismus3). Jaw swelling and trismus after a dental procedure are the typical clinical manifestations of a masticator space abscess in adults4,5). Masticator space abscess without dental procedure is an uncommon infection and can be seen with poor sucking, irritability, fever and dehydration in the infant. It is imperative that a meticulous medical history be obtained and a thorough physical examination be completed in infants with such clinical symptoms1). The clinical diagnosis is usually obvious, but it is confirmed by ultrasonography (US) or computed tomography (CT)1,5). Masticator space abscess has not been reported in newborns, and rarely been reported in infants. Here we report a 47 day old male diagnosed as masticator space abscess with nonspecific symptoms without evidence of dental disease, traumatic injuries to the head and neck, or parotid swelling1).

Introduction While most of the children who presented with primary nephrotic syndrome (NS) respond to steroid treatment, 10 to 20% of these children do not achieve remission despite receiving second or third-line of treatment (Fig. 1), and more than half of the patients progress to end-stage renal disease (ESRD) within 10 years1). Thus, various modalities have been tried to induce remission in these patients. In this review, several commonly-practiced treatments will be reviewed while simultaneously following the progression of a clinical case of pediatric steroid-resistant nephrotic syndrome (SRNS). Pharmacological treatment of SRNS 1. Case; Part 1 A 5-years-old boy was transferred to our center for treatment of steroid-resistant nephrotic syndrome. He had developed edema with proteinuria and did not respond to oral steroid treatment. Kidney biopsy revealed focal segmental glomerulosclerosis with segmental mesangial hypercellularity and segmental sclerosis in 7% of glomeruli. To achieve remission, intravenous methylprednisolone pulse therapy and cyclosporine treatment were attempted (Fig. 2).

roteinuria and did not respond to oral steroid treatment. Kidney biopsy revealed focal segmental glomerulosclerosis with segmental mesangial hypercellularity and segmental sclerosis in 7% of glomeruli. To achieve remission, intravenous methylprednisolone pulse therapy and cyclosporine treatment were attempted (Fig. 2). 1) SRNS SRNS is defined as NS that does not respond to one month's treatment with oral prednisolone at a dosage of 60 mg/m2/day. When SRNS is suspected, a meticulous search for the possibility of concurrent infection (e.g., sinusitis and skin infection), drug interaction (e.g., antiepileptic drugs), inappropriate dosage, or compliance problem is necessary. If those possibilities are ruled out, tissue diagnosis from a kidney biopsy is the next step. Histological findings of SRNS are, and occasionally, a secondary glomerulopathy such as amyloidosis is unexpectedly found. At the same time, mutational analysis for genes known to cause SRNS is recommended. Mutations of WT1, INF2, LAMB2, ACTN4, NPHS1, and NPHS2 have been found in Korean children with SRNS by Cheong et al.2-5). While more aggressive treatment is required to achieve remission in the case of SRNS of unknown cause (primary SRNS) to achieve remission, such an aggressive treatment is not effective for those with SRNSthat arises from genetic causes; therefore genetic testing may shield these children from the unnecessary side effects of immunosuppressive medications (Fig. 3).

o achieve remission in the case of SRNS of unknown cause (primary SRNS) to achieve remission, such an aggressive treatment is not effective for those with SRNSthat arises from genetic causes; therefore genetic testing may shield these children from the unnecessary side effects of immunosuppressive medications (Fig. 3). 2) Methylprednisolone pulse treatment When oral prednisolone treatment fails, intravenous methylprednisolone pulse therapy (30 mg/kg, every other day, 6 doses in total) is commonly tried. The original treatment protocol developed by Mendoza et al.6); however, remission rates as high as 70% were reported with this protocol. The current practice involves the administration of 3 to 6 doses of high-dose intravenous methylprednisolone before kidney biopsy, and patients who respond to this treatment are often regarded as responsive to steroid therapy. Commonly encountered side effects of methylprednisolone pulse treatment are infection, Cushing's syndrome, hypertension, glucose intolerance, and arrhythmia during infusion.

travenous methylprednisolone before kidney biopsy, and patients who respond to this treatment are often regarded as responsive to steroid therapy. Commonly encountered side effects of methylprednisolone pulse treatment are infection, Cushing's syndrome, hypertension, glucose intolerance, and arrhythmia during infusion. 3) Calcineurin inhibitors (CNI) Cyclosporine and tacrolimus (FK-506) were originally introduced as immunosuppressive agents for allograft transplantation due to their inhibitory effect on calcineurin, a key signal transduction molecule activating T lymphocytes. In the past, the anti-proteinuric effect of calcineurin inhibitors (CNIs) was believed to arise from their immunosuppressive effect on lymphocytes7). However, CNI CNIs have recently been found to stabilize the cytoskeleton of glomerular epithelial cells (podocytes) and thereby reduce glomerular proteinuria8). This effect explains why cyclosporine has partial success in some cases of proteinuria of proteinuria arising from genetic causes9). The response rate of SRNS to cyclosporine is roughly 40 to 60. A typical SRNS treatment protocol using cyclosporine involves the administration of cyclosporine (150 to 200 mg/m2/day) and prednisolone (30 mg/m2/day) for 1 month, followed by alternate-day prednisolone for 5 months; this has been shown to result in complete remission in 42% of recipients within the first 6 months10). Cyclosporine has a well-known spectrum of side effects such as nephrotoxicity, infection, hypertension, hyperkalemia, renal tubular acidosis, tremor, glucose intolerance, gum hypertrophy, and hirsutism. The therapeutic drug level (trough) of cyclosporine is <100-200 ng/mL.

2% of recipients within the first 6 months10). Cyclosporine has a well-known spectrum of side effects such as nephrotoxicity, infection, hypertension, hyperkalemia, renal tubular acidosis, tremor, glucose intolerance, gum hypertrophy, and hirsutism. The therapeutic drug level (trough) of cyclosporine is <100-200 ng/mL. Another CNI, tacrolimus, is also used in the treatment of SRNS, although Korean Food and Drug Administration has not approved this medication for treatment of NS11). The dosage of tacrolimus for SRNS is 0.05 to 1 mg/kg/day with a trough level <5 to 10 µg/L. Tacrolimus has a similar spectrum of side effects as cyclosporine but does not cause gum hypertrophy or hirsutism. 4) Alkylating agents and anti-proliferative agents While cyclophosphamide or chlorambucyl have been used in early reports; however, a recent review by the Children's Nephrotic Syndrome Consensus Conference concluded that these alkylating agents were not superior to steroid mono-therapy12). Additionally, mofetil13) and sirolimus14) have also been tried recently with moderate results.

sphamide or chlorambucyl have been used in early reports; however, a recent review by the Children's Nephrotic Syndrome Consensus Conference concluded that these alkylating agents were not superior to steroid mono-therapy12). Additionally, mofetil13) and sirolimus14) have also been tried recently with moderate results. Non-conventional treatment of SRNS 1. Case; Part 2 (Fig. 4) Despite various treatments, the patient's proteinuria and hypoalbuminemia did not disappear and instead progressed to endstage renal disease (ESRD) in 2 years and 1 month (Fig. 1). Peritoneal dialysis was started at the age of 8 years and 3 months. After 4 years, the patient received cadaveric donor kidney transplantation. Following the surgery, his serum creatinine level began to drop, but soon increased again to staggering levels. At the same time, his serum albumin level began to decrease as well. Urine albumin levels were found to be 3+.

8 years and 3 months. After 4 years, the patient received cadaveric donor kidney transplantation. Following the surgery, his serum creatinine level began to drop, but soon increased again to staggering levels. At the same time, his serum albumin level began to decrease as well. Urine albumin levels were found to be 3+. 1) Renal replacement therapy for children with nephrotic syndrome (1) Dialysis When kidney function deteriorates and progresses to ESRD, there are 3 options for renal replacement: hemodialysis, peritoneal dialysis, and transplantation. Peritoneal dialysis requires less strict diet control and enables a more flexible life style; therefore, peritoneal dialysis is preferred to hemodialysis in pediatric patients, despite the risk of complicating peritonitis. Protein loss through the kidneys in children with SRNS diminishes with the deterioration of kidney function and their intractable edema improves accordingly. On peritoneal dialysis. However, protein loss through the peritoneal membrane may develop with peritoneal dialysis, especially in children with SRNS, as documented at our center15). Therefore, the possibility of protein malnutrition should be considered and adequate nutritional support is required.

mproves accordingly. On peritoneal dialysis. However, protein loss through the peritoneal membrane may develop with peritoneal dialysis, especially in children with SRNS, as documented at our center15). Therefore, the possibility of protein malnutrition should be considered and adequate nutritional support is required. (2) Kidney transplantation Kidney transplantation is by far the most advantageous modality of renal replacement for children, since only with kidney transplantation normal or near-normal growth can be achieved only with kidney transplantation. Currently, the outcomes of kidney transplantation are excellent with one-year survival of 93%, 10-year survival rates of around ~80%, and a median graft survival time of >15 years. However, children with SRNSrun the risk of recurrence of NS following transplantation, as illustrated in the case. Recurrence often precipitates delayed graft function, acute rejection, and poor graft outcomes16). Nevertheless, the expected graft survival rate of kidney allograft in patients with SRNS is as good as that of cadaveric donors; therefore, SRNS is not a contraindication for kidney transplantation. (3) Recurrence of SRNS after transplantation Risk factors for SRNS recurrence following transplantation include childhood-onset SRNS, age of onset greater than 5-6 years, rapid progression to ESRD, and recurrence following a previous allograft17). On the other hand, cases of secondary SRNS, such as those secondary to infection, medication, reflux nephropathy, or obesity, and SRNS arising from genetic causes are not likely to recur18).

ood-onset SRNS, age of onset greater than 5-6 years, rapid progression to ESRD, and recurrence following a previous allograft17). On the other hand, cases of secondary SRNS, such as those secondary to infection, medication, reflux nephropathy, or obesity, and SRNS arising from genetic causes are not likely to recur18). Recurrence often develops within 48 hours of transplantation. Other possible diagnoses of post-transplant proteinuria include chronic allograft rejection, de novo glomerulopathy, and proteinuria from the native kidneys. Nevertheless, significant proteinuria following kidney transplantation in SRNS patients should be presumed to be a recurrence. In this case, aggressive and timely treatment with plasmapheresis and/or high-dose cyclosporine (250 to 350 ng/mL) or rituximab is required, since treatment within 48 hours of recurrence is the only modifiable factor that can effect the remission of recurrent SRNS. For prompt detection of recurrence, meticulous monitoring of pediatric SRNS patients is required following kidney transplantation; urinalysis with protein quantitation must be performed everyday for 2 weeks after transplantation, followed by testing once a week for 1 month, then once a month for 1 year17).

urrent SRNS. For prompt detection of recurrence, meticulous monitoring of pediatric SRNS patients is required following kidney transplantation; urinalysis with protein quantitation must be performed everyday for 2 weeks after transplantation, followed by testing once a week for 1 month, then once a month for 1 year17). 2) Plasmapheresis Observations of SRNS recurrence following graft resulted in the introduction of the concept of a 'circulating permeability factor' as a pathogenic mechanism of SRNS19). Thus, the first-line treatment to avoid recurrence is to remove the 'permeability factor' by plasmapheresis therapy. Plasmapheresis replaces patient's plasma containing the 'permeability factor' with 4 to 5% albumin solution or fresh frozen plasma. Immediate initiation of this treatment may induce remission in 50 to 90% of recurrent cases20). Reports of favorable outcomes of plasmapheresis in patients with recurrent SRNS resulted in the application of this treatment modality in primary SRNS of native kidneys, with success in some cases21). However, it is not yet possible to predict patient responsiveness to this procedure, and the effectiveness of pre-emptive plasmapheresis to prevent SRNS recurrence following transplantation has not yet been established.

ication of this treatment modality in primary SRNS of native kidneys, with success in some cases21). However, it is not yet possible to predict patient responsiveness to this procedure, and the effectiveness of pre-emptive plasmapheresis to prevent SRNS recurrence following transplantation has not yet been established. 3) Rituximab Rituximab is a monoclonal antibody against CD20, a marker of B cells, which is manufactured as a therapeutic agent for B cell lymphoma. Following the report of a case of post-transplant lymphoproliferative disease where rituximab treatment eradicated both recurrent SRNS and B cell lymphoma after kidney transplantation22), this biological agent has been used for SRNS as a rescue treatment23) with success rate of 20 to 50%. However, treatment indications and an optimal rituximab treatment protocol have not yet been established, and significant adverse effects such as opportunistic infections and rituximab-associated lung injury24) have been reported. Conclusion Case; Part 3 The patient was treated with plasmapheresis and his proteinuria and hypoalbuminemia improved gradually. To eradicate his nephrotic syndrome, we gave him one dose of rituximab, and complete remission was achieved. He has been in a state of remission for more than two years.

3) Rituximab Rituximab is a monoclonal antibody against CD20, a marker of B cells, which is manufactured as a therapeutic agent for B cell lymphoma. Following the report of a case of post-transplant lymphoproliferative disease where rituximab treatment eradicated both recurrent SRNS and B cell lymphoma after kidney transplantation22), this biological agent has been used for SRNS as a rescue treatment23) with success rate of 20 to 50%. However, treatment indications and an optimal rituximab treatment protocol have not yet been established, and significant adverse effects such as opportunistic infections and rituximab-associated lung injury24) have been reported. Conclusion Case; Part 3 The patient was treated with plasmapheresis and his proteinuria and hypoalbuminemia improved gradually. To eradicate his nephrotic syndrome, we gave him one dose of rituximab, and complete remission was achieved. He has been in a state of remission for more than two years. Although the prognosis of SRNS is complicated and unfavorable, intensive treatment in the early stage of the disease may achieve remission in more than half of the patients. Thus, timely referral of these patients to pediatric nephrology specialists for histological and genetic diagnosis and treatment is highly recommended. Acknowledgment This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A080588). Fig. 1 Outcomes of childhood-onset nephrotic syndrome. Tx, treatment; ESRD, end-stage renal disease; D/C, steroid discontinuation.

Although the prognosis of SRNS is complicated and unfavorable, intensive treatment in the early stage of the disease may achieve remission in more than half of the patients. Thus, timely referral of these patients to pediatric nephrology specialists for histological and genetic diagnosis and treatment is highly recommended. Acknowledgment This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A080588). Fig. 1 Outcomes of childhood-onset nephrotic syndrome. Tx, treatment; ESRD, end-stage renal disease; D/C, steroid discontinuation. Fig. 2 Clinical course of a case of steroid-resistant nephrotic syndrome. Cr, creatinine. Fig. 3 Approach of childhood-onset nephrotic syndrome. NS, nephrotic syndrome; GHU, Gross hematuria; BP, blood pressure; FANA, fluorescent antinuclear antibody test; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; PPD, purified protein derivative. Fig. 4 Clinical course of the case after kidney transplantation. U/A, urinalysis; Alb, albumin; P/E, plasmapheresis

Introduction Nephrotic syndrome (NS) is classically defined as massive proteinuria (>40 mg/m2/hr), hypoalbuminemia (<2.5 g/dL), generalized edema, and hyperlipidemia in most cases1). The majority of nephrotic children have minimal change lesions, and these will either remit spontaneously within three years (two-thirds of the cases) or have earlier remission without complications following treatment with corticosteroids (CS) or cytotoxic agents (95%)2). However, the minority of children who have lesions of focal segmental glomerulosclerosis and severe and prolonged proteinuria are at high risk for complications. In these children, full nephrotic syndrome may progress to renal failure and even to dialysis, ultimately requiring renal transplantation. Complications in NS may occur as a part of the disease itself or as a consequence of drug treatment. The loss of plasma proteins in the urine causes complications of NS as a direct result of the changing protein concentrations in the plasma or as a secondary result of altered cellular function3). Disease-associated complications include infections, thromboembolism, cardiovascular disease, hypovolemic crisis, anemia, and acute renal failure. CS, alkylating agents, calcineurin inhibitors, and mycophenolate mofetil (MMF) are usually related to the complications of long-term therapy in nephrotic children. Here, we focus on the complications occurring in children with NS (Table 1).

m, cardiovascular disease, hypovolemic crisis, anemia, and acute renal failure. CS, alkylating agents, calcineurin inhibitors, and mycophenolate mofetil (MMF) are usually related to the complications of long-term therapy in nephrotic children. Here, we focus on the complications occurring in children with NS (Table 1). Nephrotic syndrome-related complications 1. Infections Patients with NS are at increased risk for infections. Although the incidence of infections in NS has decreased in advanced countries, they are still a major problem in developing countries4). Sepsis remains one of the main causes of death in children with NS5). Children treated with cytotoxic drugs have a higher clinical infection rate than those treated only with prednisolone6). In children with NS, Streptococcus pneumoniae is known to be the most important organism in primary peritonitis. However, other organisms such as β-hemolytic streptococci, Haemophilus and Gram-negative bacteria are also frequently found7). Cellulitis is also the result of β-hemolytic streptococci or a variety of Gram-negative bacteria. Several immunological factors such as low serum immunoglobulin G concentrations, factor B and factor I in the alternative pathway components, transferrin, depressed T-cell function, and physiological factors such as fluid collection in cavities and dilution of local humoral defenses by edema may play a major role in the susceptibility of nephrotic patients to infection8).

globulin G concentrations, factor B and factor I in the alternative pathway components, transferrin, depressed T-cell function, and physiological factors such as fluid collection in cavities and dilution of local humoral defenses by edema may play a major role in the susceptibility of nephrotic patients to infection8). Pneumococcal vaccines against capsular antigens is recommended for all children with NS9), but vaccination should be administered when the treatment with high doses of CS or with cytotoxic therapy is discontinued. Nephrotic children taking high-dose CS or other immunosuppressive agents within three months of their use are at risk of varicella infection, requiring varicella zoster immunoglobulin treatment within 72 hours of exposure and intravenous acyclovir during active varicella zoster infection10). 2. Thromboembolism NS is a well-known risk factor for arterial or venous thromboembolism (TE), and patients with severe proteinuria have a 3.4-fold higher risk of venous TE11). It is also known that there is higher risk of TE in steroid-resistant NS than in steroid-sensitive NS12).

Pneumococcal vaccines against capsular antigens is recommended for all children with NS9), but vaccination should be administered when the treatment with high doses of CS or with cytotoxic therapy is discontinued. Nephrotic children taking high-dose CS or other immunosuppressive agents within three months of their use are at risk of varicella infection, requiring varicella zoster immunoglobulin treatment within 72 hours of exposure and intravenous acyclovir during active varicella zoster infection10). 2. Thromboembolism NS is a well-known risk factor for arterial or venous thromboembolism (TE), and patients with severe proteinuria have a 3.4-fold higher risk of venous TE11). It is also known that there is higher risk of TE in steroid-resistant NS than in steroid-sensitive NS12). Thrombosis may arise in NS from loss of proteins involved in the inhibition of systemic hemostasis, increased synthesis of prothrombotic factors or by local activation of the glomerular hemostasis system13). The predisposing factors of TE in NS are as follows14,15): 1) abnormalities in platelet activation and aggregation, 2) activation of the coagulation system; increased synthesis of factors V, VII, VIII, X, von Willebrand factor, fibrinogen, and α2-macroglobulin accumulation, 3) decreased endogenous anticoagulants; antithrombin III, protein C, protein S, and tissue factor pathway inhibitor, 4) decreased activity of fibrinolytic system; plasminogen, the precursor for plasmin, and the imbalance of two major regulators of plasmin formation, plasminogen activator inhibitor-1 and tissue plasminogen activator16), 5) changes in the glomerular hemostatic system, 6) intravascular volume depletion, and 7) exposure to CS and diuretics17,18).

ibrinolytic system; plasminogen, the precursor for plasmin, and the imbalance of two major regulators of plasmin formation, plasminogen activator inhibitor-1 and tissue plasminogen activator16), 5) changes in the glomerular hemostatic system, 6) intravascular volume depletion, and 7) exposure to CS and diuretics17,18). Doing arterial punctures should be avoided in nephrotic children due to the risk of arterial thrombosis. Gross hematuria with or without acute renal failure may suggest renal vein thrombosis in nephrotic children, which needs Doppler ultrasonography or magnetic resonance angiography19). Particularly, when nephrotic patients appear to have tachypnea and dyspnea, we should keep in mind the high probability of pulmonary embolism and perform ventilation-perfusion lung scanning or pulmonary angiography immediately20). 3. Cardiovascular complications An increased risk of cardiovascular disease exists in patients with NS because of hyperlipidemia, increased thrombogenesis, and endothelial dysfunction21). Hypercholesterolemia is strongly associated with severity of hypoalbuminemia, and persistent proteinuria or renal insufficiency also contributes to cardiovascular disease22).

ed risk of cardiovascular disease exists in patients with NS because of hyperlipidemia, increased thrombogenesis, and endothelial dysfunction21). Hypercholesterolemia is strongly associated with severity of hypoalbuminemia, and persistent proteinuria or renal insufficiency also contributes to cardiovascular disease22). There is little or no risk of cardiovascular disease in children with MCNS who are responsive to CS because hyperlipidemia is intermittent and of short duration. The risk of premature atherosclerosis is increased due to hyperlipidemia. The duration of nephrotic hyperlipidemia appears to be critical to initiating vascular damage, and patients with unremitting proteinuria and hypoalbuminemia are the most at risk23). Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and lipoprotein (a) are elevated in children with long-standing and frequently relapsing NS21). Elevated VLDL and LDL should place patients at increased risk for developing atherosclerosis. Hyperlipidemia contributes to the development of glomerular and interstitial renal disease. Endothelial damage from hyperlipidemia may favor influx of lipoprotein into the mesangium, leading to proliferation and sclerosis22).

Elevated VLDL and LDL should place patients at increased risk for developing atherosclerosis. Hyperlipidemia contributes to the development of glomerular and interstitial renal disease. Endothelial damage from hyperlipidemia may favor influx of lipoprotein into the mesangium, leading to proliferation and sclerosis22). Therapy with lipid-lowering drugs, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, should be given with extreme caution in children as it remains controversial. Although Prescott et al.24) reported that lowering cholesterol levels during childhood might reduce the risk for atherosclerotic changes and suggested short-term safety and efficacy of HMG-CoA reductase inhibitors, others showed that excessive free lipid-lowering drugs with low albumin levels may affect proximal muscle pain and malaise even at a normal dose25,26). Therefore, more prospective controlled studies in children are needed in the future to evaluate the efficacy and safety of lipid-lowering drugs. 4. Hypovolemic crisis Hypovolemic shock is one of the attentive presentations in NS27). Risk factors for hypovolemic crisis include severely depressed albumin levels, high dose diuretics, and vomiting. The clinical manifestations are tachycardia, cold extremities, poor capillary refill, and moderate to severe abdominal pain, and laboratory tests may show elevated hematocrit and uric acid levels.

in NS27). Risk factors for hypovolemic crisis include severely depressed albumin levels, high dose diuretics, and vomiting. The clinical manifestations are tachycardia, cold extremities, poor capillary refill, and moderate to severe abdominal pain, and laboratory tests may show elevated hematocrit and uric acid levels. It is useful to measure urinary sodium (UNa) excretion or fractional excretion of sodium (FENa) when evaluating physical volume status. Donckerwolcke et al.28) found a better correlation between log aldosterone and urinary potassium / urinary potassium + urinary sodium (UK / UNa + UK) ratio than with other parameters measuring renal potassium and sodium handling. In patients with renal sodium retention (FENa: <0.5%), UK / UNa + UK ratio of higher than 0.6 (UK / UNa + UK: >60%) identifies patients with increased aldosterone levels and functional hypovolemia29). This index may therefore be used to assess which patients will benefit from intravenous normal saline (20 mL/kg over 1 to 2 hours) or albumin administration at maximum dose of 1 g/kg over 3 to 5 hours with blood pressure monitoring29). The administration of albumin is not routinely given to all patients in relapse and may be dangerous in children who are not volume depleted due to the risk of pulmonary edema.

al saline (20 mL/kg over 1 to 2 hours) or albumin administration at maximum dose of 1 g/kg over 3 to 5 hours with blood pressure monitoring29). The administration of albumin is not routinely given to all patients in relapse and may be dangerous in children who are not volume depleted due to the risk of pulmonary edema. 5. Anemia Mild anemia is observed on occasion in patients with NS. Anemia is usually microcytic and hypochromic, typical of iron deficiency, but is resistant to therapy with iron because of large loss of serum transferrin in the urine of some nephrotic patients30). Vaziri31) reported some data on the metabolism and regulation of erythropoietin (EPO) and transferrin, which are essential for erythropoiesis in nephrotic children. Urinary loss of EPO causes EPO-deficiency anemia and transferrinuria, and increased transferrin catabolism induces hypotranferrinemia and iron-deficiency anemia in some cases. Subcutaneous administration of recombinant EPO and iron supplementation can be used for the treatment of EPO- and iron-deficiency anemia, respectively32). However, correction of the underlying proteinuria will be the ideal approach to reversing these complications.

anferrinemia and iron-deficiency anemia in some cases. Subcutaneous administration of recombinant EPO and iron supplementation can be used for the treatment of EPO- and iron-deficiency anemia, respectively32). However, correction of the underlying proteinuria will be the ideal approach to reversing these complications. 6. Acute renal failure Acute renal failure (ARF) is an uncommon but alarming complication of NS33). When massive proteinuria develops and the levels of albumin are profoundly decreased, the circulating volume in the plasma is reduced to produce circulatory collapse or pre-renal uremia, usually of mild degree. However, much less commonly, ARF that is unresponsive to volume replacement and aggressive diuretic therapy may be seen in certain forms of NS without the features of volume depletion. This may be due to severe disturbance in visceral epithelial cells that results in almost total obliteration of the slit pores and severe reduction in surface area for filtration34). With severe proteinuria, occlusion of the distal nephron lumina from cast formation or extratubule compression from renal interstitial edema may result in an increase in proximal tubular pressure, leading to a fall in glomerular filtration rate35). ARF is usually precipitated by sepsis, radiocontrast agents, acute tubular necrosis from nephrotoxic antibiotics and non-steroidal anti-inflammatory agents. If renal failure persists for more than a few days, dialysis may be necessary for complete recovery.

6. Acute renal failure Acute renal failure (ARF) is an uncommon but alarming complication of NS33). When massive proteinuria develops and the levels of albumin are profoundly decreased, the circulating volume in the plasma is reduced to produce circulatory collapse or pre-renal uremia, usually of mild degree. However, much less commonly, ARF that is unresponsive to volume replacement and aggressive diuretic therapy may be seen in certain forms of NS without the features of volume depletion. This may be due to severe disturbance in visceral epithelial cells that results in almost total obliteration of the slit pores and severe reduction in surface area for filtration34). With severe proteinuria, occlusion of the distal nephron lumina from cast formation or extratubule compression from renal interstitial edema may result in an increase in proximal tubular pressure, leading to a fall in glomerular filtration rate35). ARF is usually precipitated by sepsis, radiocontrast agents, acute tubular necrosis from nephrotoxic antibiotics and non-steroidal anti-inflammatory agents. If renal failure persists for more than a few days, dialysis may be necessary for complete recovery. 7. Edema Edema is often observed in nephrotic children and where tissue pressure is low. Ascites and pleural effusions frequently occur, but pericardial effusion is rare unless cardiac function is abnormal. Edema is caused by increased glomerular permeability and hypoalbuminemia, resulting in decreased plasma oncotic pressure and functional hypovolemia. These stimulate secondary sodium retention by the kidney36).

and pleural effusions frequently occur, but pericardial effusion is rare unless cardiac function is abnormal. Edema is caused by increased glomerular permeability and hypoalbuminemia, resulting in decreased plasma oncotic pressure and functional hypovolemia. These stimulate secondary sodium retention by the kidney36). Treatment of edema consists of dietary sodium restriction and judicious use of loop-acting diuretics such as furosemide and bumetanide. Hyperoncotic salt-poor albumin and furosemide may be administered in cases of severe and refractory edema36). 8. Hormonal, mineral alterations and intussusceptions Urinary loss of hormone-binding proteins contributes to various hormonal abnormalities in patients with NS. While thyroid function tests are in the normal range in most nephrotic patients, the mean values for triiodothyronine (T3) and thyroid-binding globulin (TBG) are lower than those in non-NS children because of a significant increase in urinary excretion of T3, T4 and TBG37). Routine thyroid screening and early replacement therapy of thyroid hormone are necessary for infants with severe NS and clinical hypothyroidism.

r triiodothyronine (T3) and thyroid-binding globulin (TBG) are lower than those in non-NS children because of a significant increase in urinary excretion of T3, T4 and TBG37). Routine thyroid screening and early replacement therapy of thyroid hormone are necessary for infants with severe NS and clinical hypothyroidism. Hypocalcemia in NS is also attributed to the decreased albumin level, which results in reduced bound and ionized calcium in 50 to 80% of NS cases38). Children with NS often have hypocalciuria due to decreased gastrointestinal absorption of calcium and increased renal tubular reabsorption of calcium. These suggest the possibility of an abnormality in vitamin D metabolism. The abnormalities are due to increased filtration of vitamin D metabolites bound to vitamin D-binding globulin39). However, bone disease is rarely shown in NS patients, and therefore, routine treatment with vitamin D is not recommended. Nevertheless, special concern should be given to subclinical mineral bone disorder like secondary hyperparathyroidism. Intussusceptions can occur within the ileocolic junction and the small intestines in patients with NS, causing acute abdominal pain. They are caused by a combination of patches of bowel wall edema and peristaltic incoordination. Cho et al.40) reported a case involving reversal of intussusceptions associated with nephrotic syndrome by infusion of albumin.

e ileocolic junction and the small intestines in patients with NS, causing acute abdominal pain. They are caused by a combination of patches of bowel wall edema and peristaltic incoordination. Cho et al.40) reported a case involving reversal of intussusceptions associated with nephrotic syndrome by infusion of albumin. Adverse effects of long-term drug therapy 1. Corticosteroids CS have reduced the NS mortality rate to around 3%41). However, CS have well-recognized potentially serious adverse effects such as cushingoid features, obesity, growth retardation, hypertension, osteoporosis, cataracts, impaired glucose metabolism, dyslipidemia, emotional deprivation, behavioral changes, and avascular necrosis of the femoral head42). Two major causes of growth retardation in patients with NS are the loss of insulin-like growth factors (IGFs) and/or IGF-binding proteins (IGFBPs) and CS therapy. Several reports have suggested that there are changes in serum levels of IGFs and IGFBPs among nephrotic children43,44). CS induce overt elevation of serum IGF-1 levels, which results in the potential development of IGF resistance, one of the main factors responsible for persistent growth retardation45). Bone maturation and linear growth are delayed and arrested by long-term, high-dose CS therapy46), particularly when the dosage exceeds 0.5 mg/kg/day47). Therefore, the initial dose should be low in the range of 0.2 to 0.4 mg/kg (5 to 15 mg/m2) per dose for treatment maintenance.

le for persistent growth retardation45). Bone maturation and linear growth are delayed and arrested by long-term, high-dose CS therapy46), particularly when the dosage exceeds 0.5 mg/kg/day47). Therefore, the initial dose should be low in the range of 0.2 to 0.4 mg/kg (5 to 15 mg/m2) per dose for treatment maintenance. Jeon et al.48) reported that alternate-day steroid therapy, as a single morning dose, does not affect growth but may lead to decrement of serum vitamin D3 levels and bone mineral density in children with NS. The best way to avoid growth retardation is to stop unnecessarily extended courses of therapy with high doses of CS. To reduce the complications associated with CS therapy, the following strategies may be helpful: Adrenal suppression: alternate-day steroid therapy. Impairment of statural growth: CS-sparing agents, and growth hormone therapy. Osteoporosis: Calcium, vitamin D supplementation, and use of steroid-sparing protocols. Peptic ulceration: H2 blockers. Hypertension: anti-hypertensive agents. Cataract: low dose and short duration of CS treatment, regular examination by ophthalmologists. Increased intracranial pressure: investigate papilledema. Behavioral changes49): reduce or withdraw CS.

Osteoporosis: Calcium, vitamin D supplementation, and use of steroid-sparing protocols. Peptic ulceration: H2 blockers. Hypertension: anti-hypertensive agents. Cataract: low dose and short duration of CS treatment, regular examination by ophthalmologists. Increased intracranial pressure: investigate papilledema. Behavioral changes49): reduce or withdraw CS. 2. Cyclophosphamide (CPM) Alkylating agents impair DNA transcription by attaching alkyl chains to purine bases. Latta et al.6) addressed the side effects of alkylating agents, including early complications of bone marrow suppression, alopecia, gastrointestinal upset, hemorrhagic cystitis, and infections, and late complications of possible malignancies and impaired fertility, especially in males. There is a dose-dependent relationship between sperm counts and the cumulative dose of CPM50). To avoid gonadal toxicity, CPM should not be used for more than 12 weeks (2 mg/kg, single oral dose) and should be withheld if the white blood cell count is less than 5,000/mm3 during CPM use. High fluid intake is recommended to elude hemorrhagic cystitis during the use of CPM.

counts and the cumulative dose of CPM50). To avoid gonadal toxicity, CPM should not be used for more than 12 weeks (2 mg/kg, single oral dose) and should be withheld if the white blood cell count is less than 5,000/mm3 during CPM use. High fluid intake is recommended to elude hemorrhagic cystitis during the use of CPM. 3. Cyclosporin A (CsA) CsA is an immunosuppressive fungal metabolite that acts by modifying T-cell function and inhibiting the release of interleukin-2 from activated T helper cells51). Long-term use of CsA causes reduced renal function, gingival hyperplasia, hirsuitism, hypertension, hyperkalemia, and encephalopathy52). CsA-induced tubulointerstitial lesions are found in 30 to 40% of children who have received CsA for more than 12 months53). Several publications have shown risk factors for CsA complications, such as the long duration of CsA treatment, a high CsA trough level, and a younger age at the start of CsA treatment54-56). Therefore, the lowest effective dose of CsA is recommended for the maintenance treatment in nephrotic children, with slow tapering over one year to 1 to 3 mg/kg/day. Yang et al.57) found that the combined treatment of CsA and MMF did not prevent the development of chronic CsA nephrotoxicity, but MMF treatment after CsA withdrawal improves chronic CsA nephrotoxicity. Recently, Hara et al.58) also reported protective effects of Mizoribine on CsA nephropathy in rats.

1 to 3 mg/kg/day. Yang et al.57) found that the combined treatment of CsA and MMF did not prevent the development of chronic CsA nephrotoxicity, but MMF treatment after CsA withdrawal improves chronic CsA nephrotoxicity. Recently, Hara et al.58) also reported protective effects of Mizoribine on CsA nephropathy in rats. 4. Others Complications of MMF include gastrointestinal disturbances, bone marrow suppression, and headache, requiring dose reduction or even withdrawal59). Tacrolimus is a calcineurin inhibitor that has similar action to CsA but can have several side effects, such as hypertension, abnormal renal function, tremor, muscle cramps, hyperkalemia, hypophosphatemia, leukopenia, and hyperglycemia. Levamisole, the antihelminthic agent, can be used in steroid-dependent patients, but is ineffective as a permanent therapy for NS. Levamisole may have the minor side effects of leukopenia, gastrointestinal effects, and vasculitis, but no important side effects were reported60). Rituximab has recently been introduced and may be applied to steroid-dependent or refractory nephrotic syndrome61). Complicatons of Rituximab include life-threatening bronchospasm, myocardial infarction, progressive multifocal leukoencephalopathy, and reactivation of viruses such as cytomegalovirus and hepatitis B virus62).

imab has recently been introduced and may be applied to steroid-dependent or refractory nephrotic syndrome61). Complicatons of Rituximab include life-threatening bronchospasm, myocardial infarction, progressive multifocal leukoencephalopathy, and reactivation of viruses such as cytomegalovirus and hepatitis B virus62). Conclusions The complications of the NS can be divided into two categories, disease-associated and treatment-related. When we treat children with NS, it is important to start with early identification and appropriate treatment for acute complications. Regular examinations and monitoring for chronic complications will improve outcomes for children with NS. Table 1 Major Complications of the Nephrotic Syndrome

Introduction The pandemic influenza A/H1N1 viral infection was first identified in March 20091); this virus was antigenically and genetically unrelated to human seasonal influenza viruses, but genetically related to viruses known to circulate in swine2). The world experienced its first wave of pandemic influenza A/H1N1 activity in the spring of 2009, followed by a second wave in the fall, peaking at the end of October. An early report on 18 hospitalized patients who were victims of the initial outbreak in Mexico showed that the pandemic H1N1 2009 virus caused severe illness and death in previously healthy young to middle-aged individuals; it has since been noted that the majority of patients continue to experience mild illness1). There have been a few reports of H1N1 characteristics and outcomes among children hospitalized with pandemic influenza A/H1N1 2009 viral infection3,4). Although children are considered to be more vulnerable to pandemic influenza pneumonia, few reports describe the characteristics of this pneumonia in pediatric patients5,6). This study describes the clinical and epidemiologic features of the viral infection among pediatric patients hospitalized with pandemic influenza A/H1N1 pneumonia from September 2009 to February 2010 at a tertiary medical center in Korea. Materials and methods We reviewed the medical charts and radiologic and laboratory findings of all children admitted to Asan Children's Hospital in Korea between September 2009 and February 2010; the hospital is a tertiary, academic medical center.

There have been a few reports of H1N1 characteristics and outcomes among children hospitalized with pandemic influenza A/H1N1 2009 viral infection3,4). Although children are considered to be more vulnerable to pandemic influenza pneumonia, few reports describe the characteristics of this pneumonia in pediatric patients5,6). This study describes the clinical and epidemiologic features of the viral infection among pediatric patients hospitalized with pandemic influenza A/H1N1 pneumonia from September 2009 to February 2010 at a tertiary medical center in Korea. Materials and methods We reviewed the medical charts and radiologic and laboratory findings of all children admitted to Asan Children's Hospital in Korea between September 2009 and February 2010; the hospital is a tertiary, academic medical center. We included children with pandemic influenza H1N1 confirmed by reverse-transcription polymerase chain reaction (RT-PCR). The clinical criteria for a diagnosis of H1N1 pneumonia in the hospitalized pediatric patients was based on abnormal breath sound such as crackle, rale, or rhonchi and opacities found on the chest radiography at admission. The chest radiographs were reviewed by two radiologists, and final decisions on the findings were reached by consensus.

for a diagnosis of H1N1 pneumonia in the hospitalized pediatric patients was based on abnormal breath sound such as crackle, rale, or rhonchi and opacities found on the chest radiography at admission. The chest radiographs were reviewed by two radiologists, and final decisions on the findings were reached by consensus. Clinical characteristics were compared between patients with pandemic A/H1N1 pneumonia and those with pandemic A/H1N1 infection and between children less than 5 years and those older than 5 years. Patients who were admitted because of pandemic influenza A/H1N1 infection were also subcategorized by clinical outcome as those requiring respiratory support by nasal cannula, those requiring mechanical ventilation, and those requiring admission to the intensive care urnit (ICU). 1. Microbiological studies Nasopharyngeal swab specimens (Flexible Minitip 503CS01 Flock Swabs, Diagnostic Hybrids, Athens, OH, USA) were collected at admission. Specimens were placed in 3 Ml Universal Transport Medium (Diagnostic Hybrids) and kept at 2 to 4℃. RT-PCR testing was done in accordance with published guidelines from the U.S. Centers for Disease Control and Prevention.

ible Minitip 503CS01 Flock Swabs, Diagnostic Hybrids, Athens, OH, USA) were collected at admission. Specimens were placed in 3 Ml Universal Transport Medium (Diagnostic Hybrids) and kept at 2 to 4℃. RT-PCR testing was done in accordance with published guidelines from the U.S. Centers for Disease Control and Prevention. 2. Statistical analysis We compared data between patients with pandemic H1N1 pneumonia and those with pandemic H1N1 infection without pneumonia. Logistic regression was used to identify the characteristics of the children in each group. The Fisher's exact test was used to compare categorical variables. Statistical analysis was performed with the SPSS ver. 16.0 (SPSS Inc., Chicago, IL, USA). A P value of less than 0.05 indicated a significant difference.

umonia. Logistic regression was used to identify the characteristics of the children in each group. The Fisher's exact test was used to compare categorical variables. Statistical analysis was performed with the SPSS ver. 16.0 (SPSS Inc., Chicago, IL, USA). A P value of less than 0.05 indicated a significant difference. Results 1. Patient characteristics In our institution, 11,662 pediatric patients (all under 18 years of age) were tested for pandemic influenza A/H1N1 2009 from September 2009 to February 2010 (Table 1). Among them, 5,367 patients (46%) tested positive; 72 of the 5,367 patients were admitted to the hospital, and 54 of these 72 patients had pandemic influenza A/H1N1 pneumonia confirmed by means of RT-PCR (Table 2). The epidemic curve of pediatric patients hospitalized with pandemic influenza A/H1N1 with or without pneumonia in Korea is shown in Fig. 1. Of these 72 patients, 54 (75%) were male. The median age was 6.0 years. Fig. 2 shows the age distribution of children hospitalized with pandemic H1N1 pneumonia or pandemic H1N1 infection alone. Of the 18 children without pneumonia, 17 were diagnosed with upper respiratory infection and the remaining 1 patient was diagnosed with Kawasaki disease. 2. Preexisting medical conditions A total of 40% of patients had at least 1 preexisting medical condition: 30% and 72% in the H1N1 pneumonia group and the group without pneumonia (P=0.24), respectively. In the H1N1 pneumonia group, asthma was the most common medical condition (25%), and the children presented with exacerbation of asthma or a first attack.

otal of 40% of patients had at least 1 preexisting medical condition: 30% and 72% in the H1N1 pneumonia group and the group without pneumonia (P=0.24), respectively. In the H1N1 pneumonia group, asthma was the most common medical condition (25%), and the children presented with exacerbation of asthma or a first attack. 3. Clinical features Fever (temperature above 37.8℃) and cough were the most common presentations at admission in both groups (Table 3). The next most common symptom was dyspnea in the pandemic H1N1 pneumonia group (n=35, 65%), and rhinorrhea (n=7, 39%) in the group without pneumonia. Nausea and vomiting were more common in the group without pneumonia (22% for both symptoms) compared with the pandemic pneumonia group (6% and 9%, respectively); however, this difference was not significant. Sputum was a more common symptom in children older than 5 years than those aged less than 5 years. 4. Laboratory tests on admission Children with pandemic H1N1 pneumonia were more likely to have a lower lymphocyte ratio (P=0.02), higher platelet counts (P=0.02), and a higher level of serum glucose (P=0.003) than those without pneumonia (Table 4).

3. Clinical features Fever (temperature above 37.8℃) and cough were the most common presentations at admission in both groups (Table 3). The next most common symptom was dyspnea in the pandemic H1N1 pneumonia group (n=35, 65%), and rhinorrhea (n=7, 39%) in the group without pneumonia. Nausea and vomiting were more common in the group without pneumonia (22% for both symptoms) compared with the pandemic pneumonia group (6% and 9%, respectively); however, this difference was not significant. Sputum was a more common symptom in children older than 5 years than those aged less than 5 years. 4. Laboratory tests on admission Children with pandemic H1N1 pneumonia were more likely to have a lower lymphocyte ratio (P=0.02), higher platelet counts (P=0.02), and a higher level of serum glucose (P=0.003) than those without pneumonia (Table 4). 5. Radiographic evaluation Chest radiography was performed in all children admitted with pandemic influenza A/H1N1 infection; 54 children (75%) had findings consistent with pneumonia. On an average, the initial chest radiographs for all patients (n=72) were obtained 1.2 days (range, 0 to 7 days) after the onset of clinical symptoms. In the pandemic H1N1 pneumonia group, initial chest radiography revealed unilateral abnormalities in 37%, bronchopneumonial pattern in 57% (n=31), consolidation patterns in 43% (n=20), and mixed patterns in 6% (n=3) (Table 5). The chest computed tomography scans obtained for 11 of these patients showed bilaterally distributed lung parenchymal lesions that had peribronchial ground-glass opacities (n=7), patchy consolidations (n=5), and interstitial thickening (n=1). The mediastinal and perihilar lymph nodes were detected in 1 patient, pleural effusion was noted in 3 patients, and pneumomediastinum was detected in 2 patients.

ally distributed lung parenchymal lesions that had peribronchial ground-glass opacities (n=7), patchy consolidations (n=5), and interstitial thickening (n=1). The mediastinal and perihilar lymph nodes were detected in 1 patient, pleural effusion was noted in 3 patients, and pneumomediastinum was detected in 2 patients. 6. Severity of illness and outcomes Oxygen supplementation was provided to 67% of the children hospitalized with pandemic H1N1 pneumonia, and to 6% of children without pneumonia. Three patients were admitted to the ICU. Of the 3 pediatric patients who required mechanical ventilation, 2 were male, and the sole female had a preexisting hematologic malignancy, and hers was the only death in this study. This patient had a 2-day history of fever, cough, and sputum. Her initial laboratory results were as follows: leukocyte count 3,300/mm3, platelet count 75,000/mm3, aspartate aminotransferase 400 IU/L, alanine aminotransferase 305 IU/L, lactate dehydrogenase 977 IU/L, C-reactive protein 0.82 mg/dL, and creatine kinase 24 IU/L. She received oseltamivir (150 mg twice a day), amatadine (100 mg twice a day), azithromycin, ceftazidime and vancomycin until her death on hospital day 17. She remained positive for influenza A RNA as assessed by RT-PCR 2 days after administration of antiviral medication; no other viral pathogens were cultured and amplified by PCR when bronchoalveolar lavage (BAL) and sputum samples were taken, and bacterial cultures from the same specimens showed no growth. Complications in this patient included hypovolemic shock and respiratory failure.

ys after administration of antiviral medication; no other viral pathogens were cultured and amplified by PCR when bronchoalveolar lavage (BAL) and sputum samples were taken, and bacterial cultures from the same specimens showed no growth. Complications in this patient included hypovolemic shock and respiratory failure. 7. Treatment All pediatric patients suspected having pandemic H1N1 infection were administered oseltamivir before the results of the H1N1 RT-PCR were known. The median time from the onset of symptoms to the initiation of antiviral therapy was 1.1 days (range, 0 to 5 days) in the pneumonia group and 1.7 days (range, 0 to 7 days) in the group without pneumonia; this difference was not significant (P=0.24). Antibiotics were administered to 94% of patients in the pandemic H1N1 pneumonia group, and to 61% of those without pneumonia. Oseltamivir resistance does not performed in all patients. Discussion Children admitted to a tertiary hospital in Korea with pandemic influenza A/H1N1 2009 infection during the second wave of the pandemic showed a wide spectrum of disease, ranging from upper respiratory infection alone to severe illness and death.

7. Treatment All pediatric patients suspected having pandemic H1N1 infection were administered oseltamivir before the results of the H1N1 RT-PCR were known. The median time from the onset of symptoms to the initiation of antiviral therapy was 1.1 days (range, 0 to 5 days) in the pneumonia group and 1.7 days (range, 0 to 7 days) in the group without pneumonia; this difference was not significant (P=0.24). Antibiotics were administered to 94% of patients in the pandemic H1N1 pneumonia group, and to 61% of those without pneumonia. Oseltamivir resistance does not performed in all patients. Discussion Children admitted to a tertiary hospital in Korea with pandemic influenza A/H1N1 2009 infection during the second wave of the pandemic showed a wide spectrum of disease, ranging from upper respiratory infection alone to severe illness and death. The chest radiography findings on admission were consistent with those for pneumonia in 54 (75%) of the pediatric patients hospitalized with pandemic influenza A/H1N1 2009 infection. However, no significant differences were observed between the pandemic influenza A/H1N1 2009 pneumonia group and the pandemic influenza A/H1N1 2009 infection group with respect to age, sex, or the presence of preexisting conditions. In addition, no significant differences were observed between these groups with respect to the time between the onset of symptoms and the initiation of oseltamivir therapy (pneumonia group: mean period, 1.1 days; non-pneumonia group: mean period, 1.7 days). The patients from the pandemic influenza A/H1N1 2009 pneumonia group had higher leukocyte counts, higher glucose levels and lower lymphocyte ratios than did the patients from the group without pneumonia.

tiation of oseltamivir therapy (pneumonia group: mean period, 1.1 days; non-pneumonia group: mean period, 1.7 days). The patients from the pandemic influenza A/H1N1 2009 pneumonia group had higher leukocyte counts, higher glucose levels and lower lymphocyte ratios than did the patients from the group without pneumonia. Some reports have suggested that children less than 5 years old are at the highest risk of seasonal influenza-associated hospitalizations7-9); in our study, pediatric patients aged 5 to 18 years accounted for 83% of patients in the pandemic H1N1 pneumonia group and 72% of those in the pandemic H1N1 group without pneumonia (Table 2). In a study on patients hospitalized with 2009 H1N1 influenza in the United States, the study population included a greater proportion of children older than 5 years (29%) than of children younger than 5 years (15%)10). Children aged less than 5 years were hospitalized more frequently because of either different admission criteria or diagnostic method for pneumonia in each hospital. Therefore, we cannot definitely conclude that children aged less than 5 years are at the highest risk for influenza-associated hospitalization. The median duration of viral shedding, as determined by positive RT-PCR results, was 2.0 days for children younger than 5 years and 3.81 days for children older than 5 years (P=0.59). The reason for this age distribution and for the difference in the duration of viral shedding for each age group is uncertain; however, these findings may be related to the higher possibilities of contact with and of repeated or prolonged exposure to this virus in the case of children older than 5 years at schools.

9). The reason for this age distribution and for the difference in the duration of viral shedding for each age group is uncertain; however, these findings may be related to the higher possibilities of contact with and of repeated or prolonged exposure to this virus in the case of children older than 5 years at schools. Approximately one-quarter to one-half of patients with pandemic influenza A/H1N1 2009 viral infection who were hospitalized or who died had no reported coexisting medical conditions10-13). In our study, 40% of pediatric patients with pandemic H1N1 infection had preexisting conditions. However, there was no significant difference between patients in the pandemic H1N1 pneumonia group and those in the group without pneumonia. The pandemic influenza A/H1N1 2009 virus causes pneumonia regardless of preexisting medical conditions; this may be because the virus has a strong affinity for the lower respiratory tract and the affected population did not have antibodies specific to this virus1,2,14). In our study, dyspnea was the only clinical feature at presentation that differed significantly between patients in the pandemic H1N1 pneumonia group and those in the group without pneumonia. Because we considered shortness of breath or breathing discomfort to be indicative of dyspnea, there was no significant difference in respiratory rates between the groups.

feature at presentation that differed significantly between patients in the pandemic H1N1 pneumonia group and those in the group without pneumonia. Because we considered shortness of breath or breathing discomfort to be indicative of dyspnea, there was no significant difference in respiratory rates between the groups. The risk factors for pandemic influenza A/H1N1 pneumonia are still unclear; however, a significantly greater number of the patients with pneumonia presented with higher leukocyte counts, higher glucose levels and lower lymphocyte ratios than did the patients without pneumonia. In a few studies, patients admitted with pandemic influenza A/H1N1 infection showed increased serum concentrations of lactate dehydrogenase and creatinine kinase1,15). In our study, the presence of pandemic H1N1 pneumonia did not affect these levels, but the level of glucose was elevated in the pandemic H1N1 pneumonia group, compared with the group without pneumonia. The most likely explanation for this may be the stress effect of H1N1 infection complicated by pneumonia.

kinase1,15). In our study, the presence of pandemic H1N1 pneumonia did not affect these levels, but the level of glucose was elevated in the pandemic H1N1 pneumonia group, compared with the group without pneumonia. The most likely explanation for this may be the stress effect of H1N1 infection complicated by pneumonia. The radiographs for patients with pandemic influenza A/H1N1 pneumonia showed prominent peribronchial marking with hyperinflation, similar to that observed in other common viral respiratory infections16). In contrast, the radiographs for children with a more severe clinical course of pandemic influenza A/H1N1 infection typically show a bilateral symmetrical distribution pattern of areas of consolidation that are often associated with ground-glass opacification. In this study, the patients (n=6) who were admitted to the ICU or required mechanical ventilation had bilateral symmetric distribution of consolidation or ground-glass opacities. The rate of bacterial or other viral co-infection was 4.2%; 1 patient was co-infected with respiratory syncytial virus and mycoplasma in the pandemic influenza A/H1N1 pneumonia group, and 2 patients with adenovirus and streptococcal pneumonia, in the pandemic influenza A/H1N1 group without pneumonia. We could not find any relationship between co-infections and the severity of disease; these 3 patients did not need any oxygen supplementation and were not admitted to the ICU.

a A/H1N1 pneumonia group, and 2 patients with adenovirus and streptococcal pneumonia, in the pandemic influenza A/H1N1 group without pneumonia. We could not find any relationship between co-infections and the severity of disease; these 3 patients did not need any oxygen supplementation and were not admitted to the ICU. A study performed between May and July 2009 showed that the hospitalization rate for pandemic influenza A/H1N1 among children was twice that for 2008 seasonal influenza in the same population. Moreover, the death rate was 10 times the rate associated with seasonal influenza for the same population in 20074,17). In contrast to the findings of these studies, the results of another study reported that the overall hospital mortality rates for all age groups was 1.1% and that for children was 0.24% in Japan18). In our study, the death rate due to pandemic influenza A/H1N1 2009 was low (1.4%), although there is some limitation due to small sample size. These differences may be partially due to the recommendation, which was put forth in September 2009 in Korea, that empirical therapy with oseltamivir be administered to patients with influenza-like symptoms-especially to children at high-risk and children who were hospitalized; the differences may also exist because the other studies included both pediatric and adult patients.

n, which was put forth in September 2009 in Korea, that empirical therapy with oseltamivir be administered to patients with influenza-like symptoms-especially to children at high-risk and children who were hospitalized; the differences may also exist because the other studies included both pediatric and adult patients. Our study includes a limited number of cases and was of short duration. The need for hospitalization due to pandemic influenza A/H1N1 2009 infection was decided by several attending physicians without any objective indications. The availability of hospital or ICU beds may have influenced assessment of the severity of disease. This study cannot represent the full spectrum of pandemic influenza A/H1N1 2009 influenza infections because it was performed at a tertiary hospital. In conclusion, hospitalization with pandemic H1N1 influenza infection affected children without any significant differences in age, sex, or the presence of preexisting conditions between the pandemic H1N1 pneumonia group and those without pneumonia. A higher leukocyte count, higher glucose level and a lower lymphocyte ratio together with dyspnea were associated with the development of pandemic influenza A/H1N1 2009 influenza pneumonia. Acknowledgement The authors thank all the patients involved in this report and all the pediatricians and hospital staff involved in their care. Fig. 1 Seasonal pattern of hospitalization of children for pandemic H1N1 influenza with or without pneumonia. Fig. 2 Age distribution of children hospitalized for pandemic H1N1 influenza with or without pneumonia.

Acknowledgement The authors thank all the patients involved in this report and all the pediatricians and hospital staff involved in their care. Fig. 1 Seasonal pattern of hospitalization of children for pandemic H1N1 influenza with or without pneumonia. Fig. 2 Age distribution of children hospitalized for pandemic H1N1 influenza with or without pneumonia. Table 1 Analyses of Patient Variables from September 2009 to February 2010 Values are presented as no. of patients or no. of patients (%). RT-PCR, reverse-transcriptase polymerase-chain-reaction. Table 2 Epidemiologic Features, Preexisting Conditions, Clinical Symptoms in Children Hospitalized with 2009 H1N1 Influenza *Fisher's exact test was used when cell sizes were small. Table 3 Clinical Symptoms in Children Hospitalized with 2009 H1N1 Pneumonia or without Pneumonia Values are presented as no. of patients (%). Table 4 Results of Laboratory Tests in Children Hospitalized with Pandemic Influenza A/H1N1 2009 Pneumonia or without Pneumonia IQR, interquartile range; CRP, C-reactive protein. Table 5 Distribution and Radiologic Findings in the H1N1 Pneumonia Group Values are presented as number/total number (%).

Introduction Kawasaki disease (KD) is a generalized vasculitis affecting young children. As a complication, the development of coronary artery lesions (CALs) are frequent, manifesting in about 20% of KD patients. KD is the most common cause of acquired heart disease1,2). The cause of KD remains unknown, but one current hypothesis is that KD is caused by various infectious agents that trigger clinically apparent disease in certain genetically predisposed individuals1). Hyperhomocysteinemia has emerged as an independent risk factor for atherosclerosis3-7). Hyperhomocysteinemia may enhance vascular inflammation which contributes to the development of atherosclerosis5). The relationship between hyperhomocysteinemia and KD is unclear. Hyperhomocysteinemia may induce subclinical endothelial dysfunction that leads to late coronary arteritis in KD8). Preclinical arteriosclerosis in KD patients even in the absence of CALs was reported9) and the development of premature atherosclerosis was accelerated in adult post-KD patients8,10).

ia and KD is unclear. Hyperhomocysteinemia may induce subclinical endothelial dysfunction that leads to late coronary arteritis in KD8). Preclinical arteriosclerosis in KD patients even in the absence of CALs was reported9) and the development of premature atherosclerosis was accelerated in adult post-KD patients8,10). 5,10-methylenetetrahydrofolate reductase (MTHFR) is the enzyme that reduces 5,10-MTHF to 5-MTHF. 5-MTHF is the main circulating form of folate and the methyl donor for the remethylation of homocysteine to methionine. The MTHFR gene is one of the candidate genes for the development of atherosclerosis regardless of localization. Polymorphisms in the MTHFR gene result in reduced enzyme activity, which lead to high plasma homocysteine concentrations and decreased folic acid levels. A variant of MTHFR with reduced activity and increased thermolability has been reported to be associated with the development of coronary artery disease11,12). Tsukahara et al.13) have reported an association of the MTHFR gene (677C->T), in which the TT genotype may protect female KD patients against aneurysm formation and predispose male KD patients to severe coronary complications. Therefore, we hypothesized that non-synonymous polymorphisms of 3 MTHFR genes (rs2274976, Agr594Gln; rs1801131, Glu429Ala; rs1801133, Ala222Val) which induce functional polymorphisms of the MTHFR genes may be correlated with the pathogenesis of KD and CALs. Furthurmore, we hypothesized that homocystein-lowering diet may have a possible role in the treatment of KD if they have such risk factor.

s (rs2274976, Agr594Gln; rs1801131, Glu429Ala; rs1801133, Ala222Val) which induce functional polymorphisms of the MTHFR genes may be correlated with the pathogenesis of KD and CALs. Furthurmore, we hypothesized that homocystein-lowering diet may have a possible role in the treatment of KD if they have such risk factor. Materials and methods 1. Subjects Between June 2003 and December 2005, 101 patients diagnosed as having KD who fulfilled the established criteria1) participated in our study. Patients with CALs who have less than 4 diagnostic criteria were diagnosed as having atypical KD1). They were from Eulji Medical Center and Kyung Hee University Medical Center, Seoul, Korea. During the acute phase of the disease, treatment included high-dose intravenous immunoglobulin (IVIG; 2 g/kg) infusion and moderate-dose aspirin (50 mg/kg) as initial therapy. If fever persisted for 36 hours after the completion of IVIG infusion, a second dose of IVIG was given. Clinical characteristics of participants are described in Table 1. In the KD group, the male to female ratio was 2.5:1 and the mean age was 33±25.6 months (range, 7 to 59 months; Table 1). Two-dimensional echocardiography was done at least 3 times per patient by two expert pediatric cardiologists. The definition of CALs was an internal diameter of the coronary artery larger than 3 mm (4mm in patients older than 5 years) or aneusym formation.

Materials and methods 1. Subjects Between June 2003 and December 2005, 101 patients diagnosed as having KD who fulfilled the established criteria1) participated in our study. Patients with CALs who have less than 4 diagnostic criteria were diagnosed as having atypical KD1). They were from Eulji Medical Center and Kyung Hee University Medical Center, Seoul, Korea. During the acute phase of the disease, treatment included high-dose intravenous immunoglobulin (IVIG; 2 g/kg) infusion and moderate-dose aspirin (50 mg/kg) as initial therapy. If fever persisted for 36 hours after the completion of IVIG infusion, a second dose of IVIG was given. Clinical characteristics of participants are described in Table 1. In the KD group, the male to female ratio was 2.5:1 and the mean age was 33±25.6 months (range, 7 to 59 months; Table 1). Two-dimensional echocardiography was done at least 3 times per patient by two expert pediatric cardiologists. The definition of CALs was an internal diameter of the coronary artery larger than 3 mm (4mm in patients older than 5 years) or aneusym formation. The control group was composed of 306 healthy adults who did not have a history of KD, hypertension, hyperlipidemia, and cardiac disease. In the control group, the male to female ratio was 1.06:1 and the mean age was 36.6±6.8 years (range, 29.8 to 43.4 years).

Introduction The masticator space is defined as the separate fascial compartment containing the pterygoid, masseter and temporalis muscles and the mandible1,2). Masticator space abscess represents an advanced stage of a commonly odontogenic infection indicated by buccal pain, swelling and trismus3). Jaw swelling and trismus after a dental procedure are the typical clinical manifestations of a masticator space abscess in adults4,5). Masticator space abscess without dental procedure is an uncommon infection and can be seen with poor sucking, irritability, fever and dehydration in the infant. It is imperative that a meticulous medical history be obtained and a thorough physical examination be completed in infants with such clinical symptoms1). The clinical diagnosis is usually obvious, but it is confirmed by ultrasonography (US) or computed tomography (CT)1,5). Masticator space abscess has not been reported in newborns, and rarely been reported in infants. Here we report a 47 day old male diagnosed as masticator space abscess with nonspecific symptoms without evidence of dental disease, traumatic injuries to the head and neck, or parotid swelling1). Case report A 47 day old male was admitted for fever, poor oral intake, irritability and right side mild bluish buccal swelling which have persisted for two days ago. He was born 3.47 kg at term by repeated Caesarean section. He was admitted for neonatal jaundice at the 5th day of life, but was generally healthy after discharge. He had no airway compromise, respiratory symptoms, or traumatic injuries. He received a bacille de calmette-guerin vaccine, and a first and second hepatitis B vaccination on schedule. He was fed by breast milk. He had no known drug allergies and was not taking any medication. He had no specific family history of recurrent infections except the cervical cancer of his aunt.

Two-dimensional echocardiography was done at least 3 times per patient by two expert pediatric cardiologists. The definition of CALs was an internal diameter of the coronary artery larger than 3 mm (4mm in patients older than 5 years) or aneusym formation. The control group was composed of 306 healthy adults who did not have a history of KD, hypertension, hyperlipidemia, and cardiac disease. In the control group, the male to female ratio was 1.06:1 and the mean age was 36.6±6.8 years (range, 29.8 to 43.4 years). 2. Single nucleotide polymorphism (SNP) selection and genotyping All typed SNPs of the MTHFR genes were downloaded from SNP database (www.ncbi.nlm.nih.gov/SNP, dbSNP BUILD 131) of National Center for Biotechnology Information, and three nonsynonymous SNPs (rs2274976, rs1801131, and rs1801133) in the coding regions were selected. The rs2274976 (Arg594Gln) is located on exon 12 of the MTHFR gene region, the rs1801131 located on exon 8, and the rs1801133 located on exon 5. DNA was isolated from a peripheral blood sample using a genomic DNA isolation reagent kit (CoreBioSystem, Seoul, Korea). The genotypes were determined by direct sequencing. Genomic DNA was amplified using the following primers: rs2274976 (sense, 5'-CACACCCAGCTCTGACTCACC-3'; antisense, 5'-CTCCACTCTCCTTCGTGTCTCT-3'; 726 bp); rs1801131 (sense, 5'-CCTGAAGATCAAGCCAGTTCTCC-3'; antisense, 5'-ACCCTGGCCTGTGTCTCAAGCA-3'; 525 bp); rs1801133 (sense, 5'-TCTATGGCCACCAAGTGCAGGCCT-3'; antisense, 5'-CTCTCAGGTCCAGAACTTGCAC-3'; 649 bp). The samples were sequenced using an ABI Prism 377 automatic sequencer (PE Applied Biosystems, Foster City, CA, USA). Sequence data were analyzed using the SeqManII software (DNASTAR Inc., Madison, WI, USA).

-3'; 525 bp); rs1801133 (sense, 5'-TCTATGGCCACCAAGTGCAGGCCT-3'; antisense, 5'-CTCTCAGGTCCAGAACTTGCAC-3'; 649 bp). The samples were sequenced using an ABI Prism 377 automatic sequencer (PE Applied Biosystems, Foster City, CA, USA). Sequence data were analyzed using the SeqManII software (DNASTAR Inc., Madison, WI, USA). 3. Statistical Analysis Statistical analysis was performed with SAS ver. 9.13 (SAS Institute Inc., Cary, NC, USA). A linkage disequilibrium block of polymorphisms was tested using Haploview version 3.32. Statistical differences in genotype between case and control were determined using chi-square test and Fisher's exact test. The odds ratio and 95% confidence intervals were calculated to quantify the association between case and control at the 5% level of significance. Results The clinical characteristics of KD patients and controls are described in Table 1. The mean age of KD group was 33±25.6 months and 36.6±6.8 years in control group. In KD group, 19 patients were diagnosed as having incomplete or atypical KD. Normal coronary arteries were seen in 62 patients (61.4%). CALs were seen in 38 (37.6%) and coronary aneurysms were seen in 8 (7.9%) of 38 patients with CALs (Table 1).

an age of KD group was 33±25.6 months and 36.6±6.8 years in control group. In KD group, 19 patients were diagnosed as having incomplete or atypical KD. Normal coronary arteries were seen in 62 patients (61.4%). CALs were seen in 38 (37.6%) and coronary aneurysms were seen in 8 (7.9%) of 38 patients with CALs (Table 1). In the analysis of SNPs of each candidate gene, the genetic distribution and allele frequency of the 3 MTHFR genes (rs2274976, rs1801131, and rs1801133) in patients with KD were not significantly different than that of the control group (P values: 0.71, 0.17, 0.96, respectively) (Table 2). We did not find any significant differences in 3 SNPs between the normal coronary patients group and the CALs group (P values: 0.61, 0.97, 0.41, respectively) (Table 3). There was no difference of the genetic distribution of the MTHFR genes in the normal control group compared with the abnormal coronary patients group (P value: 0.43, 0.39, 0.52 respectively) (Table 4). Discussion 5,10-MTHFR is the enzyme that reduces 5,10-MTHF to 5-MTHF. 5-MTHF is the main circulating form of folate and the methyl donor for the remethylation of homocysteine to methionine. The MTHFR gene has been mapped to the chromosomal region 1p36.3. Severe MTHFR deficiency is a rare autosomal recessive disorder which results in hyperhomocysteinemia and homocysteinemia presenting as a variety of neurological and vascular problems.

Discussion 5,10-MTHFR is the enzyme that reduces 5,10-MTHF to 5-MTHF. 5-MTHF is the main circulating form of folate and the methyl donor for the remethylation of homocysteine to methionine. The MTHFR gene has been mapped to the chromosomal region 1p36.3. Severe MTHFR deficiency is a rare autosomal recessive disorder which results in hyperhomocysteinemia and homocysteinemia presenting as a variety of neurological and vascular problems. Milder deficiencies of the MTHFR genes are more common in the general population and have resulted from some common polymorphisms. 677C>T (rs2274976, Agr594Gln), which changes alanine into a valine residue, results in a thermolabile enzyme. This polymorphism is known as a risk factor for cardiovascular disease. Among studies of the 677C>T mutation in cardiovascular patients and controls, Kluijtmans et al.14), Klerk et al.15), and Morita et al.11) revealed an association of the 677C>T polymorphism as a risk factor for coronary artery disease. However, van Bockxmeer et al.16) and Schwartz et al.17) concluded that this polymorphism was not a risk factor for myocardial infarction in their population. In KD patients, Tsukahara et al.13) showed statistically insignificant differences for 677C>T polymorphisms. But, they suggested that the TT genotype may protect female patients against initial aneurysm formation and predispose male patients to severe coronary complications. In our study, there was no genetic association of 677C>T (rs1801133) polymorphisms with KD and CALs.

insignificant differences for 677C>T polymorphisms. But, they suggested that the TT genotype may protect female patients against initial aneurysm formation and predispose male patients to severe coronary complications. In our study, there was no genetic association of 677C>T (rs1801133) polymorphisms with KD and CALs. Martin et al.18) resequenced exons, splice junctions, and portions of the 5-prime flanking region of the human MTHFR gene using 240 DNA samples from 4 ethnic groups. A total of 65 polymorphisms were observed, 11 of which were nonsynonymous coding SNPs (cSNPs). They also suggested that a major mechanism by which nonsynonymous cSNPs influence the function of this gene is by alteration in the quantity of protein. Other nonsynonymous cSNPs include the 1298A>C missense mutation, which results in a substitution of glutamine to alanine at 429 position (rs1801131, Glu429Ala). Allen et al.19) reported that the 1298C allele was associated with susceptibility to schizophrenia. In other studies, an MTHFR 1298 A>C gene polymorphism conferred an increased risk for subclinical atherosclerosis and cardiovascular events in patients with rheumatoid arthritis20). Therefore, we selected 3 nonsynonymous cSNPs of the MTHFR genes that may have a major role in the pathogenesis of KD and CALs.

Martin et al.18) resequenced exons, splice junctions, and portions of the 5-prime flanking region of the human MTHFR gene using 240 DNA samples from 4 ethnic groups. A total of 65 polymorphisms were observed, 11 of which were nonsynonymous coding SNPs (cSNPs). They also suggested that a major mechanism by which nonsynonymous cSNPs influence the function of this gene is by alteration in the quantity of protein. Other nonsynonymous cSNPs include the 1298A>C missense mutation, which results in a substitution of glutamine to alanine at 429 position (rs1801131, Glu429Ala). Allen et al.19) reported that the 1298C allele was associated with susceptibility to schizophrenia. In other studies, an MTHFR 1298 A>C gene polymorphism conferred an increased risk for subclinical atherosclerosis and cardiovascular events in patients with rheumatoid arthritis20). Therefore, we selected 3 nonsynonymous cSNPs of the MTHFR genes that may have a major role in the pathogenesis of KD and CALs. Reports are rare that reveal the association of the three functional polymorphisms of the MTHFR genes, ones which regulate MTHFR , with KD and CALs. Our results were not significant. Therefore, the SNPs of the MTHFR genes may not have a pathogenic role in KD and CALs in the Korean population. This study may have value in that the study population was racially homogeneous, but it has some limitations in that patients with severe coronary complications such as giant coronary aneurysm or myocardial infarction were absent. Because the number of cases was not large, a more extended study population may be required to confirm an association of the MTHFR genes and KD. Another limitation of this study may be that the control group who are older than KD patients may have subclinical atherosclerosis despite of excluding cardiovascular disease history. Age and gender-matched control study may elucidate the association of MTHFR gene polymorphisms in KD patients.

f the MTHFR genes and KD. Another limitation of this study may be that the control group who are older than KD patients may have subclinical atherosclerosis despite of excluding cardiovascular disease history. Age and gender-matched control study may elucidate the association of MTHFR gene polymorphisms in KD patients. In conclusions, we did not find any difference of genetic polymorphisms of the MTHFR genes (rs2274976, rs1801131, and rs1801133) in the KD patients group from the control group. The genetic polymorphisms of these genes were not different in CAL group from the control group in our study. Our results may imply the genetic polymorphisms of the MTHFR genes are not risk factors in the pathogenesis of KD nor in the development of CAL in KD patients. To verify these conclusions, larger KD patients with various CALs might be included in the study of genetic polymorphism of the MTHFR genes. Acknowledgement This research was supported by the Kyung Hee University Research Fund in 2006(KHU-2006-039). Table 1 Clinical Characteristics of Kawasaki Disease Patients KD, Kawasaki disease. Table 2 Genotype Distribution and Allele Frequencies of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms in Kawasaki Disease Patients and Controls MTHFR, methylenetetrahydrofolate reductase; SNP, single nucleotide polymorphism; KD, Kawasaki disease; OR, odds ratio; CI, confidence interval; NA, not available.

Table 2 Genotype Distribution and Allele Frequencies of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms in Kawasaki Disease Patients and Controls MTHFR, methylenetetrahydrofolate reductase; SNP, single nucleotide polymorphism; KD, Kawasaki disease; OR, odds ratio; CI, confidence interval; NA, not available. Table 3 Genotype Distribution of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Single Nucleotide Polymorphisms in Normal Coronary Group Patients and Abnormal Coronary Group Patients with Kawasaki Disease MTHFR, methylenetetrahydrofolate reductase; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; NA, not available. Table 4 Genotype Distribution of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms in the Normal Control Group and the Abnormal Coronary Group MTHFR methylenetetrahydrofolate reductase; SNP single nucleotide polymorphism; OR odds ratio; CI confidence interval; NA, not available.

Introduction Brain natriuretic peptide (BNP) has been considered a biochemical marker for myocarditis during the acute phase of Kawasaki disease1-4). Plasma BNP levels increased more than 16.8 pg/mL during the acute phase in 87.5% of patients2), and decreased to nearly normal levels during the convalescent phase in most of the patients1,2). Although increased plasma concentrations of BNP (>50 pg/mL) have been regarded as an indicator of myocarditis in Kawasaki disease during the acute phase1,4), the association between BNP quantitation and other parameters, including cardiac systolic dysfunction and coronary arterial dilatation, has been in controversy1,4-6). A recent study reported a significant relation between diastolic function with BNP, but data of diastolic function in that study did not differ between patients and controls3). We have therefore sought to determine the clinical, laboratory and echocardiographic variables independently associated with quantitative variations in BNP in a relatively large number of patients with Kawasaki disease.

Introduction Brain natriuretic peptide (BNP) has been considered a biochemical marker for myocarditis during the acute phase of Kawasaki disease1-4). Plasma BNP levels increased more than 16.8 pg/mL during the acute phase in 87.5% of patients2), and decreased to nearly normal levels during the convalescent phase in most of the patients1,2). Although increased plasma concentrations of BNP (>50 pg/mL) have been regarded as an indicator of myocarditis in Kawasaki disease during the acute phase1,4), the association between BNP quantitation and other parameters, including cardiac systolic dysfunction and coronary arterial dilatation, has been in controversy1,4-6). A recent study reported a significant relation between diastolic function with BNP, but data of diastolic function in that study did not differ between patients and controls3). We have therefore sought to determine the clinical, laboratory and echocardiographic variables independently associated with quantitative variations in BNP in a relatively large number of patients with Kawasaki disease. Materials and methods The study subjects consisted of 81 children registered at the Asan Medical Center from March 2009 through March 2010 who fulfilled the diagnostic criteria for Kawasaki disease7). All patients were in acute phase and underwent echocardiographic examination before intravenous immunoglobulin infusion therapy. One patient had a familial history of Kawasaki disease. Dilatation of coronary arteries according to criteria of Japanese Ministry of Health and Welfare8) was found in 4 patients, one among them had aneurysmal dilatation. Of the 81 patients, 20 were enrolled in another study on myocardial deformation during the acute phase of Kawasaki disease9).

history of Kawasaki disease. Dilatation of coronary arteries according to criteria of Japanese Ministry of Health and Welfare8) was found in 4 patients, one among them had aneurysmal dilatation. Of the 81 patients, 20 were enrolled in another study on myocardial deformation during the acute phase of Kawasaki disease9). Demographic and laboratory data were surveyed by reviewing medical records. Plasma BNP concentration was determined by a chemiluminescent immunoassay (Siemens Healthcare Diagnostics, Deerfield, IL, USA), and was log transformed (log-BNP). Because BNP concentrations >50 pg/mL during the acute phase of Kawasaki disease have been reported to be an qualitative indicator of myocarditis1,4), patients were divided into 2 groups based on their BNP concentrations, with group 1 consisting of 37 patients with BNP >50 pg/mL and group 2 consisting of 44 patients with BNP ≤50 pg/mL. The study protocol was approved by the Institutional Review Board, Asan Medical Center, Seoul, Korea. All subjects or their parents provided informed consent.

Demographic and laboratory data were surveyed by reviewing medical records. Plasma BNP concentration was determined by a chemiluminescent immunoassay (Siemens Healthcare Diagnostics, Deerfield, IL, USA), and was log transformed (log-BNP). Because BNP concentrations >50 pg/mL during the acute phase of Kawasaki disease have been reported to be an qualitative indicator of myocarditis1,4), patients were divided into 2 groups based on their BNP concentrations, with group 1 consisting of 37 patients with BNP >50 pg/mL and group 2 consisting of 44 patients with BNP ≤50 pg/mL. The study protocol was approved by the Institutional Review Board, Asan Medical Center, Seoul, Korea. All subjects or their parents provided informed consent. 1. Echocardiographic examinations Subjects were prepared for echocardiography by administering a sedative and/or antipyretic, as required. All echocardiographic examinations were performed by a single echocardiographer, and images were obtained using a Vivid 7 Vantage machine equipped with 7-MHz and 5-MHz transducers (GE Vingmed, Horten, Norway). All recordings of 2D, M-mode, and Doppler images were obtained according to the recommendations of the American Society of Echocardiography10-12). Moving images (40 to 100 frames/sec) were stored for analysis of tissue velocity from apical four-chamber view, and measurements performed off-line using EchoPAC PC ver. 7 (GE Vingmed, Horten Norway) by another author blinded to patient status. Left ventricular fractional shortening was calculated from dimensions measured from the standard M-mode using the parasternal long axis view. Left ventricular mass was calculated using the formula derived by Devereux and Reichek13), and the index was obtained by dividing the mass by body surface area.

o patient status. Left ventricular fractional shortening was calculated from dimensions measured from the standard M-mode using the parasternal long axis view. Left ventricular mass was calculated using the formula derived by Devereux and Reichek13), and the index was obtained by dividing the mass by body surface area. Tissue velocities of the basal lateral segment of the left ventricle were determined by analysis of 2D strain using speckle tracking imaging. Data were approved when considered acceptable by the software. In 7 patients, tissue velocity data were abandoned owing to failure to meet approval. We also calculated the ratio of peak early diastolic velocity of mitral inflow (E) to peak early diastolic tissue velocity of the lateral basal segment (Em). Fifteen moving images were randomly selected, and tissue velocities of the basal lateral segment of the left ventricle (peak systolic tissue velocity [Sm], Em, and peak late diastolic tissue velocity [Am]) were determined by 1 observer on 2 occasions and by 2 observers on 2 occasions. Reproducibility of measurement of tissue velocities was tested though Pearson correlation analysis. Results of intraobserver test were P=0.0010 / R=0.78 in Sm, P<0.0001 / R=0.84 in Em, and P<0.0001 / R=0.96 in Am. Results of interobserver test were P=0.0242 / R=0.60 in Sm, P=0.0019 / R=0.75 in Em, and P=0.1559 / R=0.40 in Am.

cibility of measurement of tissue velocities was tested though Pearson correlation analysis. Results of intraobserver test were P=0.0010 / R=0.78 in Sm, P<0.0001 / R=0.84 in Em, and P<0.0001 / R=0.96 in Am. Results of interobserver test were P=0.0242 / R=0.60 in Sm, P=0.0019 / R=0.75 in Em, and P=0.1559 / R=0.40 in Am. 2. Statistical analysis All data are presented as means±standard deviations (SDs). All statistical analyses were performed using SAS ver. 9.1 (SAS Institute Inc., Cary, NC, USA), and statistical significance was defined as a P value<0.01. The skewness of distribution of BNP / log-BNP was calculated using the formula: Skewness = 3×(mean-median)/SD Chi-squared analysis was used to determine whether the distribution of categorical variables differed between groups. Student's t-tests were used to compare numerical variables between groups. Correlations between the BNP / log-BNP and clinical, laboratory and echocardiographic variables were assessed using Pearson correlation analysis. Stepwise multiple linear regression analysis (SLS 0.15, SLE 0.15) was used to determine the variables significantly associated with log-BNP. Results The demographic and anthropometric data did not differ significantly among groups (Table 1). The distributions of BNP and log-BNP are shown in Fig. 1. The mean±SD, median, and skewness of BNP were 136.5±291.5 pg/mL, 40.7 pg/mL, and 0.99, respectively, whereas them of log-BNP were 1.68±0.63, 1.61, and 0.31, respectively.

he demographic and anthropometric data did not differ significantly among groups (Table 1). The distributions of BNP and log-BNP are shown in Fig. 1. The mean±SD, median, and skewness of BNP were 136.5±291.5 pg/mL, 40.7 pg/mL, and 0.99, respectively, whereas them of log-BNP were 1.68±0.63, 1.61, and 0.31, respectively. Serum C-reactive protein (CRP) concentration was significantly higher (P=0.0004), whereas hemoglobin (P=0.0032), serum albumin (P<0.0001) and Na+ (P=0.0007) concentrations were significantly lower, in group 1 than in group 2. Mitral regurgitation and pericardial effusion was detected in 20 and in 10 patients respectively, but severities of them looked to be less than hemodynamic significance and the distribution of them was not different between groups (Table 2). When we compared numerical echocardiographic variables, we found that heart rate (P=0.0023) and E/Em ratio (P=0.0066) were significantly higher, and Sm (P=0.0079) was significantly lower, in group 1 than in group 2 (Table 2).

odynamic significance and the distribution of them was not different between groups (Table 2). When we compared numerical echocardiographic variables, we found that heart rate (P=0.0023) and E/Em ratio (P=0.0066) were significantly higher, and Sm (P=0.0079) was significantly lower, in group 1 than in group 2 (Table 2). The laboratory and echocardiographic variables significantly related to BNP and/or log-BNP are shown in Table 3. White blood cell count, hemoglobin and serum alanine aminotransferase concentrations, left ventricular fractional shortening and Em were significantly related to log-BNP, but not to BNP. CRP, serum albumin and Na+ concentrations were significantly related to both BNP and log-BNP, but correlation coefficients were higher for log-BNP than for BNP. Heart rate was not significantly related to BNP (P=0.3267) and log-BNP (P=0.0319). Diameters of coronary arteries were not related to BNP (left main coronary artery, P=0.5497; left anterior descending coronary artery, P=0.4443; right coronary artery, P=0.2351) and log-BNP (P=0.5621, P=0.3136, P=0.2259). Significant independent variables resulted from stepwise multiple linear regression analysis, in which log-BNP was the dependent variable, were serum albumin (R2=0.31, P=0.0098), left ventricular mass index (R2=0.09, P=0.0004), CRP (R2=0.06, P=0.0073), fractional shortening (R2=0.05, P=0.0006), and end diastolic dimension (R2=0.05, P<0.0001).

variables resulted from stepwise multiple linear regression analysis, in which log-BNP was the dependent variable, were serum albumin (R2=0.31, P=0.0098), left ventricular mass index (R2=0.09, P=0.0004), CRP (R2=0.06, P=0.0073), fractional shortening (R2=0.05, P=0.0006), and end diastolic dimension (R2=0.05, P<0.0001). Discussion Limitations of previous studies1-4,6) on the relationship between the myocardial dysfunction and increased BNP levels during the acute phase of Kawasaki disease might be the small numbers of subjects and the rightward skewness of the distribution of BNP. We found, however, that this skewness could be overcome by log transformation of BNP, allowing successful correlation and multiple regression analyses of various clinical factors with log-BNP.

e acute phase of Kawasaki disease might be the small numbers of subjects and the rightward skewness of the distribution of BNP. We found, however, that this skewness could be overcome by log transformation of BNP, allowing successful correlation and multiple regression analyses of various clinical factors with log-BNP. Log-BNP showed significant correlation with laboratory variables that reflecting the severity of disease during the acute phase, and/or that were laboratory diagnostic criteria for incomplete presentation of Kawasaki disease7,14,15), indicating that log-BNP may quantitatively reflect the severity of Kawasaki disease during the acute phase. Moreover, log-BNP may be a better marker of myocarditis in Kawasaki disease than of coronary artery complications. We found that the diameters of the coronary arteries were not significantly related to BNP or log-BNP, although several left ventricular systolic and diastolic function indices were significantly related to log-BNP in multiple regression and correlation analyses. Moreover, several systolic and diastolic function variables showed more significantly deviated values in patients with high than with low BNP. The relation between pericardial effusion and elevation of BNP has been in controversy2,16), but we found no significant relationship between them.

ion and correlation analyses. Moreover, several systolic and diastolic function variables showed more significantly deviated values in patients with high than with low BNP. The relation between pericardial effusion and elevation of BNP has been in controversy2,16), but we found no significant relationship between them. We found that serum albumin concentration and left ventricular mass index were significant independent predictors of log-BNP, with relatively higher R square values than other variables. Increased vascular permeability from vasculitis and resultant vascular leakage are key features of the pathophysiology of Kawasaki disease, and increased vascular leakage may cause hypoalbuminemia and tissue edema15). We previously showed that serum albumin concentration and left ventricular mass index were significantly associated during the acute phase of Kawasaki disease, which suggests that increases in left ventricular mass index may result from myocardial swelling caused by increased vascular permeability17). Increases in left ventricular mass have been significantly associated with diastolic dysfunctions17). Thus, our findings that log-BNP was significantly associated with serum albumin concentration and left ventricular mass index, indicate a causative association between increases in left ventricular mass caused by myocardial swelling and myocardial systolic/diastolic dysfunction that induces secretion of BNP from the myocardium. It is generally well known mechanism of elevation of BNP level, that ventricular production of BNP is enhanced in the presence of left ventricular hypertrophy and in the presence of associated systolic/diastolic dysfunction18). Is this mechanism unchanged in patients with Kawasaki disease during the acute phase? The answer is not confirmative because the elevation of left ventricular mass during the acute phase of Kawasaki disease may not be a compensatory result against an overwelming hemodynamic load. Whatever the mechanism of left ventricular hypertrophy, we speculate that it may be a cause of myocardial dysfunction, which induced the increased secretion of BNP. Already we showed the association between an increased left ventricular mass and the myocardial systolic/diastolic dysfunction in the acute phase of Kawasaki disease9,17).

hanism of left ventricular hypertrophy, we speculate that it may be a cause of myocardial dysfunction, which induced the increased secretion of BNP. Already we showed the association between an increased left ventricular mass and the myocardial systolic/diastolic dysfunction in the acute phase of Kawasaki disease9,17). Our study had several limitations. First, the dataset used for analysis was not complete. In seven patients, tissue velocity analyses had to be excluded due to failure of imaging approval. Second, some results of reproducibility tests were unsatisfactory. In conclusion, the elevation of BNP during the acute phase of Kawasaki disease may be due to cardiac dysfunction associated with the increase in left ventricular mass. Log-BNP was significantly related to laboratory variables reflective of disease severity and to systolic/diastolic myocardial dysfunction, suggesting that log-BNP may be a quantitative biochemical marker of myocarditis in Kawasaki disease. Fig. 1 Distribution of (A) brain natriuretic peptide (BNP) and (B) log-transformed BNP concentration (log-BNP) in 81 patients with Kawasaki disease. Table 1 Between-Group Comparisons of Clinical and Laboratory Data Values are presented as number (%) or mean±SD. BNP, brain natriuretic peptide; Log-BNP, log transformed BNP; CRP, C-reactive protein; WBC, white blood cell count; sALT, serum alanine aminotransferase. *Group 1, BNP >50 pg/mL. †Group 2, BNP ≤50 pg/mL. Table 2 Between-Group Comparisons of Echocardiographic Data Values are presented as mean±SD or number (%).

Values are presented as number (%) or mean±SD. BNP, brain natriuretic peptide; Log-BNP, log transformed BNP; CRP, C-reactive protein; WBC, white blood cell count; sALT, serum alanine aminotransferase. *Group 1, BNP >50 pg/mL. †Group 2, BNP ≤50 pg/mL. Table 2 Between-Group Comparisons of Echocardiographic Data Values are presented as mean±SD or number (%). bpm, beats per minute; LMCA, diameter of left main coronary artery; LAD, diameter of left anterior descending coronary artery; RCA, diameter of right coronary artery; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVFS, left ventricular fractional shortening; E peak, early diastolic velocity of mitral inflow; A peak, atrial diastolic mitral inflow; Sm, systolic tissue velocity; Em, early diastolic tissue velocity; Am, late diastolic tissue velocity. *Group 1, BNP >50 pg/mL, †Group 2, BNP ≤50 pg/mL. Table 3 Correlations between Laboratory and Echocardiographic Variables, and BNP and log-BNP Levels BNP, brain natriuretic peptide; Log-BNP, log transformed BNP; R, Pearson's correlation coefficient; CRP, C-reactive protein; WBC, white blood cell count; sGPT, serum alanine aminotransferase; LVFS, left ventricular fractional shortening; Em, early diastolic tissue velocity.

Introduction The first severe case of H1N1 influenza-related pneumonia in a young adult was reported in April 20091), and the 2009 H1N1 influenza A virus spread rapidly thereafter. The World Health Organization (WHO) declared a pandemic in June 2009. By February 2010, at least 15,921 fatal cases as confirmed by laboratory tests were reported by the WHO2). In South Korea, the first fatal case was reported in August 2009, and 196 intensive care unit (ICU) patients were reported by December 7, 20093). Some patients with H1N1 influenza virus infection experienced rapidly progressing respiratory symptoms and ultimately required respiratory support, including mechanical ventilation, nitric oxide inhalation, and/or extracorporeal membrane oxygenation (ECMO). In Canada, over 80% of ICU patients required mechanical ventilation and of those patients 17 to 40% died4). It was recently found that 64.6% of H1N1 ICU patients in Australia and New Zealand needed mechanical ventilation during the winter of 2009 and that 11.6% of those patients were subsquently treated with ECMO5,6). In this report, we present a child with acute respiratory distress syndrome (ARDS) due to a 2009 H1N1 influenza virus infection complicated by necrotizing pneumonia who was successfully rescued with ECMO.

ical ventilation during the winter of 2009 and that 11.6% of those patients were subsquently treated with ECMO5,6). In this report, we present a child with acute respiratory distress syndrome (ARDS) due to a 2009 H1N1 influenza virus infection complicated by necrotizing pneumonia who was successfully rescued with ECMO. Case report A 3-year-old girl was referred to the Samsung Medical Center, Seoul, Korea emergency department due to fever, respiratory distress, and decreased mental status during the peak influenza pandemic period in October 2009. She had been healthy until she developed fever and cough 7 days prior to hospitalization. Two days after her initial symptoms, she was seen by a general practitioner and was started on oseltamivir based on a positive rapid antigen test result. However, her condition deteriorated and she experienced difficult breathing and sleepiness despite antiviral treatment. She was taken to a general hospital near her home and was eventually referred to our center due to impending respiratory failure and decreased mental status. She did not have any significant past medical or family history, and she had not been vaccinated against 2009 H1N1 influenza or seasonal influenza.

ral treatment. She was taken to a general hospital near her home and was eventually referred to our center due to impending respiratory failure and decreased mental status. She did not have any significant past medical or family history, and she had not been vaccinated against 2009 H1N1 influenza or seasonal influenza. On arrival, the patient's blood pressure was 117/67 mmHg, heart rate 181 beats/min, respiratory rate 40/min, and body temperature 37.5℃. Percutaneous oxygen saturation was 91% on 7 liters/min of oxygen via face mask. On physical examination, chest wall retraction was observed and left lung sounds were decreased. The patient did not have any abnormal focal neurological signs although she appeared drowsy. She was admitted to the pediatric intensive care unit and intubated immediately.

was 91% on 7 liters/min of oxygen via face mask. On physical examination, chest wall retraction was observed and left lung sounds were decreased. The patient did not have any abnormal focal neurological signs although she appeared drowsy. She was admitted to the pediatric intensive care unit and intubated immediately. Her initial blood gas analysis showed pH 7.193, PaCO2 53.9 mmHg, PaO2 30.3 mmHg, bicarbonate 20.3 mmoL/L, and base excess -7.9 on 7 liters/min of oxygen via face mask. A complete blood count showed pancytopenia (white blood cell [WBC] count 710/µL, absolute neutrophil count 210/µL, hemoglobin 10.6 g/dL, platelets 81,000/µL) and her C-reactive protein was markedly elevated up to 37.18 mg/dL. Her immunoglobulin G level was decreased to 399 mg/dL. The patient was placed on high dose oseltamivir (60 mg/dose, body weight 13 kg) and intravenous immunoglobulin G was also given as 500 mg/kg/day for 2 days. The 2009 H1N1 influenza virus was detected by reverse transcriptase-polymerase chain reaction assay in both a respiratory specimen and spinal fluid. Her initial chest radiograph showed diffuse haziness in the entire left lung field and the right upper lung field (Fig. 1). Thoracentesis was performed and 100 mL of turbid chocolate-colored fluid was drained from the left lung (pleural fluid analysis results: red blood cell >1,000/µL, WBC >1,000/µL, polymorphonuclear neutrophil 93%, pH 7.4, glucose 11 mg/dL, protein 3,564.6 mg/dL). A culture of the pleural fluid did not grow any organisms.

Thoracentesis was performed and 100 mL of turbid chocolate-colored fluid was drained from the left lung (pleural fluid analysis results: red blood cell >1,000/µL, WBC >1,000/µL, polymorphonuclear neutrophil 93%, pH 7.4, glucose 11 mg/dL, protein 3,564.6 mg/dL). A culture of the pleural fluid did not grow any organisms. On hospital day 3, a chest tube was inserted into the left pleural space due to increased pleural effusion causing tracheal deviation. On hospital day 6, chest computed tomography showed necrotizing pneumonia with a significant left pleural effusion (Fig. 2). She also had persistent high fever (39.1℃) and a striking leukocytosis (WBC count 24,250/µL, absolute neutrophil count 19,640/µL) despite broad spectrum antibiotics (cefotaxime and vancomycin). On hospital day 7, pneumothorax developed in the left lung (Fig. 3) and the chest tube was replaced by one with a bigger sized lumen. As pneumothorax was waxed-and-waned on hospital day 8, more ventilator support (volume control mode, FiO2 1.0, positive end-expiratory pressure [PEEP] 5 cmH2O, TV 90 mL) was needed to maintain percutaneous oxygen saturation level near 90%. Peak inspiratory pressure was recorded at 23 to 34 cmH2O depending on the relief of pneumothorax. Due to her poor response to antibiotic treatment, cefotaxime was changed to meropenem. On hospital day 9, percutaneous oxygen saturation level was dropped to 77% due to progressive respiratory failure with a persistent purulent pleural effusion and a recurrent, massive pneumothorax (Fig. 4). To rescue the patient from progressing respiratory failure without raising positive airway pressure, which might aggravate pneumothorax, venovenous ECMO support was initiated.

ropped to 77% due to progressive respiratory failure with a persistent purulent pleural effusion and a recurrent, massive pneumothorax (Fig. 4). To rescue the patient from progressing respiratory failure without raising positive airway pressure, which might aggravate pneumothorax, venovenous ECMO support was initiated. Of note, multidrug resistant Acinetobacter baumannii started to grow from both blood and tracheal aspirate cultures on hospital day 10. Follow-up cultures persistently grew A. baumannii and Stenotrophomonas maltophilia from both tracheal aspirates and pleural fluid. Blood cultures became negative 5 days after ECMO discontinuation (bacteremia persisted from day 10 to day 18). The tracheal aspirate cultures were positive from hospital days 10 to 34, and pleural fluid cultures were positive from hospital days 11 to 41. The total duration of ECMO support was 6 days, and successful weaning was achieved without cardiovascular complications. At the time of ventilator weaning, blood gas analysis showed pH 7.371, PaCO2 64.0 mmHg, PaO2 111.9 mmHg, bicarbonate 36.3 mmoL/L, and base excess 9.2 with conventional mechanical ventilation. Various combinations of antibiotics were used including isepamicin, minocyclin, rifampicin, ceftazidime, TMP-SMX, and colistin in an attempt to control persistent infections due to multidrug resistant A. baumannii and S. maltophilia. Total duration of oseltamivir medication was 23 days (high dose for 18 days and usual dose for 5 days).

ons of antibiotics were used including isepamicin, minocyclin, rifampicin, ceftazidime, TMP-SMX, and colistin in an attempt to control persistent infections due to multidrug resistant A. baumannii and S. maltophilia. Total duration of oseltamivir medication was 23 days (high dose for 18 days and usual dose for 5 days). The patient was weaned from mechanical ventilation on hospital day 37, and all antimicrobials were discontinued on day 57. On day 63, the left chest tube was removed and she was discharged from the hospital alert and spontaneously breathing without difficulty in room air (Fig. 5). At the time this manuscript was submitted, the patient had no respiratory symptoms and a chest radiograph was markedly improved.

als were discontinued on day 57. On day 63, the left chest tube was removed and she was discharged from the hospital alert and spontaneously breathing without difficulty in room air (Fig. 5). At the time this manuscript was submitted, the patient had no respiratory symptoms and a chest radiograph was markedly improved. Discussion About 1-10% of patients with clinical illness due to the H1N1 influenza virus infection were hospitalized, and the overall case fatality ratio has been estimated to be <0.5%7). Patients with dyspnea, tachypnea, evidence of hypoxemia, and pulmonary infiltrates on chest radiograph should be hospitalized8), and most deaths have been related to respiratory failure resulting from severe pneumonia with multifocal infiltrates and ARDS9,10). Mechanical ventilation is usually necessary to support gas exchange in patients with ARDS, although its use can be associated with lung injury. Despite attempts to optimize ventilator settings, hypoxemia or hypercapnia refractory to conventional mechanical ventilation may persist in a small subset of patients, and these patients may be treated with ECMO11). Furthermore, The Korean Society of Critical Care Medicine recommended early ECMO application if ARDS were not be maintained appropriately12). Recent studies have also shown significant improvement in the survival of patients transferred to a specialist center for ECMO treatment compared to conventional management13). This patient had recurrent, massive pneumothorax and pleural effusion, we were concerned that ventilation with high PEEP might aggravate lung parenchymal destruction and air leak and decided ECMO support in this patient.

ients transferred to a specialist center for ECMO treatment compared to conventional management13). This patient had recurrent, massive pneumothorax and pleural effusion, we were concerned that ventilation with high PEEP might aggravate lung parenchymal destruction and air leak and decided ECMO support in this patient. In general, venovenous ECMO is used for isolated pulmonary support in cases of reversible pulmonary failure14). In older children, the most common diagnoses for ECMO support are viral pneumonia, bacterial pneumonia, ARDS, and aspiration pneumonia15). On the other hand, active irreversible respiratory injury is not an adequate indication for ECMO support. Although some complications associated with ECMO such as coagulopathy, thromboembolism could happen, the worldwide pandemic H1N1 influenza virus in 2009 caused many serious cases of ARDS and some of those patients were successfully treated with short term ECMO support5). H1N1 influenza virus infection caused severe lung parenchymal destruction in certain patients, and these patients often do not respond to conventional respiratory care. ECMO support is recommended as the alternative treatment modality, and it is occasionally the only rescue method in pediatric patients.

In general, venovenous ECMO is used for isolated pulmonary support in cases of reversible pulmonary failure14). In older children, the most common diagnoses for ECMO support are viral pneumonia, bacterial pneumonia, ARDS, and aspiration pneumonia15). On the other hand, active irreversible respiratory injury is not an adequate indication for ECMO support. Although some complications associated with ECMO such as coagulopathy, thromboembolism could happen, the worldwide pandemic H1N1 influenza virus in 2009 caused many serious cases of ARDS and some of those patients were successfully treated with short term ECMO support5). H1N1 influenza virus infection caused severe lung parenchymal destruction in certain patients, and these patients often do not respond to conventional respiratory care. ECMO support is recommended as the alternative treatment modality, and it is occasionally the only rescue method in pediatric patients. The patient in this report had serious lung parenchymal injury, was septic, and had an uncertain neurological status. The severe lung parenchymal destruction (initially due to influenza virus and then secondary bacterial infection) with massive pneumothorax was responsible for the subsequent acute respiratory distress syndrome (ARDS) which was resistant to conventional mechanical ventilation. ECMO and aggressive antimicrobial treatment were used simultaneously to allow for oxygenation and to control the bacterial coinfection.

bacterial infection) with massive pneumothorax was responsible for the subsequent acute respiratory distress syndrome (ARDS) which was resistant to conventional mechanical ventilation. ECMO and aggressive antimicrobial treatment were used simultaneously to allow for oxygenation and to control the bacterial coinfection. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Streptococcus mitis, and Haemophilus influenza have all been identified as co-pathogens among the fatal H1N1 viral infection cases described in the US16). However, our patient developed secondary bacterial pneumonia and bacteremia due to a nosocomial infection; A. baumannii is a well-known gram-negative pathogen responsible for healthcare-associated infection in the ICU17). In conclusion, we report a 3-year-old female patient with an acute H1N1 influenza virus infection and necrotizing pneumonia rescued with ECMO. This is the first reported successful pediatric ECMO rescue case in South Korea during the pandemic period. We will continue to follow up our patient's growth, lung function, and neurological development. Fig. 1 Initial chest radiograph showed diffuse left lung haziness and a right upper lung infiltration. Fig. 2 Chest computed tomography (CT) scan showed destruction of lung parenchyma and a pleural effusion. Fig. 3 Massive pneumothorax at the time of extracorporeal membrane oxygenation (ECMO) initiation Fig. 4 The massive pneumothorax at the time of ECMO initiation. Fig. 5 The patient's chest x-ray on discharge.

traumatic injuries. He received a bacille de calmette-guerin vaccine, and a first and second hepatitis B vaccination on schedule. He was fed by breast milk. He had no known drug allergies and was not taking any medication. He had no specific family history of recurrent infections except the cervical cancer of his aunt. There were no inflammatory sign in the oral cavity and no discharge from Stensen's duct orifice. There were no other abnormal findings on physical examination. Laboratory findings were as following: leukocytes 19,110/µL (segmented neutrophil 47.3%), platelet 516,000/µL, hemoglobin 12.6 g/dL, sodium 137 mmoL/L, potassium 5.47 mmoL/L, chloride 100 mmoL/L, amylase 7 IU/L, CRP 7.425 mg/dL, and mumps virus immunoglobulin M negative. Staphylococcus aureus (methicillin sensitive staphylococcus aureus, MSSA) was cultured from blood. The first US taken at second hospital day revealed a mild cellulitis of the right cheek and soft tissue. Follow up ultrasonography was taken at the 5th hospital day. Early abscess formation at the right masticator space was suspected, but there was no inflammatory sign at the right parotid area on the second US (Fig. 1A). CT scan taken at 8th hospital day showed abscess formation at the right masticator space with adjacent cellulitis (Fig. 2). The patient was referred to the Dental and Otorhinolaryngologic Department for a complete evaluation of odontogenic and oral/pharyngeal inflammation. No dental or gingival disease were observed.

The first US taken at second hospital day revealed a mild cellulitis of the right cheek and soft tissue. Follow up ultrasonography was taken at the 5th hospital day. Early abscess formation at the right masticator space was suspected, but there was no inflammatory sign at the right parotid area on the second US (Fig. 1A). CT scan taken at 8th hospital day showed abscess formation at the right masticator space with adjacent cellulitis (Fig. 2). The patient was referred to the Dental and Otorhinolaryngologic Department for a complete evaluation of odontogenic and oral/pharyngeal inflammation. No dental or gingival disease were observed. The abscess was aspirated under the third US guidance at the 10th hospital day. One milliliter of turbid pus was aspirated and sent for culture and susceptibility tests. Ampicillin and cefotaxime was given intravenously to cover gram positive and gram negative bacteriae from the date of admission and clindamycin was added to cover anaerobes after the confirmation of abscess formation and aspiration of pus. S. aureus was isolated from the aspirated pus. The second blood culture sampled at the 6th hospital day showed no bacterial growth.

o cover gram positive and gram negative bacteriae from the date of admission and clindamycin was added to cover anaerobes after the confirmation of abscess formation and aspiration of pus. S. aureus was isolated from the aspirated pus. The second blood culture sampled at the 6th hospital day showed no bacterial growth. Fever had been subsided and swollen area had been reduced in size. The patient was discharged on the 16th hospital day with oral cefnidir. Antibiotics were continued for 5 days in outpatient clinic. Follow up US taken after a week from discharge showed no abscess in right masticator space, but right masseter muscle swelling and cortical irregularity on right mandible were still present. We checked the US taken after a month from discharge showed an improved state of the previously observed right masseter muscle and mandible lesion (Fig. 1B). Discussion A lesion arising within the masticator space tends to displace the parapharyngeal space posteromedially as it expands6). Children with deep neck abscesses, defined as involving the retropharyngeal or parapharyngeal regions; anterior or posterior triangle; the submandibular or submental areas and the parotid glands, present clinically different from adults7). Children younger than 4 years of age sometimes present with fever, agitation, nutritional problems caused by dysphagia, drooling, poor oral intake and respiratory illnesses like cough, stridor and respiratory distress7). Children younger than 6 years of age do not often present with trismus1).

different from adults7). Children younger than 4 years of age sometimes present with fever, agitation, nutritional problems caused by dysphagia, drooling, poor oral intake and respiratory illnesses like cough, stridor and respiratory distress7). Children younger than 6 years of age do not often present with trismus1). The hallmark of masticator space abscesses under one year of age is not obvious, but it may manifest by the swelling of the cheek2) and irritability during pressure on the affected site. The most common lesions underlying the masticator space abscess are odontogenic infections, which are encountered more frequently than neoplasm3,6). Most infections of the masticator space arise from the molars, especially the third molar2). The most common route of spread is posteriorly and medially extending to the temporal space without breakdown of the space barriers or it can break through the cervical fascia and spread medially to the parapharyngeal space2). Infiltration of the muscles by infectious spread from dental caries or as a complication of tooth extractions are frequently seen6). However, there was no case originated from odontogenic infections in children without dental procedure. The patient in this report had the masticator space abscess without a dental procedure and no obvious source of infection in the oral cavity.

al caries or as a complication of tooth extractions are frequently seen6). However, there was no case originated from odontogenic infections in children without dental procedure. The patient in this report had the masticator space abscess without a dental procedure and no obvious source of infection in the oral cavity. Daramola et al.8) reported that there were parotid space, submandibular space, posterior neck and submandibular masticator space abscesses in pediatric patients and other studies showed that pediatric neck abscesses may arise from necrotic lymph nodes in limited cases. Small uncomplicated deep neck space abscesses may respond to intravenous antibiotics alone or antibiotics with needle aspiration7,9,10). Recently, ultrasonography had been recognized not only as diagnostic tool in the management of abscesses in the maxillofacial region but also as therapeutic tool11).

in limited cases. Small uncomplicated deep neck space abscesses may respond to intravenous antibiotics alone or antibiotics with needle aspiration7,9,10). Recently, ultrasonography had been recognized not only as diagnostic tool in the management of abscesses in the maxillofacial region but also as therapeutic tool11). This patient presented with right posterior buccal swelling, thus parotitis had to be excluded2). Palpation is quite helpful in differential diagnosis since in parotid swelling, tenderness is mostly felt at the region of the gland along the posterior border of the masseter muscle, while a submasseteric abscess causes tenderness anteriorly2). A thorough history must always be taken, and parotid disease can be suspected if pain increases during meals2). Clinical suspicion of masticator space abscess could be given in this patient because he showed irritability during pressure on the anterior border of the affected parotid region and no abnormality of the right parotid gland was observed by ultrasonogarphy. CT scanning with contrast is performed as an important tool because it can locate the site of lesion and extent of head and neck infections. Whether it is a cellulitis or an abscess, its size, and its location are particularly revealed in relation to the great vessels12).

This patient presented with right posterior buccal swelling, thus parotitis had to be excluded2). Palpation is quite helpful in differential diagnosis since in parotid swelling, tenderness is mostly felt at the region of the gland along the posterior border of the masseter muscle, while a submasseteric abscess causes tenderness anteriorly2). A thorough history must always be taken, and parotid disease can be suspected if pain increases during meals2). Clinical suspicion of masticator space abscess could be given in this patient because he showed irritability during pressure on the anterior border of the affected parotid region and no abnormality of the right parotid gland was observed by ultrasonogarphy. CT scanning with contrast is performed as an important tool because it can locate the site of lesion and extent of head and neck infections. Whether it is a cellulitis or an abscess, its size, and its location are particularly revealed in relation to the great vessels12). In this patient, CT scan showed abscess formations in the right masseter muscle with adjacent cellulitis with no parotid space inflammation. Ultrasound-guided aspiration of masticator space abscess was done and 1ml of pus from the abscess was obtained. The S. aureus we obtained from the culture of pus is also the most common organism responsible for parotid disease13). According to Coticchia et al.7), it is also the most common causative organism in infants younger than 12 months of age with deep neck infections, whereas group A streptococcus is more frequently identified in older children. The patient has no clearly identifiable source of infection, but S. aureus was cultured from the initial blood test.

et al.7), it is also the most common causative organism in infants younger than 12 months of age with deep neck infections, whereas group A streptococcus is more frequently identified in older children. The patient has no clearly identifiable source of infection, but S. aureus was cultured from the initial blood test. Daramola et al.8) reported that empiric antibiotic coverage for deep neck space abscesses must consider aerobic and anaerobic pathogens that synthesize beta-lactamase. According to Yang et al.14), Penicillin G is the drug of choice for infections caused by streptococci, and non-penicillinase-producing staphylococci, which represent the majority of aerobic organisms. Clindamycin is effective against all streptococci, most pneumococci, and most penicillin-resistant (but not methicillin-resistant) staphylococci. Third-generation parenteral cephalosporins have a broad spectrum of activity against enteric gram-negative rods. The patient was managed with ampicillin, cefotaxime, and clindamycin and the result of second blood culture showed no growth. He took the third generation cephalosporin drug, cefnidir, after discharge. MSSA cultured from this patient was sensitive to cephalothin, cefazolin, and cefotaxime. However, we think the first generation cephalosporin drugs, cephalothin or cefazolin, were better than the third generation cephalosporin drug. The patient had a follow-up US which showed an improved state of the previously observed right masseter muscle swelling after about 1 month from the hospital discharge. We will continue to observe for any changes in it.

Daramola et al.8) reported that empiric antibiotic coverage for deep neck space abscesses must consider aerobic and anaerobic pathogens that synthesize beta-lactamase. According to Yang et al.14), Penicillin G is the drug of choice for infections caused by streptococci, and non-penicillinase-producing staphylococci, which represent the majority of aerobic organisms. Clindamycin is effective against all streptococci, most pneumococci, and most penicillin-resistant (but not methicillin-resistant) staphylococci. Third-generation parenteral cephalosporins have a broad spectrum of activity against enteric gram-negative rods. The patient was managed with ampicillin, cefotaxime, and clindamycin and the result of second blood culture showed no growth. He took the third generation cephalosporin drug, cefnidir, after discharge. MSSA cultured from this patient was sensitive to cephalothin, cefazolin, and cefotaxime. However, we think the first generation cephalosporin drugs, cephalothin or cefazolin, were better than the third generation cephalosporin drug. The patient had a follow-up US which showed an improved state of the previously observed right masseter muscle swelling after about 1 month from the hospital discharge. We will continue to observe for any changes in it. In conclusion, an infant with nonspecific symptoms such as fever, poor oral intake, irritability and right side mild bluish buccal swelling may indicate deep neck infections. US and CT scans of the head and neck, detailed history taking and physical examination would be important in identifying and adequately treating this infection.

an infant with nonspecific symptoms such as fever, poor oral intake, irritability and right side mild bluish buccal swelling may indicate deep neck infections. US and CT scans of the head and neck, detailed history taking and physical examination would be important in identifying and adequately treating this infection. Fig. 1 Ultrasonography of face and neck. (A) At the 5th hospital day, early abscess formation was seen in the right masticator space. (B) The previously seen masseter muscle swelling was decreased at about 1 month after discharge. Fig. 2 Computed tomography scan showed abscess formation (arrow) in the right masticator space combined with adjacent cellulitis at the 7th hospital day.

Introduction Despite a gradual reduction in the pediatric population in Korea due to low birth rates, the number of children's visits to emergency departments (EDs) each year has been increasing1). According to the National Emergency Department Information System (NEDIS) data from 2008, the percentage of pediatric patients who visited EDs was about 31.2% of total ED patients (Fig. 1)2). This figure is larger even considering a proportion of pediatric aged population (<19 years) in Korea (23.8%) and higher than that of US data3). However, a significant number of children who visit an ED do not receive appropriate level of care and are pushed back on the priority list. This is because their symptoms are usually relatively mild compared to that of adult patients, and the care of children in ED is considered very time-consuming and cumbersome. Recently, due to a decreased number of pediatric residents, who are responsible for the care of the majority of pediatric patients in ED, the neglect of pediatric patients in ED has become an increasing concern. This situation is also exacerbated due to a lack of sufficient numbers of emergency physicians having adequate knowledge and skill to care of children.

atric residents, who are responsible for the care of the majority of pediatric patients in ED, the neglect of pediatric patients in ED has become an increasing concern. This situation is also exacerbated due to a lack of sufficient numbers of emergency physicians having adequate knowledge and skill to care of children. Current state of pediatric emergency medicine in Korea The results of a survey by the Korean Society of Pediatric Emergency Medicine in April 2010 revealed a lack of preparation for pediatric emergency care throughout the country4). Among 81 EDs that responded to the survey, only a quarter were equipped with pediatric emergency carts, and just about 60% of the EDs had pediatric endotracheal tubes for every age. Intraosseous needles which are essential for vascular access in critically-ill children were prepared only in 40% of the EDs. Moreover, the nighttime or weekend consultations to pediatric departments were mainly addressed by relatively inexperienced residents (first- and second-year). Monitoring services for children sedated for radiologic studies were not available in 53.1% of the EDs. The survey showed that a huge unpreparedness exists in current pediatric emergency service in Korea.

ions to pediatric departments were mainly addressed by relatively inexperienced residents (first- and second-year). Monitoring services for children sedated for radiologic studies were not available in 53.1% of the EDs. The survey showed that a huge unpreparedness exists in current pediatric emergency service in Korea. An analysis of the NEDIS data for 3 years, from 2006 to 2008, provides us an estimate of the point of preparedness for pediatric emergency care in Korea2). The main reason for seeking pediatric ED was different between age groups. For children younger than 9 years, fever was a major complaint, while abdominal pain and headache were the most common symptoms for children over the age of 10. Admission to the hospital was required in 15% of patients, and the admission rate was above 20% in infants younger than 1 year. During the 3 years, about 6,000 patients were critically ill or injured so as to require care in intensive care units (an average of 16 patients per day).

toms for children over the age of 10. Admission to the hospital was required in 15% of patients, and the admission rate was above 20% in infants younger than 1 year. During the 3 years, about 6,000 patients were critically ill or injured so as to require care in intensive care units (an average of 16 patients per day). Need for regionalization in pediatric emergency care Originally, the emergency medical system was initiated to provide proper care for adult patients, and the need for pediatric emergency care has not been met adequately for a long time. The resources that need to be established for pediatric patients who visit the ED are different from those needed for adult patients. For adequate care for children, experienced staff, who understand the anatomical and physiological differences between adults and children is needed. Considering the growth and development of children, emergency medical equipment and appliances of various appropriate sizes must also be prepared. Moreover, a child-friendly environment, preferably separated from adult patients, is strongly recommended in order to reduce the psychological trauma and discomfort to the child.

dering the growth and development of children, emergency medical equipment and appliances of various appropriate sizes must also be prepared. Moreover, a child-friendly environment, preferably separated from adult patients, is strongly recommended in order to reduce the psychological trauma and discomfort to the child. A comprehensive and regionalized system should be prepared, in addition to proper preparation for basic pediatric emergency care. Without specialized pediatric emergency and critical care, the outcome of critical pediatric illnesses is poor5,6). In reality, it is impossible that all EDs can be made ready to support high-quality pediatric emergency care. The occurrence of serious pediatric emergency cases is not only relatively low compared to adult cases, but also the pool of experts for pediatric advanced care is limited. Especially in Korea, the facilities and human resources for the pediatric field are greatly limited. Considering both cost-effectiveness and efficiency, a critically-ill or severely-injured child should be transferred to a specified referral center, which can take a charge of the definite treatment7). In addition, a child who needs a special procedure such as air-reduction or endoscopic foreign body removal, should be directed to a center with adequate personnel and equipment without delay.

verely-injured child should be transferred to a specified referral center, which can take a charge of the definite treatment7). In addition, a child who needs a special procedure such as air-reduction or endoscopic foreign body removal, should be directed to a center with adequate personnel and equipment without delay. The term "regionalization" in healthcare refers to the development of a structured system of care "to improve patient outcomes by directing patients to facilities with optimal capabilities for a given type of illness or injury"8). Historically, the landmark report 'Accidental Death and Disability: The Neglected Disease of Modern Society'9) has been a powerful driving force for regionalization in the United States (US) since the 1970s. Regionalization improves patient outcomes through 2 primary mechanisms: specialized care at high-volume, high-specialty centers and increased coordination of care within a given geographic area10). The first successful model for regionalization is a trauma care system in the US. There is substantial evidence that regionalization of services to designated hospitals with greater experience improves outcomes and reduces costs of care for severely injured patients11,12). Although the number of studies addressing pediatric experience of trauma centers is limited compared to adult trauma centers, the main results are that regionalized pediatric trauma system reduced the mortality of pediatric patients with severe damage13,14). Another successful regionalization model in pediatrics is neonatal care system. All hospitals cannot be prepared to house neonatal intensive care units (NICUs) for a fraction of complex preterm neonate. With regard to consideration of efficiency, the US and European countries have operated a regionalized NICU, which is invested in facilities and personnel. Substantial data from NICUs in these regions showed that NICU regionalization programs contributed to a low infant mortality15,16).

tion of complex preterm neonate. With regard to consideration of efficiency, the US and European countries have operated a regionalized NICU, which is invested in facilities and personnel. Substantial data from NICUs in these regions showed that NICU regionalization programs contributed to a low infant mortality15,16). Regionalization of pediatric emergency care The 2006 Institute of Medicine (IOM) Report "Emergency Care for Children: Growing Pains" concluded that pediatric emergency care is uneven in the US17). Fifty percent of all US EDs see fewer than 10 pediatric patients per day. In the US, a comprehensive and definite care for critically-ill or injured pediatric emergency cases has been performed mainly at 226 children's hospital and 170 trauma centers with pediatric capabilities. As a categorization model for the regionalization of pediatric emergency care, the Emergency Department Approved for Pediatrics (EDAP) model was established in Los Angeles County in 198518). In this model, only those hospitals meeting requirements as an EDAP in Los Angeles County could receive children brought in by emergency medical services (EMS). However, parents or guardians usually transport their child directly, by themselves, rather than by using EMS system and they tend to visit the ED nearest to their home, and not necessarily one with pediatric capabilities. This is referred to as one of the barriers to developing the regionalized network of pediatric emergency care in the US10).

ans usually transport their child directly, by themselves, rather than by using EMS system and they tend to visit the ED nearest to their home, and not necessarily one with pediatric capabilities. This is referred to as one of the barriers to developing the regionalized network of pediatric emergency care in the US10). Based on previous reports8,10,17), there are some suggestions for success of the regionalization of pediatric emergency care in Korea. First of all, the appropriate categorization should be achieved in all areas in pediatric emergency care. While a transfer of patient by EMS must be achieved according to a level of patient's acuity, properly assessed at pre-hospital field, a critically-ill child should be transferred to an ED with staffed with certified personnel and equipment. Training and continuing education of pediatric emergency care for EMS providers should be introduced as an essential EMS education course and the classification of pediatric patients must be made using well-established protocols. Information from emergency information center should also be properly matched with the patient's severity level, along with efforts to better inform the community about the level of critical care and services available for pediatric emergency care at the ED within a region.

ust be made using well-established protocols. Information from emergency information center should also be properly matched with the patient's severity level, along with efforts to better inform the community about the level of critical care and services available for pediatric emergency care at the ED within a region. The categorization of EDs according to their capability for pediatric emergency care is essential for a successful regionalization program. To eliminate controversies, the development of categories should be evidence-based and supported by multidisciplinary expertise. Further, as the IOM report recommended, the coordination of all elements of child healthcare from an EMS system to hospital care, should be governed by legislation and be followed as a matter of policy. A process of accreditation, to dedicate and approve a healthcare facility as a specialized provider of pediatric care from a certifying authority, is also required. In this respect, the current "pediatric exclusive emergency department projects" conducted by Ministry of Health and Welfare should be reviewed. The role of the pediatric exclusive ED in the current project is not a comprehensive regional pediatric emergency center for resource-intensive care of critically-ill children, but rather just a well-equipped pediatric ED without a higher level function. Rather, a flock of children with low acuity to the center could make a delay of adequate care for critically-ill patient. This program has been initiated without a sufficient thought and long-term planning, and is focused only the facilities and equipment supply. Actually, it does not provide a plan for managing the human resource, which is the most important factor for the success of pediatric emergency care system.

itically-ill patient. This program has been initiated without a sufficient thought and long-term planning, and is focused only the facilities and equipment supply. Actually, it does not provide a plan for managing the human resource, which is the most important factor for the success of pediatric emergency care system. One of the concerns surrounding regionalization of pediatric emergency care is that transfer of too many patients from community hospitals would reduce the chance of appropriate pediatric care, raising the concern that there may be an eventual degradation of the quality of pediatric emergency care in whole community. However, the basis for regionalization is that all emergency center scaring for pediatric patients must be prepared to some baseline extent. Further, regionalized systems need a back-transport of patients to non-specialty hospitals after they have been stabilized and their condition improved. Parents or guardians may be reluctant to back-transport, because of their comfort and belief in the high level hospital19). However, if not supported by a re-distribution system, the referred hospital could become crowded with patients awaiting treatment.

ls after they have been stabilized and their condition improved. Parents or guardians may be reluctant to back-transport, because of their comfort and belief in the high level hospital19). However, if not supported by a re-distribution system, the referred hospital could become crowded with patients awaiting treatment. Other aspects to be addressed in establishing regionalization are a specialist on-call system and financial incentives. It may be difficult to get the on-call personnel to come to the ED, even though their privacy has been compromised by calling them directly, since financial incentives for their participation in emergency care cannot be provided easily under current Korean health insurance policies. For these reasons, it has become increasingly difficult for EDs to find specialists who will be ready for on call for the ED, and the resulting shortage of on-call specialists in pediatric emergency care leads to sometimes tragic results. Currently, the Korean Society of Pediatrics and the Korean Society of Emergency Medicine have been carrying out some efforts to increase medical insurance fees for emergency and pediatric areas. In addition to an introduction of appropriate medical fees, a special compensation and/or financial incentives must be offered to regional pediatric emergency centers to attract highly qualified pediatric emergency care personnel.

ng out some efforts to increase medical insurance fees for emergency and pediatric areas. In addition to an introduction of appropriate medical fees, a special compensation and/or financial incentives must be offered to regional pediatric emergency centers to attract highly qualified pediatric emergency care personnel. Summary The pediatric emergency care system in Korea is still in its infancy. We took a first step towards understanding the basic status of pediatric emergency care and for determining its preparedness in providing adequate pediatric emergency care. Many resources have been focused on pediatric emergency care regionalization in some developed countries. We need to take some different regionalization strategies in consideration of the different circumstances in medical practices in Korea. To do so, medical personnel, resources, and facilities that are closely related to pediatric emergency care should be identified and adequately categorized before implementation of a regionalization system. Based on this, information in all phases of emergency medical systems, including data from patients, paramedics, and hospitals, should be collected and share efficiently for building an information system in regionalization. A win-win strategy, to create a bi-directional flow of the patient between referral center and referring community hospitals that participate in the regionalization should be established. Efforts to set up a pediatric emergency care regionalization program based on the national healthcare system are urgently needed. The first step to building a safe and effective pediatric emergency system will be made possible through regional networks of health care.

ipate in the regionalization should be established. Efforts to set up a pediatric emergency care regionalization program based on the national healthcare system are urgently needed. The first step to building a safe and effective pediatric emergency system will be made possible through regional networks of health care. Fig. 1 Emergency department visits by age, 2008.

Introduction The fertility rate in Korea has reduced to 1.149 per woman of childbearing age in 2009, which is one of the lowest in the world1). This low birth rate is emerging as one of the nation's most serious problems in Korea. Recently, the average age of mothers giving birth has significantly increased due to social and economic changes, and the fertility rate is dropping with this increasing maternal age2). In addition, the increased use of recently developed assisted reproductive technologies has led to a simultaneous increase in multiple and preterm births3). Providing adequate neonatal intensive care for high-risk newborns is essential for decreasing their mortality and morbidity, which ultimately reduces the future costs for their morbidity of whole nation. Therefore, in the current period of low birth rate, absolute increases in the number of high-risk newborns, including premature and low-birth weight infants, requiring neonatal intensive care, has to be considered as the nation's most urgent health problem. Solving this problem requires a systematic national health plan, which needs to be established and followed as soon as possible. Most developed countries, including the United States (US) and Japan, despite having higher fertility rates compared to Korea, have already recognized the importance of improvement and regionalization of neonatal intensive care. Governments in many developed countries systemically support and manage the neonatal intensive care and the linked perinatal centers, and provide a health care system in which high-risk pregnancies and high-risk newborns can be treated adequately and efficiently, in a timely manner. To deliver efficient perinatal and neonatal intensive care, the governments have built a network through nationwide regionalization.

are and the linked perinatal centers, and provide a health care system in which high-risk pregnancies and high-risk newborns can be treated adequately and efficiently, in a timely manner. To deliver efficient perinatal and neonatal intensive care, the governments have built a network through nationwide regionalization. The neonatal intensive care unit (NICU) in Korea has been developed since the 1980s and there has been much progress until now. However, there is still a lack of a large number of NICU beds. Moreover, sufficient official investment and discussion for achieving a well-distributed nationwide network and regionalization has not been undertaken yet. Recently, the Committee for Data Collection and Statistics in the Society of Korean Neonatology has undertaken the survey for the nationwide status of NICU in 2010 with the support of the Management Center for Health Promotion4). Here, a short review of the status of neonatal care in developed countries, including the US and Japan, and the current condition for networking and regionalization of neonatal intensive care in Korea are described.

the nationwide status of NICU in 2010 with the support of the Management Center for Health Promotion4). Here, a short review of the status of neonatal care in developed countries, including the US and Japan, and the current condition for networking and regionalization of neonatal intensive care in Korea are described. Status and regionalization of neonatal intensive care in the US In the US, more than 30 years earlier than in Korea, in 1970s, management and regionalization of not only neonatal intensive care, but also perinatal care, including high-risk pregnancies, was systemized and established5). The system focused on decreasing perinatal morbidity and mortality, along with providing high quality of care for high-risk pregnancies and high-risk newborns by the most efficient use of facilities and equipment, as well as highly trained personnel, and maximizing the effect of medical resource investments6). In 1975, the perinatal and neonatal management was classified into 3 levels under the motto "Toward Improving Outcome of Pregnancy (TIOP)" (Committee on Perinatal Health, 1975)5,7) as follows. <Level I: Primary medical center> Pregnancies without complications Nursery for normal newborns and newborns with minor medical problems <Level II: Secondary medical center> Pregnancies with mild complications Neonatal intensive care unit for newborns with moderate medical problems <Level III: Tertiary medical center> Pregnancies with severe complications Neonatal intensive care unit for newborns with severe medical problems.

Nursery for normal newborns and newborns with minor medical problems <Level II: Secondary medical center> Pregnancies with mild complications Neonatal intensive care unit for newborns with moderate medical problems <Level III: Tertiary medical center> Pregnancies with severe complications Neonatal intensive care unit for newborns with severe medical problems. Quantitative and qualitative improvement in NICUs, as well as NICU regionalization, resulted in integrative improvement of neonatal intensive care around the nation. In 1993, TIOPII (Toward Improving Outcome of Pregnancy II, The 90s and Beyond) was launched to emphasize the importance of integrated and regionalized care system and classify the previous classification in more detail (Committee on Perinatal Health, 1993)8,9). The levels of perinatal (Table 1)9) and intensive neonatal care treatment recently used in US are as following (Table 2)10). Newborn transfer system holds a great value in the regionalized medical system. Transfer between levels I, II and III neonatal care centers is an important tool used to effectively distribute medical resources around the region. Transfer team is composed of nurses, respiratory treatment personnel, neonatal care doctors, residents or by other personnel, and ambulances, helicopters and fixed-wing aircrafts were being used as transport vehicles11). Following the introduction of a centralized neonatal transfer service, response times improved significantly12).

is composed of nurses, respiratory treatment personnel, neonatal care doctors, residents or by other personnel, and ambulances, helicopters and fixed-wing aircrafts were being used as transport vehicles11). Following the introduction of a centralized neonatal transfer service, response times improved significantly12). Status and regionalization of neonatal intensive care in Japan Neonatal care in Japan was supported by the government early on. Medical support for premature infants and reporting system for low-birth weight infants were introduced in 1958. In 1979, parts of obstetric and pediatric departments were combined as perinatal care system and operated regionalized perinatal medical centers based on the "Regionalization of neonatal care to improve newborn death rate" project. In 1984, Maternal Fetal Intensive Care Unit was set up as perinatal care units. In 1991, "Doctor Car" was first introduced to operate ambulances that focus on transfer of high-risk newborns between the medical centers. In 1995, Maternal and Child Health Law was revised and from the following year, one general perinatal care medical center per 1 million began to be built around the nation. These medical centers have been maintained and supported until today. A total of 242 regional perinatal care centers and 77 integrated general maternal-fetal medical centers now serve as the backbone of Japan's perinatal care. Three central (super) perinatal care units were established in the most populated regions of Tokyo to deal with the highest-risk pregnancies and neonates from the entire nation13). A total of 80 million Yens (Japanese currency) (1 billion KRW [Korean currency]) for regional centers, 140 million Yens (1.8 billion KRW) for integrated general centers, and 190 million Yens (2.5 billion KRW) for central centers are being supported by the government14).

egnancies and neonates from the entire nation13). A total of 80 million Yens (Japanese currency) (1 billion KRW [Korean currency]) for regional centers, 140 million Yens (1.8 billion KRW) for integrated general centers, and 190 million Yens (2.5 billion KRW) for central centers are being supported by the government14). According to the Ministry of Health and Welfare in Japan, the Japanese government allocated 1.7 billion Yens (17.9 billion KRW) for the care of premature infants and 2.3 billion Yens (24.4 billion KRW) for perinatal care. The support and network for perinatal care is still increasing in Japan15). The death rate of low-birth weight newborns has been decreasing for the past 30 years in Japan due to continuous and systemic efforts driven by the government. The survival rate of extremely-low-birth weight newborn infants (<1,000 g) that requires the highest intensive care was improved from 44.7 in 198016) to 83.0% in 200517). Currently, 80% of newborns survive regardless of their birth weight and finally, Japan currently has the lowest premature infant death rate in the world.

survival rate of extremely-low-birth weight newborn infants (<1,000 g) that requires the highest intensive care was improved from 44.7 in 198016) to 83.0% in 200517). Currently, 80% of newborns survive regardless of their birth weight and finally, Japan currently has the lowest premature infant death rate in the world. Status and regionalization of neonatal intensive care in Korea 1. Changes in the number of total and regional NICU beds From the national survey of the Committee for Data Collection and Statistics in the Society of Korean Neonatology for NICU status reported at October, 20104), number of real operating NICUs was 93 hospitals and operating NICU beds were 1,252. Compared to previous reports in 200618), the 2010 survey showed markedly decreased operating NICUs and NICU beds throughout the nation. Although a few NICUs and NICU beds were added or expanded due to regional demands, with or without support from the government, such as the project of "Regional NICU expansion" and "Regional Children's Hospital" of the Ministry of Health and Welfare, a considerable number of NICUs have been closed or cut in size over the last 5 years (Table 3). The reasons behind this reduction were manifold. First, the inability of the hospital running the NICU to meet the requirement of legal NICU classification and standards for the facility and manpower enacted in 2006, thereby closing their NICU or reducing the number of beds. Secondly, a reduction in the number of obstetrical staff, which led to a decrease in deliveries, and a lack of medical staff available to treat high-risk newborns in NICU also led to the decrease in of functioning NICU beds. All of the regional operating NICU and NICU beds were reduced, except in the Gyeongsangdo and Ulsan areas, as shown in Table 3.

ber of obstetrical staff, which led to a decrease in deliveries, and a lack of medical staff available to treat high-risk newborns in NICU also led to the decrease in of functioning NICU beds. All of the regional operating NICU and NICU beds were reduced, except in the Gyeongsangdo and Ulsan areas, as shown in Table 3. 2. Shortage of regional beds and medical resources of NICU There were 444,849 total live births in 2009, in Korea1). Comparison of the number of regional NICU beds to the total number of regional live births is shown in Table 4. Number of NICU beds are 0.3 to 5.3 per 1,000 live births, depending on the region, with large variability. Seoul has the highest number of beds and Jollanamdo has the lowest number of beds. Large cities such as Seoul, Daejeon, Busan, and Gwangju have more than 3.2 beds per 1,000 live births. However, the number of beds is very small in regions neighboring the 4 areas Gyeonggido, Chungcheongnamdo, Gyeongsangnamdo, and Jollanamdo. When the regions are classified based on larger geographical features, or areas (Table 5), variability in the number of NICU beds are slightly decreased, to 1.8 to 3.2 per 1,000 live births, depending on the area. It can be expected that high-risk newborns are being transferred to neighboring regions. For instance, Seoul may be used to compensate for the required beds in the Gyeonggido region.

eas (Table 5), variability in the number of NICU beds are slightly decreased, to 1.8 to 3.2 per 1,000 live births, depending on the area. It can be expected that high-risk newborns are being transferred to neighboring regions. For instance, Seoul may be used to compensate for the required beds in the Gyeonggido region. On the scope of medical resources, Gyeongsangbukdo, Ulsan, and Jollanamdo, still have less than 0.3 mechanical ventilators per NICU bed (Table 5), and only 1 or 0 neonatologists (Table 6), as well as the lowest number of NICU beds per 1000 live births amongst all the national regions. Therefore, those regions do not have enough medical resources to provide adequate emergency neonatal intensive care. According to the national survey report for 200618) and 20104), 3.2 to 3.4 neonatal intensive care beds are needed per 1,000 live births, and 4.1 to 4.5 beds per 1,000 live births are needed, including the operation of supplementary beds. Therefore, more than 1.0 bed per 1,000 live births is needed in all of the regions, and even more in larger areas. Therefore, it is required to increase the number of beds and medical resources, including medical equipment and manpower, nationwide with proper allocation for the establishment of regionalization and network for neonatal care.

.0 bed per 1,000 live births is needed in all of the regions, and even more in larger areas. Therefore, it is required to increase the number of beds and medical resources, including medical equipment and manpower, nationwide with proper allocation for the establishment of regionalization and network for neonatal care. 3. Transfer flow of high-risk newborn Table 7 shows the flow of 929 neonatal patients in July 2010, reported in the 2010 survey4). When the nation is divided into 16 regions by cities and provinces, 749 newborns (80.6%) were transferred within the region and 180 newborns (19.4%) were transferred out of region. Therefore, approximately 20% of the high-risk newborns were transferred out of the region. If the nation was divided into 8 integral areas by grouping: Seoul, Incheon, and Gyunggido as Region 1; Gangwondo as region 2; Chungcheongbukdo, Chungcheongnamdo, and Daejeon as Region 3; Daegu and Gyeongsangbukdo as Region 4; Jollabukdo as Region 5; Gwangju and Jollanamdo as Region 6; Gyeongsangnamdo, Busan, and Ulsan as Region 7; and Jejudo as Region 8. Except the transfer to Seoul from all other integral regions, all of the transfers were made within each integral area. Therefore, in the future, regionalization of neonatal intensive care has to be set up by establishment of integral area NICU centers with careful consideration of proximity of neighboring regions, availability of traffic routes, and effective use of available beds. It is also evident that there are special needs for transfer of high-risk newborns, because of the need for highly-selective specialized surgery or high-end specialized care, or of lack of availability of regional NICU beds for super-emergent cases. Like super perinatal care centers in Tokyo, Japan, we need to create national integrative care centers to serve the purpose of high-end and super-emergency neonatal care, and a final referral center. Since very large NICUs that handle more than 100 very-low birth weight newborn infants are located in Seoul, rather than to expand NICU beds in the Seoul area, it is advisable to set up or use big centers in Seoul as the final referral super center for the entire nation. Moreover, it is important to create a network with other regional and more integrative area NICUs around the nation. There is a need to classify the level of neonatal intensive care units in Korea, like in the US.

advisable to set up or use big centers in Seoul as the final referral super center for the entire nation. Moreover, it is important to create a network with other regional and more integrative area NICUs around the nation. There is a need to classify the level of neonatal intensive care units in Korea, like in the US. Therefore, it is needed to effectively distribute the medical resources for neonatal care through proper leveling, regionalization and networking of neonatal care in Korea.

advisable to set up or use big centers in Seoul as the final referral super center for the entire nation. Moreover, it is important to create a network with other regional and more integrative area NICUs around the nation. There is a need to classify the level of neonatal intensive care units in Korea, like in the US. Therefore, it is needed to effectively distribute the medical resources for neonatal care through proper leveling, regionalization and networking of neonatal care in Korea. 4. Transfer flow of high-risk pregnancies Table 8 shows the transfer flow of high-risk pregnancies during 2 weeks of July 2010, reported in the 2010 survey4). A total of 400 high-risk pregnant women were transferred to other hospitals and 83 patients (21%) were transferred out of region. Among 447 transfer contacts, 311 patients (69.6%) were actually accepted in the first hospital/ medical center to which they were requested for being transferred; however, 127 patients were denied their transfer in the first contact to transfer. The reason for denying the transfer was, 50% due to lack of NICU beds, 29.3% due to unavailability of mechanical ventilator in the NICU, 7.1% due to difficulties in surgery and special care, and 5.0% due to lack of medical personnel resources in NICU and delivery room. The transfer flow of high-risk pregnant women was very similar to transfer flow of high-risk newborns. Approximately 20% of the patients were transferred out of region and 70% of the patients were accepted on the first hospital/medical center to which they were requested for being transferred whereas the remaining 30% were wandering to find a hospital for their care. Since most of the denials for transfer were due to lack of medical resources in the NICU, management of high-risk pregnancies and high-risk newborns cannot be separated from one another. A perinatal approach, that includes both high-risk pregnancies and newborns, is needed when establishing the policies for their care.

Since most of the denials for transfer were due to lack of medical resources in the NICU, management of high-risk pregnancies and high-risk newborns cannot be separated from one another. A perinatal approach, that includes both high-risk pregnancies and newborns, is needed when establishing the policies for their care. Conclusion Neonatal intensive care for high-risk newborns is a major health issue that should be supported by the government, as discussed in the cases of the US and Japan. Neonatal intensive care policies of advanced countries may be summarized as follows. First, the policies accommodate perinatal care and transport systems, including high-risk pregnant women and high-risk newborns. Second, the policies level and regionalize the high-risk newborn infant care system using expert groups and instating clear legislation. Third, there is continuous support from the government for systematically constructing high-risk neonatal and perinatal care systems. Fourth, there is an effective distribution and use of medical resources, by establishment of a clear transfer system and regionalization.

g expert groups and instating clear legislation. Third, there is continuous support from the government for systematically constructing high-risk neonatal and perinatal care systems. Fourth, there is an effective distribution and use of medical resources, by establishment of a clear transfer system and regionalization. In Korea, it is evident that there is a shortage of NICU beds and medical resources nationwide, with varying degrees across regions, and a lack of systemic perinatal and neonatal regional networking. In the recent analysis on transferred high-risk newborns and pregnant women, about 20% were transferred beyond their location, while most of them were transferred in the vicinity of their original location. Seoul tended to have patients transferred from all the parts of the country. As most high-risk newborn infants are transferred within the neighboring region, regional care centers should be upgraded, and there seems to be a need to bolster a few national central centers in Seoul for taking care of patients transferred from other regional medical centers, to provide challenging high-end treatments. The main cause for the transfer of high-risk pregnant women was the deficits of beds and medical resources of NICU, which were the same deficits that applied to high-risk newborn transfers. The success rate of transfers was only about 70%. Ultimately, to complete the health care system of high-risk newborns in the era of low-birth rates, an absolute increase in the number of NICU beds, along with proper equipment, facilities, and manpower, and the completion of proper transfer system through regionalization and leveling of NICUs are needed. Further, a systematic approach toward perinatal care that includes both high-risk pregnancies and newborns is needed, as well as the establishment of an integrative advisory board to drive the momentum of systematic approach. Establishment of regionalized perinatal centers, including those that can accommodate high-risk pregnancies and neonatal intensive care through a nationwide network will result in improving the outcome of high-risk newborns. Such a system will help improve the health and save the lives of thousands of newborns and provide an effective solution for low-birth rate issues in Korea.

ose that can accommodate high-risk pregnancies and neonatal intensive care through a nationwide network will result in improving the outcome of high-risk newborns. Such a system will help improve the health and save the lives of thousands of newborns and provide an effective solution for low-birth rate issues in Korea. Acknowledgement This study was supported by the Health Promotion Fund, Ministry for Health, Welfare and Family Affairs, Republic of Korea (Policy 10-11). Table 1 Definitions of Care at Perinatal Centers in the United States NICU, neonatal intensive care unit. Table 2 Proposed Uniform Definition of Levels of Neonatal Intensive Care in United States NICU, neonatal intensive care unit; GA, gestational age; CT, computed tomography; MRI, magnetic resonance imaging; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; TEF, tracheoesophageal fistula; ECMO, extrcoporeal membrane oxygenation. Table 3 Changes in Number of Regional Operating NICUs and NICU Beds Values are presented as no. of NICUs (no. of NICU Beds). NICU, neonatal intensive care unit. Table 4 Regional NICU Beds per 1,000 Live-Births NICU, neonatal intensive care unit. Table 5 Areal NICU Beds per 1,000 Live-Births NICU, neonatal intensive care unit. Table 6 Regional Medical Resources of Neonatal Intensive Care NICU, neonatal intensive care unit. *Hospital surveyed. Table 7 Regional Transfer of High-Risk Newborn Infant during July, 20104) Table 8 Regional Transfer of High-Risk Pregnant Women during Two Weeks of July, 20104)

Introduction In the Republic of Korea (ROK), the "Prevention of Contagious Diseases Act" was first enacted in the year 1954 and this law laid the foundation of the "National Notifiable Disease Surveillance System (NNDSS)", by designating 20 infectious diseases for mandatory reporting. The first major revision of this law in 2000 provided the current structure of the NNDSS, which collects individual patient information using an electronic reporting system. As of August 2008, this system covered 50 infectious diseases1). Recently, as of December 30, 2010, the "Prevention of Contagious Diseases Act" and "Parasite Diseases Prevention Act" were merged and completely revised to the "Law for Control and Prevention of Infectious Diseases" and "Quarantine Act". Major changes in the "Law for Control and Prevention of Infectious Diseases" included a change in terminology from "contagious diseases" to "infectious diseases" which includes both contagious and non-contagious diseases, and extended disease entities, to enable the government to conduct surveillance or management. This new law classifies infectious diseases into 11 categories with 78 disease entities2). Table 1 shows these details.

contagious diseases" to "infectious diseases" which includes both contagious and non-contagious diseases, and extended disease entities, to enable the government to conduct surveillance or management. This new law classifies infectious diseases into 11 categories with 78 disease entities2). Table 1 shows these details. Compared to the past, environmental and hygienic conditions have improved with economic developments in the ROK, and incidence of most infectious diseases, especially vaccine-preventable diseases (VPDs), has remarkably decreased due to active immunization with the developed level of health care3). However, with advances in diagnosis of specific diseases or international travel becoming more common, other diseases, such as those that are acquired through travel abroad, and re-emerging or newly emerging diseases, are increasing in incidence4). In this review, the past and recent status of infectious diseases in the ROK was investigated with reference to data accumulated in the NNDSS5). The range of infectious diseases is too broad; therefore, the analysis was limited to significant infectious diseases that fall under categories I, II and III of the currently revised law.

w, the past and recent status of infectious diseases in the ROK was investigated with reference to data accumulated in the NNDSS5). The range of infectious diseases is too broad; therefore, the analysis was limited to significant infectious diseases that fall under categories I, II and III of the currently revised law. Past and recent status of notifiable infectious diseases 1. Category I infectious diseases Category I infectious diseases include diseases that can spread through water or foodstuff, requiring immediate control measures upon outbreak, and require immediate reporting by a health care provider upon occurrence. Six diseases, cholera, typhoid fever, paratyphoid fever, shigellosis, entero-hemorrhagic Escherichia coli, and hepatitis A, are included in this category (Table 1)2). 1) Cholera According to data from 1960, the number of reported cholera cases was 414 in 1963, 1,538 in 1969, and 206 in 1970, and the incidence remarkably decreased thereafter. However, there were intermittent outbreaks, 145 in 1980, 113 in 1991, and 68 in 19955). Since then, less than 10 cases have been reported every year, and in 2001, cholera was epidemic nationwide, centered on the Gyeongsangdo province, and 162 cases (including 142 confirmed cases) were reported. With the exception of 10 and 16 cases reported in 2004 and 2005, respectively, less than 10 cases were reported, and with the exception of 2 cases in 2002 and 1 case in 2007, all were imported cases (Fig. 1)6).

tionwide, centered on the Gyeongsangdo province, and 162 cases (including 142 confirmed cases) were reported. With the exception of 10 and 16 cases reported in 2004 and 2005, respectively, less than 10 cases were reported, and with the exception of 2 cases in 2002 and 1 case in 2007, all were imported cases (Fig. 1)6). For the past decade (2001 to 2010), the total number of reported cases was 218, and patients aged <10 years and 10 to 19 years accounted for 1.4% (3 cases) and 3.7% (8 cases), respectively5). 2) Typhoid fever Typhoid fever is one of the indigenous infectious diseases in ROK, and 3,000 to 5,000 cases had been reported yearly before the 1970s, but 200 to 400 cases have been reported every year thereafter (Fig. 1)5). According to the 2008 Infectious Diseases Surveillance Yearbook6), 158 out of 188 cases in 2008 were laboratory-confirmed cases and tended to occur year-round. As an example of a regional trend, the cases were reported in Gyeongsangnamdo, Gyeonggido, Seoul, and Busan, in descending order in terms of frequency, and 10 were imported cases. Although they were distributed across all ages, the incidence was markedly higher in patients in their 40s (23.4%) and 50s (27.1%). For the past decade, the total number of reported cases was 2,097, and patients aged <10 years and 10 to 19 years accounted for 9.5% (200 cases) and 11.0% (231 cases), respectively5).

2) Typhoid fever Typhoid fever is one of the indigenous infectious diseases in ROK, and 3,000 to 5,000 cases had been reported yearly before the 1970s, but 200 to 400 cases have been reported every year thereafter (Fig. 1)5). According to the 2008 Infectious Diseases Surveillance Yearbook6), 158 out of 188 cases in 2008 were laboratory-confirmed cases and tended to occur year-round. As an example of a regional trend, the cases were reported in Gyeongsangnamdo, Gyeonggido, Seoul, and Busan, in descending order in terms of frequency, and 10 were imported cases. Although they were distributed across all ages, the incidence was markedly higher in patients in their 40s (23.4%) and 50s (27.1%). For the past decade, the total number of reported cases was 2,097, and patients aged <10 years and 10 to 19 years accounted for 9.5% (200 cases) and 11.0% (231 cases), respectively5). 3) Paratyphoid fever Paratyphoid fever is an infectious disease, showing sporadic outbreaks of dozens of patients every year. However, in the epidemic event centered in Busan in 2002, 413 cases were reported. Since then, just a few cases have been reported again (Fig. 1)5). In 2008, a total of 44 cases were reported and of these, 39 were laboratory-confirmed cases. The cases occurred in all age groups year-round, and 8 were imported cases6). For the past decade, the total number of reported cases was 843, and patients aged <10 years and 10 to 19 years accounted for 13.4% (113 cases) and 7.4% (62 cases), respectively5).

3) Paratyphoid fever Paratyphoid fever is an infectious disease, showing sporadic outbreaks of dozens of patients every year. However, in the epidemic event centered in Busan in 2002, 413 cases were reported. Since then, just a few cases have been reported again (Fig. 1)5). In 2008, a total of 44 cases were reported and of these, 39 were laboratory-confirmed cases. The cases occurred in all age groups year-round, and 8 were imported cases6). For the past decade, the total number of reported cases was 843, and patients aged <10 years and 10 to 19 years accounted for 13.4% (113 cases) and 7.4% (62 cases), respectively5). 4) Shigellosis Hundreds of cases of shigellosis were reported in the 1960s, less than 100 cases were reported between 1970 and 1991. One to two hundred cases were reported between 1992 and 1994, less than 100 cases were reported thereafter, and then its incidence increased abruptly as 1,000 to 2,500 cases were reported between 1998 and 2003. Since then, 200 to 300 cases have reported yearly (Fig. 1)5). Among the 209 cases reported in 2008, 192 were laboratory-confirmed cases, and in 62 cases, the infection acquired during an overseas trip. More cases were reported in January and November6). For the past decade, the total number of reported cases was 4,752, and patients aged <10 years and 10 to 19 years accounted for 28.4% (1,349 cases) and 17.4% (828 cases), respectively5).

4) Shigellosis Hundreds of cases of shigellosis were reported in the 1960s, less than 100 cases were reported between 1970 and 1991. One to two hundred cases were reported between 1992 and 1994, less than 100 cases were reported thereafter, and then its incidence increased abruptly as 1,000 to 2,500 cases were reported between 1998 and 2003. Since then, 200 to 300 cases have reported yearly (Fig. 1)5). Among the 209 cases reported in 2008, 192 were laboratory-confirmed cases, and in 62 cases, the infection acquired during an overseas trip. More cases were reported in January and November6). For the past decade, the total number of reported cases was 4,752, and patients aged <10 years and 10 to 19 years accounted for 28.4% (1,349 cases) and 17.4% (828 cases), respectively5). 5) Entero-hemorrhagic Escherichia coli Data on entero-hemorrhagic E.coli infections has been collected since it was designated as a notifiable infectious disease in 2000. One case in 2000, 11 in 2001, and 8 in 2002 were reported, and the incidence has increased since 2003, when surveillance of hemolytic uremic syndrome was implemented and the monitoring was reinforced. Except for 118 cases in 2004, about 50 cases have been reported yearly (Fig. 2)5). Among the 58 cases reported in 2008, 32 cases were men and 26 women, indicating that there was no significant difference between genders, and 24 cases (41.4%) were reported between June and August6).

ed and the monitoring was reinforced. Except for 118 cases in 2004, about 50 cases have been reported yearly (Fig. 2)5). Among the 58 cases reported in 2008, 32 cases were men and 26 women, indicating that there was no significant difference between genders, and 24 cases (41.4%) were reported between June and August6). For the past decade, the total number of reported cases was 486 and patients aged <10 years and 10 to 19 years accounted for 59.9% (291 cases) and 14.2% (69 cases), respectively5). 6) Hepatitis A Hepatitis A was included in category I notifiable infectious diseases under the "Law for Control and Prevention of Infectious Diseases" in the version revised on December 30, 20102). Since hepatitis A was officially followed up from 2001, exact data enabling us to examine the previous incidence do not exist. However, according to a published report7), among all patients who had been hospitalized in the department of pediatrics over 10 years from 1968 to 1977, patients with hepatitis A accounted for 2.5% (1.7 to 3.9%) on the average. A similar trend continued until the early 1980s, and sharply decreased thereafter, and increased again in 19968).

a published report7), among all patients who had been hospitalized in the department of pediatrics over 10 years from 1968 to 1977, patients with hepatitis A accounted for 2.5% (1.7 to 3.9%) on the average. A similar trend continued until the early 1980s, and sharply decreased thereafter, and increased again in 19968). According to the sentinel surveillance system started from 2001, hepatitis A incidence showed a sharply increasing trends for several years, with less than 400 cases in 2001 to 2004, about 800 in 2005, 2,000 in 2006 to 2007, 7,900 in 2008, and 15,000 in 2009, and then tended to decrease from 2010 with 7,700 cases5) (Table 2), but the actual incidence is expected to be several folds higher8). Moreover, there was huge difference in incidence between regions, such that the incidence was 75 to 80% in Seoul, Gyeonggido and Incheon areas but the incidence was much lower in Gyeongsangbukdo and Gyeongsangnamdo areas, including Daegu and Busan5). Regarding the age of cases, most occurrences were reported in patients in their 10s and 20s, and few cases occurred in patients in their 30s in 1990s. However, most occurrences during 2001 to 2007 were reported in patients in their 20s, followed by those in their 30s and 10s, and the order of the ages of occurrence was the 30s, 20s, 40s, and 10s after 20085). Hepatitis A vaccine has still not been included in the national immunization program, but since its first use in the end of 1997, it is currently expected to be vaccinated in about 70% of infants and toddlers.

Regarding the age of cases, most occurrences were reported in patients in their 10s and 20s, and few cases occurred in patients in their 30s in 1990s. However, most occurrences during 2001 to 2007 were reported in patients in their 20s, followed by those in their 30s and 10s, and the order of the ages of occurrence was the 30s, 20s, 40s, and 10s after 20085). Hepatitis A vaccine has still not been included in the national immunization program, but since its first use in the end of 1997, it is currently expected to be vaccinated in about 70% of infants and toddlers. 2. Category II infectious diseases The category II infectious diseases are VPDs, and once a case occurs, it is required to be reported by a health care provider without delay. Ten diseases, diphtheria, pertussis, tetanus, measles, mumps, rubella, polio, hepatitis B, Japanese encephalitis, and chicken pox, are included in this category (Table 1)2). 1) Diphtheria In the 1950s, 340 to 1,250 cases were reported every year with a peak of 2,534 cases in 1951. Since the diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccine was introduced in 1958, 500 to 1,000 cases were reported in the 1960s and 100 to 500 cases by the end of the 1970s. Less than 100 cases had been reported since 1979, and with use of the diphtheria, tetanus, and acellular pertussis (DTaP) vaccine from 1982, and with the vaccination rate maintained at 90% or more, no occurrences have been reported after 1987 (Fig. 2)5,9).

rted in the 1960s and 100 to 500 cases by the end of the 1970s. Less than 100 cases had been reported since 1979, and with use of the diphtheria, tetanus, and acellular pertussis (DTaP) vaccine from 1982, and with the vaccination rate maintained at 90% or more, no occurrences have been reported after 1987 (Fig. 2)5,9). 2) Pertussis Fifteen to twenty thousand cases of pertussis were reported in the 1950s, 8,000 to 17,000 cases were reported between 1960 and 1963, and 500 to thousands of cases had been reported every year from 1964 to 1988. After introduction of the DTwP and DTaP vaccines in 1958 and 1982, the vaccination rate has been maintained at 90% or more, and the incidence of pertussis has significantly decreased. Just dozens of cases have been reported yearly from 1992, until now (Fig. 2)5). For the past decade, the total number of reported cases was 185, and patients aged <10 years and 10 to 19 years accounted for 93.0% (172 cases) and 2.2% (4 cases), respectively, and in patients <10 years old, most were aged <6 months5). 3) Tetanus Tetanus data has been collected since it was designated as a category II infectious disease in 1976. In 1980, the DTaP vaccination rate exceeded 90% and few neonatal tetanus cases were reported, and after the 1990s, about 10 cases have been reported yearly. However, in the 2000s, 10 to 20 cases have been reported yearly (Fig. 2).

a has been collected since it was designated as a category II infectious disease in 1976. In 1980, the DTaP vaccination rate exceeded 90% and few neonatal tetanus cases were reported, and after the 1990s, about 10 cases have been reported yearly. However, in the 2000s, 10 to 20 cases have been reported yearly (Fig. 2). For the past decade, the total number of reported cases was 107, and the number of cases patients aged <10 years and 10 to 19 years was 0 and 1, respectively. Few cases occurred in the pediatric age group, and those aged 40 years or more accounted for 94.4%5).

a has been collected since it was designated as a category II infectious disease in 1976. In 1980, the DTaP vaccination rate exceeded 90% and few neonatal tetanus cases were reported, and after the 1990s, about 10 cases have been reported yearly. However, in the 2000s, 10 to 20 cases have been reported yearly (Fig. 2). For the past decade, the total number of reported cases was 107, and the number of cases patients aged <10 years and 10 to 19 years was 0 and 1, respectively. Few cases occurred in the pediatric age group, and those aged 40 years or more accounted for 94.4%5). 4) Measles Ten to twenty thousand cases of measles were reported every year, but since the measles vaccine was introduced in 1965, the incidence had continuously decreased, except for an epidemic at an interval of 4 to 6 years. An average of 4,000 to 6,000 cases was reported yearly by the beginning of the 1980s, but with continuation of the immunization program, the incidence decreased to 1,000 to 2,000 cases per year after 1985. There was a nationwide epidemic event during 1993 to 1994. Compared to the period between 1989 and 1990, during the above mentioned period, the epidemic occurred more often in those aged 6 years or more, and thus in 1994, the Korean Pediatric Society temporarily recommended that those aged 6 years should be revaccinated with the measles, mumps, and rubella (MMR) vaccine, in addition to vaccination at the recommended age of 15 months. Since 1997, the government has reduced the time of primary MMR vaccination to 12 to 15 months and adjusted the immunization schedule for revaccination in those aged 4 to 6 years5,6,10).

ld be revaccinated with the measles, mumps, and rubella (MMR) vaccine, in addition to vaccination at the recommended age of 15 months. Since 1997, the government has reduced the time of primary MMR vaccination to 12 to 15 months and adjusted the immunization schedule for revaccination in those aged 4 to 6 years5,6,10). From the latter half of 2000 to the first half of 2001, a large epidemic event occurred with about 56,000 cases reported, and the incidence has greatly decreased since in May 2001, the measles catch-up immunization program was executed in all school-aged populations10). Except 194 cases in 2007 and 114 in 2010, just 10 to 30 cases were reported every year (Fig. 3)5). According to reports in 2007 and 2010, patients aged <10 years and 10 to 19 years accounted for 88.7% and 3.1%, and 14.9% and 82.5%, respectively. The age difference between two outbreaks might be dependent upon the age of the first case as the source of infection5).

From the latter half of 2000 to the first half of 2001, a large epidemic event occurred with about 56,000 cases reported, and the incidence has greatly decreased since in May 2001, the measles catch-up immunization program was executed in all school-aged populations10). Except 194 cases in 2007 and 114 in 2010, just 10 to 30 cases were reported every year (Fig. 3)5). According to reports in 2007 and 2010, patients aged <10 years and 10 to 19 years accounted for 88.7% and 3.1%, and 14.9% and 82.5%, respectively. The age difference between two outbreaks might be dependent upon the age of the first case as the source of infection5). 5) Mumps (epidemic parotitis) Before introduction of the immunization program, mumps had occurred mostly in elementary school-aged population, but since the program was introduced, those incidence in patients aged 15 years or more has tended to increase in all years. In the beginning of 1960, 5,000 or more cases of mumps were reported and then gradually decreased thereafter, and to less than 1,000 cases in the middle of the 1990s. However, it started to increase thereafter and 5,000 or more cases have been reported for in the past 5 years (Fig. 3)5,11). This phenomenon not only might result from an actual increase of incidence, but also from increased reporting through the consolidated report system.

than 1,000 cases in the middle of the 1990s. However, it started to increase thereafter and 5,000 or more cases have been reported for in the past 5 years (Fig. 3)5,11). This phenomenon not only might result from an actual increase of incidence, but also from increased reporting through the consolidated report system. According to data collected in 2008, mumps occurred year-round, but occurred mostly in April through September (71.0%), and occurred more frequently in men than in women6). For the past decade, the total number of reported cases was 31,238 and patients aged <10 years and 10 to 19 years accounted for 34.4% (10,754 cases) and 59.7% (18,656 cases), respectively5). 6) Rubella Rubella was designated as a category II infectious disease in 2000; therefore, it is difficult to estimate the before 2000. In 1963, a small outbreak was reported in Seoul, and from a mass outbreak in the middle of 1990s, "Rubella Warning" was issued by the Ministry of Health & Welfare in March 1996. One hundred seven cases were reported in 2000, 128 in 2001, and 10 to 40 cases yearly thereafter (Fig. 3). Before the vaccine program was introduced, it occurred mostly in children aged 5 to 14 years, but after it was introduced, the incidence tended to increase in young adults. The incidence is reported on a yearly basis, and it is higher in late winter and early spring6,11). For the past decade, the total number of reported cases was 349 and patients aged <10 years and 10 to 19 years accounted for 50.1% (175 cases) and 31.5% (110 cases), respectively5).

6) Rubella Rubella was designated as a category II infectious disease in 2000; therefore, it is difficult to estimate the before 2000. In 1963, a small outbreak was reported in Seoul, and from a mass outbreak in the middle of 1990s, "Rubella Warning" was issued by the Ministry of Health & Welfare in March 1996. One hundred seven cases were reported in 2000, 128 in 2001, and 10 to 40 cases yearly thereafter (Fig. 3). Before the vaccine program was introduced, it occurred mostly in children aged 5 to 14 years, but after it was introduced, the incidence tended to increase in young adults. The incidence is reported on a yearly basis, and it is higher in late winter and early spring6,11). For the past decade, the total number of reported cases was 349 and patients aged <10 years and 10 to 19 years accounted for 50.1% (175 cases) and 31.5% (110 cases), respectively5). 7) Polio Polio occurred in 1,000 to 2,500 patients between 1955 and 1963, 100 to 300 cases had been reported thereafter until 1973. Only several to dozens of cases were reported between 1974 and 1983, and since 5 cases were reported in 1983, wild poliovirus infections have not been reported, thus far (Fig. 3)5). According to a study of polio cases between 1962 and 1964, those aged 1 year were most common and those aged 3 years or more accounted for 70%. Inactivated vaccines for injection were used in 1962, oral live attenuated vaccines were added in 1965, and improved inactivated vaccines for injection have been used from 20045,9,11).

g to a study of polio cases between 1962 and 1964, those aged 1 year were most common and those aged 3 years or more accounted for 70%. Inactivated vaccines for injection were used in 1962, oral live attenuated vaccines were added in 1965, and improved inactivated vaccines for injection have been used from 20045,9,11). 8) Hepatitis B In the 1980s, hepatitis B surface antigen (HBsAg) positive rate was shown to be 6.6 to 8.6% in all populations12). However, since hepatitis B vaccine was first introduced in 1982, and then subsequently included in the immunization schedule table of the Korean Pediatric Society in 1991, and also in the national immunization program in 1995, HBsAg positive rate has significantly decreased9,13). According to the 2008 National Health and Nutrition Survey in Korea, it has significantly decreased to 2.9% in populations aged 10 years or more (Fig. 4)14). Specifically, HBsAg positive rate in those aged 4 to 6 years was found to be 0.2%15) from a study with nationwide sampling in 2006. This data could be a basis for certification from the WHO that hepatitis B has been well-controlled in the ROK.

ficantly decreased to 2.9% in populations aged 10 years or more (Fig. 4)14). Specifically, HBsAg positive rate in those aged 4 to 6 years was found to be 0.2%15) from a study with nationwide sampling in 2006. This data could be a basis for certification from the WHO that hepatitis B has been well-controlled in the ROK. 9) Japanese encephalitis Since it was first reported in an American soldier in the ROK in 1946, 5,616 cases occurred in 1949 and of these, 2,729 died. In 1958, 6,897 cases occurred and of these, 2,177 died in a large epidemic. Since then, 1,000 to 3,000 cases had occurred between 1960 and 1968, and 300 to 900 cases died every year. Since the vaccine was first introduced in 1971, the incidence has sharply decreased, and after the last epidemic in 1982, when 1,197 cases occurred and of these, 10 died, 10 or less cases have occurred yearly, nearly reaching an elimination level (Fig. 5)5,11,16). In the past epidemic period, most of the cases were aged 3 to 15 years, but for the most recent 10 years, the total number of reported cases was 59 and the number of cases aged <10 years and 10 to 19 years was 0 and 2, respectively, indicating that few cases were reported in children or adolescents, and rather those aged 40 years or more accounted for most occurrences (81.4%, 48 cases)5).

but for the most recent 10 years, the total number of reported cases was 59 and the number of cases aged <10 years and 10 to 19 years was 0 and 2, respectively, indicating that few cases were reported in children or adolescents, and rather those aged 40 years or more accounted for most occurrences (81.4%, 48 cases)5). 10) Chicken pox Since it was designated as a category II notifiable infectious disease in 2005, 11,014 cases of chicken pox were reported in 2006, 20,284 in 2007, 22,849 in 2008, 25,197 in 2009, and 24,400 in 20105). Such an escalating trend of cases might result from the increased reporting through improved educations and public relations after its designation as a notifiable infectious disease. According to a report in 2010, those aged 3 to 7 years accounted for most cases at 61%, and those aged under 15 years accounted for 95%5). According to data from the "Health Insurance Review and Assessment Service" between 2000 and 2007, the number of cases of chicken pox was as low as 179,500 in 2006, but as high as 234,897 in 2000. Although there have been no exact data about chicken pox vaccination rates in the ROK, according to a nationwide head-to-head interview of about 1,000 parents of children aged ≥16 months to ≤6 years in 2008, the vaccination rate was 96.2%11,17).

chicken pox was as low as 179,500 in 2006, but as high as 234,897 in 2000. Although there have been no exact data about chicken pox vaccination rates in the ROK, according to a nationwide head-to-head interview of about 1,000 parents of children aged ≥16 months to ≤6 years in 2008, the vaccination rate was 96.2%11,17). 3. Category III infectious diseases Category III infectious diseases involve possibilities of intermittent outbreak; therefore, surveillance of occurrence should be performed and control measures need to be taken. Once a case occurs, it should be reported by a health care provider without delay. Nineteen diseases, malaria, tuberculosis, Hansen disease, scarlet fever, meningococcal meningoencephalitis, legionellosis, Vibrio vulnificus sepsis, epidemic typhus, murine typhus, tsutsugamushi disease, leptospirosis, brucellosis, anthrax, rabies, hemorrhagic fever with renal syndrome (HFRS), influenza, acquired immune deficiency syndrome (AIDS), syphilis, and Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD), are included in this category (Table 1)2). 1) Malaria As a typical re-emerging infectious disease, it had not been reported from the latter half of the 1970s since it was epidemic in the beginning of the 1970s, and then the occurrence of cases was reported again from 1993. In the 2000s, 1,000 to 2,000 cases were continuously reported every year (Fig. 5)5).

3. Category III infectious diseases Category III infectious diseases involve possibilities of intermittent outbreak; therefore, surveillance of occurrence should be performed and control measures need to be taken. Once a case occurs, it should be reported by a health care provider without delay. Nineteen diseases, malaria, tuberculosis, Hansen disease, scarlet fever, meningococcal meningoencephalitis, legionellosis, Vibrio vulnificus sepsis, epidemic typhus, murine typhus, tsutsugamushi disease, leptospirosis, brucellosis, anthrax, rabies, hemorrhagic fever with renal syndrome (HFRS), influenza, acquired immune deficiency syndrome (AIDS), syphilis, and Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD), are included in this category (Table 1)2). 1) Malaria As a typical re-emerging infectious disease, it had not been reported from the latter half of the 1970s since it was epidemic in the beginning of the 1970s, and then the occurrence of cases was reported again from 1993. In the 2000s, 1,000 to 2,000 cases were continuously reported every year (Fig. 5)5). According to the 2008 Infectious Diseases Surveillance Yearbook6), among 1,052 cases, 1,023 were local cases, 29 were imported cases, and 787 were soldiers and veterans, indicating that military-related cases accounted for 74.8%. The number of cases in July and August was 235 and 228, respectively, indicating that 44.0% of total cases occurred in the middle of summer, and 901 cases were men and 151 women, indicating that most of the cases occurred in men.

87 were soldiers and veterans, indicating that military-related cases accounted for 74.8%. The number of cases in July and August was 235 and 228, respectively, indicating that 44.0% of total cases occurred in the middle of summer, and 901 cases were men and 151 women, indicating that most of the cases occurred in men. For the past decade, the total number of reported cases was 16,206 and patients aged <10 years and 10 to 19 years accounted for 0.9% (148 cases) and 4.1% (659 cases), respectively5). 2) Tuberculosis In the 1970s, the total registered number of treated cases for tuberculosis was 100,000 or more yearly, and tuberculosis tended to decrease gradually thereafter. However, after 2001, 30,000 to 35,000 new cases have occurred yearly, not showing a decreasing trend any more (Fig. 5)5). The total number of tuberculosis cases reported in 2009 was 47,302 (97.0/100,000 populations). The number of new cases was 35,845 (73.5/100,000 populations), and of these, the number of pulmonary tuberculosis cases was 28,922 (59.3/100,000 populations), and the number of sputum acid fast bacilli -positive cases was 11,285 (23.1/100,000 populations). The number of extra-pulmonary cases was 6,923 (14.2/100,000 populations), accounting for 19.3%. Those aged <10 years and 10 to 19 years accounted for 0.3% (97 cases) and 6.8% (2,421 cases), respectively18).

0 populations), and the number of sputum acid fast bacilli -positive cases was 11,285 (23.1/100,000 populations). The number of extra-pulmonary cases was 6,923 (14.2/100,000 populations), accounting for 19.3%. Those aged <10 years and 10 to 19 years accounted for 0.3% (97 cases) and 6.8% (2,421 cases), respectively18). According to a study by 9 medical institutions on pediatric tuberculosis between 1980 and 2006, the prevalence of tuberculosis in 2006 decreased to about a tenth of that in 1980, and, in particular, central nervous system and miliary tuberculosis cases decreased to about 1/50th. On the other hand, pulmonary tuberculosis cases decreased just to about 1/5th during the same period19). 3) Hansen disease Since the 1970s, Hansen disease has sharply decreased, and 200 to 500 cases between 1980 and 1985, and 100 to 200 cases between 1986 and 2000, have been reported annually. Since then, 41 cases in 2003, 43 in 2004, 38 in 2005, and 56 in 2006 were registered as new patients, and 12 in 2007 and 7 in 2008 were new active patients among newly registered patients, and all patients reported in 2008 were aged 50 years or more, and 6 were women6). 4) Scarlet fever Reports on scarlet fever have been made on a full scale from 1978, and the incidence was highest in 1986, with about 350 cases, and 50 to 150 cases have been reported yearly after 19905). Such numbers might result from the fact that many patients who contracted the disease were not reported properly because its severity was mild20).

rlet fever have been made on a full scale from 1978, and the incidence was highest in 1986, with about 350 cases, and 50 to 150 cases have been reported yearly after 19905). Such numbers might result from the fact that many patients who contracted the disease were not reported properly because its severity was mild20). For the past decade, the total number of cases reported was 1,015 and patients aged <10 years and 10 to 19 years accounted for 95.7% (971 cases) and 3.7% (38 cases), respectively5). 5) Meningococcal meningoencephalitis About 20 cases were reported yearly in the 1960s, under 5 in the 1970s, and 5 to 15 after the 1980s. There were small outbreaks, 42 cases were reported in 1988, 27 cases in 2002, and 38 in 2003 (Fig. 5). For the past decade, the total number of reported cases was 122 and patients aged <10 years and 10 to 19 years accounted for 33.6% (41 cases) and 42.6% (52 cases), respectively5). 6) Legionellosis Since legionellosis was designated as a notifiable infectious disease in 2000, less than 5 cases were reported yearly in the beginning of the 2000s and 20 to 30 cases have been reported after 2005 (Fig. 6). For the past decade, the total number of cases reported was 136 and the number of those aged <10 years and 10 to 19 years was each 1, and it mostly occurred in patients in their fifties or over5).

6) Legionellosis Since legionellosis was designated as a notifiable infectious disease in 2000, less than 5 cases were reported yearly in the beginning of the 2000s and 20 to 30 cases have been reported after 2005 (Fig. 6). For the past decade, the total number of cases reported was 136 and the number of those aged <10 years and 10 to 19 years was each 1, and it mostly occurred in patients in their fifties or over5). 7) V. vulnificus sepsis Since V. vulnificus sepsis was designated as a notifiable infectious disease in 2000, about 50 cases have been reported yearly (Fig. 6). For the past decade, the total number of cases reported was 588 and just 3 cases were reported in those aged 10 to 19 years, and it mostly occurred in patients in their forties or over5). 8) Epidemic typhus Less than 100 cases had been reported by the middle of the 1960s and no cases have been reported thereafter5). 9) Murine typhus Few cases had been reported by the end of the 1980s, the cases started to increase in the 1990s, and 50 to 100 cases were reported yearly in the 2000s (Fig. 6). For the past 10 years, the total number of patients reported was 392 and the number of those aged <10 years and 10 to 19 years was 2 and 1, respectively, and it mostly occurred in patients in their fifties or over5).

cases started to increase in the 1990s, and 50 to 100 cases were reported yearly in the 2000s (Fig. 6). For the past 10 years, the total number of patients reported was 392 and the number of those aged <10 years and 10 to 19 years was 2 and 1, respectively, and it mostly occurred in patients in their fifties or over5). 10) Tsutsugamushi disease Since it was included in the Korean NNDSS in 1994, 1,000 to 3,000 cases were reported yearly in the end of the 1990s and the early 2000s, and 5,000 to 7,000 cases have been reported yearly after 2004 (Fig. 6)5). According to data in 200921), 90.9% of the cases were reported in October to November, and 73.3% were in patients in their fifties or over, and female cases were 1.7-fold higher than male cases. For the past 10 years, the total number of reported cases was 46,674 and patients aged <10 years and 10 to 19 years accounted for 1% (489 cases) and 1.1% (542 cases), respectively5). 11) Leptospirosis Since it was included in the Korean NNDSS in 1994, 100 to 200 cases were reported yearly after 1998, and the incidence decreased to less than 100 cases from 2009 (Fig. 7)5). According to data in 2008, 77% of the cases were reported in September to November, and those in their forties or over accounted for 88%, and it occurred 1.7-fold more often in men6). For the past 10 years, the total number of reported cases was 1,153, and the number of those aged <10 years and 10 to 19 years was 3 and 11, respectively, and most occurrences were in patients in their forties or over5).

11) Leptospirosis Since it was included in the Korean NNDSS in 1994, 100 to 200 cases were reported yearly after 1998, and the incidence decreased to less than 100 cases from 2009 (Fig. 7)5). According to data in 2008, 77% of the cases were reported in September to November, and those in their forties or over accounted for 88%, and it occurred 1.7-fold more often in men6). For the past 10 years, the total number of reported cases was 1,153, and the number of those aged <10 years and 10 to 19 years was 3 and 11, respectively, and most occurrences were in patients in their forties or over5). 12) Brucellosis Since brucellosis was designated as a notifiable infectious disease in 2000, 100 to 200 cases were reported between 2005 and 2007 but less than 50 cases have been reported yearly thereafter (Fig. 7). For the past 10 years, the total number of reported cases was 651, and the number of cases aged <10 years and 10 to 19 years was 1 and 3, respectively, and it mostly occurred in patients in their forties or over5). 13) Anthrax Since anthrax was designated as a notifiable infectious disease in 2000, no cases have been reported yet5).

12) Brucellosis Since brucellosis was designated as a notifiable infectious disease in 2000, 100 to 200 cases were reported between 2005 and 2007 but less than 50 cases have been reported yearly thereafter (Fig. 7). For the past 10 years, the total number of reported cases was 651, and the number of cases aged <10 years and 10 to 19 years was 1 and 3, respectively, and it mostly occurred in patients in their forties or over5). 13) Anthrax Since anthrax was designated as a notifiable infectious disease in 2000, no cases have been reported yet5). 14) Rabies In 1963 and 1966, 103 and 101 cases, respectively, were reported, and few cases were reported after 1975. No cases had been reported after 1984, when just 1 case was reported. However, 1 rabies patient and 2 patients with suspicious rabies were reported in 1999, 1 or 2 cases were reported yearly between 2001 and 2004, and no cases have been reported thereafter (Fig. 7). For the past 10 years, the total number of reported cases was 7, and the number of those aged <10 years and 10 to 19 years was 1 each5,22).

s patient and 2 patients with suspicious rabies were reported in 1999, 1 or 2 cases were reported yearly between 2001 and 2004, and no cases have been reported thereafter (Fig. 7). For the past 10 years, the total number of reported cases was 7, and the number of those aged <10 years and 10 to 19 years was 1 each5,22). 15) Hemorrhagic fever with renal syndrome Since about 3,200 HFRS cases occurred in the United Nations forces and hundreds of them died during the Korean War between 1951 and 1953, scholars became interested in this condition11). Since it was designated as a category III notifiable infectious disease in 1976, the incidence has increased from the latter half of 1990, and 300 to 500 cases were reported yearly in the 2000s (Fig. 7)5). According to a report in 2008, 71.5% of the cases were reported in October to December, those aged in their forties to sixties accounted for 93.3%, and male cases were more than female ones6). For the past 10 years, the total number of reported cases was 3,953 and patients aged <10 years and 10 to 19 years accounted for 0.3% (12 cases) and 1.6% (63 cases), respectively5). 16) Influenza Since it was designated as a category III notifiable infectious disease and the Korea Influenza Surveillance Scheme consisting of clinical sentinel surveillance and laboratory sentinel surveillance was started in 2000, the domestic prevalence of influenza has been reported23).

For the past 10 years, the total number of reported cases was 3,953 and patients aged <10 years and 10 to 19 years accounted for 0.3% (12 cases) and 1.6% (63 cases), respectively5). 16) Influenza Since it was designated as a category III notifiable infectious disease and the Korea Influenza Surveillance Scheme consisting of clinical sentinel surveillance and laboratory sentinel surveillance was started in 2000, the domestic prevalence of influenza has been reported23). Except the seasons of 2009 to 2010, when an influenza A (H1N1) pdm 09 epidemic occurred, the domestic weekly prevalence of influenza-like illness (ILI) for the 5 seasons from 2006 to 2007 usually started to increase from around November, reached the peak from the end of December to the beginning of January, and tended to decrease, and then showed an increased trend once more between March and May of the following year. The peak ratio of ILI was 10 to 25/1,000 cases in the winter, and was generally lower in the spring (Fig. 8)11,23). 17) Acquired immune deficiency syndrome For AIDS, since the first human immunodeficiency virus (HIV)-infected case was reported in 1985, the accumulated number of HIV-infected cases was about 1,000 by 1999. In 2008, 797 infected cases were newly reported and the accumulated number of infected cases by the end of 2008 was 6,120. Among infected cases in 2008, occurrences in men were 14-folds higher than in women, those aged twenties to forties accounted for 73.3%, and the identified route of infection was always sexual contact24).

, 797 infected cases were newly reported and the accumulated number of infected cases by the end of 2008 was 6,120. Among infected cases in 2008, occurrences in men were 14-folds higher than in women, those aged twenties to forties accounted for 73.3%, and the identified route of infection was always sexual contact24). 18) Syphilis Regarding syphilis, the sentinel surveillance system was established in 2001, and 312 private medical institutions and health centers were involved in 2008. Other venereal diseases tended to decrease after 2004, while the number of reported syphilis cases increased, to 1,415 in 2007 and to 1,548 in 20086). 19) Creutzfeldt-Jakob disease or variant Creutzfeldt-Jakob disease Since CJD was designated as a notifiable infectious disease in 2001, the total number of diagnosed cases of CJD or vCJD in the past 10 years was 141, and 10 to 20 cases have been reported yearly. The male-female ratio was close to 1:1 and the mean age of the patients was 64±10 years25).

ariant Creutzfeldt-Jakob disease Since CJD was designated as a notifiable infectious disease in 2001, the total number of diagnosed cases of CJD or vCJD in the past 10 years was 141, and 10 to 20 cases have been reported yearly. The male-female ratio was close to 1:1 and the mean age of the patients was 64±10 years25). 4. Category IV infectious diseases Category IV infectious diseases are newly emerging cases in the ROK or likely to be imported, and once a case occurs, it should be reported by a health care provider without delay. Seventeen diseases, plague, yellow fever, dengue fever, viral hemorrhagic fever (Marburg fever, Lassa fever, Ebola fever, etc.), small pox, botulism, severe acute respiratory syndrome, avian influenza, new H1N1 influenza, tularemia, Q fever, West Nile fever, newly-emerging infectious diseases syndrome, Lyme disease, tick-borne encephalitis, melioidosis, and Chikungunya fever, are included in this category (Table 1)2). 5. Category V infectious diseases Category V infectious diseases are parasitic infectious diseases, requiring periodic investigation. Once a case occurs, it should be reported by a health care provider within 7 days. Six diseases, ascariasis, trichuriasis, enterobiasis, clonorchiasis, paragonimiasis, and intestinal trematodiasis, are included in this category (Table 1)2).

s diseases are parasitic infectious diseases, requiring periodic investigation. Once a case occurs, it should be reported by a health care provider within 7 days. Six diseases, ascariasis, trichuriasis, enterobiasis, clonorchiasis, paragonimiasis, and intestinal trematodiasis, are included in this category (Table 1)2). 6. Designated contagious infectious diseases For designated contagious infectious diseases, any epidemic events are required to be investigated, and once a case occurs, it should be reported by a health care provider within 7 days. Seventeen diseases, hepatitis C, hand-foot-mouth disease, gonorrhea, chlamydiosis, chancroid, genital herpes simplex, condyloma acuminatum, vancomycin-resistant Staphylococcus aureus infections, vancomycin-resistant Enterococcus infections, methicillin-resistant S. aureus infections, multidrug-resistant Pseudomonas aeruginosa infections, multidrug-resistant Acinetobacter baumannii infections, carbapenem-resistant Enterobacteriaceae species infections, enteric infectious diseases, acute respiratory infectious diseases, imported parasitic diseases, and enterovirus infectious diseases, are included in this category (Table 1)2).

onas aeruginosa infections, multidrug-resistant Acinetobacter baumannii infections, carbapenem-resistant Enterobacteriaceae species infections, enteric infectious diseases, acute respiratory infectious diseases, imported parasitic diseases, and enterovirus infectious diseases, are included in this category (Table 1)2). Conclusions As described above, there have been huge circumstances changes in infectious diseases in the ROK. In particular, changes in VPDs were remarkable. Such changes might result from a combination of multiple factors, such as environmental improvements with socioeconomic developments, improvements in the reporting system with consolidated administration of the government, increased collaboration in the private medical fields, and increased vaccination rate in infants and toddlers. To maintain and improve the current situation of infectious diseases in the ROK, high coverage rate of vaccines in the national immunization program need to be maintained. Moreover, vaccines that are not included in the national immunization program should be added, and surveillance and control of emerging or re-emerging diseases, especially imported infectious diseases, should be performed properly. Besides, the governmental and medical associations should coordinate their efforts to build an efficient and practical NNDSS. Acknowledgement The authors would like to thank Ms. Chris Lee for English translation of this article. Fig. 1 Reported cases of cholera, typhoid fever, paratyphoid fever, and shigellosis from 1960 to 2010 in the Korean National Notifiable Disease Surveillance System.

To maintain and improve the current situation of infectious diseases in the ROK, high coverage rate of vaccines in the national immunization program need to be maintained. Moreover, vaccines that are not included in the national immunization program should be added, and surveillance and control of emerging or re-emerging diseases, especially imported infectious diseases, should be performed properly. Besides, the governmental and medical associations should coordinate their efforts to build an efficient and practical NNDSS. Acknowledgement The authors would like to thank Ms. Chris Lee for English translation of this article. Fig. 1 Reported cases of cholera, typhoid fever, paratyphoid fever, and shigellosis from 1960 to 2010 in the Korean National Notifiable Disease Surveillance System. Fig. 2 Reported cases of entero-hemorrhagic Escherichia coli (2000 to 2010), diphtheria (1960 to 2010), pertussis (1960 to 2010), and tetanus (1977 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 3 Reported cases of measles (1960 to 2010), mumps (1960 to 2010), rubella (2000 to 2010), and polio (1960 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 4 Changes in the prevalence rates of chronic hepatitis B viral infections from 1980 to 2007.

Fig. 2 Reported cases of entero-hemorrhagic Escherichia coli (2000 to 2010), diphtheria (1960 to 2010), pertussis (1960 to 2010), and tetanus (1977 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 3 Reported cases of measles (1960 to 2010), mumps (1960 to 2010), rubella (2000 to 2010), and polio (1960 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 4 Changes in the prevalence rates of chronic hepatitis B viral infections from 1980 to 2007. Fig. 5 Reported cases of Japanese encephalitis (1960 to 2010), malaria (1963 to 2010), tuberculosis (1964 to 2010), and meningococcal meningoencephalitis (1960 to 2010) in the Korean National Notifiable Disease Surveillance System. *Tuberculosis: In 1964-1979, number was total registered treated patients. In 1980 to 1993, number was new diagnosed patients. After 2001, number was registered patients in both public and private health institutions. Fig. 6 Reported cases of legionellosis (2000 to 2010), Vibrio vulnificus sepsis (2000 to 2010), murine typhus (1960 to 2010), and tsutsugamushi disease (1994 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 7 Reported cases of leptospirosis (1994 to 2010), brucellosis (2000 to 2010), rabies (1962 to 2010), and hemorrhagic fever with renal syndrome (1977 to 2010) in the Korean National Notifiable Disease Surveillance System.

Fig. 6 Reported cases of legionellosis (2000 to 2010), Vibrio vulnificus sepsis (2000 to 2010), murine typhus (1960 to 2010), and tsutsugamushi disease (1994 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 7 Reported cases of leptospirosis (1994 to 2010), brucellosis (2000 to 2010), rabies (1962 to 2010), and hemorrhagic fever with renal syndrome (1977 to 2010) in the Korean National Notifiable Disease Surveillance System. Fig. 8 The weekly proportion of influenza-like illness (ILI) visits per 1,000 patients according to the weekly reporting system. *Proportion of ILI visits per 1,000 patients (‰): No. of weekly ILI visits / No. of total weekly patients ×1,000. Table 1 Classifications and Lists of Nationally Notifiable Infectious Diseases by "Law for Control and Prevention of Infectious Diseases" in the Republic of Korea (announced on December 30, 2010) CJD, Creutzfeldt-Jakob disease; CRE, carbapenem-resistant Enterobacteriaceae species; MRAB, multidrug-resistant Acinetobacter baumannii; MRPA, multidrug-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus; SARS, severe acute respiratory syndrome; vCJD, variant Creutzfeldt-Jakob disease; VRE, vancomycin-resistant enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus, E. coli, Escherichia coli.

etobacter baumannii; MRPA, multidrug-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus; SARS, severe acute respiratory syndrome; vCJD, variant Creutzfeldt-Jakob disease; VRE, vancomycin-resistant enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus, E. coli, Escherichia coli. *Enteric infectious diseases: Salmonellosis, Vibrio parahaemolyticus infections, enterotoxigenic E. coli infections, enteroinvasive E. coli infections, enteropathogenic E. coli infections, campylobacteriosis, Clostridium perfringens infections, Staphylococcus aureus infections, Bacillus cereus infections, Yersinia enterocoliticainfections, Listeria monocytogenes infections, group A rotavirus infections, astrovirus infections, enteric adenovirus infections, norovirus infections, sapovirus infections, Entamoeba histolytica infections, lambliasis, Cryptosporidium parvum infections, cyclosporiasis. †Acute respiratory infectious diseases: adenovirus infections, human bocavirus infections, parainfluenza virus infections, respiratory syncytial virus infections, rhinovirus infections, human metapneumovirus infections, human coronavirus infections, Streptococcus pneumoniae infections, Haemophilus influenzae infections, mycoplasma infections, chlamydiosis. ‡Imported parasitic diseases: leishmaniasis, babesiosis, African trypanosomiasis, schistosomiasis, Chagas disease, angiostrongylosis, gnathostomiasis, filariasis, echinococcosis, toxoplasmosis, dracunculiasis Table 2 Reported Cases of Hepatitis A from 2001 to 2010 in the Korean National Sentinel Surveillance System5)

Introduction The prevalence of allergy-related diseases has increased over the last decades. A combination of environmental exposures and inherent biological and genetic vulnerabilities implicate allergy-related diseases1,2). It is difficult to elucidate the relationship between air pollution and allergy-related diseases. Some studies have shown that exposure to air pollutants increases the response to aeroallergens3,4). One study has shown that respiratory-related allergies are more common in urban areas than in rural areas of industrialized countries4). There are also some reports that air pollution is strongly associated with the aggravation of asthma, visits to emergency centers, hospitalizations and medications5,6). Previously, we found that a statistically significant relation between air pollutants [nitric oxide (NO2), ozone (O3), sulfur dioxide (SO2) and particulate matter (PM) of 10 µm or less (PM10)] and the increased number of patients visiting the outpatient department and emergency center with respiratory diseases7,8). From a study of 368 middle school students, we found that PM10 had adverse effects on forced expiratory volume in one second. By measuring the levels of biomarkers such as muconic acid and 1-OH pyrene, we also found that volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) play a role in the presentation of asthma9,10).

school students, we found that PM10 had adverse effects on forced expiratory volume in one second. By measuring the levels of biomarkers such as muconic acid and 1-OH pyrene, we also found that volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) play a role in the presentation of asthma9,10). Other studies, however, have suggested that there is little relation between air pollution and asthma. Nicolai and von Mutius11) reported no significant difference in the prevalence of asthma in elementary school students between East Germany, an industrialized area, and West Germany, an urban area. In addition, Charpin et al.12) reported that air pollution and atopy were not significantly related. To analyze the relation between air pollution and allergy-related diseases, we investigated the levels of air pollutants and the prevalence of allergy-related diseases in Incheon, an industrialized area, and Jeju, a non-industrialized area.

Other studies, however, have suggested that there is little relation between air pollution and asthma. Nicolai and von Mutius11) reported no significant difference in the prevalence of asthma in elementary school students between East Germany, an industrialized area, and West Germany, an urban area. In addition, Charpin et al.12) reported that air pollution and atopy were not significantly related. To analyze the relation between air pollution and allergy-related diseases, we investigated the levels of air pollutants and the prevalence of allergy-related diseases in Incheon, an industrialized area, and Jeju, a non-industrialized area. Materials and methods 1. Subjects This study was performed in Incheon and Jeju, Korea. Air pollution in Incheon originates mainly from the photochemical industry. Because there are three highways and an international airport in the district, exhaust from automobiles also contributes to air pollution. The air in Jeju, however, is not exposed to any major industrial plants. Second grade students from 56 elementary schools (11 schools in the metropolitan city of Incheon and 45 schools in the Seogwipo city, Jeju Special Self-Governing Province) were enrolled in this study between October 6th, 2008 and December 5th, 2008. Written informed consent was provided by parents or guardians for all subjects. A modified version of the International Study of Asthma & Allergies in Children (ISAAC) written questionnaire (1,315 students from Incheon and 1,829 from Jeju) regarding their history of allergy-related disease, environment, life style and diet was completed for all students by their parents or guardians. Of these, 89 students in Incheon and 81 students in Jeju were excluded because of insufficient completion. In addition, some of the students were submitted to a skin prick test (1,221 students from Incheon and 170 students from Jeju). The institutional review board of our hospital approved the study.

ents or guardians. Of these, 89 students in Incheon and 81 students in Jeju were excluded because of insufficient completion. In addition, some of the students were submitted to a skin prick test (1,221 students from Incheon and 170 students from Jeju). The institutional review board of our hospital approved the study. 2. Methods 1) Measurement of air pollutants From December 17th to December 24th, a single measurement from 13 elementary schools (11 schools in Incheon and 2 schools in Jeju) was performed during the same period. In Incheon 11 schools were selected evenly according to pre-examined PM levels. But in Jeju, one school was in urban area (Seogwipo city) and the other was rural area. In 13 elementary schools, the levels of CO, CO2, O3, NO2, PM10/2.5, formaldehyde, total volatile organic compounds (t-VOCs), house dust mites and endotoxins were checked indoors (i.e., in classrooms, cafeterias and infirmaries) and outdoors (i.e., at the playgrounds and rooftops of the schools). A Gray Wolf Sensing Solution IQ604 Indoor Air Quality Probe (GrayWolf Sensing Solutions, Shelton, CT, USA) was used to measure CO, CO2, O3, NO2, temperature and humidity. PM10 and PM2.5 were measured using a GT-331 monitor (Met One Instruments Inc., Grants Pass, OR, USA) and formaldehyde was measured using a Formaldehyde Mater w/Pump Model Z- 300XP (Environmental Sensors Co., Boca Raton, FL, USA). A ppbRAE3000 (Rae Systems Inc., San Jose, CA, USA) was used to measure t-VOC, and mite kits were used to measure house dust mites.

331 monitor (Met One Instruments Inc., Grants Pass, OR, USA) and formaldehyde was measured using a Formaldehyde Mater w/Pump Model Z- 300XP (Environmental Sensors Co., Boca Raton, FL, USA). A ppbRAE3000 (Rae Systems Inc., San Jose, CA, USA) was used to measure t-VOC, and mite kits were used to measure house dust mites. 2) Skin prick tests In Incheon, 12 common allergen extracts (Allergopharma, Reinbeck, Germany) were measured, including grass, trees I mixture (alder, hazel, poplar, elm, and willow), trees II mixture (birch, beech, oak, and plane tree), mugwort, ragweed, Dermatophagoides farinae, Dermatophagoides pteronyssinus, cockroaches, Aspergillus furmigatus, molds I mixture (alternaria, botrytis, cladosporium, curvularia, fusarium, helminthosporium), molds II mixture (aspergillus, mucor, penicillium, pullularia, rhizopus, and serpula), dog hair, cat fur. Histamine and isotonic saline were used as positive and negative controls, respectively. In Jeju, cedar, citrus red mite, hop japanese pollens and Tyrophagus were added to the 12 allergen extracts used in Incheon. After a drop of allergen extracts, the skin was pricked through the drop using the tip of a lancet and then wiped cautiously. After 15 minutes, we measured the size of the wheal and erythema. Positive results were recorded if the size of the wheal was larger than the positive control13,14).

2) Skin prick tests In Incheon, 12 common allergen extracts (Allergopharma, Reinbeck, Germany) were measured, including grass, trees I mixture (alder, hazel, poplar, elm, and willow), trees II mixture (birch, beech, oak, and plane tree), mugwort, ragweed, Dermatophagoides farinae, Dermatophagoides pteronyssinus, cockroaches, Aspergillus furmigatus, molds I mixture (alternaria, botrytis, cladosporium, curvularia, fusarium, helminthosporium), molds II mixture (aspergillus, mucor, penicillium, pullularia, rhizopus, and serpula), dog hair, cat fur. Histamine and isotonic saline were used as positive and negative controls, respectively. In Jeju, cedar, citrus red mite, hop japanese pollens and Tyrophagus were added to the 12 allergen extracts used in Incheon. After a drop of allergen extracts, the skin was pricked through the drop using the tip of a lancet and then wiped cautiously. After 15 minutes, we measured the size of the wheal and erythema. Positive results were recorded if the size of the wheal was larger than the positive control13,14). 3. Statistical analysis Data are presented as means±standard deviations (SDs) or as geometric means and a range of 1 SD. Statistical analysis for the levels of air pollutants and pulmonary function test were performed using Student's t-test. A X2 test was used to analyze the prevalence of allergy related diseases and the skin prick test. All calculations were performed with the SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA). A probability value of less than 0.05 was considered statistically significant.

ry function test were performed using Student's t-test. A X2 test was used to analyze the prevalence of allergy related diseases and the skin prick test. All calculations were performed with the SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA). A probability value of less than 0.05 was considered statistically significant. Results 1. Anthropometric measurements The children's mean height in Incheon was 128.7±5.9 cm and 129.3±6.0 cm in Jeju. The children's mean weight was 28.4±6.1 kg and 29.6±6.2 kg in Incheon and Jeju, respectively. The mean body mass index (BMI) percentiles in the children from Incheon was 110.6±19.2% vs. 114.7±19.5% in the children from Jeju. We found no significant differences in any of the anthrometric measurements between Incheon and Jeju students [height (P=0.36), weight (P=0.07) and BMI percentiles (P=0.17)] (Table 1). 2. Level of indoor and outdoor air pollutants at the elementary schools In outdoor measurements, the levels of CO, PM10 and PM2.5 in Incheon were higher than those in Jeju (0.4114±0.0735 ppm, 52.37±5.78 µg/m3, 14.30±2.25 µg/m3, respectively, in Incheon vs. 0.0975±0.0448 ppm, 20.00±2.28 µg/m3, 4.10±0.10 µg/m3, respectively, in Jeju). Ozone levels were higher in Jeju (0.0230±0.0063 ppm) (Table 2). In indoor measurements, the levels of CO, CO2, PM10, PM2.5, t-VOC were higher in Incheon than in Jeju (1.2525±0.0812 ppm, 2,001.6±100.4 ppm, 154.20±13.02 µg/m3, 17.78±1.47 µg/m3, and 226.25±62.74 µg/m3 vs. 0.5317±0.1428 ppm, 1,038.5±102.2 ppm, 59.36±5.86 µg/m3, 5.61±0.68 µg/m3, 64.51±36.85 µg/m3, respectively) (Table 3).

indoor measurements, the levels of CO, CO2, PM10, PM2.5, t-VOC were higher in Incheon than in Jeju (1.2525±0.0812 ppm, 2,001.6±100.4 ppm, 154.20±13.02 µg/m3, 17.78±1.47 µg/m3, and 226.25±62.74 µg/m3 vs. 0.5317±0.1428 ppm, 1,038.5±102.2 ppm, 59.36±5.86 µg/m3, 5.61±0.68 µg/m3, 64.51±36.85 µg/m3, respectively) (Table 3). 3. Prevalence of allergic rhinitis (AR) and asthma as determined by written questionnaire The prevalences of "sneezing or blocked nose without a cold or flu, ever", "sneezing or blocked nose without a cold or flu, last 12 months", "diagnosis of rhinitis, ever", "treatment of AR, last 12 months", and "treatment of non-AR, last 12 months" in Incheon were 48.34%, 44.44%, 34.13%, 27.42%, and 35.92% significantly higher than in Jeju 36.05%, 28.69%, 20.02%, 14.59%, and 17.08%. The prevalences of "wheeze or whistling ever", and "wheezing, last 12 months" in Incheon were 24.80% and 9.50% significantly higher than in Jeju 18.80%, and 6.83% (Table 4). 4. Sensitization to allergens The sensitization rate to D. farinae was significantly different between Incheon and Jeju (24.58% vs. 31.40%, P=0.03). Statistical analysis was not possible for most allergens, except for house dust mites (Table 5).

3. Prevalence of allergic rhinitis (AR) and asthma as determined by written questionnaire The prevalences of "sneezing or blocked nose without a cold or flu, ever", "sneezing or blocked nose without a cold or flu, last 12 months", "diagnosis of rhinitis, ever", "treatment of AR, last 12 months", and "treatment of non-AR, last 12 months" in Incheon were 48.34%, 44.44%, 34.13%, 27.42%, and 35.92% significantly higher than in Jeju 36.05%, 28.69%, 20.02%, 14.59%, and 17.08%. The prevalences of "wheeze or whistling ever", and "wheezing, last 12 months" in Incheon were 24.80% and 9.50% significantly higher than in Jeju 18.80%, and 6.83% (Table 4). 4. Sensitization to allergens The sensitization rate to D. farinae was significantly different between Incheon and Jeju (24.58% vs. 31.40%, P=0.03). Statistical analysis was not possible for most allergens, except for house dust mites (Table 5). Discussion We found that the children living in Incheon, which was polluted with higher levels of PM had a higher prevalence of the symptoms of AR and asthma compared to children in Jeju. During the last decade, the respective annual mean airborne PM10 levels in Incheon and Jeju were 57 µg/m3 vs. 38 µg/m3 in 2002, 61 µg/m3 vs. 35 µg/m3 in 2003, 62 µg/m3 vs. 40 µg/m3 in 2004, 61 µg/m3 vs. 42 µg/m3 in 2005, 68 µg/m3 vs. 45 µg/m3 in 2006, and 64 µg/m3 vs. 39 µg/m3 in 200715). The level of airborne PM10 in Incheon has been consistently higher than in Jeju over the last decade. This is consistent with our measurements. Traffics from diesel trucks and buses on the roads contribute a large proportion of PM10 level in urban areas16), and three express highways cross the Incheon area. Airborne PM less than 10 µm in aerodynamic diameter (PM10) is a complex mixture of materials having a carbonaceous core and associated materials such as organic compounds, acids, and fine particles of metals17). PM10 or diesel extract particles augment lung inflammation by inhalant allergens or respiratory viral infection via acting as an adjuvant. The response may lead to enhancement of already existing allergies or immunoglobulin E response to neoallergens and susceptibility to respiratory infection. This adjuvant effect is exerted by the enhanced production of inflammatory Th2 and/or Th1 cytokines18,19).

r respiratory viral infection via acting as an adjuvant. The response may lead to enhancement of already existing allergies or immunoglobulin E response to neoallergens and susceptibility to respiratory infection. This adjuvant effect is exerted by the enhanced production of inflammatory Th2 and/or Th1 cytokines18,19). Choudhury et al.20) reported that a significant positive association between asthma morbidity and PM10 pollution was observed. This finding also support the hypothesis that air pollution, at levels below the current ambient air quality standards is harmful to sensitive subjects, such as asthmatic children. In this study, the level of outdoor ozone was higher in Jeju than in Incheon. However, the prevalence of allergy-related symptoms was not higher in children living in Jeju compared to those in Incheon. Thus, we can conclude that airborne PM and not ozone primarily influences development and aggravation of allergy-related symptoms.

y, the level of outdoor ozone was higher in Jeju than in Incheon. However, the prevalence of allergy-related symptoms was not higher in children living in Jeju compared to those in Incheon. Thus, we can conclude that airborne PM and not ozone primarily influences development and aggravation of allergy-related symptoms. ISAAC, which Korea joined in 1995, has enabled us to compare prevalence between countries. Korea has participated in three ISAAC surveys: two nationwide surveys in 1995 and 2000, and one regional survey in Seoul city in 2005. According to the survey results of Seoul city, the last 12-month prevalence of wheezing decreased from 10.5% in 1995 to 5.2% in 2000, and then to 5.5% in 2005; the lifetime prevalence of asthma diagnosis has been relatively constant: 8.7% in 1995, 9.4% in 2000, and 7.6% in 2005; the lifetime prevalence of AR diagnosis has increased 16.8% in 1995, 22.0% in 2000, 26.4% in 200521-23). According to previous study in the Songpa area of Seoul in 2008, the prevalence of AR symptoms ever was 42.5%, AR symptoms during the last 12 months was 39.0%, AR diagnosis from the doctor was 38.5%, treatment of AR, last 12 months was 29.5%. This is consistent with our results in Incheon24). The prevalence of allergic diseases tends to be lower in rural areas, which may have high exposure rates to microbial environments, than in urban areas25).

ISAAC, which Korea joined in 1995, has enabled us to compare prevalence between countries. Korea has participated in three ISAAC surveys: two nationwide surveys in 1995 and 2000, and one regional survey in Seoul city in 2005. According to the survey results of Seoul city, the last 12-month prevalence of wheezing decreased from 10.5% in 1995 to 5.2% in 2000, and then to 5.5% in 2005; the lifetime prevalence of asthma diagnosis has been relatively constant: 8.7% in 1995, 9.4% in 2000, and 7.6% in 2005; the lifetime prevalence of AR diagnosis has increased 16.8% in 1995, 22.0% in 2000, 26.4% in 200521-23). According to previous study in the Songpa area of Seoul in 2008, the prevalence of AR symptoms ever was 42.5%, AR symptoms during the last 12 months was 39.0%, AR diagnosis from the doctor was 38.5%, treatment of AR, last 12 months was 29.5%. This is consistent with our results in Incheon24). The prevalence of allergic diseases tends to be lower in rural areas, which may have high exposure rates to microbial environments, than in urban areas25). In our study, the number of enrolled students in the skin prick test in Jeju is lower than in Incheon. So it is difficult to compare the atopic status of both area. But the most common allergens identified by skin prick tests in Korean students are house dust mites. And the sensitization rate of house dust mite in Jeju corresponds with the results of a recent study26). Thus we could compare atopic status of both area. We found that the sensitization rate of children to house dust mites (D. farinae and D. pteronyssinus) was lower in Incheon children compared to Jeju children. This finding does not correspond with the results of a recent study, which reported that the sensitization rate was higher in Seoul than in Jeongeup27). Ahn and Choi28) reported that, in 661 randomly selected 6 to 12 years old children at a school in Seoul, the positive skin reaction rates were 40.7% for D. pteronyssinus and 44.3% for D. farinae. Yang et al.29) reported a skin prick positivity of D. farinae (20.4%) and house dust (14.7%). Lee et al.30) reported that the prevalence of skin reactivity in D. pteronyssinus and D. farinae was 17.0% and 15.5%, respectively, in a group of 6 to 8 years old. In addition, in rural areas of Jeju island, the sensitization rates to D. pteronyssinus and D. farinae, among the younger age groups (7 to 12 years) were 20.6% and 24.4%, respectively31). The results of the skin test among young medical students in Seoul with or without respiratory allergy or, atopy were present for D. pteronyssinus 37.9%, and D. farinae 35.7%32).

e sensitization rates to D. pteronyssinus and D. farinae, among the younger age groups (7 to 12 years) were 20.6% and 24.4%, respectively31). The results of the skin test among young medical students in Seoul with or without respiratory allergy or, atopy were present for D. pteronyssinus 37.9%, and D. farinae 35.7%32). In this study, we found that the increase of PM10/2.5 could be associated with the development and aggravation of AR and asthma in children, independent of allergic sensitization. The small number of enrolled students in the skin prick test in Jeju is a limitation. Thus we cannot claim a definitive association between air pollution and atopic status of the children living in the different communities. In the near future, we will continue this comparison study to elucidate the relationship between air pollution and allergy-related disease. In this cross-sectional analysis, the children living in Incheon, who were exposed to a higher level of outdoor PM10/2.5 and CO than children living in Jeju, showed more allergy-related symptoms by questionnaire. In conclusion, in the area of higher air pollutants such as CO, PM10 and PM2.5, the higher prevalence of allergy by questionnaire such as AR symptoms, diagnosis rate and treatment rate and asthma symptoms was found. Further studies are needed to elucidate the relationship between air pollution and allergy-related disease. Acknowledgement This work was supported by Ministry of Environment, Korea and Inha University. Table 1 The Characteristics and Anthropometric Measurements of Second Grade Elementary Students

In conclusion, in the area of higher air pollutants such as CO, PM10 and PM2.5, the higher prevalence of allergy by questionnaire such as AR symptoms, diagnosis rate and treatment rate and asthma symptoms was found. Further studies are needed to elucidate the relationship between air pollution and allergy-related disease. Acknowledgement This work was supported by Ministry of Environment, Korea and Inha University. Table 1 The Characteristics and Anthropometric Measurements of Second Grade Elementary Students Values are presented as mean±SD or number (%). AR, allergic rhinitis; BMI, body mass index. *Calculated by t-test & chi-square test. Table 2 Comparison of Elementary School Outdoor Air Pollutants in Incheon and Jeju Values are presented as mean±SD. HCHO, formaldehyde; PM, particulate matter. *Calculated by Student's t-test. Table 3 Comparison of Elementary School Indoor Air Pollutants in Incheon and Jeju Values are presented as mean±SD. TSB, total suspended bacteria; HCHO, formaldehyde; PM, particulate matter; TVOC, total volatile organic compound. *Calculated by Student's t-test. Table 4 Prevalence of Allergy According to the ISAAC Questionnaire Values are presented as number (%). ISAAC, International Study of Asthma & Allergies in Children; Allergic rhinitis (AR) symptoms was defined as sneezing or blocked nose without a cold or flu. *Calculated by chi-square tests. Table 5 Skin Test Positivity Values are presented as percentage. *Calculated by chi-square tests.

Introduction Wolff-Parkinson-White (WPW) syndrome presents the risk of sudden cardiac death (SCD) from ventricular fibrillation related to atrial fibrillation (AF) or flutter in individuals whose accessory pathway (AP) shows a short anterograde refractory period1), although the frequency of SCD is low (0.3%)2-4). Radiofrequency ablation (RFA) of the AP has been shown to be both safe and effective in symptomatic and asymptomatic WPW patients, and provides a 'cure' in more than 95% of the patients5-9). Recent studies have described the active use of electrophysiologic studies (EPS) for the risk stratification of arrhythmia in asymptomatic WPW patients, and have emphasized that the electrophysiologic findings, such as, the locations and numbers of APs, should be considered when considering a procedure involving RFA10-12). The clinical and electrophysiological characteristics of subjects with WPW syndrome may vary according to age13-17). The aim of the present study was to evaluate the characteristics of EPS and RFA performed in subjects aged less than 30 years with WPW syndrome, especially pediatric patients under 18 years of age, based on our experience. Materials and methods Two-hundred and one patients with WPW syndrome aged from 6 to 75 who consecutively underwent EPS from January 2003 to May 2010 in Keimyung University Dongsna Medical Center and Kyungpook National University Hospital were recruited for this retrospective study.

Introduction Wolff-Parkinson-White (WPW) syndrome presents the risk of sudden cardiac death (SCD) from ventricular fibrillation related to atrial fibrillation (AF) or flutter in individuals whose accessory pathway (AP) shows a short anterograde refractory period1), although the frequency of SCD is low (0.3%)2-4). Radiofrequency ablation (RFA) of the AP has been shown to be both safe and effective in symptomatic and asymptomatic WPW patients, and provides a 'cure' in more than 95% of the patients5-9). Recent studies have described the active use of electrophysiologic studies (EPS) for the risk stratification of arrhythmia in asymptomatic WPW patients, and have emphasized that the electrophysiologic findings, such as, the locations and numbers of APs, should be considered when considering a procedure involving RFA10-12). The clinical and electrophysiological characteristics of subjects with WPW syndrome may vary according to age13-17). The aim of the present study was to evaluate the characteristics of EPS and RFA performed in subjects aged less than 30 years with WPW syndrome, especially pediatric patients under 18 years of age, based on our experience. Materials and methods Two-hundred and one patients with WPW syndrome aged from 6 to 75 who consecutively underwent EPS from January 2003 to May 2010 in Keimyung University Dongsna Medical Center and Kyungpook National University Hospital were recruited for this retrospective study. Among all patients, seventy-three patients (36%) were <30 years of age, and they were defined as young people. Patients were divided into three age groups group 1, 6 to 17 years, group 2, 18 to 29 years, and group 3, 30 to 60 years. EPS was indicated 1) when WPW patients had suspected or documented tachycardia or syncope, 2) when asymptomatic WPW patients had the need for further evaluation, 3) when asymptomatic WPW patients wanted EPS and RFA. The location of the AP was confirmed by EPS using standard electrophysiological mapping methods. AF or reentrant tachycardia was induced by rapid and continuous atrial (A) or ventricular (V) pacing, or extrastimulus technique. Effective refractory period (ERP) was defined as the longest coupling interval between the basic drive and the premature impulse that fails to propagate through AP. After the location of the AP was confirmed, RFA was tried 1) when AV reentrant tachycardia was induced, 2) when AF was induced, 3) when patient wanted RFA for abnormal electrocardiogram (ECG) findings. Successful RFA was considered if antegrade conduction through AP during A pacing or retrograde conduction during V pacing did not recur for at least 30 minutes after the RFA. The clinical, electrophysiological, and therapeutic data of these patients were reviewed from their medical records.

rocardiogram (ECG) findings. Successful RFA was considered if antegrade conduction through AP during A pacing or retrograde conduction during V pacing did not recur for at least 30 minutes after the RFA. The clinical, electrophysiological, and therapeutic data of these patients were reviewed from their medical records. 1. Statistical analysis Statistical analysis was performed using IBM SPSS ver. 18.0 (IBM, New York, NY, USA). The independent t-test and crosstabulation analysis (the chi-square test) were used to compare clinical and electrophysiological data. P values of <0.05 were considered statistically significant. Results 1. Clinical data The clinical and electrophysiological characteristics of patients are summarized in Table 1. Group 1 consisted of 16 boys and 15 girls, group 2 of 31 men and 11 women, and group 3 of 80 men and 48 women. Male preponderance was statistically significant in group 2 (male:female, 31:11), there was no gender preponderance in group 1 (male:female, 16:15).

Results 1. Clinical data The clinical and electrophysiological characteristics of patients are summarized in Table 1. Group 1 consisted of 16 boys and 15 girls, group 2 of 31 men and 11 women, and group 3 of 80 men and 48 women. Male preponderance was statistically significant in group 2 (male:female, 31:11), there was no gender preponderance in group 1 (male:female, 16:15). Patients in group 1 were admitted for supraventricular tachycardia in 28 cases and for unexplained syncope in 1 case. Two patients were totally asymptomatic but had an abnormal surface ECG result, which was found incidentally. Patients in group 2 were admitted for supraventricular tachycardia in 36 cases, for unexplained syncope in 3 cases, and for the evaluation of an abnormal ECG finding in 3 asymptomatic cases. Patients in group 3 were admitted for supraventricular tachycardia in 118 cases, for unexplained syncope in 1 case, and for the evaluation of an abnormal ECG finding in 9 asymptomatic cases. In group 1, two patients had congenital heart disease (Ebstein anomaly, EA) and 1 patient had dilated cardiomyopathy. The mean time for the follow-up was 13.8±16.5 months (range, 1 to 89 months) and 65% of the patients had follow-up duration below 12 months.

valuation of an abnormal ECG finding in 9 asymptomatic cases. In group 1, two patients had congenital heart disease (Ebstein anomaly, EA) and 1 patient had dilated cardiomyopathy. The mean time for the follow-up was 13.8±16.5 months (range, 1 to 89 months) and 65% of the patients had follow-up duration below 12 months. 2. Electrophysiological data In terms of surface ECG findings, AF was showed in 15 patients ≥30 years age and 6 patients <30 years age. Five patients in group 2 and 1 patient in group 1 showed AF by surface ECG. Regarding EPS findings, AF was induced in 9 patients ≥30 years age and 9 patients <30 years age. AF induction during EPS was more frequent in group 2 (8/42) than in group 1 (1/31) or in group 3 (9/128) (P=0.069, P=0.036, respectively). Failure to induce AV reentrant tachycardia by EPS occurred in 14% of the 201 study subjects (2 in group 1, 4 in group 2, and 23 in group 3). The failure rate was not significantly different between patients ≥30 years age (23/128) and <30 years age (6/73) (P=0.063), nor was it significantly different between groups (group 1 vs. group 2, P=1.000; group 2 vs. group 3, P=0.232; group 1 vs. group 3, P=0.168). Left AP was detected significantly more frequently in group 2 (24/42) and in group 3 (81/128) than in group 1 (10/31) (P=0.023, P=0.002, respectively). However, no significant difference was found between groups 2 and 3 (P=0.722).

Failure to induce AV reentrant tachycardia by EPS occurred in 14% of the 201 study subjects (2 in group 1, 4 in group 2, and 23 in group 3). The failure rate was not significantly different between patients ≥30 years age (23/128) and <30 years age (6/73) (P=0.063), nor was it significantly different between groups (group 1 vs. group 2, P=1.000; group 2 vs. group 3, P=0.232; group 1 vs. group 3, P=0.168). Left AP was detected significantly more frequently in group 2 (24/42) and in group 3 (81/128) than in group 1 (10/31) (P=0.023, P=0.002, respectively). However, no significant difference was found between groups 2 and 3 (P=0.722). Multiple AP was detected in 17 patients (4 in group 1, 2 in group 2, and 11 in group 3, P=0.464). The incidence of multiple AP was not significantly different between patients ≥30 years age (11/128) and <30 years age (6/73) (P=1.000), and was also not significantly different between groups (group 1 vs. group 2, P=0.391; group 2 vs. group 3, P=0.523; group 1 vs. group 3, P=0.495). An anteroseptal AP location, which is known to be associated with the risk of complete AV block 18,19) was detected in 11 patients (3 in group 1, 2 in group 2, and 6 in group 3). The incidence of anteroseptal AP was not significantly different between patients ≥30 years age (6/128) and <30 years age (5/73) (P=0.532), or between groups (group 1 vs. group 2, P=0.645; group 2 vs. group 3, P=1.000; group 1 vs. group 3, P=0.379).

etected in 11 patients (3 in group 1, 2 in group 2, and 6 in group 3). The incidence of anteroseptal AP was not significantly different between patients ≥30 years age (6/128) and <30 years age (5/73) (P=0.532), or between groups (group 1 vs. group 2, P=0.645; group 2 vs. group 3, P=1.000; group 1 vs. group 3, P=0.379). ERP of the AP was measured in 20 subjects (4 of the group 2, 16 of the group 3). ERP of the AP showed positive correlation with age, but it was not significant (P=0.093). After RFA of the AP, 13 of the study subjects showed recur of their WPW syndrome (3 in group 1, 3 in group 2, and 7 in group 3). Of the three recurred patients in group 1, 2 had right AP and 1 had left AP. The three recurred patients in group 2 had right AP, and of the seven recurred patients in group 3, 4 had right AP and 3 had left AP. Ablation failure was occurred in 10 patients (4 of group 1, 3 of group 2, 3 of group 3). The localizations of the APs associated with ablation failure in group 1 were anteroseptal in 2, posteroseptal AP in 1, and lateral in one, in group 2 were anteroseptal in 3, and in group 3 were right sided in 3. Discussion In this study, the characteristics of pediatric WPW syndrome are; 1) no gender preponderance and 2) less incidence of left sided AP than in any other age group.

Ablation failure was occurred in 10 patients (4 of group 1, 3 of group 2, 3 of group 3). The localizations of the APs associated with ablation failure in group 1 were anteroseptal in 2, posteroseptal AP in 1, and lateral in one, in group 2 were anteroseptal in 3, and in group 3 were right sided in 3. Discussion In this study, the characteristics of pediatric WPW syndrome are; 1) no gender preponderance and 2) less incidence of left sided AP than in any other age group. WPW is a developmental anomaly as well as a congenital anomaly20), and WPW syndrome in infancy often disappears and may recur in later childhood21,22). Epidemiological studies suggest that the prevalence of WPW syndrome is significantly lower in children aged 6 to 13 years (0.07%) than in those aged 14 to 15 years (0.17%)23). Previous studies have also reported gender preponderance for WPW syndrome according to age. One study reported that the male proportion of WPW syndrome was 43% in children aged 6 to 7 years, 50% in children aged 12 to 13 years, and 56% in those aged 14 to 15 years23). Although there are twice as many men as women in the adult WPW syndrome population, no male predominance was found in children23). Another study also reported that the male proportion among WPW syndrome patients was 47% in children aged 14 years or less, 60% in children aged 15 to 16 years, and 69% in those aged 17 years or more24).

are twice as many men as women in the adult WPW syndrome population, no male predominance was found in children23). Another study also reported that the male proportion among WPW syndrome patients was 47% in children aged 14 years or less, 60% in children aged 15 to 16 years, and 69% in those aged 17 years or more24). In previous studies, the AP ERP increased with age and nature of AP conduction changed13-17), and this is particularly well known in young children. In the present study, we did not evaluate the refractoriness of the AP in the majority of the patients, because the main purposes of EPS in WPW syndrome patients are the detection, localization, and ablation of APs. However, in 20 patients whose the AP ERP was checked, the AP ERP showed positive correlation with age although it was not statistically significant. In relation to the property of the AP ERP, the risk of AF increases with age25). Our study showed lower frequencies of AF by surface ECG and AF induced by EPS in pediatric patients, although these did not differ significantly from that observed in adults. About the more frequent AF induction during EPS in group 2 than in group 3, we think that it may be affected by artificial and aggressive pacing technique and it is questionable whether it is the characteristics for young adult with WPW syndrome.

although these did not differ significantly from that observed in adults. About the more frequent AF induction during EPS in group 2 than in group 3, we think that it may be affected by artificial and aggressive pacing technique and it is questionable whether it is the characteristics for young adult with WPW syndrome. In addition, the present study showed that the detection of left side AP was less frequent in children and adolescents with WPW syndrome. A previous study on elderly patients with WPW syndrome revealed that left lateral AP was more frequent and AF was induced more in older patients (>60 years of age)26). The present study also showed similar results, that is, left AP was more frequent in patients ≥18 years age (105/170) than <18 years age (10/31). The anteroseptal location of AP, which is associated with a risk of complete atrioventricular block, was not found to differ significantly with age. However, a previous study reported that an anteroseptal AP location is more frequent in children than in adults and that its incidence decreases after 40 years of age 18,19).

The anteroseptal location of AP, which is associated with a risk of complete atrioventricular block, was not found to differ significantly with age. However, a previous study reported that an anteroseptal AP location is more frequent in children than in adults and that its incidence decreases after 40 years of age 18,19). In the present study, 3 children and adolescents with WPW syndrome had combined heart disease, but adults had none. Of these three, 2 patients had EA with right side AP and 1 patient had dilated cardiomyopathy with right side AP. All underwent successful RFA. In a previous study, it was reported that patients with EA showed only right-sided APs, and it was suggested that this might be due to malformation of the right side heart in EA27). In this previous study, five of nine patients who underwent RFA of AP were completely symptomfree after the procedure. Regarding ablation failure cases, most cases in our study had right side APs. For right side AP, due to the structure of the right heart, it might be difficult to keep the tip of the ablation catheter on the annular portion during radiofrequency current application as firmly as during RFA of a left side AP. Therefore, RFA of right side AP requires more radiofrequency current application than left side AP and the process is more frequently interrupted. The limitations of the present study are a short term follow-up period and a lack of an EPS on AP. Furthermore, we need to perform longerterm follow-up on our patients and to study changes in the characteristics of AP by age.

Regarding ablation failure cases, most cases in our study had right side APs. For right side AP, due to the structure of the right heart, it might be difficult to keep the tip of the ablation catheter on the annular portion during radiofrequency current application as firmly as during RFA of a left side AP. Therefore, RFA of right side AP requires more radiofrequency current application than left side AP and the process is more frequently interrupted. The limitations of the present study are a short term follow-up period and a lack of an EPS on AP. Furthermore, we need to perform longerterm follow-up on our patients and to study changes in the characteristics of AP by age. In conclusion, the present study describes several different electrophysiological characteristics in children and adolescence with WPW syndrome. Therefore, when EPS and RFA are performed in children and adolescence with WPW syndrome, we recommend that these characteristics be considered. Table 1 Comparison of Clinical, Electrophysiological Study, and Ablation Data between the Groups Values are presented as number or median (range). AP, accessory pathway; AF, atrial fibrillation; ECG, electrocardiogram; EPS, electrophysiologic studies. *P <0.05 vs. group 1. †P <0.05 vs. group 2.

Introduction Congenital syphilis, caused by Treponema pallidum is still a public health issue worldwide, especially in developing countries1). Accordingly, it is important to be familiar with its symptoms, which can be subtle and nonspecific2). Recently, an increase in the incidence and prevalence of early congenital syphilis was observed in Korea as well as other Western countries despite prenatal serologic screening and treatment programs which are included in the routine antenatal examination1,3). Therefore, physicians should be aware of the diverse clinical features of syphilis to enable early diagnosis of the disease. We report here a case of congenital syphilis in a 3-month-old infant who had whole body skin eruption and no other specific symptoms, which led to a delay in diagnosis. His mother was tested for the disease during the prenatal period and the test was negative; however, she tested positive for syphilis later.

e disease. We report here a case of congenital syphilis in a 3-month-old infant who had whole body skin eruption and no other specific symptoms, which led to a delay in diagnosis. His mother was tested for the disease during the prenatal period and the test was negative; however, she tested positive for syphilis later. Case report A 3-month-old boy was admitted due to a 3-week history of an asymptomatic, widespread skin eruption. He was given the Diphtheria-Tetanus-acellular Pertussis (DTaP) vaccination 2 days prior to skin rash and his parents had taken him to several pediatric and dermatologic clinics, but could not identify his illness. He had been born to a 24-year-old, G1P1A0 mother who had adequate prenatal care at other clinics. She was tested for syphilis at 12 and 38 weeks of gestational age and was told that the tests were negative. The patient was delivered at 39+6 weeks of gestational age by normal spontaneous vaginal delivery and the birth weight was 3,270 g. Upon physical examination, his height was 61.5 cm (25 to 50th percentile), weight was 6.5 kg (25 to 50th percentile), and head circumference was 39.5 cm (10 to 25th percentile). He ate only a small amount of milk and his activity was decreased. His abdomen was soft and liver and spleen were not palpable. He had generalized erythematous, targetoid, scaly macules, papules, pustules (Fig. 1A) and desquamation at the hand and foot (Fig. 1B).

head circumference was 39.5 cm (10 to 25th percentile). He ate only a small amount of milk and his activity was decreased. His abdomen was soft and liver and spleen were not palpable. He had generalized erythematous, targetoid, scaly macules, papules, pustules (Fig. 1A) and desquamation at the hand and foot (Fig. 1B). Complete blood cell counts demonstrated normocytic normochromic anemia (hemoglobin 8.3 g/dL and hematocrit 27.8%) with leukocytosis (white blood cell [WBC] 20,000/mm3 with neutrophils 43%, lymphocytes 52%, monocytes 4%, eosinophils 1%) and thrombocytopenia (86,000/µL). His serum total protein was 4.9 g/dL with an albumin level of 2.7 g/dL. Result of liver function tests were normal with aspartate aminotransferase activity 47 IU/L, alanine aminotransferase activity 18 IU/L, and total bilirubin 0.4 mg/dL, with a direct bilirubin of 0.2 mg/dL. Serum iron levels were normal and the results of a Coombs' test were negative. Serologic tests for cytomegalovirus, Rubella, Herpes simplex virus and Toxoplasmosis were all negative.

sferase activity 47 IU/L, alanine aminotransferase activity 18 IU/L, and total bilirubin 0.4 mg/dL, with a direct bilirubin of 0.2 mg/dL. Serum iron levels were normal and the results of a Coombs' test were negative. Serologic tests for cytomegalovirus, Rubella, Herpes simplex virus and Toxoplasmosis were all negative. His blood venereal disease research laboratory (VDRL) test was positive in was positive in 1:32 dilutions and cerebrospinal fluid (CSF) VDRL analysis positive with 1:1 dilution. Laboratory studies of the CSF showed the following values: WBCs, 5/mm3; red blood cells, 40/mm3; protein, 26.3 mg/dL; glucose, 68 mg/dL, with a plasma glucose level of 156 mg/dL. As his non-treponemal test for syphilis was positive, treponemal test was done. His syphilis serology test showed a positive fluorescent-treponemal antibody-absorbed test immunoglobulin M as well as T. pallidum hemagglutination assay test. No organism was identified in any culture specimen, such as blood, urine or CSF. Although radiographic examination of the infant's long bones showed diaphyseal periostitis (Fig. 2), no abnormality was detected on brain magnetic resonance imaging. And hearing test was normal. After we diagnosed his illness as congenital syphilis, his parents were tested for syphilis and the mother's VDRL was found to be reactive with 1:4 dilutions and the father's VDRL was found to be reactive with a 1:1 dilution. Nevertheless this result, his mother had no specific symptoms. Based on these findings, the mother's VDRL results during prenatal care were erroneous.

is parents were tested for syphilis and the mother's VDRL was found to be reactive with 1:4 dilutions and the father's VDRL was found to be reactive with a 1:1 dilution. Nevertheless this result, his mother had no specific symptoms. Based on these findings, the mother's VDRL results during prenatal care were erroneous. We treated the patient with procaine penicillin G for 14 days. His skin eruption was resolved within several days. After 4 days of penicillin, results of serology test returned to normal with platelet count of 235,000/µL, WBC count of 13,670/mm3. During two weeks of hospitalization, the anemia slowly improved. Hemoglobin was increased to 10.0 g/dL with hematocrit 31.4%. Also, total protein was elevated slowly to 5.6 g/dL with albumin 4 g/dL. His parents were also treated with benzathine penicillin G. The patient was 5 month olds at the last visit and his physical examination was normal, including neurologic examination. In addition, the baby showed a reduction in seroreactivity from 1:32 to 1:8 dilutions.

as elevated slowly to 5.6 g/dL with albumin 4 g/dL. His parents were also treated with benzathine penicillin G. The patient was 5 month olds at the last visit and his physical examination was normal, including neurologic examination. In addition, the baby showed a reduction in seroreactivity from 1:32 to 1:8 dilutions. Discussion This 3-month-old infant presented only with skin eruption, which led to difficulty in diagnosis. Several physicians could not establish what his illness was, and his symptoms were misinterpreted as adverse reactions caused by DTaP vaccination. In addition, the maternal self report that she was VDRL-negative caused a further delay in diagnosis of the patient. Diagnosis of early congenital syphilis is difficult because more than half of the infants are asymptomatic, and signs in symptomatic infants may be subtle and nonspecific4). We found a report of an infant with a skin rash whose mother had adequate prenatal care, similar to our patient2). If diagnosis is missed, death may result, despite the fact that syphilis is a very easy and inexpensive disease to treat5).

e asymptomatic, and signs in symptomatic infants may be subtle and nonspecific4). We found a report of an infant with a skin rash whose mother had adequate prenatal care, similar to our patient2). If diagnosis is missed, death may result, despite the fact that syphilis is a very easy and inexpensive disease to treat5). Congenital syphilis occurs when T. pallidum crosses the placenta from the mother to the fetus during pregnancy or by contact with an infectious lesion during birth6). Manifestations of congenital syphilis are divided into early and late signs based on the first 2 years of life. Mucocutaneous involvement is present in as many as 70 percent of infants and may be apparent at birth or develop during the first few weeks of life6). Cutaneous findings of early congenital syphilis is classically a vesiculobullous or maculopapular rash on the palms and soles and may be associated with desquamation7). Other types of rashes such as erythema multiforme have also been reported7,8). In addition, symptoms of early congenital syphilis include fever, failure to thrive, hepatosplenomegaly, lymphadenopathy, osteochondritis, pneumonitis, and rhinitis6). Leukocytosis, Coombs-negative hemolytic anemia, thrombocytopenia, hypoproteinemia, hypoalbuminemia, hyperbilirubinemia, and elevated liver enzyme levels may be present6,9). Because these laboratory findings are difficult to identify upon physical examination, a high index of suspicion is necessary to make the right diagnosis early. Although acral dermatitis, vitamin or nutrient deficiency, and hand eczema might mimic this disorder, skin rash of early congenital syphilis is relatively recalcitrant to classical eczema treatment, which might be differential diagnostic point10,11). Characteristic mucocutaneous rash, presenting with erythematous maculopapular or bullous lesions, followed by desquamation involving hands and feet, are common in congenital syphilis12).

rly congenital syphilis is relatively recalcitrant to classical eczema treatment, which might be differential diagnostic point10,11). Characteristic mucocutaneous rash, presenting with erythematous maculopapular or bullous lesions, followed by desquamation involving hands and feet, are common in congenital syphilis12). For definitive diagnosis, the Centers for Disease Control (CDC) recommends identification of syphilis in the mother; lack of evidence of adequate maternal treatment; presence of clinical, laboratory or radiological evidence of syphilis in the infant; and comparison of maternal and infant non-treponemal serologic titers using the same test and preferably the same laboratory, as was conducted in this case13). In addition, The CDC recommends serologic VDRL testing of pregnant women during the first prenatal visit and additional serologic testing and evaluation of sexual history at 28 weeks of gestation and soon after delivery in communities in which there is a high risk of congenital syphilis13). Congenital syphilis is a preventable and treatable disease if physicians are aware of its diverse clinical symptoms. Therefore, clinical suspicion and formal confirmation of antenatal screening results as well as a detailed maternal history provide important clues for the diagnosis of congenital syphilis. Fig. 1 Generalized erythematous, targetoid, scaly macules, papules, and pustules (A), and desquamation of the patient's hand (B). Fig. 2 Radiographic examination of the long bones demonstrated diaphyseal periostitis, indicating syphilitic changes.

Introduction The importance of the hypoglossal nerve, or cranial nerve XII, is often devalued; many times its description is reduced to a few words under "the last four cranial nerves," because damage to the 12th nerve rarely causes much inconvenience. Indeed, this nerve is considered a convenient "spare", suitable for transplantation surgery to reanimate a paralyzed face1). The motor composition of cranial nerve XII is highly complex and incompletely understood, and the nucleus consists of 4 topographically distinct subnuclear columns. Hypoglossal nerve palsy (HNP) is an uncommon neurological abnormality. Damage to this nerve produces characteristic clinical manifestations, including unilateral atrophy of the tongue musculature. The causes of HNP include known tumors (49%), trauma (12%), stroke (6%), hysteria (6%), surgery (5%), multiple sclerosis (5%), infection (4%), Guillain-Barre neuropathy (4%) and idiopathic (3%)2). This report describes a pediatric case of idiopathic isolated HNP with Solumedrol treatment for 12 days with complete recovery after 15 days. Case report A 11-year-old Korean male was admitted to the outpatient department with sudden onset dysarthria, tongue fasciculations, and right-sided tongue weakness upon awakening (Fig. 1A).

Introduction The importance of the hypoglossal nerve, or cranial nerve XII, is often devalued; many times its description is reduced to a few words under "the last four cranial nerves," because damage to the 12th nerve rarely causes much inconvenience. Indeed, this nerve is considered a convenient "spare", suitable for transplantation surgery to reanimate a paralyzed face1). The motor composition of cranial nerve XII is highly complex and incompletely understood, and the nucleus consists of 4 topographically distinct subnuclear columns. Hypoglossal nerve palsy (HNP) is an uncommon neurological abnormality. Damage to this nerve produces characteristic clinical manifestations, including unilateral atrophy of the tongue musculature. The causes of HNP include known tumors (49%), trauma (12%), stroke (6%), hysteria (6%), surgery (5%), multiple sclerosis (5%), infection (4%), Guillain-Barre neuropathy (4%) and idiopathic (3%)2). This report describes a pediatric case of idiopathic isolated HNP with Solumedrol treatment for 12 days with complete recovery after 15 days. Case report A 11-year-old Korean male was admitted to the outpatient department with sudden onset dysarthria, tongue fasciculations, and right-sided tongue weakness upon awakening (Fig. 1A). His medical history included a normal spontaneous vaginal delivery at 39 weeks with a birth weight of 3,200 g. He had normal developmental milestones, his medical history was unremarkable, and his family history was non-specific. His vaccination history was complete. He had no recent history of upper respiratory track infection and had no snoring at night. There was no history of surgery or trauma.

th a birth weight of 3,200 g. He had normal developmental milestones, his medical history was unremarkable, and his family history was non-specific. His vaccination history was complete. He had no recent history of upper respiratory track infection and had no snoring at night. There was no history of surgery or trauma. Upon initial physical examination, his body temperature was 36.2℃, heart rate 72 beats/min and blood pressure 120/70 mm Hg. The neurological examination revealed right-sided deviation of his tongue upon protrusion, but cranial nerve function, cerebellar function and upper motor neuron function were non-specific; otherwise, physical exam findings were non-specific. A laboratory investigation, neck computed tomography (CT), brain magnetic resonance imaging (MRI) and otorhinolaryngology consultation were done. Laboratory evaluations revealed: hemoglobin 13.1 g/dL, hematocrit 37.5%, white blood cell 9,300/mm3, platelets 382,000/mm3, peripheral blood smear non-specific, sodium 139.1 mmol/L, potassium 3.9 mmol/L, GOT/GPT 27/23 IU/L and blood urea nitrogen/creatinine 10.1/0.6. Epstein-Bare virus (EBV) viral capsid antigen (VCA) immunoglobulin (Ig) M negative, Epstein-Barr virus nuclear antigen positive, EBV VCA IgG positive, Cytomegalovirus (CMV) IgM negative, CMV IgG negative. Neck MRI (Fig. 2) and brain MRI (Fig. 3) findings were normal. The otorhinolaryngology consultation disclosed non-specific anatomical problems and no evidence of inflammation.

Upon initial physical examination, his body temperature was 36.2℃, heart rate 72 beats/min and blood pressure 120/70 mm Hg. The neurological examination revealed right-sided deviation of his tongue upon protrusion, but cranial nerve function, cerebellar function and upper motor neuron function were non-specific; otherwise, physical exam findings were non-specific. A laboratory investigation, neck computed tomography (CT), brain magnetic resonance imaging (MRI) and otorhinolaryngology consultation were done. Laboratory evaluations revealed: hemoglobin 13.1 g/dL, hematocrit 37.5%, white blood cell 9,300/mm3, platelets 382,000/mm3, peripheral blood smear non-specific, sodium 139.1 mmol/L, potassium 3.9 mmol/L, GOT/GPT 27/23 IU/L and blood urea nitrogen/creatinine 10.1/0.6. Epstein-Bare virus (EBV) viral capsid antigen (VCA) immunoglobulin (Ig) M negative, Epstein-Barr virus nuclear antigen positive, EBV VCA IgG positive, Cytomegalovirus (CMV) IgM negative, CMV IgG negative. Neck MRI (Fig. 2) and brain MRI (Fig. 3) findings were normal. The otorhinolaryngology consultation disclosed non-specific anatomical problems and no evidence of inflammation. The working diagnosis was that of idiopathic isolated HNP. The patient was treated with Solumedrol (60 mg/day #3) for 12 days. Fifteen days after symptom onset, the patient completely recovered (Fig. 1B).

Neck MRI (Fig. 2) and brain MRI (Fig. 3) findings were normal. The otorhinolaryngology consultation disclosed non-specific anatomical problems and no evidence of inflammation. The working diagnosis was that of idiopathic isolated HNP. The patient was treated with Solumedrol (60 mg/day #3) for 12 days. Fifteen days after symptom onset, the patient completely recovered (Fig. 1B). Discussion The hypoglossal nerve is underrated, relegated to a few words under "the last 4 cranial nerves" in most neurology texts. Damage to the 12th nerve rarely causes much inconvenience; indeed, this nerve is often used in transplantation surgery to reanimate a paralyzed face. In addition to having complex afferent input within the brain stem and rich anastamoses in the neck, the hypoglossal nerve probably carries small proprioceptive and sympathetic contributions. Its motor composition is highly complex and incompletely understood, and the nucleus consists of 4 topographically distinct subnuclear columns1).

ving complex afferent input within the brain stem and rich anastamoses in the neck, the hypoglossal nerve probably carries small proprioceptive and sympathetic contributions. Its motor composition is highly complex and incompletely understood, and the nucleus consists of 4 topographically distinct subnuclear columns1). Keane2) published a review of 26 years of personal experience with cases of HNP in a large public hospital. He reported on 100 patients ranging in ages from 8 to 73 years; 51 cases were men and 49 cases were women. Thirty-one patients had right side HNP, 36 had left side, and 33 had HNP on both sides. He also reported that HNP usually appears as signs rather than symptoms. Tumors, predominantly malignant, produced nearly half of the palsies (49 cases). Trauma due to gunshots (12 cases) was the second most common cause. Stroke (6 cases), hysteria (6 cases), multiple sclerosis (6 cases), surgery (5 cases), Guillain-Barre neuropathy (4 cases), infection (4 cases), and idiopathic (3 cases) together accounted for about one third of the patients. Boban et al.3) reported on 4 patients with isolated HNP due to different etiologies. The different etiologies were pseudoaneurysm of the right internal carotid artery, 2 aneurysms on the right and left middle cerebral artery, postinfectious acute disseminated encephalomyelitis, and metastatic tumor on the right ventrolateral surface of the medulla oblongata.

th isolated HNP due to different etiologies. The different etiologies were pseudoaneurysm of the right internal carotid artery, 2 aneurysms on the right and left middle cerebral artery, postinfectious acute disseminated encephalomyelitis, and metastatic tumor on the right ventrolateral surface of the medulla oblongata. Combarros et al.4) reported 9 cases of isolated unilateral HNP. In 4 cases, no cause was found, and all the patients had an excellent outcome. In 3 cases, metastatic disease prompted the unilateral HNP. In the other 2 cases, the causes of isolated unilateral HNP were Chiari malformation and dural arteriovenous fistula of the transverse sinus. Tommasi-Davenas et al.5) reported 32 cases of HNP. Seventeen cases were related to predominant malignant tumors. Six cases were of vascular origin, 4 cases were due to head or neck trauma, 4 cases were from various inflammatory processes, and 1 case was caused by Chiari's malformation. Other case reports of HNP have revealed the causes to be multiple myeloma6), adenoid cystic carcinoma7), pyogenic meningitis8), a late complication of radiation therapy of head and neck carcinoma9), infectious mononucleosis10-11), a complication of post streptococcal infection12), possibly linked to influenza vaccination13), and multiple sclerosis14).

vealed the causes to be multiple myeloma6), adenoid cystic carcinoma7), pyogenic meningitis8), a late complication of radiation therapy of head and neck carcinoma9), infectious mononucleosis10-11), a complication of post streptococcal infection12), possibly linked to influenza vaccination13), and multiple sclerosis14). Giuffrida et al.15) reported 3 patients with isolated unilateral HNP who experienced an excellent outcome. In 2 cases, the patients had idiopathic HNP, and 1 patient was found to have right-sided occipital trauma. Giuffrida et al.15) believed that the occurrence of benign and idiopathic isolated unilateral HNP is more frequent than previously reported and proposed that no therapy is required in patients with HNP that is likely viral in origin. In the diagnosis of benign HNP, neuroimaging studies (X-ray, CT scan, MR, MR angiography) remain mandatory in order to exclude tumoral, spontaneous, traumatic, or vascular causes in view of the possibility of a specific or early anticoagulant treatment. Our case represents idiopathic isolated HNP in a patient who completely recovered within 15 days. However, isolated HNP in children is often an ominous sign of underlying malignancy. Details regarding the patient's trauma and vaccination history were necessary. An MRI scan of the brain, brain stem and skull base is mandatory, and viral serology, particularly for EBV, were useful supplementary investigations. Fig. 1 (A) The patient's tongue showed right deviation at first visit. (B) Fifteen days after the first visit, the patient's tongue showed complete recovery.

Our case represents idiopathic isolated HNP in a patient who completely recovered within 15 days. However, isolated HNP in children is often an ominous sign of underlying malignancy. Details regarding the patient's trauma and vaccination history were necessary. An MRI scan of the brain, brain stem and skull base is mandatory, and viral serology, particularly for EBV, were useful supplementary investigations. Fig. 1 (A) The patient's tongue showed right deviation at first visit. (B) Fifteen days after the first visit, the patient's tongue showed complete recovery. Fig. 2 Neck magnetic resonance image of coronal T2W1 showed normal features. Fig. 3 Brain magnetic resonance image of sagittal T1W1 showed normal features.

Introduction There is no consensus on which specific anthropometric criteria should be used to define failure to thrive (FTT)1-4). In routine clinical practice, the three weight criteria that can be used to described FTT are a child younger than 2 years whose weight is below the 3rd or 5th percentile for age on more than one occasion, a child younger than 2 years whose weight is less than 80% of the ideal weight for age, and a child younger than 2 years whose weight crosses two major percentiles downward in a standardized growth grid using the 90th, 75th, 50th, 25th, 10th, and 5th percentiles as the major percentiles5). A combination of anthropometric criteria, rather than one criterion, should be used to more accurately identify children at risk of FTT. Weight for length is a better indicator of acute under-nutrition and is helpful in identifying children who need prompt nutritional treatment6). This is an index of fat stores that defines whether a patient suffers from acute malnutrition. Any weight change below the 5th percentile may indicate a child is at risk of FTT7). Finally, some children who falter in growth parameters actually demonstrate a normal variant of growth, such as children of small parents who are growing to their full genetic potential, large for gestational age infants who regress toward the mean, children with constitutional delay in growth, or premature infants whose growth parameters are normal when corrected for gestational age8). When uncertain, a weight for age that falls below the 5th percentile or a weight deceleration that crosses two major percentile lines should prompt the use of additional growth indices, such as weight for length or weight velocities, to confirm the growth trend.

rameters are normal when corrected for gestational age8). When uncertain, a weight for age that falls below the 5th percentile or a weight deceleration that crosses two major percentile lines should prompt the use of additional growth indices, such as weight for length or weight velocities, to confirm the growth trend. Prevalence Most of the time, insufficient growth is detected in a routine visit to the pediatrician or the family practitioner. Many parents do not seem to notice the situation until it is brought to their attention. In most instances, FTT is insidious and gradual. It can be missed by a carefully maintained growth chart. Estimates of the incidence of FTT vary widely depending on the terminology and the population studied: Growth deficiency affects 10% of the rural outpatient population. The same percentage applies to high risk groups such as the homeless9). FTT accounts for 1 to 5% of pediatric hospital admission for children younger than 2 years in the United State. National and state surveys indicate that as many as 10% of the children seen in primary care practice have signs suggesting inadequate growth5). In inner city emergency department, approximately 15 to 30% of young children who receive acute care services show signs of growth deficits5). Up to 15 to 20% of hospitalized children younger than 2 years from a medically indigent population met the criteria of FTT5).

FTT accounts for 1 to 5% of pediatric hospital admission for children younger than 2 years in the United State. National and state surveys indicate that as many as 10% of the children seen in primary care practice have signs suggesting inadequate growth5). In inner city emergency department, approximately 15 to 30% of young children who receive acute care services show signs of growth deficits5). Up to 15 to 20% of hospitalized children younger than 2 years from a medically indigent population met the criteria of FTT5). Etiology Failure to thrive may result from a variety of "organic" and "nonorganic" causes for a combination of both. In evaluation of a child with FTT, the diagnostic efforts should be directed toward determining whether the child has one or a combination of the following factors contributing to the etiology: inadequate caloric intake, inadequate caloric absorption, or excessive caloric expenditure8,10). There is increasing recognition that in many children the cause is multi-factorial and includes biologic, psychosocial and environmental contributors11). Furthermore, in more than 80 percent of cases, a clear underlying medical condition is never identified. Table 1 provides a differential diagnosis of FTT. In adequate caloric intake is the most common etiology seen in primary care settings. In infants younger than eight weeks, problems with feeding (e.g., poor sucking and swallowing) and breast feeding difficulties are prominent12). After then, transitioning to solid foods, insufficient breast milk or formula consumption, excessive juice consumption, and parental avoidance of high-calorie foods often lead to FTT13).

younger than eight weeks, problems with feeding (e.g., poor sucking and swallowing) and breast feeding difficulties are prominent12). After then, transitioning to solid foods, insufficient breast milk or formula consumption, excessive juice consumption, and parental avoidance of high-calorie foods often lead to FTT13). Family factors can contribute to inadequate caloric intake at any age. These include mental health disorders, inadequate nutritional knowledge, and financial difficulties. Poverty is the greatest single risk factor for FTT in developed and developing countries. Importantly, child neglect of abuse must be considered, because children with FTT are four times more likely to be abused than children without FTT14). Inadequate caloric absorption includes disorders causing frequent emesis (e.g., metabolic disorders, food insensitivities) or malabsorption (e.g., chronic diarrhea, protein losing enteropathy). Excessive caloric expenditure usually occurs in the setting of a chronic condition, such as congenital heart disease, chronic pulmonary disease, or hyperthyroidism. In these instances, FTT often develops during the first eight weeks of life.

vities) or malabsorption (e.g., chronic diarrhea, protein losing enteropathy). Excessive caloric expenditure usually occurs in the setting of a chronic condition, such as congenital heart disease, chronic pulmonary disease, or hyperthyroidism. In these instances, FTT often develops during the first eight weeks of life. Clinical approach to failure to thrive The parents often do not recognize the subtle slowing of growth in their child in close day to day living. The family and the child's caregiver should be carefully evaluated with a thorough review of family history. Thus, history taking is the most important investigative technique in the evaluation of FTT. The differential diagnosis is vast, but in most cases, there are sufficient symptoms and signs that lead to a specific diagnosis. The following data should be included in the history6). Feeding: breast feeding or formula feeding, formula preparation, volume consumed, who feeds the infants, position and placement of the infant for feeding, timing and introduction of solids, stool or vomiting patterns associated with feeding, strength of suck. Accurate measurement of caloric intake of infants and children should be done by proper diet history. Developmental history: gestational and perinatal history (age and parity of mother, medical complication of pregnancy, use of medications, use of drugs, use of alcohol, substance abuse, smoking, complications during delivery), developmental milestones, temperament.

Feeding: breast feeding or formula feeding, formula preparation, volume consumed, who feeds the infants, position and placement of the infant for feeding, timing and introduction of solids, stool or vomiting patterns associated with feeding, strength of suck. Accurate measurement of caloric intake of infants and children should be done by proper diet history. Developmental history: gestational and perinatal history (age and parity of mother, medical complication of pregnancy, use of medications, use of drugs, use of alcohol, substance abuse, smoking, complications during delivery), developmental milestones, temperament. There may be specific behavior characteristics of the child that play an important role. These characteristics include disrupted sleeping and eating patterns and behavior that is moody, demanding, rejecting, or distractible. Some authors have suggested that a subset of infants may refuse to eat in an attempt to achieve some degree of autonomy and control over their mothers and have termed this infantile anorexia nervosa. Psychosocial history: family composition, employment and financial status, stress, potential isolation, child rearing beliefs, history of maternal depression, the caretaker's history of childhood neglect or abuse. Family history: heights, weights, illness, development that may indicate constitutional short stature, inherited disease, developmental delay.

ountries; however, these are not currently available in Korea. In these situations, early introduction of complementary foods may be an option to supplement nutrient deficits. Multidisciplinary approaches with dieticians, nurses, and pharmacists may be a good solution to support patients with specific chronic problems. 2. Excessive nutrients 1) Carbohydrates and energy In Korea, the prevalence of excessive energy intake in the general population is 13.9% (±0.3 SE)11). According to an AAP position paper published in 2009, fruit juice for infants should be limited to less than 180 mL (6 oz) per day. In the epidemic of obesity, carbohydrate excess including fruit juice over-consumption should be controlled to reduce discretionary calories. In addition, fruit juices are also a major cause of dental caries, functional gastrointestinal disorders, and chronic diarrhea. In a National Health Screening Program for Infants in Korea, fruit juices and beverages were also considered restricted foods for infants23).

Psychosocial history: family composition, employment and financial status, stress, potential isolation, child rearing beliefs, history of maternal depression, the caretaker's history of childhood neglect or abuse. Family history: heights, weights, illness, development that may indicate constitutional short stature, inherited disease, developmental delay. It is important to observe the infant and caretaker while feeding and playing. This provides clues about their interactions, the caretaker's feeding technique, or inappropriate response to the infant's physiologic or social cues. The infant may avoid eye contact or withdraw from physical attention or may show poor suck or swallow or aversion to oral stimulation. Physical examination A complete and carefully physical examination is essential. Plot the patient's weight, recumbent length in infants younger than 2 years, and the head circumference on a standard growth curve specific for gender. This information helps to narrow the etiology of FTT. Head circumference, weight and height are proportionately reduced in infants and children who have hereditary and congenital defects. Head circumference is normal and weight is slightly reduced proportionate to height in children with constitutional growth delay, genetic dwarfism or endocrinologic disorders. Head circumference is normal and weight is reduced out of proportion to height in most infants with FTT, especially if malnutrition results from inadequate caloric intake, malabsorption, or altered metabolism.

Head circumference is normal and weight is slightly reduced proportionate to height in children with constitutional growth delay, genetic dwarfism or endocrinologic disorders. Head circumference is normal and weight is reduced out of proportion to height in most infants with FTT, especially if malnutrition results from inadequate caloric intake, malabsorption, or altered metabolism. Other decisions the physician must make after examination is whether to admit the child to the hospital. Such decisions may be influenced if abuse or neglect is suspected; if the caretaker is psychosocially impaired; or if serious malnutrition (60% below ideal body weight)15), traumatic injury, hypothermia, low pulse rate, or low blood pressure is present. Physicians should also seek red flag signs or symptoms of medical conditions that might be causing FTT13) (Table 2). Further examination beyond growth parameters should include a thorough general examination including inspection for any physical signs of neglect or abuse, dysmorphic features, skin rashes, examination of the mouth for the presence of a cleft palate and quality of sucking movements. The chest reveals signs of chronic respiratory or cardiac disease. The abdomen may be distended due to malabsorption, or there may be organomegaly. Observe the child's general appearance and look for body fat and muscle wasting. Examination of skin, hair, and mails is in valuable.

late and quality of sucking movements. The chest reveals signs of chronic respiratory or cardiac disease. The abdomen may be distended due to malabsorption, or there may be organomegaly. Observe the child's general appearance and look for body fat and muscle wasting. Examination of skin, hair, and mails is in valuable. Investigations Investigation should be guided by the history and examination. Infants who are either unwell or have significant positive physical findings will require immediate investigation and consideration of pediatric referral, while those who are generally well with no positive findings may no immediate investigations16). In those requiring investigation, full blood examination, erythrocyte sedimentation rate, electrolytes including urea, creatinine, calcium and magnesium, and urine for culture and urinalysis are helpfully as an initial group of screening tests. If there are specific concerns raised in the history, other investigation may be indicated. In children where significant doubt persists and tests have been unhelpful, pediatric review and sometimes a period of hospitalization for a trial of observed feeding and further investigation may be helpful17). Management FTT has serious implications, especially for brain development. If malnutrition becomes severe and chronic during the first year of life, the child's neurologic development may be permanently affected, making early recognition and prompt intervention critical.

Investigations Investigation should be guided by the history and examination. Infants who are either unwell or have significant positive physical findings will require immediate investigation and consideration of pediatric referral, while those who are generally well with no positive findings may no immediate investigations16). In those requiring investigation, full blood examination, erythrocyte sedimentation rate, electrolytes including urea, creatinine, calcium and magnesium, and urine for culture and urinalysis are helpfully as an initial group of screening tests. If there are specific concerns raised in the history, other investigation may be indicated. In children where significant doubt persists and tests have been unhelpful, pediatric review and sometimes a period of hospitalization for a trial of observed feeding and further investigation may be helpful17). Management FTT has serious implications, especially for brain development. If malnutrition becomes severe and chronic during the first year of life, the child's neurologic development may be permanently affected, making early recognition and prompt intervention critical. A multidisciplinary team approach is essential for management, with the involvement of a pediatric gastroenterologist, a nutritionist, a social worker, an occupational therapist, a speech and physical therapist, a psychologist and behavioral and developmental specialists18). The goals of management of FTT are following: Provision of adequate calories, protein, and other nutrients Nutritional counseling to the family Monitoring of growth and nutritional status

A multidisciplinary team approach is essential for management, with the involvement of a pediatric gastroenterologist, a nutritionist, a social worker, an occupational therapist, a speech and physical therapist, a psychologist and behavioral and developmental specialists18). The goals of management of FTT are following: Provision of adequate calories, protein, and other nutrients Nutritional counseling to the family Monitoring of growth and nutritional status Specific treatment of complications or deficiencies Long term monitoring and follow up Education of the family on social land nurturing techniques Supportive economic assistance Whenever possible, the underlying cause of FTT should be addressed and treated. However, caloric supplementation is the major contributor to the management of FTT. Nutritional requirements can be assessed with the use of a formula for calories and protein19). Catch -up growth requirement (kcal/kg/d) = [calories required for age (kcal/kg/d) × ideal weight for age (kg)]/[actual weight (kg)] If a diagnosis of FTT is made and no medical conditions are suggested on examination, appropriate guidance for catch-up growth should be made. Age appropriate nutritional counseling should be provided to parents16,17,20,21). For parents of breastfed infants, recommending breastfeeding more often, ensuring lactation support, or discussing formula supplementation until catch up growth is achieved may helpful17). Parents of formula fed infants may be instructed on how to make energy dense formula by concentrating the ratio of formula to water during periods of catch up growth20,21).

nding breastfeeding more often, ensuring lactation support, or discussing formula supplementation until catch up growth is achieved may helpful17). Parents of formula fed infants may be instructed on how to make energy dense formula by concentrating the ratio of formula to water during periods of catch up growth20,21). The child's diet must be fortified for caloric density by using concentrated formula or by adding glucose polymers or extra lipids. Toddlers should be offered solid food before liquids and avoid excessive juice or milk consumption because this can interfere with proper nutrition22). Nutritional supplements may be given until catch up growth is achieved. During period of catch up growth, parents may also be instructed to provide calorie dense foods such as peanut butter, cheese, dried fruits, and cream sauces for older children or adolescents. A supplement with a multivitamin with additional specific nutrients is recommended. The rule of 3's is quite helpful - 3 meals, 3 snacks, and 3 choices23). If a disease or medical condition is identified on history, physical examination, or additional testing, the correct approach will vary depending on the condition. Appropriate management may include instituting specific treatment of the condition, or seeking consultation from a subspecialist or other health care professional for further evaluation and management recommendations. Enteral tube feedings or gastrostomy should be considered for patients in whom oral enteral feeding dose not achieve adequate caloric intake.

ituting specific treatment of the condition, or seeking consultation from a subspecialist or other health care professional for further evaluation and management recommendations. Enteral tube feedings or gastrostomy should be considered for patients in whom oral enteral feeding dose not achieve adequate caloric intake. Refeeding should proceed cautiously, because significantly undernourished children may develop diarrhea, vomiting, and circulatory decompensation24). Close follow up should be performed in the physician's office, including evaluation of height and weight. Multi-disciplinary interventions should be considered to improve weight gain, parent child relationships, and cognitive development. The catch-up height will lag several months behind the catch-up weight. Thus the nutritional intervention should be until appropriate height for age is reached. Finally, although medications such as megestrol (Megace) or cyproheptadine have been shown to help promote weight gain in children with cancer related cachexia, they have not been studied in other causes of FTT25). Growth hormone therapy also has not been widely studied in children and adolescents who are not growth hormone deficient and is not recommended for management of FTT26).

oheptadine have been shown to help promote weight gain in children with cancer related cachexia, they have not been studied in other causes of FTT25). Growth hormone therapy also has not been widely studied in children and adolescents who are not growth hormone deficient and is not recommended for management of FTT26). Prognosis There is consensus that severe, prolonged malnutrition, which is common in developing countries, can negatively affect a child's future growth and cognitive development27). A history of FTT was associated with short stature, poor math performance, and poor work habits. A systemic review showed that FTT during the first two years of life was not associated with a significant reduction in intelligence quotient, although some long term reductions in weight and height were present28). The possibility of long term cognitive and behavioral sequelae is present. Lastly, child with a history of FTT are at increased risk of recurrent FTT, and their growth should be monitored closely. Table 1 Pathological Causes of Failure to Thrive Table 2 Red Flag Signs and Symptoms Suggesting Medical Causes of Failure to Thrive

ld be controlled to reduce discretionary calories. In addition, fruit juices are also a major cause of dental caries, functional gastrointestinal disorders, and chronic diarrhea. In a National Health Screening Program for Infants in Korea, fruit juices and beverages were also considered restricted foods for infants23). 2) Obesity The global obesity epidemic is an ongoing problem. Several lines of evidence have shown that BMF itself is the best way to prevent obesity. Although there are few large-scale studies, BMF can reduce or prevent obesity in infants8). Before 6 months of age, normal weight gain in breastfed infants is usually considerably greater than in cow's milk-fed infants; thereafter, the breastfed group shows "faltering" even up to 12 to 15 months24). Nowadays, this phenomenon is accepted as normal to some extent according to extensive research studies by several groups, including WHO. However, recent research has shown that it is important to differentiate groups that require intervention25). Body Mass Index (BMI) or weight for height screening was not considered helpful in infants less than 2 years of age. However, recently, WHO has published new BMI charts for children less than 2 years of age for early intervention to prevent obesity26).

Introduction The importance of breast milk feeding (BMF) has been emphasized by many academic bodies and health authorities in the world, including WHO and UNICEF1,2). For many years the Korean Pediatric Society has also been a strong advocate of the need to increase BMF in Korea3,4). The superior benefits of BMF compared to those of alternative nutritional sources for infants are well known, and include more optimal infantile neurobehavioral development, reduced tendency to catch infectious diseases, reduced tendency toward obesity, and fewer allergenic properties. Therefore, there is little need for similar additional comments in this review5-8). However, there is still much debate about the details of BMF in specific regions such as North and South Korea, particularly how long exclusive BMF should be maintained, and what type of dietary supplements could be helpful to BMF infants. Recently in Korea, we have encountered re-emerging nutritional problems in the era of increased BMF rates, such as iron deficiency anemia (IDA) and vitamin D deficiency rickets; thus, questions of how we can detect and manage nutritional deficiencies related to BMF should be addressed9). In this article, an overview of BMF status in Korea will be briefly summarized, and the practical aspects of nutritional management in BMF infants, focusing on recently emerging nutritional issues, will be discussed.

uestions of how we can detect and manage nutritional deficiencies related to BMF should be addressed9). In this article, an overview of BMF status in Korea will be briefly summarized, and the practical aspects of nutritional management in BMF infants, focusing on recently emerging nutritional issues, will be discussed. Current epidemiology of breast milk feeding in Korea Breastfeeding rates in Korea have changed dramatically in recent decades, concomitant with socioeconomic advances (Fig. 1)3,10-12). Before 1970, BMF rates were very high, because there were few alternatives to breast milk. Then, many dairy products were introduced with commercial marketing, and cow's milk-based formulae became more and more popular in Korea. Eventually, BMF rates fell to approximately 10% in the early 1990s. Since the late 1990s, UNICEF, along with many Korean pediatricians, developed community-based movements to enhance BMF in Korea, and several programs, such as the "Baby-friendly hospital initiative," were launched with governmental support. A recent epidemiologic survey in 2009 showed that the overall BMF rate in Korea was 89.0% (±1.2 SE) and the exclusive BMF rate at 6 months of age was 49.3% (±2.0 SE)11).

sed movements to enhance BMF in Korea, and several programs, such as the "Baby-friendly hospital initiative," were launched with governmental support. A recent epidemiologic survey in 2009 showed that the overall BMF rate in Korea was 89.0% (±1.2 SE) and the exclusive BMF rate at 6 months of age was 49.3% (±2.0 SE)11). Common clinical problems associated with increased breastfeeding rates 1. Nutrient Deficiencies 1) Iron: iron deficiency anemia IDA can be a relatively common problem encountered by clinicians in exclusively breastfed infants. Most infantile cases with mild IDA can easily recover to normal hemoglobin levels if appropriate complementary feeding is initiated, even with continued BMF13). However, many experts are concerned about IDA and iron deficiency without clinical symptoms, which may lead to detrimental neurodevelopment14-16). In order to avoid the possibility of IDA or iron deficiency, the American Academy of Pediatrics (AAP) recommends a prophylactic dose of oral iron (1 mg/kg/day) for infants who are exclusively breastfed after 4 months of age17). However, this guideline has been questioned by the Section on Breastfeeding in the AAP, due to concerns about unnecessary iron therapy and weak evidence13). In Korea, there is no consensus on the prophylactic use of iron supplements; however, many reports on IDA rates in breastfed infants have been published recently9,18).

ver, this guideline has been questioned by the Section on Breastfeeding in the AAP, due to concerns about unnecessary iron therapy and weak evidence13). In Korea, there is no consensus on the prophylactic use of iron supplements; however, many reports on IDA rates in breastfed infants have been published recently9,18). 2) Vitamin D: vitamin D deficiency rickets Normal vitamin D levels typically vary greatly according to ethnic groups, seasonal sun exposure, and dietary intake, and so on19,20). Therefore, it is very difficult to establish normal levels in children and determine the prevalence of vitamin D deficiency in this population. The AAP recommends a minimum intake of 200 IU of vitamin D per day for infants in the first 2 months of life21). Currently, there are no official prevalence data and clinical guidelines available for vitamin D deficiency in Korean children. According to the guidelines in developed countries, introduction of meats to the daily complementary foods may be helpful to prevent this vitamin deficiency and iron deficiency anemia.

ife21). Currently, there are no official prevalence data and clinical guidelines available for vitamin D deficiency in Korean children. According to the guidelines in developed countries, introduction of meats to the daily complementary foods may be helpful to prevent this vitamin deficiency and iron deficiency anemia. 3) Calcium A recent nutritional survey report showed that the prevalence of low calcium intake over the age of 1 year was 71.1% (±0.4 SE)11). Although there are many sources of calcium in Korean foods, dairy products are the best source, especially in respect of the availability. Infants over the age of 1 year should be offered two cups of milk daily. Low-fat milk can be used if the child's body mass index (BMI) is above the 95th percentile according to standard growth charts. However, low-fat milk should not be given to an infant under 2 years of age22). 4) Special conditions such as preterm infants and infants with chronic diseases Infants with chronic diseases and preterm babies with BMF may have relative nutritional deficiencies. Calories, calcium, vitamin D, iron, or zinc, etc., may be in short supply as a result of the disease. For these patients, several human milk fortifiers have been developed in Western countries; however, these are not currently available in Korea. In these situations, early introduction of complementary foods may be an option to supplement nutrient deficits. Multidisciplinary approaches with dieticians, nurses, and pharmacists may be a good solution to support patients with specific chronic problems.

is important to differentiate groups that require intervention25). Body Mass Index (BMI) or weight for height screening was not considered helpful in infants less than 2 years of age. However, recently, WHO has published new BMI charts for children less than 2 years of age for early intervention to prevent obesity26). Recent research in the US has shown that there are large differences in discretionary calorie allowance among sedentary, moderately active, and active children27). Energy intake needs to be moderated in less active children. It is very important for parents to encourage their children to exercise moderately for at least 1 hour per day and limit video screen time to less than 2 hours per day28). Nutritional guideline updates In 2007, the National Health Screening Program for Infant s was launched in Korea. The purpose of this government-driven program is to screen for failure of growth and development in children, Providing proper information about child health was also an important issue in this program. Nutritional guidelines are a key element for health education in the National Health Screening Program of Korea. The target issues in the nutritional guidelines are summarized in Table 1. This program is focused on exclusive breastfeeding for 6 months duration, restricting consumption of fruit juices and other beverages, teaching good dietary habits, preventing obesity, and encouraging exercise.

Health Screening Program of Korea. The target issues in the nutritional guidelines are summarized in Table 1. This program is focused on exclusive breastfeeding for 6 months duration, restricting consumption of fruit juices and other beverages, teaching good dietary habits, preventing obesity, and encouraging exercise. Recent guidelines published in 2008 by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), summarize new evidence on breastfeeding and complementary feeding7,8). ESPGHAN reported that the ideal period to start complementary feeding in European infants is between 17 and 26 weeks. They also stressed that there is very little evidence to restrict any type of food to prevent allergy in normal infants. Too many recommendations have been given for the restriction of complementary foods despite a lack of evidence, and anticipatory restriction without evidence can only lead to nutritional inadequacies. Summary - Exclusive breastfeeding for 6 months is usually optimal in a typical clinical situation. - Complementary feeding should be initiated at 6 months of age. ESPGHAN reported that the ideal period to start complementary feeding in European infants is between 17 and 26 weeks. Further research is needed to verify this recommendation in local regions. - There is very little evidence to support the restriction of any kind of food to prevent allergy in normal infants.

- Complementary feeding should be initiated at 6 months of age. ESPGHAN reported that the ideal period to start complementary feeding in European infants is between 17 and 26 weeks. Further research is needed to verify this recommendation in local regions. - There is very little evidence to support the restriction of any kind of food to prevent allergy in normal infants. - Routine iron supplementation for breastfed infants has not been supported by good quality evidence; thus, a personalized approach would be the best in this matter. Therefore, detailed guidelines for iron deficiency screening are urgently needed. - Infants over the age of 1 year should be offered two cups of whole milk daily. - To prevent obesity, moderate exercise of at least 1 hour per day, and restriction of TV viewing should be stressed to all parents. - Consumption of fruit juice and beverages in infants should be curtailed to prevent calorie excess, gastrointestinal discomfort, and dental caries.

- Infants over the age of 1 year should be offered two cups of whole milk daily. - To prevent obesity, moderate exercise of at least 1 hour per day, and restriction of TV viewing should be stressed to all parents. - Consumption of fruit juice and beverages in infants should be curtailed to prevent calorie excess, gastrointestinal discomfort, and dental caries. Fig. 1 The trend in breast milk feeding (BMF) rates has changed dramatically in Korea, accompanied by rapid socioeconomic advances. The boxes represent gross national income per capita, and the line represents the trend of BMF rates in Korea. Easy availability of cow's milk formulae and aggressive marketing might have contributed to the rapid fall in BMF rates nationwide. Recent survey data showed much-improved BMF rates after reinforced government regulations and community-based efforts to enhance BMF were applied. In 2009, the data showed that overall BMF rates recovered up to 89%. Gross national income per capita data were obtained from the Economic Statistics System, Bank of Korea (available at http://ecos.bok.or.kr/). Table 1 Target Issues in the National Health Screening Program for Infants in Korea (Reprinted from Moon JS, Kim JY, Chang SH, Hae CK, Yang HR, Seo JK, et al. Korean J Pediatr Gastroenterol Nutr 2008;11:42-55, with permission of The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition23).)

Introduction adolescent period is different between studies, but is usually defined as age 10 to 20, and the second rapid growth spurt is developed at this period. And they experience many changes on body structure and physiologic, psychologic, and social functioning1). Because of rapid growth and development on self-awareness at this age, many adolescents die prematurely due to accidents, suicide, violence, pregnancy related complications and other illnesses that are either preventable or treatable2). Adolescents are usually influenced by peers rather than parents, and can be at risk for dietary excesses such as excess of total fat, saturated fat, cholesterol, sodium and sugar and deficiencies caused by insufficient intake of fruits, vegetables and calcium rich foods. As a result, deficiencies of iron, vitamins, minerals and calcium, obesity and obesity-related health risks-diabetes and liver diseases and cardiovascular disease and can be developed in these stages. Also poor nutrition can have lasting consequences on adolescents' cognitive development, resulting in decreased learning ability, poor concentration, and impaired school performance3). In Korean adolescents, there are insufficient intakes of nutrients such as calcium, iron and potassium, and distorted thinking about obesity is also common4).

have lasting consequences on adolescents' cognitive development, resulting in decreased learning ability, poor concentration, and impaired school performance3). In Korean adolescents, there are insufficient intakes of nutrients such as calcium, iron and potassium, and distorted thinking about obesity is also common4). In this review I will discuss the nutritional needs in adolescent according to the guidelines of the 2010 Korean Dietary Reference Intakes (KDRI), and encountered nutritional problems in Korean adolescents, and what to do as a pediatrician to improve the adolescent nutritional status. Nutrition requirements for adolescents The range for adolescents was changed to 12-18 years in 2010 KDRI that was revised according to the 2007 Korean National Growth Chart compared to 2005 KDRI. Also the Dietary Reference Intakes (DRI) with Recommended Nutrient intake (RNI) and Adequate Intake (AI) as its center of each nutrient have changed with the contents below (Table 1).

cents was changed to 12-18 years in 2010 KDRI that was revised according to the 2007 Korean National Growth Chart compared to 2005 KDRI. Also the Dietary Reference Intakes (DRI) with Recommended Nutrient intake (RNI) and Adequate Intake (AI) as its center of each nutrient have changed with the contents below (Table 1). 1. Energy and macronutrients The proportion of three nutrients - carbohydrates, protein and fat - and RDI of macronutrients is not changed, but Estimated Average Requirement (EAR) of protein is increased with 5 g/day than EAR of 2005 KDRI in female adolescent because of increased weight. The Estimated Energy Requirements (EER) is increased due to increased height and weight standards in adolescents, but the calculated value is rounded down considering the increasing obesity. Because of the insufficient evidences, the KDRIs for lipids are not established in children and adolescents. The AI of dietary fiber was decreased with 4-7 g/day in both sexes, and the AI of water is also decreased with 100 mL/day6). The past AI of dietary fiber and water were based on the adult standards, so these were revised by the KNHANES8). 2. Vitamins The dietary intakes of lipid-soluble vitamins have no differences compared to the value of 2005 KDRIs except vitamin D. The AI of vitamin D was 10 µg/day in 2005 that was based on the lower levels of 25-hydroxy (OH) vitamin D than adults because of less exposure to the sunlight, but that was changed to 5 µg/day because mean of adolescents' vitamin D intake was 4.4-4.9 µg/day on the Korean Health Behavior Online Survey4).

cept vitamin D. The AI of vitamin D was 10 µg/day in 2005 that was based on the lower levels of 25-hydroxy (OH) vitamin D than adults because of less exposure to the sunlight, but that was changed to 5 µg/day because mean of adolescents' vitamin D intake was 4.4-4.9 µg/day on the Korean Health Behavior Online Survey4). The RNI of water-soluble vitamin such as thiamine, riboflavin, niacin and vitamin B6 are lowered slightly in older adolescent because of decreased weight, and the upper intake level of folic acid is also lowered because the larger population intakes relatively excessive amount of it and the toxic effects can be developed indirectly. But the RNI of vitamin B12 and Biotin is increased little bit than the past according to the adult standards. 3. Macrominerals The RNI of calcium in older adolescent is decreased than the past that was based on the mean of Canadian adolescents' the total body bone mineral content and the report of Food and Agriculture Organization/World Health Organization (WHO) about calcium loss, and compared with the weight and the height of Korean adolescent6). The AI of potassium is revised lower than the past according to the 2005 Korean National Health and Nutrition Examination Survey (KNHANES).

content and the report of Food and Agriculture Organization/World Health Organization (WHO) about calcium loss, and compared with the weight and the height of Korean adolescent6). The AI of potassium is revised lower than the past according to the 2005 Korean National Health and Nutrition Examination Survey (KNHANES). 4. Microminerals For the result of the calculation according to the body surface, the RNI of iron is changed for boys with age, and increased for girls. There were no research results about the EAR of manganese, but the AI of manganese is increased due to the calculated result that was based on the KNHANES9). At the estimated result based on the report of WHO/United Nations Children's Fund/International Council for Control of Iodine Deficiency Disorders 2007, the RNI of iodine is decreased10). Common nutritional problems in adolescents About nutritional problems on the adolescents, large portion of the size, lower fruit and vegetable intake, higher consumption of sweetened beverages, frequent consumption of fast food long hours of television viewing and skipping breakfast, etc were known as the risk factors of excessive weight gain and nutritional imbalance11-13).

nal problems on the adolescents, large portion of the size, lower fruit and vegetable intake, higher consumption of sweetened beverages, frequent consumption of fast food long hours of television viewing and skipping breakfast, etc were known as the risk factors of excessive weight gain and nutritional imbalance11-13). Neumark-Sztainer D et al.11) has been reported that less than one third of adolescents eat five or more servings of fruits and vegetables on a daily basis and these trends tend to decline as adolescents get older11). American national survey in 2000 shows that 25% of the adolescents were overweight, and 45% of the girls and 20% of boys had at some point been on a diet, and eating disorder was reported by 13% of the girls and 7% of the boys14). Girls reported more frequent consumption of beverages than boys in the group of adolescents who watched television for 2 hours per day in recent European study15). Because of costs, easy accessibility and exposure to television advertisement, many adolescents choose the fast foods. Regardless of genders, races, ethnics and regions, 30.3% of the adolescents consumed fast food which contains more total energy, fat, carbohydrate with added sugar and sugar sweetened beverage, and less fiber, milk, fruit, and non-starchy vegetables16). The ratio of skipping breakfast was 31.5% in American adolescents, and breakfast skippers had higher body mass index than others17).

olescents consumed fast food which contains more total energy, fat, carbohydrate with added sugar and sugar sweetened beverage, and less fiber, milk, fruit, and non-starchy vegetables16). The ratio of skipping breakfast was 31.5% in American adolescents, and breakfast skippers had higher body mass index than others17). According to the online survey of Korean children and adolescents4) major sources of energy supply for different age groups says rice and cereal is the first and second most common foods at all groups of age. However the third common food is milk on age between 1 to and instant noodles on ages 50 to 75%; it means that instant foods has been increased with the major source of the excessive energy intake. Major sources of lipid intake are pork, instant noodles and milk for adolescence in order, and especially instant noodles is increased as age increases. Rice, cereals and pork are investigated in order as major sources of carbohydrate. As a result of estimation of each nutrient, each mean of intake ratio of calcium and iron is 58.1% and 89.9% which is below the RNI, and the ratio of the insufficient calcium intake is 96.9% in adolescent age between 13 and 19. Forty six percent of female adolescent age between 13 and 19 think they are obese, but among them only 63.1% of them are not obese in fact. The obese adolescents consumed larger portion sizes and less fruits and vegetables compared to the non-obese adolescents. It is similar to other western studies that as many as 50 to 75% of adolescent girls are dissatisfied with their weight and body image because of the implication of mass media.

re not obese in fact. The obese adolescents consumed larger portion sizes and less fruits and vegetables compared to the non-obese adolescents. It is similar to other western studies that as many as 50 to 75% of adolescent girls are dissatisfied with their weight and body image because of the implication of mass media. Among adolescent dietary intake and eating patterns are influenced by multiple factors such as individual factors, social environmental factors, physical environmental factors and societal factors. Individual factors contain psychosocial and biological influences and life styles18). Food preferences, taste and sensory perceptions of food, health and nutrition, meanings of food, self-efficacy and knowledge are influenced as psychosocial aspect19). For example, the symbolic meanings of the attaching to junk food in adolescents is important to understand the eating behaviors because eating and liking this food is seen as normal behavior for them. Persistent use of unhealthful weight control behaviors is reported by approximately 45% of females and 17% of males, and healthful weight control behaviors are only 10% of females and 15% of males in American study20). Interpersonal relations influence on adolescents' eating behavior. In spite of social changes of the family structure and diet, parental influence is still critical during adolescence. The role of peers in influencing food choices was not important, in other words, peers exert on eating behaviors may be indirect rather than direct19).

lations influence on adolescents' eating behavior. In spite of social changes of the family structure and diet, parental influence is still critical during adolescence. The role of peers in influencing food choices was not important, in other words, peers exert on eating behaviors may be indirect rather than direct19). Community settings such as schools, fast-food restaurants, vending machines, and convenient stores and societal factors, such as media and food advertisings also affect adolescents' eating behaviors. Adolescents consume a large proportion of their total daily energy intake at school, therefore schools should be an environment where healthful eating behavior is normative, modeled, and reinforced19). Recently, as a result of strategy of advertising on the increased portion of the beverage, total energy intake is overall increased21). Mass media effects on eating habit are also considered as important factors especially in female adolescents. Recent advances in adolescent nutrition A recent report of the protection against obesity found the high protein/low glycemic index combination, the prebiotic supplementation and the avoidance of a low calcium intake are effective for children and adolescent22,23).

Community settings such as schools, fast-food restaurants, vending machines, and convenient stores and societal factors, such as media and food advertisings also affect adolescents' eating behaviors. Adolescents consume a large proportion of their total daily energy intake at school, therefore schools should be an environment where healthful eating behavior is normative, modeled, and reinforced19). Recently, as a result of strategy of advertising on the increased portion of the beverage, total energy intake is overall increased21). Mass media effects on eating habit are also considered as important factors especially in female adolescents. Recent advances in adolescent nutrition A recent report of the protection against obesity found the high protein/low glycemic index combination, the prebiotic supplementation and the avoidance of a low calcium intake are effective for children and adolescent22,23). Estimation of the dietary requirement for vitamin D was unclear for many past decades, because of different sunlight exposure on the subject and difficult estimation methods24). Therefore, there are many studies about the RNI of vitamin D, but there are no studies about Korean adolescent until now. During adolescence, one of the major factors of Ca absorption is the serum level of 25-(OH) vitamin D, and IGF-1 is also known as another factor in recent study25). The calcium homeostasis and bone metabolism are known as the major roles of vitamin D, but this can influence to the muscle functions on recent study23,26).

uring adolescence, one of the major factors of Ca absorption is the serum level of 25-(OH) vitamin D, and IGF-1 is also known as another factor in recent study25). The calcium homeostasis and bone metabolism are known as the major roles of vitamin D, but this can influence to the muscle functions on recent study23,26). Gastrointestinal dysfunction is selected as the critical endpoint among several harmful effects of excessive iron intake; this setting was supported by recent report that iron fortification can produce a potentially more pathogenic gut microbiota profile and increase gut inflammation6,27). Because number of family members has been decreasing, lack of time with their parents and the increasing role of the peer group, there are many difficulties on the modification of adolescent eating behavior. Recent studies report that the strategy focused at the age-appropriate curriculum intervention and the role of school is important19,28). One of the interesting recent study reported that misperceptions of peer sugar-sweetened beverage consumption norms are pervasive and associated with unhealthy sugar-sweetened beverage consumption behaviors; this result partially explains the complexity of adolescents' psychosocial influences and their own particular teen culture19,29).

ting recent study reported that misperceptions of peer sugar-sweetened beverage consumption norms are pervasive and associated with unhealthy sugar-sweetened beverage consumption behaviors; this result partially explains the complexity of adolescents' psychosocial influences and their own particular teen culture19,29). Conclusion Because of the expression of the secondary sex characteristics and rapid growth and development during the adolescent period, many chronic diseases of adulthood and variable physical and psychosocial problems can be influenced by the adolescent nutrition. Therefore, it is important that the pediatrician should understand the adolescent nutritional guidelines and the appropriate strategies to correct the nutritional imbalance. Also, in order to improve adolescents' nutritive condition not only do the studies for the nutritional requirements that are suitable for Korean adolescents are needed but also do the understanding of the adolescent periods and the awareness as a pediatrician on the social environments is needed. Table 1 Dietary Reference Intakes for Korean Adolescents (15-18 year of age) by Korean Nutrition Society, 2010 DRI, dietary reference intakes; RE, retinol equivalent; TE, tocopherol equivalents; NE, niacin equivalent; EER, estimated energy requirements; RNI, recommended nutrient intake; AI, adequate intake. *RE=1 µg retinol or 6 µg β-carotene. †1α-TE=1 mg D-α tocopherol. ‡NE=1 mg niacin or 60 mg dietary tryptophan.

Introduction Recently in Korea, childhood and adolescent obesity has increased rapidly because of socio-economic development, westernization of eating lifestyles, and the increased use of computers. Obesity leads to complications such as hypertension, hyperlipidemia, insulin resistance, and non-alcoholic hepatitis. The prevalence of these complications has increased and they are life-threatening factors on adolescent health, on which lifelong health is based. Childhood obesity ultimately contributes to the prevalence of adult diabetes, hypertension, and cardiovascular disease. Marked sex differences have been reported in regards to the degree of insulin resistance, body composition and energy balance in adults1). Adolescents in high school present some features like abdominal fat distribution of both childhood and adulthood. To date, most researches have focused on adolescent obesity itself without mentioning sex differences. Physiological changes during this period include increased secretion of sex hormone and growth hormone, and the development of insulin resistance, which influences differences in sex hormone and subcutaneous fat between the two sexes2-5). In this study, we evaluated clinical features of obese high school students according to the sex, and we focused on the finding relations between metabolic index, cardiovascular risk factors and abdominal fat indices.

Marked sex differences have been reported in regards to the degree of insulin resistance, body composition and energy balance in adults1). Adolescents in high school present some features like abdominal fat distribution of both childhood and adulthood. To date, most researches have focused on adolescent obesity itself without mentioning sex differences. Physiological changes during this period include increased secretion of sex hormone and growth hormone, and the development of insulin resistance, which influences differences in sex hormone and subcutaneous fat between the two sexes2-5). In this study, we evaluated clinical features of obese high school students according to the sex, and we focused on the finding relations between metabolic index, cardiovascular risk factors and abdominal fat indices. Materials and methods 1. Subjects One hundred fifty four students (68 boys, 86 girls) aged between 15 and 17 in a high school participated in this study. They were divided into two groups: the obese group and control group. The obese group (48 boys, 55 girls) included those who had body mass index (BMI) above the 85th percentile for age and sex and the control group (20 boys, 31 girls) included those who had BMI below the 85th percentile for age and sex by the survey of Korean Centers of Disease Control and Prevention in 2007. Persons with endocrine dysfunction or other illnesses were excluded. We obtained informed consents from the guardians after explaining the procedure and purpose of the test thoroughly, and the study was approved by the Institutional Review Board.

y the survey of Korean Centers of Disease Control and Prevention in 2007. Persons with endocrine dysfunction or other illnesses were excluded. We obtained informed consents from the guardians after explaining the procedure and purpose of the test thoroughly, and the study was approved by the Institutional Review Board. 2. Methods 1) Anthropometric measurement We obtained height, weight, BMI, and body composition with Segmental Multi-frequency Bioelectrical Impedance Analysis (InBody J10, Biospace, Seoul, Korea). Waist circumference was measured with a tapeline at the expiratory phase on the horizontal plane between the lowest margin of the 12th rib and the mid portion of the superior iliac crest to the nearest 0.1 cm on standard physician's beam scales, and hip circumference was measured from the most protruding part of the hip to the nearest 0.1cm on standard physician's beam scales. 2) Blood pressure measurement We checked each subject's blood pressure in his/her right arm with a standard mercury sphygmomanometer. A cuff with a width that encircles 40 to 50% of the upper arm was chosen. After the subject was stabilized for at least 5 minutes, we checked blood pressure twice and used the average.

2. Methods 1) Anthropometric measurement We obtained height, weight, BMI, and body composition with Segmental Multi-frequency Bioelectrical Impedance Analysis (InBody J10, Biospace, Seoul, Korea). Waist circumference was measured with a tapeline at the expiratory phase on the horizontal plane between the lowest margin of the 12th rib and the mid portion of the superior iliac crest to the nearest 0.1 cm on standard physician's beam scales, and hip circumference was measured from the most protruding part of the hip to the nearest 0.1cm on standard physician's beam scales. 2) Blood pressure measurement We checked each subject's blood pressure in his/her right arm with a standard mercury sphygmomanometer. A cuff with a width that encircles 40 to 50% of the upper arm was chosen. After the subject was stabilized for at least 5 minutes, we checked blood pressure twice and used the average. 3) Biochemical analysis Venous blood was drawn after overnight fasting. Samples were kept at -70℃ for subsequent assay. The serum concentrations of glucose, insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and high-sensitive C-reactive protein (hs-CRP) were evaluated.

ubsequent assay. The serum concentrations of glucose, insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and high-sensitive C-reactive protein (hs-CRP) were evaluated. 4) Abdominal ultrasound for abdominal fat indices and fatty liver We used abdominal ultrasound Acuson XP128 (Acuson, Mountain View, CA, USA) and placed it above the navel and measured abdominal fat thickness including subcutaneous fat thickness, visceral fat thickness and preperitoneal fat thickness. The measurements were taken by an experienced radiologist. The subjects were comfortably placed in a supine position and we measured subcutaneous fat thickness from skin to anterior abdominal muscle, visceral fat thickness from posterior abdominal muscle to abdominal anterior wall of aorta, and preperitoneal fat thickness from the subcutaneous layer to the peritoneum, by placing a 3.5 MHz linear-array probe 1 cm above the navel at the end-expiratory phase. Fatty liver grading was recorded: grade 0 - no fatty liver; grade 1 - mild; grade 2 - moderate; and grade 3 - severe6). 5) Carotid artery ultrasound Carotid intima-media thickness (IMT) was measured when the subjects were supine for at least 30 minutes with neck ultrasound iU22 (Intelligent Ultrasound System, Philips Medical System, Amsterdam, The Netherlands) on 3 points of the thickest part of the intima-media 1 cm below, and the average was recorded.

ultrasound Carotid intima-media thickness (IMT) was measured when the subjects were supine for at least 30 minutes with neck ultrasound iU22 (Intelligent Ultrasound System, Philips Medical System, Amsterdam, The Netherlands) on 3 points of the thickest part of the intima-media 1 cm below, and the average was recorded. 6) Statistical analysis The average and standard deviation of all measurements were collected. Statistic analysis between the groups was processed using SPSS ver. 16.0 (SPSS Inc., Chicago, IL, USA). We used the Mann-Whitney nonparametric method to compare the average between the obese group and the control group. The degree of the fatty liver in obese group was compared between boys and girls using Chi-square test. Spearman's rho nonparametric correlation analysis was used to confirm the relationship between cardiovascular risk factors and visceral fat thickness measured by ultrasound. A P value of less than 0.05 was regarded as significant. Results 1. Anthropometric analysis In control and obese groups, there was no significant difference of BMI between boys and girls, but waist circumference, waist-hip circumference ratio and blood pressure were higher in boys than in girls. However, body fat mass and body fat percentage were significantly higher in girls than in boys in both groups (Table 1).

ntrol and obese groups, there was no significant difference of BMI between boys and girls, but waist circumference, waist-hip circumference ratio and blood pressure were higher in boys than in girls. However, body fat mass and body fat percentage were significantly higher in girls than in boys in both groups (Table 1). 2. Biochemical analysis In the control group, there was no significant difference in insulin, glucose, homeostasis model assessment of-insulin resistance (HOMA-IR), AST, ALT, TG, HDL-C and hs-CRP between boys and girls, but total cholesterol and LDL-C were higher in girls than in boys. In the obese group, there was no significant difference in insulin, glucose, HOMA-IR, total cholesterol, LDL-C and hs-CRP between boys and girls, but AST, ALT and TG were higher and HDL-C was lower in boys than in girls (Table 2). 3. Abdominal fat thickness and fatty liver In the control group, visceral fat thickness, subcutaneous fat thickness and preperitoneal fat thickness showed no significant sex difference. In the obese group, there was no significant sexual difference in visceral fat thickness and subcutaneous fat thickness but preperitoneal fat thickness was significantly larger in girls than in boys (Table 3). In obese group, the degree of fatty liver was thicker in boys compared to girls but, there was no significant difference between boys and girls. However, cross-analysis of the degree of fatty liver in the obese group showed that boys had a higher degree of fatty liver compared to girls (Table 4).

3. Abdominal fat thickness and fatty liver In the control group, visceral fat thickness, subcutaneous fat thickness and preperitoneal fat thickness showed no significant sex difference. In the obese group, there was no significant sexual difference in visceral fat thickness and subcutaneous fat thickness but preperitoneal fat thickness was significantly larger in girls than in boys (Table 3). In obese group, the degree of fatty liver was thicker in boys compared to girls but, there was no significant difference between boys and girls. However, cross-analysis of the degree of fatty liver in the obese group showed that boys had a higher degree of fatty liver compared to girls (Table 4). 4. Blood pressure and carotid intima-media thickness In control and obese groups, systolic and diastolic blood pressure was higher in boys than in girls. In control and obese groups, carotid IMT was higher in boys than in girls but there was no significant difference (Table 5). In obese group, the incidence of carotid IMT over 0.6 mm, which is over the 2 standard deviations of carotid IMT of the control group, was higher in boys (26.7%) than in girls (16.7%) but there was no significant difference.

carotid IMT was higher in boys than in girls but there was no significant difference (Table 5). In obese group, the incidence of carotid IMT over 0.6 mm, which is over the 2 standard deviations of carotid IMT of the control group, was higher in boys (26.7%) than in girls (16.7%) but there was no significant difference. Discussion For a given body mass index, men are reported to have more lean mass, and women to have higher adiposity7). Men are also found to have more visceral and hepatic adipose tissue, whereas women have more peripheral or subcutaneous adipose tissue. These differences as well as differences in sex hormones and adipokines may contribute to the more insulin-sensitive environment in women than in men8). In our study, although the BMI between boys and girls are not different in control and obesity group, waist circumference and waist-hip ratio were higher in boys but fat masses were higher in girls.

fferences in sex hormones and adipokines may contribute to the more insulin-sensitive environment in women than in men8). In our study, although the BMI between boys and girls are not different in control and obesity group, waist circumference and waist-hip ratio were higher in boys but fat masses were higher in girls. BMI is commonly used as a tool for the evaluation of obesity, but cannot discriminate body fat and muscle mass, and is inaccurate in that it is correlated more with subcutaneous fat than with abdominal fat, which is linked to metabolic disorders. Abdominal visceral fat is known to be a risk factor of insulin resistance and diabetes in both men and women. Waist circumference is easy to estimate and is a common index for epidemiologic research, but is not a direct reflection of visceral fat because abdominal fat is divided into visceral fat and subcutaneous fat. To measure visceral fat correctly, waist circumference, waist-hip circumference ratio, and the length of abdominal median-plane should be used together as they are simple and non-invasive anthropometric methods9). It has already been reported that waist circumference is more closely correlated with hypertension or metabolic disorder and insulin resistance compared to BMI10). Waist circumference is a good parameter for abdominal obesity, but cannot always be related with cardiovascular risk because waist circumference has a high correlation not only with visceral fat but also with subcutaneous fat11).

related with hypertension or metabolic disorder and insulin resistance compared to BMI10). Waist circumference is a good parameter for abdominal obesity, but cannot always be related with cardiovascular risk because waist circumference has a high correlation not only with visceral fat but also with subcutaneous fat11). Abdominal fat, especially, visceral fat is known to be a risk factor of metabolic disorder, which increases the degradation of fatty acid and is related to the increase of insulin resistance, and visceral fat cells secrete many cytokines and increase the cardiovascular factor12).

related with hypertension or metabolic disorder and insulin resistance compared to BMI10). Waist circumference is a good parameter for abdominal obesity, but cannot always be related with cardiovascular risk because waist circumference has a high correlation not only with visceral fat but also with subcutaneous fat11). Abdominal fat, especially, visceral fat is known to be a risk factor of metabolic disorder, which increases the degradation of fatty acid and is related to the increase of insulin resistance, and visceral fat cells secrete many cytokines and increase the cardiovascular factor12). Visceral fat and subcutaneous fat have not only a histological difference but also a difference in metabolic activities: visceral fat is more sensitive to lipolysis by catecholamine than to the anti-lipolytic effect of insulin13). Visceral fat transfers fatty acid to the portal circulation, increases glucogenesis and LDC, and reduces insulin degradation in the liver. As abdominal fat lipolysis increases, fatty acid in the portal and systemic circulation increases and finally induces hyperlipidemia, glucogenesis, and insulin resistance14). Visceral fat is known to increase with age and weight gain in both boys and girls. The waist-hip ratio is generally higher in boys, and it seems that visceral fat is larger in boys compared to girls15). In our study, waist circumference and waist-hip ratio were higher in boys than in girls, but body fat mass was larger in girls than in boys, which is similar to the distribution of body fat mass in adults. In addition, it is known that men have much more visceral fat and much less subcutaneous fat than women8,16). Our study revealed that abdominal fat thickness measured by ultrasound was thicker in boys than in girls among high school students but the difference was not significant. Subcutaneous fat thickness and preperitoneal fat thickness were higher in girls than in boys but were not significant. We think that the characteristic difference of fat distribution between normal men and women may be altered by obesity in adolescence. In the regulation of growth and development of puberty, estrogen and growth hormone interact closely. During growth spurt, estrogen and growth hormone take an action and change the physical development and then make a result sex different body composition change17).

n and women may be altered by obesity in adolescence. In the regulation of growth and development of puberty, estrogen and growth hormone interact closely. During growth spurt, estrogen and growth hormone take an action and change the physical development and then make a result sex different body composition change17). Adolescent obesity is known to be a major risk factor of non-alcoholic fatty liver and atherosclerosis, and combined with hyperlipidemia, hypertension, elevation of liver enzymes, and insulin resistance. Non-alcoholic steatohepatitis is a chronic liver dysfunction and has been reported to progress finally to fibrosis, hepatocirrhosis18). Jang et al.19) reported that obese first-year high school students have an abnormal ALT level, 23.7% in boys and 11.8% in girls. In the obesity group, boys had a statistically higher abnormal rate of AST, ALT, and total cholesterol, but in the normal weight group, the abnormal rate of AST, ALT, and total cholesterol was significantly higher in girls than in boys. In a large cohort of overweight and obese European children and adolescents, the markers of nonalcoholic liver disease, especially elevated ALT, were frequently predicted by severe obesity group and male gender20,21). Recent studies study about estrogen effect to obesity. Pediatric non-alcoholic steatohepatitis is common in boys22) and this sex difference may be due to the defense mechanism of estrogen as non-alcoholic steatohepatitis appears to be more common in menopause women than in premenopausal women as estrogen can reduce the oxidation of fat20).

about estrogen effect to obesity. Pediatric non-alcoholic steatohepatitis is common in boys22) and this sex difference may be due to the defense mechanism of estrogen as non-alcoholic steatohepatitis appears to be more common in menopause women than in premenopausal women as estrogen can reduce the oxidation of fat20). We can elude that lipid metabolism of sex steroid may start from the adolescent period; eventually these differences can be related with sex steroid, cytokine and lipid metabolism. The association of elevated ALT in obese boys supports the hypothesis that the pubertal increase of sex steroid may be important in predisposition for pediatric non-alcoholic steatohepatitis22). The underlying mechanisms of sex difference appeared to be due to the change of gene expression, which is dependent on estrogen. Estrogen reduced reactive oxygen species with increased antioxidant gene expression and reduced proinflammatory cytokine production24). Nonalcoholic fatty liver disease (NAFLD) is a disorder associated with obesity. Studies reported the prevalence rate of suspected fatty liver in overweight children between 6 and 23%25).

We can elude that lipid metabolism of sex steroid may start from the adolescent period; eventually these differences can be related with sex steroid, cytokine and lipid metabolism. The association of elevated ALT in obese boys supports the hypothesis that the pubertal increase of sex steroid may be important in predisposition for pediatric non-alcoholic steatohepatitis22). The underlying mechanisms of sex difference appeared to be due to the change of gene expression, which is dependent on estrogen. Estrogen reduced reactive oxygen species with increased antioxidant gene expression and reduced proinflammatory cytokine production24). Nonalcoholic fatty liver disease (NAFLD) is a disorder associated with obesity. Studies reported the prevalence rate of suspected fatty liver in overweight children between 6 and 23%25). Interestingly, epidemiological studies and most of published case series demonstrate a clear male predominance in the diagnosis of nonalcoholic fatty liver disease. In this study, the incidence of fatty liver in obese adolescents measured by ultrasound was 30% in both sexes. However, compared to the severity of fatty liver, the boys showed a mild to severe degree but the girls showed mostly a mild or moderate degree and no severe degree. This led to the assumption that estrogen might be an important mediator in the pathogenesis of nonalcoholic fatty liver disease. Changes in estrogen metabolism and physiological insulin resistance may determine susceptibility to fatty liver disease and contribute to the gender-specific prevalence pattern which is supported by previous studies26,27).

estrogen might be an important mediator in the pathogenesis of nonalcoholic fatty liver disease. Changes in estrogen metabolism and physiological insulin resistance may determine susceptibility to fatty liver disease and contribute to the gender-specific prevalence pattern which is supported by previous studies26,27). Carotid intima-media thickness is a measure of subclinical atherosclerosis and predictive of future myocardial infarction and stroke. Obesity during childhood has been associated with higher carotid IMT during adulthood28,29). Caserta et al.30) reported that NAFLD, BMI, waist circumference, and systolic blood pressure are independent markers of increased IMT in a random sample of adolescents. Lee et al.31) reported that obesity in adolescence was related to an increase in carotid IMT among healthy young Korean men but not in women. In our study, the incidence of carotid IMT over 0.6 mm, which is over the 2 standard deviations of carotid IMT of the control group, was higher in obese boys (26%) than in obese girls (16.7%) but there was no significant difference. Limitations of this study were first, only 154 of a high school in Seoul were included and the number of the objectives was small. Second, although, the mean BMI of boys was not different from that of girls, we did not adjust the BMI on the results statistically. In conclusion, comorbidities of obesity in adolescents are more prevalent and severe in the male sex. We can infer that these characteristics reflect some parts of adult obesity. This study was supported by a grant from Korean Heart Research Foundation (2008).

Limitations of this study were first, only 154 of a high school in Seoul were included and the number of the objectives was small. Second, although, the mean BMI of boys was not different from that of girls, we did not adjust the BMI on the results statistically. In conclusion, comorbidities of obesity in adolescents are more prevalent and severe in the male sex. We can infer that these characteristics reflect some parts of adult obesity. This study was supported by a grant from Korean Heart Research Foundation (2008). Table 1 Anthropometric Measurements of the Subjects Values are presented as mean±SD. BMI, body mass index; WC, waist circumference; WHR, waist hip ratio; NS, not significant. Table 2 Metabolic Parameters of the Subjects Values are presented as mean±SD. HOMA-IR, homeostasis model assessment of-insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; hs CRP, high-sensitive C-reactive protein; NS, not significant. Table 3 Abdominal Fat Thickness and Grade of Fatty Liver of the Subject Values are presented as mean±SD. VFT, visceral fat thickness; SFT, subcutaneous fat thickness; PFT, peritoneal fat thickness; NS, not significant. Fatty liver grade 0-332) Table 4 Comparisons of Incidence of Fatty Liver Grades in the Obese Subjects Values are presented as n (%). P<0.01 between boys and girls. Table 5 Blood Pressure and Carotid Intima-Media Thickness of the Subjects Values are presented as mean±SD.

VFT, visceral fat thickness; SFT, subcutaneous fat thickness; PFT, peritoneal fat thickness; NS, not significant. Fatty liver grade 0-332) Table 4 Comparisons of Incidence of Fatty Liver Grades in the Obese Subjects Values are presented as n (%). P<0.01 between boys and girls. Table 5 Blood Pressure and Carotid Intima-Media Thickness of the Subjects Values are presented as mean±SD. BP, blood pressure; IMT, intima-media thickness; NS, not significant.

Introduction Vitamin D deficiency causes rickets by bone demineralization. In the affluent twentieth century, vitamin D deficiency was thought to be infrequent, but reports on this condition have been on the increase recently1-5). Several studies encompassing large Unites States of America (USA) populations have demonstrated that infants, children and pregnant women have significantly high prevalence of vitamin D deficiency6-9). In addition, numerous studies on vitamin D deficiency have been reported in the Korean literature. Furthermore, there have been increasing number of reports on subclinical vitamin D deficiency and subclinical rickets. Our previous studies on subclinical rickets showed that children who were breast-fed without vitamin D supplement, or those admitted from outpatient clinics with infections, were frequently found to have high prevalence of this condition, which is also associated with iron deficiency anemia (IDA). As such, it is thought that there is need to screen children with vitamin D deficiency, and to administer vitamin D supplements10,11). Previously, Grindulis et al.12) have documented concurrent iron and vitamin D deficiency in Asian infants. In a recent surveillance, vitamin deficiency and insufficiency was so common in Korean mothers and their newborn infants, that 8.3% of mothers and 22.2% of newborns were vitamin D deficiency, and 70% of both mothers and newborns were insufficiency13). In breast feeding infants, cases with both of vitamin deficiency and IDA were reported. Canpro analysis performed on IDA infants showed that iron and vitamin D were less than 40% and 30% of recommended intakes, respectively14,15). The aim of this study was to evaluate the clinical characteristics of subclinical rickets in children, and its association with IDA.

of vitamin deficiency and IDA were reported. Canpro analysis performed on IDA infants showed that iron and vitamin D were less than 40% and 30% of recommended intakes, respectively14,15). The aim of this study was to evaluate the clinical characteristics of subclinical rickets in children, and its association with IDA. Materials and methods A total of 261 outpatient and inpatient children underwent 25-hydroryvitamin D3 tests at the Department of Pediatrics, Eulji General Hospital between January 2007 and July 2009. We excluded the children with disease such as acute and chronic hepatitis, the children have elevated C-reactive protein which can affect the level of hemoglobin and ferritin. The number of children <6 months were 19, 6 to 12 months were 80, 12 to 24 months were 72. We retrospectively analyzed these 171 children, their clinical characteristics, blood test results, wrist radiograph results and treatment outcome. A serum vitamin D concentration of ≥30 ng/dL (75 nmol/L) was defined as being normal, and that of below 30 ng/dL (75 nmol/L) was defined as vitamin D insufficiency1,15-17). Subclinical rickets indicates vitamin D deficiency without clinical symptoms such as bony changes or seizure. Although subclinical rickets is not officially recognized medical term, it was used in several recent studies. In other words, subclinical rickets only manifest as reduced serum levels of vitamin D and/or increased alkaline phosphatase (ALP), as well as minimal radiological/biochemical bony changes10,18-20).

r seizure. Although subclinical rickets is not officially recognized medical term, it was used in several recent studies. In other words, subclinical rickets only manifest as reduced serum levels of vitamin D and/or increased alkaline phosphatase (ALP), as well as minimal radiological/biochemical bony changes10,18-20). We defined osteopenia and rickets on X-ray by reading of radiologist. The cortex thinning and trophic lines are characteristic of osteopenia, and findings such as ill-demarcated, central cup-shaped depression in the end of ulna or radius are characteristic of rickets. In all children, serum levels of 25-hydroxy vitamin D3, hemoglobin (Hb), hematocrit (Hct), iron, ferritin, transferrin saturation, calcium, phosphate, ALP and intact parathyroid hormone (iPTH) were measured. Birth history, past medical history, and clinical information such as height and body weight were collected from the medical records. Data are expressed as the mean±SD. Statistical analyses were performed using SPSS ver.13.0 (SPSS Inc., Chicago, IL, USA). All statistical comparisons were made with the independent sample test. Factors affecting serum vitamin D concentration were examined by using Pearson's correlation coefficients and multiple regression analysis. A P value of less than 0.05 (P<0.05) was considered to be statistically significant.

nc., Chicago, IL, USA). All statistical comparisons were made with the independent sample test. Factors affecting serum vitamin D concentration were examined by using Pearson's correlation coefficients and multiple regression analysis. A P value of less than 0.05 (P<0.05) was considered to be statistically significant. Results 1. Clinical characteristics 1) Normal group Of the 171 children enrolled, 120 (70.2%) had a vitamin D concentration of ≥30 ng/dL (normal group), and their mean age was 12.5±7.0 months. The mean body weight was 9.3 kg (standard deviation score [SDS], -0.32±0.9), and the mean height was 76.8 cm (SDS, 0.15±1.1). The mean birth weight was 3.2±0.4 kg, the mean gestational age was 38.4±1.4 weeks, and the mean annual frequency of hospitalization until the time of initial diagnosis was 0.9±1.9. Children in the normal group suffered respiratory disease most frequently (40.3%), followed by gastrointestinal disease and atopic dermatitis. Ninety-three children (78%) were breast-fed (Table 1).

age was 38.4±1.4 weeks, and the mean annual frequency of hospitalization until the time of initial diagnosis was 0.9±1.9. Children in the normal group suffered respiratory disease most frequently (40.3%), followed by gastrointestinal disease and atopic dermatitis. Ninety-three children (78%) were breast-fed (Table 1). 2) Vitamin D insufficiency group Of the 171 children analyzed, 51 (29.8%) had a vitamin concentration of less than 30 ng/dL (insufficiency group). The mean age was 9.9±5.4 months, which was significantly younger than that of the normal group (P<0.05). The mean height was 75.1 cm (SDS, -0.22±0.9), which was significantly lower than in that of the normal group. Although there was no significant difference in the mean hospitalization frequency between the 2 groups, the frequency tended to be higher in the insufficiency group, albeit without statistical significance. Similar to the normal group, respiratory and gastrointestinal diseases were frequently found in the insufficiency group. There were more breast-fed children in the insufficiency group than in the normal group (92% vs. 78%, P<0.05) (Table 1). As for seasonal distribution, in the spring (March through May), vitamin D insufficiency was diagnosed in 25 of 57 (44%) children who underwent 25-hydroxyvitamin D3 tests. In summer, autumn and winter, the children of vitamin D insufficiency diagnosed respectively 9 of 41 (22%), 5 of 33 (15%), 12 of 40 (30%).

2) Vitamin D insufficiency group Of the 171 children analyzed, 51 (29.8%) had a vitamin concentration of less than 30 ng/dL (insufficiency group). The mean age was 9.9±5.4 months, which was significantly younger than that of the normal group (P<0.05). The mean height was 75.1 cm (SDS, -0.22±0.9), which was significantly lower than in that of the normal group. Although there was no significant difference in the mean hospitalization frequency between the 2 groups, the frequency tended to be higher in the insufficiency group, albeit without statistical significance. Similar to the normal group, respiratory and gastrointestinal diseases were frequently found in the insufficiency group. There were more breast-fed children in the insufficiency group than in the normal group (92% vs. 78%, P<0.05) (Table 1). As for seasonal distribution, in the spring (March through May), vitamin D insufficiency was diagnosed in 25 of 57 (44%) children who underwent 25-hydroxyvitamin D3 tests. In summer, autumn and winter, the children of vitamin D insufficiency diagnosed respectively 9 of 41 (22%), 5 of 33 (15%), 12 of 40 (30%). 2. Blood test results 1) Normal group At the time of initial diagnosis, the mean 25-hydroxyvitamin D3 level was 60.8±26.4 ng/mL, the mean Hb was 11.3±1.4 g/dL. The mean serum calcium level was 9.9±0.5 mg/dL, the mean serum phosphorus level was 5.1±0.6 mg/dL, the mean serum ALP level was 798.4±1073.9 IU/L, and the mean serum iPTH level was 40±73 pg/mL. The mean serum ferritin level was 29.3±29.4 ng/mL, the mean serum iron level was 28.2±16.0 mg/dL, and the mean transferrin saturation level was 8.4±5.5%. Iron deficiency anemia was detected in 12% of children. Of the 120 children, 25 showed increased ALP levels or clinical symptoms and signs suspicious of rickets. Wrist radiographs taken in these 25 children demonstrated rickets (n=5) and normal findings (n=20) (Table 2).

mean transferrin saturation level was 8.4±5.5%. Iron deficiency anemia was detected in 12% of children. Of the 120 children, 25 showed increased ALP levels or clinical symptoms and signs suspicious of rickets. Wrist radiographs taken in these 25 children demonstrated rickets (n=5) and normal findings (n=20) (Table 2). 2) Vitamin D insufficiency group At the time of initial diagnosis, the mean serum 25-hyctroxyvitamin D3 level was 22.8±5.0 ng/mL. The mean serum Hb level was 10.7±1.4 g/dL, which was significantly lower than that of the normal group (P<0.05). The mean serum ALP level was 1,018.8±843.8 IU/L, which was significantly higher than that of the normal group (P<0.05). No child experienced hypocalcemia. The mean serum phosphate was 4.9±1.9 mg/dL, and hypophosphatemia (≤3.8 mg/dL) was observed in 2 children. The mean serum iPTH level was 122.8±133 pg/mL, which was significantly higher than that of the normal group (P<0.05). The mean serum ferritin level was 20.5±24.3 ng/mL, which was not significantly different from the normal group. However, it tended to be lower than the normal group. The mean serum iron level was 26.2±20.2 ug/dL, and the mean transferrin saturation level was 5.4±2.2% which was lower than that of the normal group (P<0.05). IDA was more common in the deficient group than in the normal group (25.5% vs. 12.0%, P<0.05). In multiple regression analysis, young age and low Hb level were independent factors for vitamin D insufficiency (Figs. 1, 2).

transferrin saturation level was 5.4±2.2% which was lower than that of the normal group (P<0.05). IDA was more common in the deficient group than in the normal group (25.5% vs. 12.0%, P<0.05). In multiple regression analysis, young age and low Hb level were independent factors for vitamin D insufficiency (Figs. 1, 2). Wrist radiographs were taken in 25 of 51 children in the insufficiency group, which demonstrated osteopenia 1 child, findings suggestive of rickets in 9 and normal findings in 15 children (Table 2). Of the 51 children, 11 had a 25-hydroxy vitamin D3 level of ≤20 ng/mL. In these 11 children, the mean body weight was 8.5 kg (SDS, -0.44±0.5 kg), and the mean height was 75.7 cm (SDS, -0.23±0.7 cm), which were remarkably lower than that of the normal and insufficiency groups. The mean serum Hb level was 10.4±1.5 g/dL, and the mean serum Hct level was 31.6±4.0%, which were significantly lower than that of the normal and insufficiency groups. Of these 11 children, 10 were breast-fed, 4 (36%) experienced concurrent IDA, with its frequency being significantly higher. In addition, there was a tendency for more severe findings suggestive of rickets in these 11 children.

31.6±4.0%, which were significantly lower than that of the normal and insufficiency groups. Of these 11 children, 10 were breast-fed, 4 (36%) experienced concurrent IDA, with its frequency being significantly higher. In addition, there was a tendency for more severe findings suggestive of rickets in these 11 children. 3. Treatment outcome 1) Normal group Of the 120 children, 10 (8%) were given calcitriol for a mean duration of 2.2 months. Their 25-hydroxyvitamin D3 levels were all at the lower normal limit and 5 of them showed radiological findings suggestive of rickets. Of these 10 children, 6 underwent follow-up 25-hydroxyvitamin D3 tests, in whom the D3 level increased form a mean pretreatment D3 level of 39.6±14.6 ng/mL to a mean post-treatment D3 level of 41.8±17.2 ng/mL. Three of these 10 children were followed up with radiographs: 2 showed improvement, 1 returned to normal.

ets. Of these 10 children, 6 underwent follow-up 25-hydroxyvitamin D3 tests, in whom the D3 level increased form a mean pretreatment D3 level of 39.6±14.6 ng/mL to a mean post-treatment D3 level of 41.8±17.2 ng/mL. Three of these 10 children were followed up with radiographs: 2 showed improvement, 1 returned to normal. 2) Vitamin D insufficiency group Of the 51 children, 18 (35.2%) were given calcitriol for a mean duration of 2.5 months. Other insufficient children were missed follow-up. Of these 18 children, 13 underwent 25-hydroxy vitamin D3 tests, and the D3 level increased from a mean pretreatment level of 20.7±7.0 ng/mL to a mean post-treatment level of 43.7±23.8 ng/mL. Of these 18 children, 7 were followed up with radiographs; 2 showed improvement, 2 returned to normal. Of the 11 children with a 25-hydroxy vitamin D3 level of ≤20 ng/mL, 4 (36%) were given calcitriol for a mean duration of 4.1 months. D3 level was markedly increased from a pretreatment D3 level of 13.3±5.2 ng/mL, to a mean post-treatment D3 level of 34.5±23.8 ng/mL. Of these 4 children, 2 were followed up with radiographs, both of whom returned to normal.

vitamin D3 level of ≤20 ng/mL, 4 (36%) were given calcitriol for a mean duration of 4.1 months. D3 level was markedly increased from a pretreatment D3 level of 13.3±5.2 ng/mL, to a mean post-treatment D3 level of 34.5±23.8 ng/mL. Of these 4 children, 2 were followed up with radiographs, both of whom returned to normal. Discussion In this study, the prevalence of vitamin D insufficiency is 29.8% of children younger than 2 years old. A recent large-scale study on the US population reported that 61% of 9,757 children experienced vitamin D deficiency, which is higher than that of our study. The prevalence of vitamin D deficiency was reported to be 3.1 to 57.8% in Chinese adolescents, 0.1% in Japanese children aged 1 to 4 years and 24% in Mongolian children younger than 1 year old18,21,22). These data are comparable to the outcomes of our study.

vitamin D deficiency, which is higher than that of our study. The prevalence of vitamin D deficiency was reported to be 3.1 to 57.8% in Chinese adolescents, 0.1% in Japanese children aged 1 to 4 years and 24% in Mongolian children younger than 1 year old18,21,22). These data are comparable to the outcomes of our study. In this study, as age and serum Hb level decreased, serum vitamin D level also decreased (Figs. 1, 2). Grindulis et al.12) have demonstrated the relationship between vitamin D deficiency and IDA. Katsumata et al.23) have reported that IDA affects the synthesis and metabolism of iron-dependent enzymes for vitamin D activation, leading to osteopenia. Based on these results, serum vitamin D concentration should be measured in children with IDA, and vice versa. In this study, a considerable number of children with vitamin D insufficiency had concurrent IDA. It is suggestive that IDA associated with vitamin D insufficiency may affect bone growth. This suggestion is enhanced when considering that the height of vitamin D deficient children was found to be low, although their body weight was not significantly different from that of normal children. The reasons for lower vitamin D levels in younger children may be explained as follows. First, young children were beast-fed without vitamin supplement. Second, they undertook less outdoor activities than older children. Third, they experienced reduced exposure to sunlight, because they wore thicker clothes compared to older children while they were outdoors. To validate our results, we suggest further studies to investigate the proportion of breast-feeding in a cohort of mixed fed children, the duration of complete breast-feeding, the duration of sunlight exposure and the use of sun block.

cause they wore thicker clothes compared to older children while they were outdoors. To validate our results, we suggest further studies to investigate the proportion of breast-feeding in a cohort of mixed fed children, the duration of complete breast-feeding, the duration of sunlight exposure and the use of sun block. The diagnosis rate of vitamin D insufficiency was highest in the spring in this study. The reason may be that duration of sunlight exposure is short during the winter. In addition, the lowest diagnosis rate of vitamin D insufficiency in the autumn may be explained by the fact that children were sufficiently exposed to sunlight during the summer. Vitamin D production requires sunlight, it is "a vitamin of the sun". However, parents are reluctant to expose their children to sunlight due to fear of skin cancer, or respiratory viral infection. The guidelines of the American Society of Pediatrics recommend that children aged less than 6 months should avoid direct sunlight exposure, and wear long clothing or use sun block while they are outdoors24). Reluctance to be exposed to sunlight due to concern about skin cancer or upper respiratory infection may be an important cause of the increasing prevalence of vitamin D deficiency all over the world.

than 6 months should avoid direct sunlight exposure, and wear long clothing or use sun block while they are outdoors24). Reluctance to be exposed to sunlight due to concern about skin cancer or upper respiratory infection may be an important cause of the increasing prevalence of vitamin D deficiency all over the world. Grindulis et al.12) have reported that in the winter, serum vitamin D concentration is significantly different between children with vitamin D deficiency who were given vitamin D supplement and those who were not. Whereas in the summer, it is not significantly different. Because Korea is situated in 34° to 43° North Latitude (Seoul, 37° 4') and sunshine duration is considerably shorter in regions situated above 37° North Latitude25). It is therefore necessary to perform vitamin D tests and supplement with vitamin D where appropriate, especially during the winter. Further studies are needed to determine whether vitamin D dosage should be adjusted according to the season.

ration is considerably shorter in regions situated above 37° North Latitude25). It is therefore necessary to perform vitamin D tests and supplement with vitamin D where appropriate, especially during the winter. Further studies are needed to determine whether vitamin D dosage should be adjusted according to the season. We reported 8 breast-fed children with subclinical rickets10). It has been demonstrated that the risk of vitamin D deficiency rickets is higher in breast-fed infants11,22). In our study, the proportion of breast-feeding was higher in the vitamin D insufficiency group. Under the assumption that there is little sun exposure, children who ingest 750 mL of breast milk daily will in reality ingest 11 to 38 IU of vitamin D, which is much lower than the minimum requirement of 200 IU/day26-28). The American Society of Pediatrics guidelines recommend that infants aged less than 2 months should be given a daily vitamin D supplement of 400 IU, and their minimal annual vitamin D concentration should be maintained at ≥30 ng/dL29,30). In Korea, despite the fact that breast-feeding is increasing due to social emphasis on the advantage of breast milk, vitamin D tests and supplementation are still inadequately performed due to lack of understanding, and disagreement on criteria and timing for vitamin D tests and lack of pure vitamin D medication. Therefore, guidelines for these issues should be established to prevent children from becoming vitamin D deficient.

milk, vitamin D tests and supplementation are still inadequately performed due to lack of understanding, and disagreement on criteria and timing for vitamin D tests and lack of pure vitamin D medication. Therefore, guidelines for these issues should be established to prevent children from becoming vitamin D deficient. In this study, the annual frequency of hospitalization was higher in the vitamin D insufficiency group than in the normal group, albeit without statistical significance. Considering that immunological function of vitamin D, it is thought that children with vitamin D insufficiency are at high risk of serious diseases requiring hospitalization. Of 25 children in the normal vitamin D group who underwent radiological examination, 10 showed osteopenia and findings suggestive of rickets. These outcomes are suggestive that some children with normalized vitamin D concentration suffer from subclinical rickets characterized by persistent radiological changes of the bone. Additional studies on bone density and growth are needed to validate our findings. Curiously the mean level of ALP was high in the normal group. It is suggestive that there were also some children who have normalized vitamin D concentration suffer from subclinical rickets characterized by high level of ALP because of their compensative bone forming action. And another cause is some disease status may affect their ALP level in inpatients who did not meet exclusion criteria.

tive that there were also some children who have normalized vitamin D concentration suffer from subclinical rickets characterized by high level of ALP because of their compensative bone forming action. And another cause is some disease status may affect their ALP level in inpatients who did not meet exclusion criteria. Limitation to this study include the following, although the relationship of the concentration with that of hemoglobin and transferrin saturation was positive, other factors reflect iron concentration were unrelated to the status of vitamin D. In addition, the number of children who have work up for IDA was too small (43 of 171). In conclusion, this study demonstrated that approximately 30% of children aged ≤2 years experienced vitamin D insufficiency associated with subclinical rickets, and that vitamin D concentration decreased in the winter due to scanty sunlight. For these reasons, vitamin D insufficiency children should be given vitamin D supplement. In addition, vitamin D insufficiency can be associated with IDA and growth retardation, and breast-fed children are at high risk of vitamin D insufficiency. Thus, guidelines for vitamin D supplement in such children must be established. Since children with vitamin D insufficiency are also at high risk of serious diseases requiring hospitalization, and some continue to experience bony changes associated with morphological abnormalities, regular follow-up is important. Fig. 1 Linear correlation between vitamin D and hemoglobin level. 25-(OH)VITD, 25-hydroxyvitamin D; Hb, hemoglobin.

In conclusion, this study demonstrated that approximately 30% of children aged ≤2 years experienced vitamin D insufficiency associated with subclinical rickets, and that vitamin D concentration decreased in the winter due to scanty sunlight. For these reasons, vitamin D insufficiency children should be given vitamin D supplement. In addition, vitamin D insufficiency can be associated with IDA and growth retardation, and breast-fed children are at high risk of vitamin D insufficiency. Thus, guidelines for vitamin D supplement in such children must be established. Since children with vitamin D insufficiency are also at high risk of serious diseases requiring hospitalization, and some continue to experience bony changes associated with morphological abnormalities, regular follow-up is important. Fig. 1 Linear correlation between vitamin D and hemoglobin level. 25-(OH)VITD, 25-hydroxyvitamin D; Hb, hemoglobin. Fig. 2 Linear correlation between vitamin D level and age. 25-(OH)VITD, 25-hydroxyvitamin D; Hb, hemoglobin. Table 1 Comparison of Patient Characteristics by Vitamin D Status Values are presented as mean±SD or %. SDS, standard deviation score; BW, birth weight; GA, gestational age. *Admission frequency per year. Table 2 Comparison of Biochemical and Radiological Profiles by Vitamin D Status Values are presented as mean±SD or case (%). 25-(OH)VITD3, 25-hydroxyvitamin D3; MCV, mean corpuscular volume; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase; Fe, iron; TIBC, total iron-binding capacity; Ca, calcium; P, phosphorus.

Introduction Drugs which are used to prevent, treat and research diseases sometimes cause unwanted reactions, so called adverse drug reactions (ADRs) and the World Health Organization (WHO) has defined ADR as an unplanned and unintended harmful effect of a drug despite its being administered at a an adequate dose1,2). By a systemic review and meta-analysis of prospective studies, ADR has been reported to vary from 5 to 17%. The overall incidence was 10% in hospitalized children and 2% in outpatient children, and the overall rate of pediatric hospital admissions due to ADRs was 2%1). In Korea, there is a national wide survey for prevalence of asthma and other allergic diseases by internationally validated questionnaire. By this survey, last twelve-month prevalence of drug hypersensitivity was 2% in 40,429 school children aged 6 to 15 years3), but there has been almost no report of clinical studies about ADRs in children, except several case report about fixed drug eruption in children4-6).

s by internationally validated questionnaire. By this survey, last twelve-month prevalence of drug hypersensitivity was 2% in 40,429 school children aged 6 to 15 years3), but there has been almost no report of clinical studies about ADRs in children, except several case report about fixed drug eruption in children4-6). Majority of ADRs are predictable (type A) and 20% of ADRs are unpredictable (type B) which are unrelated to the dose and pharmacological mechanism of individual drugs. Many of the symptoms of type B ADRs require emergency treatments, furthermore, unpredictable ADRs are especially problematic in pediatric patients1,2,7). ADRs are common in children and can be life-threatening and but the false positive diagnosis are prevalent in clinical settings, especially in the children with fever or infections1,2,8,9). So the confirmation of the diagnosis should be performed by detailed clinical history and a physical examination, possibly followed by drug provocation tests (DPT)7,10). In this study we aimed to assess the role of DPT in children with unpredictable ADRs, and compare the causative drugs and clinical characteristics between detailed history of ADRs and result of DPTs.

Majority of ADRs are predictable (type A) and 20% of ADRs are unpredictable (type B) which are unrelated to the dose and pharmacological mechanism of individual drugs. Many of the symptoms of type B ADRs require emergency treatments, furthermore, unpredictable ADRs are especially problematic in pediatric patients1,2,7). ADRs are common in children and can be life-threatening and but the false positive diagnosis are prevalent in clinical settings, especially in the children with fever or infections1,2,8,9). So the confirmation of the diagnosis should be performed by detailed clinical history and a physical examination, possibly followed by drug provocation tests (DPT)7,10). In this study we aimed to assess the role of DPT in children with unpredictable ADRs, and compare the causative drugs and clinical characteristics between detailed history of ADRs and result of DPTs. Materials and methods 1. Patients We include 16 patients out of 32 patients under 18 years of age, who, over 4-year period (January 2006 to December 2009), were referred to the pediatric allergy department at Ajou University Hospital, due to complete past history of ADRs. Medical records were reviewed retrospectively, demographic data and detailed clinical history such as experienced allergic reactions after ingestion of drugs, severity of ADRs, and combined disease, and result of DPT with suspected drugs. ADR was considered mild if the drug was stopped or switched without any particular treatment, and severe if the patient had to be examined at a tertiary medical center or hospitalized for treatment11).

ic reactions after ingestion of drugs, severity of ADRs, and combined disease, and result of DPT with suspected drugs. ADR was considered mild if the drug was stopped or switched without any particular treatment, and severe if the patient had to be examined at a tertiary medical center or hospitalized for treatment11). All 16 patients have one of the clinical symptoms of urticaria, maculopapular eruption, isolated generalized pruritus, laryngeal edema, bronchospasm, rhinoconjunctivitis, or anaphylaxis. We excluded patient with nonimmediate chronology (8 hours after the last drug administration) (n=8), symptoms disappearing without cessation of the suspected drug. We also excluded the patients with chronic urticaria (n=2), food allergy, who had experienced severe life-threatening skin reaction (including vasculitis, exfolative dermatitis, toxic epidermal necrolysis or Stevens-Johnson syndrome), and parents' opposition about DPT (n=6).

ing without cessation of the suspected drug. We also excluded the patients with chronic urticaria (n=2), food allergy, who had experienced severe life-threatening skin reaction (including vasculitis, exfolative dermatitis, toxic epidermal necrolysis or Stevens-Johnson syndrome), and parents' opposition about DPT (n=6). 2. Skin test and drug provocation test After receiving informed consent from parents, we performed DPT in 16 patients who showed evidence of ADRs, and we followed general guidelines for DPT with the modification for skin test before DPT, dose and time interval during DPT12). DPT was performed in good health, and at least 4 weeks after disappeared ADRs in each patient. All DPTs were performed on an inpatient basis. The blood vessel was secured, and epinephrine and a short-acting steroid were prepared in advance against emergencies such as anaphylaxis and shock. During each test, physicians present to observe clinical symptoms and measure vital signs every 15 minutes for the first one hour, every 30 minutes for the next two hours, and every hour for the next three hours. In patients who were suspected to have symptoms after administration of an oral antibiotic, an intradermal skin test was done before DPT. Skin test was performed using intravenous antibiotic of the same element. For the skin test we use the 1:1,000 diluted antibiotic solutions and followed the usual method. The amount of induration or redness in response to the test measured by trained person 15 minutes after administration. When skin test reactivity in present, it causes >10 mm of induration.

s antibiotic of the same element. For the skin test we use the 1:1,000 diluted antibiotic solutions and followed the usual method. The amount of induration or redness in response to the test measured by trained person 15 minutes after administration. When skin test reactivity in present, it causes >10 mm of induration. For the DPT, we used commercial preparation of suspected drug. We use the 25% of a usual therapeutic dose as a starting dose, 50% as a 2nd dose, and 100% as a 3rd dose, and the interval was 30 to 60 minutes. If there was symptom provoked, the test were stopped and interpreted as positive. If there was no symptom during this first course of DPT, a 100% of therapeutic dose of drug was administered 4 to 6 hours after the 3rd dose of test, and the symptom were observed for at least 8 hours after the last dose of test. Then the other kinds of drugs were tested to diagnose or offer a alternative drugs with the same method.

o symptom during this first course of DPT, a 100% of therapeutic dose of drug was administered 4 to 6 hours after the 3rd dose of test, and the symptom were observed for at least 8 hours after the last dose of test. Then the other kinds of drugs were tested to diagnose or offer a alternative drugs with the same method. Results 1. Profile and clinical characteristics of patients by history Thirteen (81%) out of 16 patients were males and 3 (19%) were females, making the male-female ratio 4.3:1. Median patient age are 9.1 years (range, 1 to 15 years), with 3 patients (19%) younger than 6 years, and 13 (81%) 6 years or older. The most frequent clinical pattern of ADR observed in these patients was skin rash, which occurred in 15 children (93%) followed by angioedema and anaphylaxis in 2 each (13%). Five (31%) patients have allergic rhinitis, 2 (13%) have bronchial asthma and 1 has atopic dermatitis as underlying diseases (Tables 1, 2). And 4 patients experienced angioedema or anaphylaxis as ADRs had underlying allergic disease such as allergic rhinitis or bronchial asthma (Table 2). As to severity, 3 (16%) patients showed severe ADR.

ave allergic rhinitis, 2 (13%) have bronchial asthma and 1 has atopic dermatitis as underlying diseases (Tables 1, 2). And 4 patients experienced angioedema or anaphylaxis as ADRs had underlying allergic disease such as allergic rhinitis or bronchial asthma (Table 2). As to severity, 3 (16%) patients showed severe ADR. Twelve out of 16 patients took the drug due to febrile illness or upper respiratory illness, before or during experienced ADRs. The most common drug suspected of causing ADRs, obtained from patient inquiry and assessment of medical records, was antibiotics in 13 patients (81%), including 6 (38%) with penicillin antibiotics, 5 (31%) with cephalosporin antibiotics, and 2 with (13%) macrolide antibiotics. Non-steroidal anti-inflammatory drugs (NSAIDs) were suspected in 7 children (44%), acetaminophen in 7 (44%), and enzyme (lactose) in 1 (Table 2). The onset time of ADRs was several minutes in 3 patients, less than 2 hours in 6 patients, and unknown in 7 patients.

rin antibiotics, and 2 with (13%) macrolide antibiotics. Non-steroidal anti-inflammatory drugs (NSAIDs) were suspected in 7 children (44%), acetaminophen in 7 (44%), and enzyme (lactose) in 1 (Table 2). The onset time of ADRs was several minutes in 3 patients, less than 2 hours in 6 patients, and unknown in 7 patients. 2. Drug provocation test The results of DPTs and skin tests were shown in Table 3. In 16 patients, 71 DPTs were performed using various drugs for confirm the causes of ADRs or finding alternative drugs. There were 17 (23.9%) positive DPTs results out of 71 individual DPTs. And 11 patients (68.75%) were positive to at least one drug. Drugs causing positive reactions were acetaminophen in 5 (31%), NSAIDs in 4 (25%), penicillin in 3 (19%), cephalosporin in 2 (13%), and cotrimoxazole, macrolide and lactose in 1 (6%) each (Fig. 1). When we assessed the correlation between the drug suspected of causing ADR based on clinical history and the result of DPT, we found that 4 of 8 patients with DPTs (50%) showed positive reactions to NSAIDs. In addition, 5 of 11 (45%) showed positive reactions to acetaminophen, 3 of 10 (30%) to penicillin antibiotics, 2 of 11 (18%) to cephalosporin antibiotics, 1 of 8 (12%) to macrolide antibiotics, 1 of 2 (50%) to cotrimoxazole and 1 of 1 (100%) to lactose.

f 8 patients with DPTs (50%) showed positive reactions to NSAIDs. In addition, 5 of 11 (45%) showed positive reactions to acetaminophen, 3 of 10 (30%) to penicillin antibiotics, 2 of 11 (18%) to cephalosporin antibiotics, 1 of 8 (12%) to macrolide antibiotics, 1 of 2 (50%) to cotrimoxazole and 1 of 1 (100%) to lactose. Among 16 patients, 8 (50%) had skin tests before the DPT test in order to estimate the putative severity of ADR for treatment with antibiotics. Three patients (patient 5, 6, and 12) showed positive reactions to the same drug in both the skin and drug provocation tests, whereas 2 patients (patient 8 and 11) were negative on the skin reaction tests but positive on the DPTs. Clinical symptoms indicating positive DPTs included skin rash in 11 of 16 (68%) patients, angioedema in 2 (18%), and pruritus in 2 (18%). In addition, dizziness, anaphylaxis, dyspnea, and abdominal pain accompanied by vomiting occurred in 1 each. In 4 patient who had angioedema or anaphylaxis by previous history of ADRs, only one DPT reproduced the similar symptoms and albeit milder. DPTs provoked dyspnea or hypotension in 2 patients who had only skin rashes by history of ADRs. In 7 patients with underlying allergic diseases, 5 (71.4%) patients were positive in DPTs. In 5 patients with ADRs were related to fever, all patients reproduced positive DPTs, and in 10 patients with ADRs related with upper respiratory infection symptom (URI), DPTs positive in 7 (70%) patients.

hes by history of ADRs. In 7 patients with underlying allergic diseases, 5 (71.4%) patients were positive in DPTs. In 5 patients with ADRs were related to fever, all patients reproduced positive DPTs, and in 10 patients with ADRs related with upper respiratory infection symptom (URI), DPTs positive in 7 (70%) patients. Discussion The major result of this study is that positive DPT result occurred in 11 (69%) patients in 16 patients with a history of ADRs. According to the individual DPTs, there were 17 (23.9%) positive DPTs in 71 events of DPTs. In this study the positive rate of DPTs are relatively higher than those of other studies7,13). In one retrospective study performed in children and adult ADRs, they confirmed that 241 (17.6%) of 1,372 patients were positive on the drug provocation test7).

DPTs, there were 17 (23.9%) positive DPTs in 71 events of DPTs. In this study the positive rate of DPTs are relatively higher than those of other studies7,13). In one retrospective study performed in children and adult ADRs, they confirmed that 241 (17.6%) of 1,372 patients were positive on the drug provocation test7). In our study, we found that the majority of ADRs were due to antipyretics or NSAIDs which were used to manage febrile illness for control of proportion of positive test results was higher for NSAIDs (50%) and acetaminophen (45%) than for penicillin antibiotics (30%), cephalosporin antibiotics (18%) and macrolide antibiotics (12%). This result is similar to previous study that aspirin (47.2%), other NSAIDs (27.3%) than for macrolides (13.7%), and β-lactams (8.4%)7). A negative drug provocation test result is important to the patient with suspected drug allergy because reduce the meaningless avoidance suspicious drugs in the future. The DPT result may have been falsely negative in some patients with mild sensitivity or a long delay between drug hypersensitivity reaction and allergy evaluation. For these reason we require more careful attention to analyzed DPT in many cases. Especially in children, there is a tendency that mild ADRs are under documented in the patients' record, while there are over diagnosis of ADRs because of the general occurrence of rashes are common during a course of febrile illness in children7,9,11). However, in our study, febrile illness or URI did not cause false positive history of ADRs in patients, because 100% and 70% of patients with fever or URI showed positive reactions by DPTs which performed disease free or fever free conditions in all patients. While DPT is still the gold standard for identification of a causative drugs, a complete work-up is required to diagnose drug hypersensitivity: a detailed clinical history and physical examination, followed by 1 or more skin tests combine with DPT, measurement of tryptase of histamine in some cases10-15). Because of the discrepancy between ADR history and result from DPT, it is important to perform DPT for correct diagnosis and avoiding over diagnosis of ADRs, even though every ADR patients cannot be performed DPTs for diagnosis.

more skin tests combine with DPT, measurement of tryptase of histamine in some cases10-15). Because of the discrepancy between ADR history and result from DPT, it is important to perform DPT for correct diagnosis and avoiding over diagnosis of ADRs, even though every ADR patients cannot be performed DPTs for diagnosis. Drug hypersensitivities may be manifested by various symptoms in different organs, with skin reaction being the most common2,16). We found that 15 of 16 (93%) of our patients with ADR presented with skin lesions in detailed medical history before drug provocation tests. In our study, clinical symptoms indicating positive DPTs included skin rash in 11 of 16 (68%) patients, angioedema in 2 (18%), and pruritus in 2 (18%). In addition, dizziness, anaphylaxis, dyspnea, and abdominal pain accompanied by vomiting occurred in 1 each, and these results are similar patterns to other studies7,13). Because drug allergies may involve organs other than the skin and skin lesions may appear in various patterns, the presence of a skin lesion per se is not helpful in diagnosing the allergy or determining its method of treatment17).

miting occurred in 1 each, and these results are similar patterns to other studies7,13). Because drug allergies may involve organs other than the skin and skin lesions may appear in various patterns, the presence of a skin lesion per se is not helpful in diagnosing the allergy or determining its method of treatment17). A DPT is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions and identify a alternative drug in patient with ADR to specific drug. While there are some modification of method of doses to perform DPTs, there are recommended general considerations DPTs2,10,12). In general, DPTs start with a challenge with a low dose of drug, followed by gradual increases. In our hands, DPTs were effective and safe. With careful selection of patients, the progressive administration of the drug with a small starting dose, and strict medical surveillance, no positive reaction was too severe to respond promptly to treatment.

challenge with a low dose of drug, followed by gradual increases. In our hands, DPTs were effective and safe. With careful selection of patients, the progressive administration of the drug with a small starting dose, and strict medical surveillance, no positive reaction was too severe to respond promptly to treatment. Theoretically, skin tests for antibiotics assay for immunoglobulin E (IgE)-mediated adverse reactions18). However, in most patients, it is impossible to distinguish between IgE-mediated and non-IgE-mediated allergic reactions19). For example, among patients positive for penicillin skin reactions, 33% did not have a previous history of penicillin allergy20), and ADR after the administration of penicillin was not observed in 60.9% of patients positive on penicillin skin tests, with only a very small number of patients showing mild reactions during oral provocation tests12). In our study, three patients (patient 5, 6, and 12) showed positive reactions to the same drug in both the skin and DPTs, whereas 2 patients (patient 8 and 11) were negative on the skin reaction tests but positive on the DPTs. About 0 to 10% of such patients are resensitized; that is, they are negative on a first skin reaction test but positive on a subsequent skin reaction test21-23). These changes, however, are not relevant to the frequency of ADR in DPTs and cannot explain the discrepancy between the results of skin reaction and DPTs2). It is generally inadvisable to administer a drug to patients positive on skin tests22), but some may have been positive on a previous skin reaction test and then became negative; these patients may not experience ADRs, even after administration of the optimal dose in DPTs2,22).

the results of skin reaction and DPTs2). It is generally inadvisable to administer a drug to patients positive on skin tests22), but some may have been positive on a previous skin reaction test and then became negative; these patients may not experience ADRs, even after administration of the optimal dose in DPTs2,22). Because this study was performed retrospectively based on patient medical record, patients could be omitted by the incomplete or incorrect records. The major result of this study is that positive DPT result occurred in 69% patients with a history suggesting possible drug allergy, and we identified that the exact cause of drug for ADR in patients experienced ADRs to more than one kind of drugs at the same time. And we found that proportion of positive test results was higher for NSAIDs and acetaminophen than for other antibiotics. There was discrepancy between the results of skin reaction and DPT, we need more study about drug provocation test and guidelines for diagnosis of drug allergy. In conclusion, we performed 71 DPTs in 16 ADR patients, and confirmed causative drugs of ADRs, and identified safe drugs even though suspicious medical history of ADRs. We also confirmed DPT is a useful and safe tool for diagnose drug hypersensitivity in some patients with ADRs need to identify real causative drugs or alternative drugs.

performed 71 DPTs in 16 ADR patients, and confirmed causative drugs of ADRs, and identified safe drugs even though suspicious medical history of ADRs. We also confirmed DPT is a useful and safe tool for diagnose drug hypersensitivity in some patients with ADRs need to identify real causative drugs or alternative drugs. Fig. 1 Drugs causing positive reactions were acetaminophen in 5 (31%), non-steroidal antiinflammatory drugs (NSAIDs) in 4 (25%), penicillin in 3 (19%), cephalosporin in 2 (13%), and cotrimoxazole, macrolide and lactose in 1 (6%) each. AAP, acetaminophen. *NSAIDs include aspirin and ibuprofen in this study. Table 1 Clinical Profiles of Patients Table 2 Characteristics of Patients According to Detailed Clinical History UPN, unique patient number; ADR, adverse drug reaction; URI, upper respiratory infection symptom; AAP, acetaminophen. *NSAID, non-steroidal antiinflammatory drug, and NSAIDs include aspirin and ibuprofen in this study. Table 3 Results of the Drug Provocation Test UPN, unique patient number; AAP, acetaminophen.

Introduction Magnesium (Mg) is the fourth most common cation and the second most common intracellular cation1,2). Mg is necessary for muscle contraction and neuronal transmission, and also acts as a cofactor for carbohydrate, protein and energy metabolism1,3,4). Newborn infants with hypermagnesemia might present with respiratory depression, hypotonia, hypotension, and bradycardia mimicking septic shock syndrome5) or gastrointestinal hypomotility mimicking intestinal obstruction6). Neonatal hypermagnesemia can be caused by increased Mg load such as with maternal Mg sulfate administration, newborn Mg therapy7,8), or decreased renal Mg excretion due to prematurity and asphyxia9). However, there is one case report of non-oliguric idiopathic hypermagnesemia developing in a premature infant5). Here, the second case of extreme hypermagnesemia of unknown etiology in an extremely low birth weight infant is reported.

rn Mg therapy7,8), or decreased renal Mg excretion due to prematurity and asphyxia9). However, there is one case report of non-oliguric idiopathic hypermagnesemia developing in a premature infant5). Here, the second case of extreme hypermagnesemia of unknown etiology in an extremely low birth weight infant is reported. Case report A female infant was born at 27 weeks of gestation with a birth weight of 990 g as a result of premature rupture of membranes and preterm labor. The infant was delivered by spontaneous vaginal delivery, and the Apgar scores at 1 and 5 minutes were 5 and 8, respectively. The baby was intubated and treated with exogenous surfactant for respiratory distress syndrome after admission to the neonatal intensive care unit (NICU). The patient was started on 125 g/L dextrose solution with calcium gluconate, 300 mg/kg per day of body weight per day. The patient was relatively stable and active until 14 hour after birth, when sudden respiratory depression and apnea developed. On physical examination, the patient with plethora was hypotonic with no spontaneous movement. She was afebrile with a body temperature of 36.3℃, and the deep tendon reflexes were diminished. The heart rate decreased from 130 to 140 beats per minute to 80 to 90 beats per minute, and the blood pressure was also decreased from 38/27 mmHg to 32/21 mmHg. Pertinent laboratory data indicated that the patient was severely hypermagnesemic (Table 1). An electrocardiogram was consistent with sinus bradycardia, the head ultrasound were negative for hemorrhage. Complete blood cell counts were: hemoglobin level, 15.4 g/L; hematocrit, 0.479 and; white blood cell count, 8,020/L with 17% neutrophils, 68% lymphocytes; the platelet count, was 239,000/L; the blood urea nitrogen (BUN) and creatinine (Cr) were within normal limits, and the blood cultures were negative. Urine output before the onset of symptoms was normal, transiently decreased for a few hours, and then increased thereafter. There was no history of exposure to magnesium containing compounds administered to either the mother or the baby on the delivery floor or in the NICU. The mother's blood magnesium level was normal (2.3 mg/dL). After the diagnosis of severe hypermagnesemia, treatments with intravenous calcium gluconate, hydration and diuretics were started without symptomatic improvement; the serum Mg concentration remained high.

other or the baby on the delivery floor or in the NICU. The mother's blood magnesium level was normal (2.3 mg/dL). After the diagnosis of severe hypermagnesemia, treatments with intravenous calcium gluconate, hydration and diuretics were started without symptomatic improvement; the serum Mg concentration remained high. Next, a double volume exchange transfusion with a unit of blood was performed for a rapid decrease of the serum Mg level. Immediately after the exchange transfusion, spontaneous movement was observed, and the bradycardia and hypotension improved in association with the rapid decrease in the serum Mg level (Table 1). Once the patient became hemodynamically stabilized with adequate renal function, there was a continuous decline in the serum Mg level reaching normal values in five days (Fig. 1). The patient was extubated on day 6 and the rest of the hospital stay was uneventful. The baby was discharged on day 65.

Mg level (Table 1). Once the patient became hemodynamically stabilized with adequate renal function, there was a continuous decline in the serum Mg level reaching normal values in five days (Fig. 1). The patient was extubated on day 6 and the rest of the hospital stay was uneventful. The baby was discharged on day 65. Discussion Neonatal hypermagnesemia most commonly occurs after maternal Mg sulfate treatment for preeclampsia10,11). However, in this case, the mother did not have Mg sulfate therapy. Furthermore, no Mg therapy such as parenteral nutrition, antacids, or enemas was performed in the baby. The possibility of exogenous magnesium was considered, but there was no record of magnesium having been administered to the infant and no magnesium - containing fluid in our unit. These findings exclude an increased Mg load as the cause of hypermagnesemia in this patient. Although, the baby was very premature, the initial blood gas was normal and the renal functions including BUN, Cr and urine output during the first 12 hours after birth were normal. These findings exclude decreased renal Mg excretion due to prematurity and asphyxia as the cause of hypermagnesemia in this baby. Taken together, the patient was diagnosed with acute severe hypermagnesemia of unknown etiology.

nctions including BUN, Cr and urine output during the first 12 hours after birth were normal. These findings exclude decreased renal Mg excretion due to prematurity and asphyxia as the cause of hypermagnesemia in this baby. Taken together, the patient was diagnosed with acute severe hypermagnesemia of unknown etiology. Potassium is a major intracellular cation, and non-oliguric hyperkalemia observed in extremely low birth weight infants during the first 24 hours after birth might be due to a shift of potassium from the intracellular space to the extracellular space associated with a decrease in Na+, K+-ATPase activity12). Mg is also an essential intracellular cation1). Non-oliguric hypermagnesemia developed in this patient and a patients previously reported5). Overall, these findings suggest the possibility that the idiopathic hypermagnesemia might be attributable to an abnormal massive shift of Mg from the intracellular fluid to the extracellular fluid, and perturbations in the Mg influx/efflux regulation systems13). Further studies are necessary to confirm this possibility.

verall, these findings suggest the possibility that the idiopathic hypermagnesemia might be attributable to an abnormal massive shift of Mg from the intracellular fluid to the extracellular fluid, and perturbations in the Mg influx/efflux regulation systems13). Further studies are necessary to confirm this possibility. Although a decreased anion gap might be an indicator of hypermagnesemia, a normal anion gap, as observed in this case, has no documented negative predictive value for the diagnosis of hypermagnesemia14). The finding of transiently reduced parathyroid hormone (PTH) level during severe hypermagnesemia supports the assumption that hypermagnesemia might suppress PTH production and result in lower serum calcium (Ca) concentrations15). Furthermore, the transiently increased ionized Ca (iCa), before the exchange transfusion, suggests that hypermagnesemia might displace bound Ca in the circulation and cause the elevation of the serum iCa concentration. Clinical signs of neuromuscular depression with floppiness, lethargy, and respiratory depression are frequent manifestations of severe neonatal hypermagnesemia9,10). Acute hypotonia, apnea, hypotension, and refractory bradycardia mimicking a septic shock like syndrome have been reported in premature infants accidentally overdosed with Mg in the parenteral nutrition8).

oppiness, lethargy, and respiratory depression are frequent manifestations of severe neonatal hypermagnesemia9,10). Acute hypotonia, apnea, hypotension, and refractory bradycardia mimicking a septic shock like syndrome have been reported in premature infants accidentally overdosed with Mg in the parenteral nutrition8). Treatments such as intravenous calcium gluconate infusion, adequate hydration and loop diuretics were useful in newborn with mild hypermagnesemia with good renal function. Dialysis or exchange transfusion are effective in reducing the serum Mg level and ameliorating the clinical signs of severe hypermagnesemia. Huey et al.5) reported a newborn case with idiopathic extreme hypermagnesemia successfully treated with exchange transfusion. As dialysis is not technically feasible in these micropremies, exchange blood transfusion might be the best therapeutic option for treating severely depressed hypermagnesemic infants5). Citrated donor blood is particularly useful because it will accelerate Mg removal from the baby9). However, hypocalcemia can occur as a common adverse event of exchange transfusion due to the presence of citrate. Thromocyptopenia, metabolic acidosis, bradycardia, apnea and hyponatremia are other complication, and should be monitored16).

od is particularly useful because it will accelerate Mg removal from the baby9). However, hypocalcemia can occur as a common adverse event of exchange transfusion due to the presence of citrate. Thromocyptopenia, metabolic acidosis, bradycardia, apnea and hyponatremia are other complication, and should be monitored16). Hypermagnesemia has been suggested as a poor prognostic factor; it is associated with a higher mortality rate in critically ill pediatric patients17). However, transient neonatal hypermagnesemia even in severely symptomatic cases has not been associated with long term sequelae8,18). These findings suggest that clinical suspicion, early diagnosis, prompt and appropriate treatment is key factors for the survival and improved outcome in newborns with severe hypermagnesemia. Fig. 1 Serum magnesium concentration of our patient at various times after birth. Mg, magnesium. Table 1 Time Course of Patient's Laboratory Data PTH, parathyroid hormone. *On admission. †At the time of the event (14 hours). ‡After the exchange transfusion (24 hours). §On the sixth day after birth.

Introduction Reactive arthritis is a sterile arthritis triggered by distant gastrointestinal or urogenital infections, often with some latency. Its genesis suggests that bacterial products contribute to the induction of reactive arthritis1). The pathogenesis of reactive arthritis is incompletely understood, and no optimal treatment is available. Salmonella, Shigella, Yersinia , and Campylobacter spp. infections are implicated in the triggering of enteric reactive arthritis. When the arthritis begins, stool cultures are usually negative, and physicians have usually confirmed the background of reactive arthritis via serological methods2). The incidence of Salmonella-induced reactive arthritis varies greatly, from 5 to 14 per 100,000 persons3). In some patients, symptoms resolve within months, but in others, the symptoms may persist for years. HLA-B27 is the strongest predisposing factor of reactive arthritis. The mechanism by which HLA-B27 mediates inflammation remains unclear4). Reactive arthritis commonly affects persons between 15 to 35 years of age, and it rarely occurs in children5). Only one case of Salmonella-triggered reactive arthritis in a Korean child has been reported6). The objective of this case report is to demonstrate the clinical course and laboratory findings of human leukocyte antigen (HLA)-B27-associated reactive arthritis in a 12-year-old boy after Salmonella enteritis.

children5). Only one case of Salmonella-triggered reactive arthritis in a Korean child has been reported6). The objective of this case report is to demonstrate the clinical course and laboratory findings of human leukocyte antigen (HLA)-B27-associated reactive arthritis in a 12-year-old boy after Salmonella enteritis. Case report A 12-year-old boy was admitted to Pusan National University Hospital for further examination of multiple sites of arthralgia and arthritis. He had presented at the local clinic after experiencing fever, diarrhea, and abdominal pain for 5 days, for which he had received successful treatment. One week after the onset of the enteritis, he developed arthralgia of the bilateral sacroiliac, wrist, and ankle joints. He had balanitis without urethral discharge, hematuria, or genital ulcers. He had never received a blood transfusion and had no history of sexual contact. On admission, his body temperature was 38℃, pulse was 115 beats/min, and blood pressure was 110/70 mmHg. Physical examination revealed swelling and tenderness of left ankle joint (Fig. 1) and, tenderness on motion and pain over the bilateral wrist and left sacroiliac joints. Other joints were normal. Other systemic examinations were normal. Cardiac auscultation was normal. Laboratory studies showed hemoglobin of 12.8 g/dL, white blood cell count of 21,860/mm3, platelet count of 573,000/mm3, an erythrocyte sedimentation rate (ESR) of 74 (0 to 15) mm/hr, and C-reactive protein (CRP) of 3.97 (0 to 0.5) mg/dL. Liver and renal function tests showed no abnormalities. Venereal disease research laboratory and anti-nuclear antibody tests were negative. Urinalysis revealed pyuria, but bacterial culture of urine sample was negative. HLA class I serotyping was positive for B27. We aspirated synovial fluid from the patient's left ankle and left hip joint, which revealed severe inflammation, but Gram staining and culturing of this synovial fluid gave negative results. The stool culture was positive for Salmonella group D. Radiographs of the ankle joint showed only soft tissue swelling, without any visualization of enthesopathic lesions or erosive joint damage. In bone scintigraphy, uptake in the left ankle and sacroiliac joints and right wrist joint was increased (Fig. 2). Considering the clinical features, the preceding symptomatic enteritis, and the positive stool culture for Salmonella group D, we proposed a diagnosis of reactive arthritis.

esions or erosive joint damage. In bone scintigraphy, uptake in the left ankle and sacroiliac joints and right wrist joint was increased (Fig. 2). Considering the clinical features, the preceding symptomatic enteritis, and the positive stool culture for Salmonella group D, we proposed a diagnosis of reactive arthritis. Initially, we treated the patient with nonsteroidal anti-inflammatory drug (NSAID) (naproxen, 500 mg every 12 hour) for 7 days, but there was not significant improvement. We added prednisolone (10 mg every 8 hour). He responded well to this treatment. Discussion Hans Conrad Reiter reported an early case of urethritis, conjunctivitis, and arthritis associated with spirochete infection3). However, he was responsible for involuntary sterilizations, coerced euthanasia, and medical experiments that outraged many people. Thus, researchers have strongly recommended the name "reactive arthritis" instead of "Reiter's syndrome" due to Reiter's unethical background7).

itis associated with spirochete infection3). However, he was responsible for involuntary sterilizations, coerced euthanasia, and medical experiments that outraged many people. Thus, researchers have strongly recommended the name "reactive arthritis" instead of "Reiter's syndrome" due to Reiter's unethical background7). Reactive arthritis is a sterile synovitis triggered by a distant infection of the genitourinary or gastrointestinal tract. Researchers have proposed its classification into HLA-B27-associated and non-associated forms2) and have observed a number of other clinical features in association with reactive arthritis. According to the American Rheumatism Association criteria, patients with reactive arthritis generally have asymmetric polyarthritis that lasts at least 1 month, as well as 1 or more of the following features: urethritis, inflammatory eye disease, mouth ulcers, balanitis, or radiographic evidence of sacroilitis, periostitis, or heel spurs8).

can Rheumatism Association criteria, patients with reactive arthritis generally have asymmetric polyarthritis that lasts at least 1 month, as well as 1 or more of the following features: urethritis, inflammatory eye disease, mouth ulcers, balanitis, or radiographic evidence of sacroilitis, periostitis, or heel spurs8). The present patient developed asymmetric arthritis, balanitis, and pyuria. No features suggestive of cardiovascular, nervous, or pulmonary involvement were present. Generally, the diagnosis of reactive arthritis is clinical; there are no definite diagnostic laboratory tests or radiographic findings. In the present case, apart from the elevated ESR, CRP, and neutrophilic leukocytosis, which suggested a bacterial infection, all laboratory investigation results were negative. Reactive arthritis cases commonly show elevated ESR and acute phase reactants. In addition, reactive arthritis is closely associated with HLA-B27, and our patient was positive for HLA-B27. HLA-B27 antigen, one of the factors contributing to the disease's development, increases the disease risk, and 70 to 80% of patients with reactive arthritis have this antigen2,3). HLA-B27 probably shares some molecular characteristics with bacterial epitopes; researchers have suggested an autoimmune cross-reaction takes part in its pathogenesis3).

actors contributing to the disease's development, increases the disease risk, and 70 to 80% of patients with reactive arthritis have this antigen2,3). HLA-B27 probably shares some molecular characteristics with bacterial epitopes; researchers have suggested an autoimmune cross-reaction takes part in its pathogenesis3). The etiology of reactive arthritis is still incompletely understood. However, reportedly the development of reactive arthritis is closely associated with certain bacterial infections, including Salmonella, Shigella, Yersinia, and Chlamydia2,3). We noted that the present patient had Salmonella enteritis prior to reactive arthritis onset. General treatment of reactive arthritis still most commonly employs NSAIDs and sulfasalazine2,3). Steroids are administered when the patient's inflammatory symptoms are resistant to the NSAIDs. Experience with other disease-modifying antirheumatic drugs, such azathioprine, methotrexate, and cyclosporin, can be useful in treating patients who are unresponsive to the more usual medications. In more aggressive cases, TNF-alpha blockers could be an effective choice. Our patient showed a good response to NSAID and prednisone treatment2,3,9).

e-modifying antirheumatic drugs, such azathioprine, methotrexate, and cyclosporin, can be useful in treating patients who are unresponsive to the more usual medications. In more aggressive cases, TNF-alpha blockers could be an effective choice. Our patient showed a good response to NSAID and prednisone treatment2,3,9). The course of reactive arthritis probably varies considerably, depending on the triggering pathogen, the patient's genetic background and gender, and the presence of recurrent arthritis3). Most patients remit completely or have little active disease 6 months after presentation. A European League Against Rheumatism study of 152 patients with reactive arthritis, who were enrolled within 2 months of the onset of arthritis, illustrated this well10). By the end of an additional 24 weeks of observation, almost all patients had very low disease activity, as determined by physician and patient global assessments. After entering peripheral joint arthritis remission, patients occasionally note pain in the joints, at entheses, or in the spine. Chronic persistent arthritis, lasting more than 6 months, occurs in only a small proportion of patients. Children with reactive arthritis, who are positive for HLA-B27, have more severe involvement than children who are negative for HLA-B2811). Fig. 1 These picture show swelling of left ankle joint (A) and normal right ankle joint (B). Fig. 2 99mTc-methylene diphosphonate bone scan shows increased uptake in left sacroiliac, right wrist and left ankle joint.

Introduction An infant's crying has 2 possible consequences: it may elicit tenderness and desire to sooth, or helplessness and rage. It can be a signal that encourages attachment or one that jeopardizes the early relationship by triggering depression and, in some cases, even neglect or abuse. According to the Heird, colic is a symptom complex of paroxysmal abdominal pain, presumably of intestinal origin, and severe crying. It usually occurs in infants younger than 3 months of age1). The paroxysms may persist for several hours. The fact that the condition rarely persists beyond 3 months of age should be reassuring. However, the more persistent problems of colicky babies have recently been given a new name: disorders of behavioral and emotional regulation. The clinical evidence of these disorders is observed during the first years of life within the developing systems of parent- infant communication, attachment, and early relationships. They comprise a wide spectrum of behavioral syndromes ranging from early excessive crying, sleep and feeding disorders, failure to thrive, and problems of attention and emotional regulation, to disturbances in the regulatory balance between attachment and exploration and/or between dependence and autonomy in the second and third years of life2,3).

of behavioral syndromes ranging from early excessive crying, sleep and feeding disorders, failure to thrive, and problems of attention and emotional regulation, to disturbances in the regulatory balance between attachment and exploration and/or between dependence and autonomy in the second and third years of life2,3). They are characterized by the co-occurrence or sequential occurrence of different behavioral syndromes. Many problems that typically emerge during the second half-year of life or in later phases of early childhood development actually have precursors in the first half-year, mostly in the form of excessive crying and dysfunctional sleep-wake organization. Without timely intervention, these early disorders tend to persist and to pervade other behavioral domains. It is therefore important not to underestimate early excessive crying and to offer timely help with targeted counseling or even parent-infant psychotherapy. Critical moments in childhood development Fig. 1 lists some of the developmental and behavioral problems that are often observed during the first few years of life. Each problem tends to occur most frequently at a particular age4). For example, excessive crying typically occurs during the first 3 months; biting, scratching, or hitting other children is more likely to be seen when a child is between 2 and 5 years old.

lems that are often observed during the first few years of life. Each problem tends to occur most frequently at a particular age4). For example, excessive crying typically occurs during the first 3 months; biting, scratching, or hitting other children is more likely to be seen when a child is between 2 and 5 years old. According to the scientific literature, development in infancy is not continuous, but alternates between periods of consolidation and development spurts that are also termed biobehavioral shifts, touchpoints, critical steps, or periods of qualitative transition. The concept of touchpoints5) postulates sensitive periods shortly before each impending developmental shift (around 3, 9, 12, and 18 months), in which critical regulatory tasks must be completed. The predominance of certain syndromes at certain ages and the age-related course of these syndromes coincide remarkably well with the postulated touchpoints6). Each developmental phase places new demands on the infant's capacity to regulate, which depends on the structural and functional maturity of the brain as well as the accumulated experiences that have already been integrated. The first biopsychosocial shift promotes regulation at a higher level of integration around the ages of 2 and 3 months. Emde and Osofsky7) have stressed the emerging social capabilities (persistent eye contact, social smiling, and melodious cooing) as the "awakening of sociability." This preverbal communication provides a framework for practicing reciprocal regulation of attention, positive affective arousal, and self-efficacy.

months. Emde and Osofsky7) have stressed the emerging social capabilities (persistent eye contact, social smiling, and melodious cooing) as the "awakening of sociability." This preverbal communication provides a framework for practicing reciprocal regulation of attention, positive affective arousal, and self-efficacy. Another developmental shift occurs in the middle of the second half-year (around 9 months), during which canonical babbling begins, and object permanence, intentionality, fear of strangers, and crawling, among other things, occur at more or less the same time8). The beginning of independent locomotion allows for the child's growing need for exploration, as well as its opposite: an increased need for closeness. A third biopsychosocial developmental shift begins around the middle of the second year of life and brings with it new regulatory challenges for both toddlers and parents. Independent walking offers a child an almost limitless range of exploration. Symbolic play and a spurt in vocabulary mark new levels of symbolization, language-mediated integration of experience, imagination, and representations of the self and attachment figures. At a motivational level, the interplay between the growing need for autonomy and the need for reassurance is first and foremost; in communication, it is the balance between dependency and autonomy, and the negotiation of social rules and limits.

ence, imagination, and representations of the self and attachment figures. At a motivational level, the interplay between the growing need for autonomy and the need for reassurance is first and foremost; in communication, it is the balance between dependency and autonomy, and the negotiation of social rules and limits. Database of the Munich interdisciplinary research and intervention program for fussy babies Between the opening of the Munich program in 1991 and 2004, approximately 3,000 families were referred for diagnostic assessment, counseling, and treatment of fussy babies. The data of 701 families was analyzed9). 1. Clinical syndromes of behavioral and emotional regulation At the first visit, the most frequent problems that concerned parents were sleep disorders; feeding disorders; dysphoric fussiness/disinterest in play (hereafter referred to as dysphoric fussiness); excessive crying; dysfunctional sleep-wake organization; excessive temper tantrums with conflicts over limit setting (hereafter referred to as excessive defiance); excessive clinginess with anxiety, social withdrawal, and/or intense separation anxiety (hereafter referred to as excessive clinginess); and aggressive/oppositional behavior (Table 1)9). Most of the behavioral problems of early childhood are not distributed evenly across all ages, but are clustered in particular developmental phases. For example, excessive crying and dysfunctional sleep-wake organization are more or less confined to the first half-year of life, whereas sleep disorders were, by definition, diagnosed only above the age of 6 months.

dhood are not distributed evenly across all ages, but are clustered in particular developmental phases. For example, excessive crying and dysfunctional sleep-wake organization are more or less confined to the first half-year of life, whereas sleep disorders were, by definition, diagnosed only above the age of 6 months. 2. Phase specificity of clinical syndromes The predominance of certain syndromes at certain ages and the age-related course of these syndromes coincide remarkably well with the postulated touchpoints9). For example, excessive crying predominates during the first 3 months (97.3% of that age group), during which postnatal adjustments and maturation of physiological processes are predominant. This behavior is being seen less frequently over the rest of the first year. Dysphoric fussiness increases in frequency over the first 9 months, and thus seems to replace excessive crying. The rapid increase in the frequency of dysphoric fussiness, up to its peak in the middle of the second half-year, coincides with a developmental phase in which affective and attentional regulatory processes and exploratory needs are predominant during the waking state. Dysfunctional sleep-wake organization is typically associated with excessive crying in the first 3 months (95.5% of age group). At around the sixth month of life, diurnal problems of sleep-wake organization give way to nighttime sleep disorders, which are the most frequent diagnoses in all age cohorts.

Dysphoric fussiness increases in frequency over the first 9 months, and thus seems to replace excessive crying. The rapid increase in the frequency of dysphoric fussiness, up to its peak in the middle of the second half-year, coincides with a developmental phase in which affective and attentional regulatory processes and exploratory needs are predominant during the waking state. Dysfunctional sleep-wake organization is typically associated with excessive crying in the first 3 months (95.5% of age group). At around the sixth month of life, diurnal problems of sleep-wake organization give way to nighttime sleep disorders, which are the most frequent diagnoses in all age cohorts. Excessive clinginess peaks during the fourth quarter of the first year (21.4% of the age group) and it remains a reason for referral during the second year. Excessive clinginess appears as the child's attachment to his primary caregivers becomes established, and fear of strangers and separation anxiety emerge. 3. Early signs of later clinical syndromes Investigators found associations between excessive crying during the first months of life and later behavioral problems, such as feeding problems in the first and second years of life10) and sleep disorders in the second11) and third years of life12).

Excessive clinginess peaks during the fourth quarter of the first year (21.4% of the age group) and it remains a reason for referral during the second year. Excessive clinginess appears as the child's attachment to his primary caregivers becomes established, and fear of strangers and separation anxiety emerge. 3. Early signs of later clinical syndromes Investigators found associations between excessive crying during the first months of life and later behavioral problems, such as feeding problems in the first and second years of life10) and sleep disorders in the second11) and third years of life12). Wurmser and Papousek9) found clear indications that the clinical syndrome of excessive crying in early infancy is a precursor of clinically significant behavioral and emotional problems at 30 months. According to their data, excessive crying and feeding disorders also preceded later sleep disorders in 64.3% and 20.0% of infants, respectively. Excessive crying and dysfunctional sleep-wake organization preceded later feeding disorders in 55.5% and 59.2% of cases, respectively. Moreover, excessive crying in combination with dysfunctional sleep-wake organization was also evident within the first half-year of life in children with later excessive clinginess (69.5% of 82) and excessive defiance (64.8% of 142).

ganization preceded later feeding disorders in 55.5% and 59.2% of cases, respectively. Moreover, excessive crying in combination with dysfunctional sleep-wake organization was also evident within the first half-year of life in children with later excessive clinginess (69.5% of 82) and excessive defiance (64.8% of 142). Excessive crying in infancy The core symptoms of excessive crying in infants include unexplained, inconsolable crying and long episodes of inexplicable fussiness. Paroxysmal bouts of severe crying, with flexed knees, hypertonic extremities, overinflated abdomen, reddened face, and shrill hyperphonic crying, that do not respond to the usual soothing interventions, naturally make one suspect abdominal pain13). Many of these infants do not snuggle, but instead resist close body contact as if they were trying to struggle against their mother. 1. Definition and diagnostic criteria According to international consensus, the scientific criteria for differentiating between normal and excessive crying at the age of 6 weeks draw on the "rules of threes": crying and fussing for more than 3 hours a day, for more than 3 days a week, and for more than 3 weeks, in an infant who is well-fed and otherwise healthy14). The syndrome is more appropriately classified as a syndrome of excessive crying and an age-related subgroup of disorders of behavioral and emotional regulation in early childhood. The term "persistent excessive crying" is used when the problem persists beyond the age of 3 months2,3).

well-fed and otherwise healthy14). The syndrome is more appropriately classified as a syndrome of excessive crying and an age-related subgroup of disorders of behavioral and emotional regulation in early childhood. The term "persistent excessive crying" is used when the problem persists beyond the age of 3 months2,3). The clinical syndrome of excessive crying is characterized by a triad of symptoms. The diagnostic triad includes: 1) the infant's inconsolable crying with problems in sleep-wake organization, 2) the parents' overload and psychosocial distress, and 3) frequent interactional failure that maintains or exacerbates the behavioral problems15). Excessive crying that persists beyond the developmental spurt expected at the age of approximately 3 months takes on new qualities, depending on the infant's progress in self-regulatory capacities. In addition, problematic crying shifts increasingly to nighttime, when the infant should be asleep. Persistent excessive crying should therefore be distinguished from excessive crying during the first few months of life. The prevalence of excessive crying during the first 3 months in representative community-based samples has been reported to range between 16% and 29%15-17).

Excessive crying that persists beyond the developmental spurt expected at the age of approximately 3 months takes on new qualities, depending on the infant's progress in self-regulatory capacities. In addition, problematic crying shifts increasingly to nighttime, when the infant should be asleep. Persistent excessive crying should therefore be distinguished from excessive crying during the first few months of life. The prevalence of excessive crying during the first 3 months in representative community-based samples has been reported to range between 16% and 29%15-17). 2. A developmental dynamic systems model of the origins and maintenance of excessive crying The most frequent emotional effects of inconsolable crying on the parent and other caregivers are summarized in Fig. 2. For example, the mother will exhibit all the signs of chronic exhaustion and overload as a consequence of persistent alarm and sleep deficit. The repeated daily experiences of infant inconsolability induce feelings of failure, diminished self-esteem, powerlessness, and depression. Almost all affected parents confess that feelings of helplessness in the face of increasing arousal and alarm occasionally turn into a state of aggressive feelings and powerless rage toward the infant, impulses that in turn evoke intense feelings of guilt and make the parents increasingly vulnerable. The intensity of aroused feelings may finally become fertile ground for the revival of latent conflicts with the partner or other family members, or over the mother's abandoned professional career. Moreover, memories and feelings of abandonment, fear, or rage experienced during the parents' own childhood may easily be evoked in this context.

d feelings may finally become fertile ground for the revival of latent conflicts with the partner or other family members, or over the mother's abandoned professional career. Moreover, memories and feelings of abandonment, fear, or rage experienced during the parents' own childhood may easily be evoked in this context. Hypersensitized by the crying, these parents barely perceive the subtle signals from the infant during more quiet states of alertness, thereby missing opportunities to enter into relaxed dialogue and play. As a consequence, the dysregulated infants will miss the intuitive regulatory support from their parents. 3. Counseling and treatment model of the Munich program Developmental counseling, psychological and physical relief for the parents, guidance in parent-infant communication, and parent-infant psychotherapy were provided. After conclusion of treatment, the condition was fully improved in 48.4% of the patients and largely improved in 44.2% of the patients, that is, an overall success rate of 92.6%. Conclusions Persistence of crying beyond the first 3 months predicts a higher prevalence of behavioral and emotional disorders in children with excessive crying than in children without excessive crying. It is therefore important to offer timely help through developmental counseling, physiotherapy, or even parent-infant psychotherapy. Fig. 1 Typical developmental difficulties during the early years. Fig. 2 Effects of inconsolable crying on parents and other caregivers. Table 1 Disorder of Behavioral and Emotional Regulation in Early Childhood (n=701)

Introduction Acute disseminated encephalomyelitis (ADEM) is an immune mediated disease of the central nervous system (CNS) that produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. ADEM should be distinguished from other central inflammatory demyelinating disorders of children, including multiple sclerosis (MS) and clinically isolated syndromes that include optic neuritis, transverse myelitis, and neuromyelitis optica (Devic's disease). Most of these disorders are thought to be caused by immune system dysregulation triggered by an infectious or other environmental agent in a genetically susceptible host. ADEM is often preceded by a viral or bacterial infection, usually in the form of a nonspecific upper respiratory infection. In 3 previous studies, an antecedent infection was identified in 72 to 77 percent of ADEM patients1-3). In general, patients will present within 1 month of this initial illness. Numerous causative pathogens have been identified to date. Viruses that have been implicated include coronavirus, coxsackie virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, hepatitis A virus, human immunodeficiency virus, influenza virus, measles virus, rubella virus, varicella zoster virus, and West Nile virus4-11). Other organisms associated include Borrelia burgdorferi, Chlamydia, Leptospira, Mycoplasma pneumoniae, Rickettsia , and beta-hemolytic Streptococcus4,12).

rpes simplex virus, hepatitis A virus, human immunodeficiency virus, influenza virus, measles virus, rubella virus, varicella zoster virus, and West Nile virus4-11). Other organisms associated include Borrelia burgdorferi, Chlamydia, Leptospira, Mycoplasma pneumoniae, Rickettsia , and beta-hemolytic Streptococcus4,12). Less than 5 percent of all ADEM cases follow immunization. Postvaccinal ADEM has been associated with immunization for rabies, hepatitis B, influenza, Japanese B encephalitis, diphtheria/ pertussis/tetanus, measles, mumps, rubella, pneumococcus, polio, smallpox, and varicella12). No infectious agent is isolated in most cases. Currently, measles, mumps, and rubella vaccination are most often associated with postvaccination ADEM. It is important to recognize the significant difference between the incidence of ADEM associated with the live measles vaccination (1 to 2 per million) and the incidence of ADEM previously associated with the measles virus infection (1 in 1,000)13). The pathogenesis of ADEM is incompletely understood. The proposed mechanism of ADEM is that myelin autoantigens, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein, share antigenic determinants with those of an infecting pathogen12). This model is supported by studies of lymphocytes in children with ADEM. In 1 report, the frequency of T cell reactivity to myelin basic protein was 10 times higher in patients with ADEM than in those with encephalitis or normal controls5).

e protein, share antigenic determinants with those of an infecting pathogen12). This model is supported by studies of lymphocytes in children with ADEM. In 1 report, the frequency of T cell reactivity to myelin basic protein was 10 times higher in patients with ADEM than in those with encephalitis or normal controls5). MS is usually thought to be a disease of young adults. However, pediatric MS, defined as onset of MS before the age of 16, is being increasingly recognized. MS presents before the age of 16 in approximately 5 percent of patients14,15). In less than 1 percent of patients, the onset of MS occurs before the age of 10 years16). In addition, pediatric MS affects girls more than boys, with a female to male ratio of 2.817). Since pediatric MS is rare, a child with recurrent episodes of acute neurologic symptoms and white matter lesions on magnetic resonance imaging (MRI) might be originally misdiagnosed with one of several other disorders, including leukodystrophies, vasculopathies, lymphoma, mitochondrial defects, and other metabolic disorders, rather than MS.

are, a child with recurrent episodes of acute neurologic symptoms and white matter lesions on magnetic resonance imaging (MRI) might be originally misdiagnosed with one of several other disorders, including leukodystrophies, vasculopathies, lymphoma, mitochondrial defects, and other metabolic disorders, rather than MS. Clinical features Neurologic symptoms of ADEM commonly appear 4 to 13 days after the infection or vaccination1-3). Fever, headache, vomiting, and meningismus are often seen at the time of initial presentation and may persist during hospitalization2,18). Encephalopathy is a characteristic feature and may progress rapidly in association with multifocal neurologic deficits4). Progression of initial neurologic signs to maximum deficits usually occurs within 4 to 7 days1,3). The level of consciousness ranges from subtle lethargy to frank coma. The altered mental status often raises concern regarding the risk of seizures, although these occur in only one-third of patients3,19).

gic deficits4). Progression of initial neurologic signs to maximum deficits usually occurs within 4 to 7 days1,3). The level of consciousness ranges from subtle lethargy to frank coma. The altered mental status often raises concern regarding the risk of seizures, although these occur in only one-third of patients3,19). In addition to encephalopathy, the most common neurologic features of ADEM include long tract (pyramidal tract) signs, acute hemiparesis, cerebellar ataxia, cranial neuropathies, including optic neuritis, and spinal cord dysfunction (transverse myelitis)2-4,18,19). Symptoms of optic neuritis include vision loss, pain with eye movement, and an afferent pupillary defect. Inflammation of the optic disc may be seen by direct funduscopic examination if there is extensive involvement of the optic nerve. The imaging of the optic nerve with a gadolinium-enhanced MRI of the brain and orbits is a more sensitive means to diagnose optic neuritis in these patients. Symptoms of transverse myelitis include flaccid paralysis of the legs with a change in sensory level on examination. Bowel and bladder involvement secondary to spinal cord disease results in constipation and urinary retention. The arms can be involved if the demyelinating lesion affects the cervical cord. Respiratory failure may appear with high cervical lesions that extend into the brainstem. Aphasia, movement disorders, and sensory deficits are unusual. The severe phase of ADEM generally lasts from 2 to 4 weeks. Children may show deterioration in their condition after hospital admission, and most of them develop new neurologic signs. Patients usually recover completely from the acute illness, although some have neurologic sequelae.

s, and sensory deficits are unusual. The severe phase of ADEM generally lasts from 2 to 4 weeks. Children may show deterioration in their condition after hospital admission, and most of them develop new neurologic signs. Patients usually recover completely from the acute illness, although some have neurologic sequelae. MS is a clinical diagnosis and is characterized by spatially and temporally distinct recurrent episodes of demyelination in the CNS. Acute inflammation and demyelination in a critical area of the brain, optic nerves, or spinal cord can induce a corresponding neurologic deficit. There are no clinical signs that are unique to this disorder, but some are highly characteristic (Table 1)20). Common symptoms of MS are listed in Table 220). A European observational study of 394 children with pediatric-onset MS and 1,775 patients with adult-onset MS showed that children were more likely than adults to present with isolated optic neuritis, an isolated brainstem syndrome, or symptoms of encephalopathy17). A clinically isolated syndrome (CIS) is defined as a single monosymptomatic attack compatible with MS, such as optic neuritis. An episode of CIS can produce diagnostic and therapeutic dilemmas (Fig. 1), since the vast majority of children will not have a recurrence after a single demyelinating event of the CNS. The value of examinations, including brain MRI, cerebrospinal fluid (CSF) analyses, and other laboratory studies to identify those at high risk of recurrence, is unclear21).

c and therapeutic dilemmas (Fig. 1), since the vast majority of children will not have a recurrence after a single demyelinating event of the CNS. The value of examinations, including brain MRI, cerebrospinal fluid (CSF) analyses, and other laboratory studies to identify those at high risk of recurrence, is unclear21). Diagnosis of ADEM The diagnosis of ADEM is based on clinical and radiological features4). There is no specific biological marker or confirmatory test. ADEM should be suspected in a child who develops multifocal neurologic abnormalities with encephalopathy (e.g., confusion, excessive irritability, or an altered level of consciousness), especially if onset occurs one to two weeks after a viral infection or vaccination.

o specific biological marker or confirmatory test. ADEM should be suspected in a child who develops multifocal neurologic abnormalities with encephalopathy (e.g., confusion, excessive irritability, or an altered level of consciousness), especially if onset occurs one to two weeks after a viral infection or vaccination. The MRI abnormalities seen in ADEM are best defined using T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences (Fig. 2). Contrast enhancement is sometimes seen in acute lesions. Lesions associated with ADEM are typically bilateral but may be asymmetric and tend to be poorly marginated. Almost all patients have multiple lesions in the deep and subcortical white matter, while the periventricular white matter is generally spared. The thalami and basal ganglia are frequently affected (Fig. 2), and lesions in these locations are often symmetrical3,22). Brainstem and spinal cord abnormalities on MRI are common in ADEM12). The number of lesions varies, and their diameters range from <5 mm to 5 cm1,3). In the spinal cord, large confluent intramedullary lesions that extend over multiple segments are common3,12), and the degree of contrast enhancement is variable. Abnormal findings on MRI may progress over a relatively short period of time, consistent with progression of the disease. Sequential imaging by MRI is sometimes required to confirm the diagnosis of ADEM, as the occurrence of relapses, with new lesions on MRI, is not compatible with a diagnosis of monophasic ADEM, and suggests that the correct diagnosis is either multiphasic ADEM or MS, based upon the clinical symptoms and neuroimaging findings4).

al imaging by MRI is sometimes required to confirm the diagnosis of ADEM, as the occurrence of relapses, with new lesions on MRI, is not compatible with a diagnosis of monophasic ADEM, and suggests that the correct diagnosis is either multiphasic ADEM or MS, based upon the clinical symptoms and neuroimaging findings4). Analysis of CSF reveals pleocytosis and/or increased protein concentration in the majority of patients with ADEM1,2). However, the CSF can also be normal. Oligoclonal bands in CSF are seen in some patients with ADEM, but are a nonspecific finding more often associated with multiple sclerosis. Evaluation for infectious agents includes viral cultures of samples from the throat and nasopharynx, stool, and CSF, and serologic testing for influenza, Epstein-Barr virus, herpes, varicella, mycoplasma, cytomegalovirus, and rubella. These studies are rarely positive12).

more often associated with multiple sclerosis. Evaluation for infectious agents includes viral cultures of samples from the throat and nasopharynx, stool, and CSF, and serologic testing for influenza, Epstein-Barr virus, herpes, varicella, mycoplasma, cytomegalovirus, and rubella. These studies are rarely positive12). Diagnostic criteria for ADEM in children have been proposed by the International Pediatric Multiple Sclerosis Study Group (Table 3)23). The major criteria are a clinical attack of CNS demyelinating disease with acute or subacute onset, polysymptomatic neurologic features, and encephalopathy. Encephalopathy as a presenting symptom is essential for a diagnosis of ADEM, according to the Study Group criteria23). Encephalopathy is defined as including either behavioral changes, such as lethargy or irritability, or more severe alterations in the level of consciousness, such as coma. The onset of encephalopathy almost directly corresponds to the occurrence of the disease state. This feature helps to differentiate ADEM from other clinically isolated syndromes that are related to recurrence of MS and will lead to a subsequent MS diagnosis. Brain MRI criteria for ADEM diagnosis include focal or multifocal lesions predominantly involving the white matter, without evidence of previous white-matter changes. The diagnostic criteria can also distinguish between monophasic ADEM with early relapses, and recurrent forms of ADEM23) on the basis of the following conditions:

Diagnostic criteria for ADEM in children have been proposed by the International Pediatric Multiple Sclerosis Study Group (Table 3)23). The major criteria are a clinical attack of CNS demyelinating disease with acute or subacute onset, polysymptomatic neurologic features, and encephalopathy. Encephalopathy as a presenting symptom is essential for a diagnosis of ADEM, according to the Study Group criteria23). Encephalopathy is defined as including either behavioral changes, such as lethargy or irritability, or more severe alterations in the level of consciousness, such as coma. The onset of encephalopathy almost directly corresponds to the occurrence of the disease state. This feature helps to differentiate ADEM from other clinically isolated syndromes that are related to recurrence of MS and will lead to a subsequent MS diagnosis. Brain MRI criteria for ADEM diagnosis include focal or multifocal lesions predominantly involving the white matter, without evidence of previous white-matter changes. The diagnostic criteria can also distinguish between monophasic ADEM with early relapses, and recurrent forms of ADEM23) on the basis of the following conditions: - A single clinical episode of ADEM, monophasic ADEM, may evolve over as long as 3 months23). Any new and fluctuating symptoms occurring within 3 months of the initial event are considered to be part of the same event. In addition, symptoms that appear during tapering of glucocorticoid therapy, or within 1 month of completing a glucocorticoid taper, are considered to be part of the same episode.

as 3 months23). Any new and fluctuating symptoms occurring within 3 months of the initial event are considered to be part of the same event. In addition, symptoms that appear during tapering of glucocorticoid therapy, or within 1 month of completing a glucocorticoid taper, are considered to be part of the same episode. - Recurrent ADEM refers to the recurrence, 3 or more months after the first ADEM event, of the same symptoms that occurred at the time of the initial presentation. The MRI findings are similar to those seen at the initial event and are without new lesions, although there may be enlargement of the original lesions. - Multiphasic ADEM describes recurrent disease that fulfills criteria for ADEM but involves new anatomic areas of the CNS upon recurrence. Symptoms and signs are different from those in the initial event. The MRI must show new lesions not present during the first attack and demonstrate complete or partial resolution of the lesions associated with the first ADEM episode.

fulfills criteria for ADEM but involves new anatomic areas of the CNS upon recurrence. Symptoms and signs are different from those in the initial event. The MRI must show new lesions not present during the first attack and demonstrate complete or partial resolution of the lesions associated with the first ADEM episode. Diagnosis of pediatric MS Until 2006, the Poser criteria were considered the most useful in making a diagnosis of pediatric MS24). In 2007, the Pediatric Multiple Sclerosis Study Group proposed new working definitions for pediatric MS and related demyelinating diseases such as ADEM23). The working group suggested use of the 2001 McDonald Criteria to make a diagnosis of pediatric MS25). The McDonald criteria integrate MRI findings and allow the physician to make a diagnosis of clinically definite MS based upon the time interval preceding the development of new white matter lesions, even in the absence of new clinical findings (Tables 4, 5)25,26). The McDonald criteria for dissemination in space (Table 4) specify a minimal number of lesions, with or without MRI contrast enhancement, being present in specific areas of the CNS including periventricular, juxtacortical, infratentorial, and spinal cord regions.

he absence of new clinical findings (Tables 4, 5)25,26). The McDonald criteria for dissemination in space (Table 4) specify a minimal number of lesions, with or without MRI contrast enhancement, being present in specific areas of the CNS including periventricular, juxtacortical, infratentorial, and spinal cord regions. The McDonald criteria were revised in 2005 for adult-onset MS26), but these revisions have not been applied to pediatric MS. A main difference between the revised McDonald criteria and the 2007 Study Group criteria for pediatric MS concerns the time required between clinical attacks or the development of new MRI lesions to qualify for the "dissemination in time." The revised McDonald criteria require a minimum of only 30 days to elapse prior to the development of a new MRI lesion to qualify as dissemination in time, while the 2007 pediatric MS criteria demand that a minimum of 3 months must pass between clinical events or the appearance of new MRI lesions23).

mination in time." The revised McDonald criteria require a minimum of only 30 days to elapse prior to the development of a new MRI lesion to qualify as dissemination in time, while the 2007 pediatric MS criteria demand that a minimum of 3 months must pass between clinical events or the appearance of new MRI lesions23). A characteristic pattern of MS on MRI would include multiple well-demarcated lesions in the periventricular, juxtacortical, infratentorial, and spinal cord white matter. These areas of demyelination are best recognized using T2-weighted sequences. T2 FLAIR image sequences are the most sensitive in this evaluation, especially for periventricular lesions (Fig. 3). T1-weighted sequences may reveal "black holes" that represent complete tissue loss resulting from a previous inflammatory event (Fig. 3). Enhancement of active areas of inflammation and blood-brain barrier compromise can be seen using T1 gadolinium contrast sequences. Retrospective studies suggest that children with MS onset have more T2 bright lesions in the posterior fossa and more gadolinium-enhancing lesions than adults27). Further, the lesions in children were more likely to show reversibility on follow-up MRI than lesions in adults, suggesting better recovery of demyelination in children.

e studies suggest that children with MS onset have more T2 bright lesions in the posterior fossa and more gadolinium-enhancing lesions than adults27). Further, the lesions in children were more likely to show reversibility on follow-up MRI than lesions in adults, suggesting better recovery of demyelination in children. Detection of increased specific immunoglobulins present only in the CSF is often useful for supporting the diagnosis of MS in adult patients. A CSF sample is considered potentially positive for MS based upon the finding of either oligoclonal immunoglobulin G (IgG) bands or an increased IgG index25). In children, the utility of CSF oligoclonal bands in MS diagnosis has been questioned1). However, positive CSF findings, when associated with new lesions on follow-up MRI, can be used to make the diagnosis of MS even in the case of a single clinical attack25).

immunoglobulin G (IgG) bands or an increased IgG index25). In children, the utility of CSF oligoclonal bands in MS diagnosis has been questioned1). However, positive CSF findings, when associated with new lesions on follow-up MRI, can be used to make the diagnosis of MS even in the case of a single clinical attack25). Conclusions In the case of a child who presents with neurologic abnormalities, including signs of encephalitis, bacterial and viral meningitis or encephalitis must be considered and ruled out. In the setting of nonspecific CSF abnormalities and identification of white-matter lesions on MRI, other inflammatory demyelinating disorders should be considered. These include ADEM, MS, optic neuritis, transverse myelitis, neuromyelitis optica, and other rare disorders. At initial onset, ADEM and MS cannot be distinguished absolutely. In children, subsequent attacks of MS may not occur for months or years. Furthermore, a small number of children with ADEM may finally develop MS, but it is difficult to accurately predict in which patients this will occur. Therefore, prolonged follow-up is required to establish a diagnosis. Fig. 1 Diagnosis of a demyelinating clinical event. ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome; MRI, magnetic resonance imaging; MDEM, multiphase disseminated encephalomyelitis; MS, multiple sclerosis; NMO, neuromyelitis optica; ON, optic neuritis; TM, transverse myelitis.

Conclusions In the case of a child who presents with neurologic abnormalities, including signs of encephalitis, bacterial and viral meningitis or encephalitis must be considered and ruled out. In the setting of nonspecific CSF abnormalities and identification of white-matter lesions on MRI, other inflammatory demyelinating disorders should be considered. These include ADEM, MS, optic neuritis, transverse myelitis, neuromyelitis optica, and other rare disorders. At initial onset, ADEM and MS cannot be distinguished absolutely. In children, subsequent attacks of MS may not occur for months or years. Furthermore, a small number of children with ADEM may finally develop MS, but it is difficult to accurately predict in which patients this will occur. Therefore, prolonged follow-up is required to establish a diagnosis. Fig. 1 Diagnosis of a demyelinating clinical event. ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome; MRI, magnetic resonance imaging; MDEM, multiphase disseminated encephalomyelitis; MS, multiple sclerosis; NMO, neuromyelitis optica; ON, optic neuritis; TM, transverse myelitis. Fig. 2 (A) An axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain in a child with acute disseminated encephalopmyelitis demonstrates multifocal areas of hyperintensity in both cerebral hemispheres involving cortical gray matter, centrum semiovale, and deep gray nuclei. (B) A saggital T2-weighted MRI of the spine in the same child demonstrates high signal intrinsic to the spinal cord, consistent with longitudinally extensive transverse myelitis.

ates multifocal areas of hyperintensity in both cerebral hemispheres involving cortical gray matter, centrum semiovale, and deep gray nuclei. (B) A saggital T2-weighted MRI of the spine in the same child demonstrates high signal intrinsic to the spinal cord, consistent with longitudinally extensive transverse myelitis. Fig. 3 Axial T2-weighted (A) and axial fluid-attenuated inversion recovery (FLAIR) (B) images show multiple, ovoid shaped, hyperintense foci in the periventricular area, consistent with multiple sclerosis plaques. Sagittal FLAIR (C) image also shows these lesions to be radiating out from the corpus callosum. Axial precontrast T1-weighted (D) image shows that many of these lesions are hypointense, consistent with black holes. Axial postgadolinium fat saturated T1-weighted (E) image shows that some of these plaques enhance in a ring-like fashion consistent with active plaques. Table 1 Clinical Features of Multiple Sclerosis Table 2 Presenting Symptoms in Multiple Sclerosis Values are presented as %. Table 3 Diagnostic Criteria of Acute Disseminated Encephalomyelitis (ADEM) Encephalopathy is a required feature for the diagnosis of ADEM, but is not a typical feature of multiple sclerosis. In addition, a cerebrospinal fluid pleocytosis ≥50 white blood cells/mm can be observed in ADEM, whereas this finding is highly atypical for multiple sclerosis. CNS, central nervous system; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. Table 4 International Panel on Multiple Sclerosis (MS) Diagnostic Criteria

Encephalopathy is a required feature for the diagnosis of ADEM, but is not a typical feature of multiple sclerosis. In addition, a cerebrospinal fluid pleocytosis ≥50 white blood cells/mm can be observed in ADEM, whereas this finding is highly atypical for multiple sclerosis. CNS, central nervous system; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. Table 4 International Panel on Multiple Sclerosis (MS) Diagnostic Criteria MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; MS, multiple sclerosis. *MRI criteria include 3 or 4 of the following: 1 gadolinium enhancing lesion or 9 T2 hyperintense lesions if there is no gadolinium enhancing lesion; at least 1 infratentorial lesion; at least 1 juxtacortical lesion; at least 3 periventricular lesions; 1 spinal cord lesion can be substituted for 1 brain lesion. †For MRI dissemination in time criteria, see Table 3. Table 5 International Panel on Multiple Sclerosis (MS) MRI Criteria for Dissemination in Time MRI, magnetic resonance imaging.

Introduction TSC is an autosomal dominant disorder caused by the inactivation of either of 2 tumor suppressor genes, hamartin (TSC1) or tuberin (TSC2). In the normal state, the hamartin-tuberin complex activates the protein Ras homolog enriched in brain (Rheb), which inhibits mammalian target of rapamycin (mTOR). If a TSC mutation is present, mTOR is constitutively activated, leading to abnormal cellular proliferation, ribosome biogenesis, and mRNA translation. As a consequence, TSC is characterized clinically by the growth of benign tumors in multiple organs, including the brain, the heart, the kidneys, the lungs, and the skin1). Its incidence is estimated to be 1 in 6,000 live births2). The severity of the disease is highly variable, ranging from mild skin manifestations to intractable epilepsy, mental retardation, and autism3).

growth of benign tumors in multiple organs, including the brain, the heart, the kidneys, the lungs, and the skin1). Its incidence is estimated to be 1 in 6,000 live births2). The severity of the disease is highly variable, ranging from mild skin manifestations to intractable epilepsy, mental retardation, and autism3). Rapamycin (also called sirolimus) is an immunosuppressive drug that has recently been shown to extend lifespan in multiple species, including mammals4). This anti-aging property is presumably related to the mTOR-inhibiting properties of rapamycin. The mTOR pathway is crucial for the coordination of growth in response to energy status, stress, and nutrient availability5). The potential anti-aging properties of rapamycin and other mTOR inhibitors, such as RAD001 (everolimus), and CCI-779 (temsirolimus) are of great interest. Unfortunately, the side effects associated with these drugs preclude research trials to study their impacts on aging in healthy individuals. In view of this obstacle, experts in the field of aging have suggested that these potential anti-aging drugs should be introduced in clinical trials for the treatment of particular diseases, and then, if appropriate, be approved for prevention of all age-related diseases in healthy individuals6).

n healthy individuals. In view of this obstacle, experts in the field of aging have suggested that these potential anti-aging drugs should be introduced in clinical trials for the treatment of particular diseases, and then, if appropriate, be approved for prevention of all age-related diseases in healthy individuals6). mTOR mTOR is a 290-kDa serine/threonine protein kinase that is highly conserved among mammals and also has closely related analogs in lower eukaryotes, such as Drosophila and yeast7). mTOR has been implicated in numerous cellular functions, many of which are related to the fundamental processes of cell growth, survival, and homeostasis8). A variety of upstream signaling pathways can regulate mTOR activity in response to different extracellular stimuli or intracellular signals, including nutrient and energy status, growth factors, and stress9). In turn, mTOR responds to these upstream signals by modulating multiple downstream pathways, which mediate cellular growth, proliferation, metabolism, and survival, usually due to direct changes in the translation of relevant proteins10). Thus, during anabolic states in the presence of nutrients, growth factors, or insulin, signaling through specific upstream pathways, such as the phosphatidylinositol-3 kinase (PI3K)/Akt (protein kinase B) pathway, activates mTOR, leading to increased protein synthesis, cellular growth, and proliferation11). In catabolic states with nutrient/energy or oxygen deprivation, other upstream regulators, such as AMP-kinase, inhibit mTOR activity, thus decreasing protein translation and cellular growth, proliferation, and metabolism9). Activation or inhibition of mTOR by upstream pathways is generally accomplished through opposing effects on the tuberous sclerosis gene products, hamartin and tuberin, and on the small GTPase protein, Rheb.

inhibit mTOR activity, thus decreasing protein translation and cellular growth, proliferation, and metabolism9). Activation or inhibition of mTOR by upstream pathways is generally accomplished through opposing effects on the tuberous sclerosis gene products, hamartin and tuberin, and on the small GTPase protein, Rheb. The cell signaling pathway involving mTOR is further complicated by poorly defined intermediate steps, multiple feedback loops, and the formation of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 and mTORC2 are functional complexes of mTOR bound to the regulatory proteins raptor and rictor respectively, which differ in their sensitivity to the mTOR inhibitor, rapamycin12).

poorly defined intermediate steps, multiple feedback loops, and the formation of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 and mTORC2 are functional complexes of mTOR bound to the regulatory proteins raptor and rictor respectively, which differ in their sensitivity to the mTOR inhibitor, rapamycin12). In addition to its functions in cellular growth and proliferation, mTOR has other important and complex roles in regulating cell survival and cell death, especially in relation to the processes of autophagy, apoptosis, and immune regulation. Autophagy involves the degradation and recycling of proteins and other macromolecules, and normally promotes cell survival under conditions of bioenergetic stress or in catabolic states where resources are limited. However, in some situations, autophagy may also mediate an alternative (non-apoptotic, autophagic) form of programmed cell death (Type II PCD), thus revealing a dual role of autophagy in promoting both cell survival and death, depending on the cellular context13). In anabolic states, in addition to stimulating protein synthesis, mTOR generally inhibits autophagy and thus reduces the degradation of proteins. Conversely, mTOR inhibitors, such as rapamycin, usually stimulate autophagy, with a resultant neuroprotective effect in various models of brain injury14). Finally, mTOR plays a critical role in immune responses via regulation of antigen-presenting cells and T-cells, and rapamycin is used clinically as a potent immunosuppressant drug. While the effects of rapamycin on autophagy, apoptosis, and immune regulation may most directly translate into neuromodulatory and neuroprotective properties, these features may also have anti-epileptogenic effects.

tigen-presenting cells and T-cells, and rapamycin is used clinically as a potent immunosuppressant drug. While the effects of rapamycin on autophagy, apoptosis, and immune regulation may most directly translate into neuromodulatory and neuroprotective properties, these features may also have anti-epileptogenic effects. The clinical and therapeutic importance of mTOR is wide-reaching and continues to expand. Abnormal mTOR activity, leading to excessive cellular growth and proliferation, has been implicated in the pathophysiology of numerous human cancers, including both sporadic, isolated organ-specific and multiorgan tumors, genetic tumor syndromes. In many of these cases, specific mutations of some component of the mTOR signaling pathway has been documented, resulting in hyperactivation of mTOR or its downstream effectors. On the basis of the physiological and pathophysiological properties of mTOR, it is reasonable to hypothesize that mTOR signaling could be involved in mechanisms of epileptogenesis15). mTOR inhibitors and TSC The current main clinical complication related to TSC for which treatment with mTOR inhibitors is indicated is subependymal giant cell astrocytoma (SEGA). This complication affects approximately 15% of patients with TSC and it occurs in the pediatric age group16). SEGAs tend to lose their propensity to grow in the early twenties.

main clinical complication related to TSC for which treatment with mTOR inhibitors is indicated is subependymal giant cell astrocytoma (SEGA). This complication affects approximately 15% of patients with TSC and it occurs in the pediatric age group16). SEGAs tend to lose their propensity to grow in the early twenties. The traditional management approach is to monitor SEGAs with periodic neuroimaging, and to resect those that exhibit growth and/or are associated with clinical signs of intracranial hypertension. This approach is being challenged by recent observations that suggest that mTOR inhibitors such as rapamycin (sirolimus) and RAD001 can induce partial regression of SEGAs17,18). The first report showing clear regression of SEGAs in 5 patients with the use of rapamycin was published in 200617). Recently, a phase II trial18) using everolimus to treat SEGAs in 28 patients with TSC showed SEGA reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Everolimus was well tolerated, as only single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported.

imus to treat SEGAs in 28 patients with TSC showed SEGA reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Everolimus was well tolerated, as only single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported. These observations suggest that treatment with mTOR inhibitors could serve as an acceptable alternative to SEGA surgery. Renal angiomyolipomas and lymphangioleimyomatosis are other TSC manifestations against which mTOR inhibitors have proven potential efficacy19). In addition, animal models of TSC have suggested that mTOR inhibitors could have beneficial effects on cognitive deficits20) and on epileptogenesis15). Whether similar benefits would be observed in humans with TSC is still unknown. Research trials are ongoing and should soon provide answers to these questions. The duration of treatment is likely to be prolonged or even lifelong. There is clear evidence that SEGAs grow back after administration of the mTOR inhibitor is stopped17). Most experts currently recommend continuation of mTOR inhibitors at the lowest efficacious dose. This cohort of patients, who will experience prolonged exposure to mTOR inhibitors, should be carefully followed longitudinally to better document long-term side effects, but also to compare their longevity with that of similar patients receiving TSCs. These patients represent a unique opportunity to study the potential anti-aging properties of mTOR inhibitors in humans.

d exposure to mTOR inhibitors, should be carefully followed longitudinally to better document long-term side effects, but also to compare their longevity with that of similar patients receiving TSCs. These patients represent a unique opportunity to study the potential anti-aging properties of mTOR inhibitors in humans. In animal models, mTOR inhibitors showed that mTORC1 blockade alone and PI3K-mTOR blockade lead to suppression of tumor development and longer survival of the treated animals21). Rapamycin, the first mTOR inhibitor used in individuals with TSC-associated lesions, was able to stimulate regression of subependymal giant cell tumors (SGCTs)17). Subsequent studies have confirmed its efficacy in SGCTs, but also in other lesions such as angiomyolipomas22). The effects of mTOR inhibitors on the mTOR pathway result in decreased protein synthesis and cell-cycle arrest, as well as decreased angiogenesis. More recently, a new mTOR inhibitor, RAD001, has been used in the treatment of 28 patients with TSC-associated brain lesions but with no symptoms of increased intracranial pressure18). In particular, this study reports a reduction in tumor size of at least 30% in 75% of patients and at least 50% in 32% of treated individuals. Varying degrees of reduction of SGCT size have been observed in all the 38 patients treated with mTOR inhibitors (sirolimus or everolimus) to date. Most SGCT reductions occur in the first 3 months of mTOR inhibitor treatment, after which the rate of reduction slows. In recent case reports, a similar anti-tumor efficacy was achieved, even with lower serum levels of everolimus23). None of the patients treated with mTOR inhibitors required surgery or developed new SGCTs while receiving treatment17,18). Cerebrospinal fluid obstruction was relieved by the reduction in SGCT size18). The treatment was also associated with a clinically relevant reduction in the overall frequency of seizures and an improvement in quality of life.

with mTOR inhibitors required surgery or developed new SGCTs while receiving treatment17,18). Cerebrospinal fluid obstruction was relieved by the reduction in SGCT size18). The treatment was also associated with a clinically relevant reduction in the overall frequency of seizures and an improvement in quality of life. Unfortunately, regrowth of SGCTs occurred a few months after drug discontinuation in all but one of the reported patients24). Therefore, mTOR inhibition may need to be continuous for the benefits to persist, and the benefits and hazards of long-term treatment with low-dosage mTOR inhibitors should be evaluated. Conclusions and future perspectives An early diagnosis of SGCT in neurologically asymptomatic children with TSC may allow prompt surgical removal of the tumor before the appearance of signs of increased intracranial pressure, and this approach is being progressively adopted to lessen the morbidity/mortality rate. Surgical treatment is obviously mandatory in case of life-threatening symptoms. However, the dramatic response of TSC-associated SGCTs to mTOR inhibitors suggests that these drugs could be a potential alternative to surgery in many cases.

s approach is being progressively adopted to lessen the morbidity/mortality rate. Surgical treatment is obviously mandatory in case of life-threatening symptoms. However, the dramatic response of TSC-associated SGCTs to mTOR inhibitors suggests that these drugs could be a potential alternative to surgery in many cases. mTOR inhibitors could be recommended when an asymptomatic SGCT shows growth in 2 consecutive magnetic resonance imaging evaluations following diagnosis. mTOR inhibitors could also be used as an initial treatment to facilitate subsequent surgery in individuals with bilateral lesions. Medical therapy may also have a role when SGCTs present in an atypical location or exhibit aggressive growth. Furthermore, in case of regrowth after a first resection, considering the higher risk of further surgery, pharmacotherapy could provide an alternative method to keep lesion size under control. Little is known about the long-term efficacy and safety of low dosage use of mTOR inhibitors and whether regrowth could be prevented by a more prolonged treatment course. In animal models, rapamycin dosing comparison studies indicated that the duration of rapamycin treatment is more important than dose intensity in terms of efficacy; prolonged treatment with low doses of mTOR inhibitors resulted in more complete and durable tumor responses25,26). Our current understanding of the effects of continuous mTOR inactivation in individuals with TSC is still poor. mTOR inhibitors may also activate pathways that should not be activated, and this issue will need to be taken into account when a long-term treatment is proposed.

e complete and durable tumor responses25,26). Our current understanding of the effects of continuous mTOR inactivation in individuals with TSC is still poor. mTOR inhibitors may also activate pathways that should not be activated, and this issue will need to be taken into account when a long-term treatment is proposed. The feasibility and timeline for discontinuation of mTOR inhibitor-based pharmacotherapy also remains unclear, and further studies are required to explore the optimal duration of treatment. Since it is known that the growth of SGCTs tends to slow in early adulthood, mTOR inhibitor treatment should theoretically be undertaken until the patient reaches around 20 years of age. Strategies for future clinical trials with mTOR inhibitors may include the investigation of longer treatment durations with minimum dosage.

it is known that the growth of SGCTs tends to slow in early adulthood, mTOR inhibitor treatment should theoretically be undertaken until the patient reaches around 20 years of age. Strategies for future clinical trials with mTOR inhibitors may include the investigation of longer treatment durations with minimum dosage. When choosing between surgical and/or medical intervention, clinicians should take the risks and benefits of each option into account. There are several issues to be considered, and every decision should be discussed thoroughly with the parents and tailored to the individual case. Depending on the age of the patient, one option may be more valid than the other. For example, pharmacotherapy might be preferred when a growing SGCT is discovered in adolescents, as the therapy may only be required for a few years. On the other hand, in childhood, a single surgical removal could be preferred to many years of pharmacotherapy. The positive effect that mTOR inhibitors have on several manifestations of TSC is an important factor in favor of pharmacotherapy, and should be considered in patients presenting with problems such as renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and/or intractable epilepsy, in addition to SGCTs. Since the activation of the mTOR pathway has been implicated in epileptogenesis, mTOR inhibition could have antiepileptic effects in patients with TSC18,27).

sidered in patients presenting with problems such as renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and/or intractable epilepsy, in addition to SGCTs. Since the activation of the mTOR pathway has been implicated in epileptogenesis, mTOR inhibition could have antiepileptic effects in patients with TSC18,27). Inhibition of the mTOR pathway may provide a biologically targeted therapy that has the potential to change current clinical practice regarding management of SGCTs. Currently, it is still unclear whether pharmacotherapy is able to prevent or merely delay the need for surgical resection of SGCTs. In the coming years, medical treatment will certainly play a larger role in the management of children with TSC, as our understanding of the pathogenesis of this disorder at the molecular level improves. In conclusion, a new treatment era has begun in the field of TSC since the discovery of the potential beneficial effects of mTOR inhibitors. Although the use of mTOR inhibitors is becoming increasingly accepted, especially for the treatment of SEGAs in TSC, questions remain concerning the duration of treatment and long-term side effects. Whether mTOR inhibitors will have a significant impact on longevity in TSC is unknown, but warrants attention, as mTOR inhibitors are increasingly recognized as anti-aging drugs in animal models. Long-term prospective studies in patients with TSC will provide information on the potential anti-aging properties of mTOR inhibitors in humans.

Introduction Improved diagnostic tools and treatment modalities including surgery, chemotherapy and radiation therapy, as well as hematopoietic stem cell transplantation have dramatically increased childhood cancer survival over the last 30 years1). As the number of childhood cancer survivors grows, quality of life issues over the long term have become important. The metabolic syndrome is a cluster of features including: dyslipidemia, hyperglycemia, hypertension and obesity, especially central obesity. The metabolic syndrome is a risk factor for the subsequent development of type 2 diabetes and cardiovascular disease. Many investigators have reported adolescent prevalence data for the metabolic syndrome using numerous diagnostic criteria. Although agreement is lacking on the criteria for diagnosing the metabolic syndrome in children and adolescents, the diagnostic criteria typically involve the same five risk factors identified in adults including abdominal obesity, high triglyceride, low high-density lipoprotein cholesterol (HDL-C), high blood pressure and high fasting glucose with modification of the cut-off values2-4). According to a statement by the American Heart Association, post-cancer treatment survivors were classified as tier III, which means increased cardiovascular risk factors with epidemiological evidence for manifest cardiovascular disease early in adult life5). In 1996, Talvensaari et al.5) reported that long-term survivors of childhood cancer appeared to have an increased risk for the metabolic syndrome compared to age and gender matched healthy control children.

According to a statement by the American Heart Association, post-cancer treatment survivors were classified as tier III, which means increased cardiovascular risk factors with epidemiological evidence for manifest cardiovascular disease early in adult life5). In 1996, Talvensaari et al.5) reported that long-term survivors of childhood cancer appeared to have an increased risk for the metabolic syndrome compared to age and gender matched healthy control children. In Korea, a recent report revealed that the prevalence of the metabolic syndrome in the general childhood population was around 10%6). However, study of the metabolic syndrome in childhood cancer survivors has not been performed. The purpose of this study was to investigate the frequency of the metabolic syndrome and associated factors in childhood cancer survivors at a single center in Korea. Materials and methods 1. Subjects All surviving 98 subjects who visited endocrinology clinic and were examined for parameters of metabolic syndrome between January 2008 and December 2009 were enrolled in this study. All subjects were diagnosed and treated for childhood cancer of less than 18 years of age at the Department of Pediatrics, Samsung Medical Center, Seoul, Korea, between 1996 and 2007. The clinical characteristics of the patients are listed in Table 1. At the time of the examination, all survivors were disease free. The study was approved by the institutional review board at Samsung Medical Center, Seoul, Korea.

he Department of Pediatrics, Samsung Medical Center, Seoul, Korea, between 1996 and 2007. The clinical characteristics of the patients are listed in Table 1. At the time of the examination, all survivors were disease free. The study was approved by the institutional review board at Samsung Medical Center, Seoul, Korea. 2. Methods The medical records were reviewed for the clinical history. The patients were interviewed and a physical examination was performed. The height and weight were measured. The body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Height, weight and BMI standard deviation score (SDS) were assessed using the Korean standard growth charts7). Pubertal development was assessed according to Tanner and Whitehouse stage8). Waist and hip circumferences were measured to the nearest millimeter. The BMI at or above the 85th percentile and below 95th percentile was considered overweight. The BMI above the 95th percentile was considered obese6). The physical examination included blood pressure, measured using an automated hemadynamometer. Fat mass and percent body fat were determined by dual-energy x-ray absorptiometry (DXA, Hologic Delphi W, software 12.4.2, Hologic Inc., Bedford, MA, USA). The precision of the fat assessments was approximately 1%.

d obese6). The physical examination included blood pressure, measured using an automated hemadynamometer. Fat mass and percent body fat were determined by dual-energy x-ray absorptiometry (DXA, Hologic Delphi W, software 12.4.2, Hologic Inc., Bedford, MA, USA). The precision of the fat assessments was approximately 1%. Laboratory samples were collected in the morning after overnight fasting. The tests included plasma triglycerides, plasma total cholesterol, serum HDL-C, serum low-density lipoprotein cholesterol (LDL-C), blood glucose, serum insulin, plasma uric acid, insulin-like growth factor 1 (IGF-1), triiodothyronine, free thyroxine, and thyroid-stimulating hormone. Standard growth hormone provocation test was performed after overnight fasting with at least two separate stimuli with insulin, glucagon, clonidine or levodopa. Human-growth hormone (hGH) was measured in serial blood samples with 30 minute interval during 2 hours by commercial radioimmunoassay kit (Immunotech S.A.S., Marseille Cedex, France). Growth hormone deficiency (GHD) was diagnosed when all provocated hGHs were less than 10 ng/mL with at least two stimuli.

e or levodopa. Human-growth hormone (hGH) was measured in serial blood samples with 30 minute interval during 2 hours by commercial radioimmunoassay kit (Immunotech S.A.S., Marseille Cedex, France). Growth hormone deficiency (GHD) was diagnosed when all provocated hGHs were less than 10 ng/mL with at least two stimuli. The definition reported by the National Cholesterol Education Program/Adult Treatment Panel III was used to determine the diagnosis of the metabolic syndrome9). The findings of at least three of the following five criteria were required to diagnose the metabolic syndrome: Central obesity with a waist circumference at or over 90th percentile for age, gender, and height; Low HDL-C levels, ≤40 mg/dL; high triglyceride (TG) levels, ≥110 mg/dL; high fasting glucose, ≥110 mg/dL; elevated systolic or diastolic blood pressure, at or above the 90th percentile for age, gender, and height. 3. Statistical analysis Continuous data were analyzed using an independent sample t-test or analysis of variance in the case of normally distributed data and the Mann-Whitney U-test or Kruskal-Wallis test for skewed distribution or ordinal variables. Categorized data were analyzed using Fisher's exact test and the chi-square test as appropriate. To determine independent association of clinical parameters and metabolic syndrome prevalence, data were analyzed using multiple logistic regression test. A P value <0.05 was considered significant; all statistical analyses were performed using SPSS ver. 15.0 (SPSS Inc., Chicago. IL, USA).

i-square test as appropriate. To determine independent association of clinical parameters and metabolic syndrome prevalence, data were analyzed using multiple logistic regression test. A P value <0.05 was considered significant; all statistical analyses were performed using SPSS ver. 15.0 (SPSS Inc., Chicago. IL, USA). Results 1. Metabolic syndrome prevalence A total of 19 (19.4%) patients had the metabolic syndrome (Table 2). Fourteen were males and five were females. Their median age was 15 years. The median BMI SDS was 0.71. The median body fat percent was 31.5%. Among them, seven (36.8%) were overweight or obese. Therefore, half of them had the metabolic syndrome even though they were not overweight or obese. Seventeen (89.5%) patients had cranial irradiation. Four (21%) patients had GHD, which was diagnosed by a growth hormone stimulation test. All four patients with GHD had cranial irradiation. By multivariate analyses BMI SDS (P=0.03), the presence of GHD (P=0.04), and the type of cranial irradiation (P<0.001) were found associated with metabolic syndrome prevalence.

Results 1. Metabolic syndrome prevalence A total of 19 (19.4%) patients had the metabolic syndrome (Table 2). Fourteen were males and five were females. Their median age was 15 years. The median BMI SDS was 0.71. The median body fat percent was 31.5%. Among them, seven (36.8%) were overweight or obese. Therefore, half of them had the metabolic syndrome even though they were not overweight or obese. Seventeen (89.5%) patients had cranial irradiation. Four (21%) patients had GHD, which was diagnosed by a growth hormone stimulation test. All four patients with GHD had cranial irradiation. By multivariate analyses BMI SDS (P=0.03), the presence of GHD (P=0.04), and the type of cranial irradiation (P<0.001) were found associated with metabolic syndrome prevalence. 2. Obesity Seventeen (17.3%) patients were overweight or obese. Thirteen (13.3%) patients were overweight and 4 (4%) were obese. Central obesity was found in 13 (13.3%) patients. Subgroups classified according to the type of cranial irradiation showed significant differences in the BMI and waist circumference. However, there was no significant difference in the BMI SDS, waist circumference percentile or body fat percent (Table 3). Patients with GHD had higher BMI and increased waist circumference (Table 3). Among the parameters of obesity, the BMI and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.001, respectively, Fig. 1).

circumference percentile or body fat percent (Table 3). Patients with GHD had higher BMI and increased waist circumference (Table 3). Among the parameters of obesity, the BMI and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.001, respectively, Fig. 1). All 98 patients showed euthyroid state which include 24 patients with levo-thyroxine therapy at the time of the present study due to overt hypothyroidsm. The level of mean serum IGF-1 was 226±169 ng/mL and IGF-1 SDS was -0.13±1.59. The mean IGF-1 SDS of patients with GHD was not significantly lower than that of patients without GHD (-0.54±2.15 vs. 0.03±1.26, respectively, P=0.18). 3. Body composition The percent of whole body fat was measured in 63 patients (42 males and 21 females). The median body fat percent was 31.5%. The median body fat percent in males and females was 31.5% (26.6 to 35.6) and 32.7% (27.3 to 34.8) respectively (Table 3). The percent body fat tended to be higher in patients that had cranial irradiation with higher doses. In addition, the percent body fat tended to be higher in patient with GHD compared to patients without GHD (Table 3). 4. Lipid profile In total, 61 (62.2%) patients had at least one abnormal lipid value. Twenty two (21.4%) patients had hypercholesterolemia (total cholesterol ≥200 mg/dL), 14 (14.3%) had raised LDL-C (LDL-C ≥130 mg/dL), 25 (25.5%) had reduced HDL-C (HDL-C ≤40 mg/dL) and 57 (58.2%) had hypertriglyceridemia (TG ≥110 mg/dL) (Table 2).

file In total, 61 (62.2%) patients had at least one abnormal lipid value. Twenty two (21.4%) patients had hypercholesterolemia (total cholesterol ≥200 mg/dL), 14 (14.3%) had raised LDL-C (LDL-C ≥130 mg/dL), 25 (25.5%) had reduced HDL-C (HDL-C ≤40 mg/dL) and 57 (58.2%) had hypertriglyceridemia (TG ≥110 mg/dL) (Table 2). There was no significant difference in the lipid profile between patients with and without cranial irradiation. The TG showed significant positive correlation with the percent body fat (r=0.26, P=0.03, Fig. 2A). Moreover, the HDL-C showed significant negative correlation with the percent body fat (r=-0.26, P=0.03, Fig. 2B). 5. Glucose metabolism The fasting glucose was above 110 mg/dL in 19 (19.4%) patients. Subgroups classified according to the type of cranial irradiation showed significant differences in the fasting glucose level (Table 4). 6. Hypertension Twenty six (26.5%) patients had increased blood pressure (Table 2). Eighteen were males and eight were females. Their median age was 12.2 years (5.3 to 15). The median age at diagnosis was 3.8 years (1.5 to 9.6). The median BMI SDS was 0.23 (-0.43 to 0.79). The median percent body fat was 31.8% (28.9 to 34.3). Sixteen (61.5%) had cranial irradiation.

increased blood pressure (Table 2). Eighteen were males and eight were females. Their median age was 12.2 years (5.3 to 15). The median age at diagnosis was 3.8 years (1.5 to 9.6). The median BMI SDS was 0.23 (-0.43 to 0.79). The median percent body fat was 31.8% (28.9 to 34.3). Sixteen (61.5%) had cranial irradiation. Discussion The metabolic syndrome is an important health issue in children and adolescents with regard to the long term implications of cardiovascular morbidity and type 2 diabetes. This is one of a few reports to examine the frequency and factors associated with the metabolic syndrome among childhood cancer survivors in Korea. The results of this study showed that the frequency of the metabolic syndrome in childhood cancer survivors was 19.4%. This is about twice the frequency in the general population of children according to a study conducted by the Korean national health and nutrition survey10).

among childhood cancer survivors in Korea. The results of this study showed that the frequency of the metabolic syndrome in childhood cancer survivors was 19.4%. This is about twice the frequency in the general population of children according to a study conducted by the Korean national health and nutrition survey10). Several studies have reported an increased prevalence of overweight or obese childhood cancer survivors1,11,12). The reported prevalence of overweight or obese childhood cancer survivors has varied from 16 to 50%5,13,14). In this study, 17.3% were overweight or obese, which is consistent with previous studies. This is a higher frequency compared to the prevalence in the general Korean population, which has recently been reported to be around 10%6). Moreover, our results show that BMI SDS was positively associated with prevalence of metabolic syndrome. Therefore, continuous surveillance of BMI in childhood cancer survivor is crucial for early detection of metabolic syndrome in these patients.

Korean population, which has recently been reported to be around 10%6). Moreover, our results show that BMI SDS was positively associated with prevalence of metabolic syndrome. Therefore, continuous surveillance of BMI in childhood cancer survivor is crucial for early detection of metabolic syndrome in these patients. The basic feature of the metabolic syndrome is central obesity. An appropriate definition of central obesity for children and adolescents is challenging. Central obesity was found in 13.2% of the patients reported here, which is consistent with previous studies15). In this study, the BMI and waist circumference percentiles were correlated with the cranial irradiation dose, which could have caused hypothalamic/pituitary damage that manifested as hormonal problems. Growth hormone has been implicated not only in linear growth, but also in metabolism. The results of this study showed that the percent body fat of patients with GHD tended to be higher than in patients without GHD.

iation dose, which could have caused hypothalamic/pituitary damage that manifested as hormonal problems. Growth hormone has been implicated not only in linear growth, but also in metabolism. The results of this study showed that the percent body fat of patients with GHD tended to be higher than in patients without GHD. The amount of fat and lean body mass, and the distribution of fat are important risk factors for the prediction of cardiovascular disease and type 2 diabetes16,17). Unfortunately, there is no Korean reference data for body composition in this age group. Therefore, the reported reference data of percent body fat was used12,18). Higgins et al.19) reported that an upper cut-off point of 33% body fat is an indicator of cardiovascular disease risk in children. In this study, 41.2% (26/63) of the patients had a percent fat that was above 33%, despite a median BMI SDS of 0.14 (-0.71 to 0.9). This may suggest that the body composition of childhood cancer survivors should be considered even if they are not overweight or obese. About half of the patients in this study had at least one abnormal lipid profile. The percent body fat was positively correlated with the triglyceride and negatively correlated with the HDL-C. Vatanparast et al.20) reported that DXA-derived fat mass indices can be used for predicting blood lipid profiles in postmenopausal women. Although studies in children are lacking, our findings suggest the importance of the percent fat in predicting the lipid profile.

iglyceride and negatively correlated with the HDL-C. Vatanparast et al.20) reported that DXA-derived fat mass indices can be used for predicting blood lipid profiles in postmenopausal women. Although studies in children are lacking, our findings suggest the importance of the percent fat in predicting the lipid profile. In childhood cancer survivors, the frequency of the metabolic syndrome appears to be increased. This finding was associated with BMI SDS, presence of GHD, and cranial irradiation. The notable fact was that the body composition of childhood cancer survivors was metabolically unfavorable even if they were not obese. Therefore, childhood cancer survivors should have thorough metabolic evaluation including measurement of the percent body fat even if their BMI is in the normal range. Furthermore, more intense surveillance and education is necessary for the patients who had cranial irradiation and GHD. The major limitations of this study are as follows: a cross-sectional setting, small sample size from a single center and lack of optimal comparison group. Thereafter, a prospective long-term cohort study is needed to reproduce the results of this study.

In childhood cancer survivors, the frequency of the metabolic syndrome appears to be increased. This finding was associated with BMI SDS, presence of GHD, and cranial irradiation. The notable fact was that the body composition of childhood cancer survivors was metabolically unfavorable even if they were not obese. Therefore, childhood cancer survivors should have thorough metabolic evaluation including measurement of the percent body fat even if their BMI is in the normal range. Furthermore, more intense surveillance and education is necessary for the patients who had cranial irradiation and GHD. The major limitations of this study are as follows: a cross-sectional setting, small sample size from a single center and lack of optimal comparison group. Thereafter, a prospective long-term cohort study is needed to reproduce the results of this study. In Korea, the number of childhood cancer survivors increased to approximately 20,000 to 25,00021). However, there are no large cohort studies in Korea like The Childhood Cancer Survivor Study of USA or British Childhood Cancer Survivor Study of United Kingdom. In 2008, Children's Oncology Group published the update of Long-Term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers22) for screening and management of late effects resulting from therapeutic exposures during the treatment of malignancies. The guideline recommends annual physical examination of height, weight, BMI, blood pressure for screening metabolic syndrome. Moreover, laboratory tests including fasting blood glucose, insulin, and lipid profile are recommended every 2 years if the patient is overweight or every 5 years if the patient is in normal weight22). Now, we need the Korean cancer survivor cohort and follow-up guidelines. The primary preventive interventions for the patients with risk factors of metabolic syndrome include education of the patients and parents about the diet modification and adequate physical activities for maintaining normal BMI and body fat percent.

w, we need the Korean cancer survivor cohort and follow-up guidelines. The primary preventive interventions for the patients with risk factors of metabolic syndrome include education of the patients and parents about the diet modification and adequate physical activities for maintaining normal BMI and body fat percent. In conclusion, a better understanding of the determinants of the metabolic syndrome during adolescence might provide insights into preventive interventions for improving health outcomes and reducing the incidence of cardiovascular disease in adults. Acknowledgements The study was supported by Korea Healthcare Technology R&D Project; Grant sponsor: Ministry for Health, Welfare and Family Affairs, Republic of Korea; Grant number: A080588; Grant sponsor: Samsung Biomedical Research Institute; Grant numbers: C-A9-240-2 Grant sponsor: In-Sung Foundation for Medical Research. Fig. 1 Correlation of cranial irradiation and obesity. The body mass index (BMI) (A) and waist circumference (B) were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.001, respectively). Fig. 2 (A) Correlation of body fat percentage and triglyceride. The triglyceride showed significant positive correlation with the body fat percentage. (B) Correlation of body fat percentage and triglyceride. The high-density lipoprotein cholesterol (HDL-C) showed significant negative correlation with the body fat percentage. Table 1 Clinical Characteristics of Subjects Values are presented as mean±SD or number.

Fig. 2 (A) Correlation of body fat percentage and triglyceride. The triglyceride showed significant positive correlation with the body fat percentage. (B) Correlation of body fat percentage and triglyceride. The high-density lipoprotein cholesterol (HDL-C) showed significant negative correlation with the body fat percentage. Table 1 Clinical Characteristics of Subjects Values are presented as mean±SD or number. TBI, total body irradiation (1,000 cGy); CSRT, craniospinral radiation therapy (≥3,000 cGy); HSCT, hematopoietic stem cell transplantation. Table 2 Prevalence of Metabolic Syndrome Traits HDL-C, high-density lipoprotein cholesterol. Table 3 Clinical Parameters of Metabolic Syndrome BMI, body mass index; TBI, total body irradiation (1,000 cGy); CSRT, craniospinral radiation therapy (≥3,000 cGy); GHD, growth hormone deficiency. Table 4 Laboratory Parameters of Metabolic Syndrome HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TBI, total body irradiation (1,000 cGy); CSRT, craniospinral radiation therapy (≥3,000 cGy); GHD, growth hormone deficiency.

Introduction Hepatic tumors in children are relatively rare, accounting for 1 to 4% of all pediatric solid tumors. Infantile hepatic hemangioendothelioma (IHHE) is the most common vascular tumor of the liver in children, accounting for 12% of all childhood hepatic tumors. Almost 85% of patients with IHHE are diagnosed during the first 6 months of life, and IHHE is the most common symptomatic tumor occurring during this time period. Tumors show a female predominance, with a female to male ratio of 1.3 to 2:11-6). The most common chief complaint in patients with IHHE is abdominal mass. Other symptoms and signs include hepatomegaly, high-output cardiac failure, skin hemangioma, thrombocytopenia, hemolytic anemia and peritoneal bleeding. The natural history of IHHE varies, but up to two-thirds of symptomatic patients, especially those with heart failure and/or jaundice, may die3,7). Although children with asymptomatic lesions may experience spontaneous regression within a year, those with symptomatic lesions require aggressive management due to the risk of death once symptoms commence. The therapeutic options available for these patients include both medical and interventional modalities. Medical therapy includes treatment with corticosteroids and interferon-alpha (INF-α), whereas interventional modalities include embolization and ligation of the hepatic artery, resectional surgery, and liver transplantation1,2,8,9).

ptions available for these patients include both medical and interventional modalities. Medical therapy includes treatment with corticosteroids and interferon-alpha (INF-α), whereas interventional modalities include embolization and ligation of the hepatic artery, resectional surgery, and liver transplantation1,2,8,9). Because most previous studies of IHHE are small case series it has been difficult to formulate guidelines for the clinical assessment and therapeutic approach in patients with IHHE. This study describes the clinical features and outcomes of patients with IHHE diagnosed and treated over a 14-year period at a tertiary health center and to suggest strategies to manage such patients. Materials and methods The medical records of 23 patients diagnosed with IHHE at the Asan Medical Center between April 1996 and April 2009 were analyzed retrospectively. Factors evaluated included gender and age at presentation, presenting symptoms, diagnostic procedures, tumor location (solitary or multiple), laboratory findings (complete blood count, liver function tests [LFTs], thyroid function tests, coagulation parameters and alpha-fetoprotein [AFP] concentrations), therapeutic modality and treatment outcomes. Most patients were initially diagnosed by abdominal sonography and later evaluated by computed tomography (CT) and/or magnetic resonance imaging (MRI), based on the results of sonography. Tumors that could not be diagnosed radiologically were examined histopathologically. When required, patients with congestive heart failure were assessed by echocardiography.

abdominal sonography and later evaluated by computed tomography (CT) and/or magnetic resonance imaging (MRI), based on the results of sonography. Tumors that could not be diagnosed radiologically were examined histopathologically. When required, patients with congestive heart failure were assessed by echocardiography. Treatment was based on tumor size and symptom severity, and was at the discretion of the treating physician. Patients who were asymptomatic and had relatively small tumors were observed or treated with corticosteroids and/or interferon-α (INF-α). Patients with clinical symptoms and unilobar disease were treated by surgical resection, whereas symptomatic patients with inoperable tumors were treated medically, with or without preceding hepatic artery embolization. Treatment outcomes were classified as complete resolution, ≥90% decrease in tumor size, regression (50 to 90% deczrease), no change and progression, with complete resolution and decreasing by 90% defined as a major response to therapy.

Treatment was based on tumor size and symptom severity, and was at the discretion of the treating physician. Patients who were asymptomatic and had relatively small tumors were observed or treated with corticosteroids and/or interferon-α (INF-α). Patients with clinical symptoms and unilobar disease were treated by surgical resection, whereas symptomatic patients with inoperable tumors were treated medically, with or without preceding hepatic artery embolization. Treatment outcomes were classified as complete resolution, ≥90% decrease in tumor size, regression (50 to 90% deczrease), no change and progression, with complete resolution and decreasing by 90% defined as a major response to therapy. Results Twenty-three patients (13 girls, 10 boys) were enrolled; their demographic and clinical characteristics at the time of diagnosis are summarized in Table 1. Median age at diagnosis was 38 days (range, 1 to 381 days), with 18 (78%) patients diagnosed during their first 3 months of life, including 7 who were diagnosed by prenatal sonography. Median follow-up duration after diagnosis was 29 months (range, 1 to 156 months). Excluding the seven prenatally diagnosed patients and the five asymptomatic patients diagnosed incidentally, the main symptoms at presentation were congestive heart failure and skin hemangioma. Clinical features on physical examination and laboratory findings included hepatomegaly (43%), heart failure (30%), abnormal LFTs (22%), increased thyroid-stimulating hormone (TSH) concentration (22%), coagulopathy (11%), and thrombocytopenia (4%).

toms at presentation were congestive heart failure and skin hemangioma. Clinical features on physical examination and laboratory findings included hepatomegaly (43%), heart failure (30%), abnormal LFTs (22%), increased thyroid-stimulating hormone (TSH) concentration (22%), coagulopathy (11%), and thrombocytopenia (4%). Of the 23 patients, 22 were diagnosed by abdominal sonography, followed by CT and MRI in 11 patients each; 5 underwent both CT and MRI. In three patients, in whom hepatoblastoma could not be determined radiologically, the tumors were examined histopathologically. Two patients underwent percutaneous biopsy of the mass, with findings consistent with IHHE. The other patient with heart failure symptoms underwent right partial lobectomy and the resected specimen was confirmed as IHHE. Imaging showed that all 13 patients with single lobe disease had solitary lesions (10 in the right and 3 in the left hepatic lobe), whereas all 10 patients with bilobar disease had multinodular lesions. Serum concentrations of AFP were measured in 21 patients and shown to be increased for his/her age in 3 (14%). All three patients had multiple tumors and were treated by different modalities, but all showed complete resolution (Table 2).

Imaging showed that all 13 patients with single lobe disease had solitary lesions (10 in the right and 3 in the left hepatic lobe), whereas all 10 patients with bilobar disease had multinodular lesions. Serum concentrations of AFP were measured in 21 patients and shown to be increased for his/her age in 3 (14%). All three patients had multiple tumors and were treated by different modalities, but all showed complete resolution (Table 2). Six of our 23 patients were observed, with 2 showing major response (≥90% decrease in tumor size) after 29 months, and 3 showing spontaneous regression. One patient showed no change in tumor size, but was not treated due to decreased vascularity on follow-up imaging. Six patients received systemic corticosteroid therapy, consisting of a mean dose of 1.9 mg/kg/day of oral prednisolone for a median 43 days (range, 15 to 90 days); 3 (50%) successfully responded to treatment. All four patients treated with INF-α showed major responses to medical treatment. Two patients were treated with a combination of corticosteroids and INF-α.

therapy, consisting of a mean dose of 1.9 mg/kg/day of oral prednisolone for a median 43 days (range, 15 to 90 days); 3 (50%) successfully responded to treatment. All four patients treated with INF-α showed major responses to medical treatment. Two patients were treated with a combination of corticosteroids and INF-α. Interventional modalities included embolization (n=4) and conventional resectional surgery (n=1). One patient with Kasabach-Merritt syndrome (KMS) showed tumor progression despite embolization, eventually dying due to coagulopathy, liver failure, and sepsis. The other three patients who underwent embolization showed partial responses to subsequent corticosteroid or INF-α (Table 3). One patient with unilobar disease underwent surgical resection due to the persistence of heart failure symptoms; this patient was successfully cured without complications associated with surgery. Discussion Though IHHE is the most common hepatic vascular tumor in children, it is rarely seen in clinical practice. Over a 14-year period, we encountered only 23 patients with this lesion.

Interventional modalities included embolization (n=4) and conventional resectional surgery (n=1). One patient with Kasabach-Merritt syndrome (KMS) showed tumor progression despite embolization, eventually dying due to coagulopathy, liver failure, and sepsis. The other three patients who underwent embolization showed partial responses to subsequent corticosteroid or INF-α (Table 3). One patient with unilobar disease underwent surgical resection due to the persistence of heart failure symptoms; this patient was successfully cured without complications associated with surgery. Discussion Though IHHE is the most common hepatic vascular tumor in children, it is rarely seen in clinical practice. Over a 14-year period, we encountered only 23 patients with this lesion. IHHE showed a female predominance, with 13 of the 23 patients being girls. Previous studies have reported that the most common presenting signs of IHHE are asymptomatic hepatomegaly and abdominal mass (50%), followed by cutaneous hemangiomas (10 to 40%). Extensive arteriovenous shunting may be detected within these lesions, resulting in decreased peripheral vascular resistance. The maintenance of vascular bed perfusion may require increases in blood volume and cardiac output, which may lead to high cardiac output and congestive heart failure, observed in up to 50 to 60% of patients with IHHE10-13).

ng may be detected within these lesions, resulting in decreased peripheral vascular resistance. The maintenance of vascular bed perfusion may require increases in blood volume and cardiac output, which may lead to high cardiac output and congestive heart failure, observed in up to 50 to 60% of patients with IHHE10-13). Hematologic abnormalities may also be present; these include including anemia and especially thrombocytopenia caused by trapping of thrombocytes within the hemangioendothelioma with consumptive coagulopathy (KMS). Less common presentations include splenomegaly, jaundice, ascites, gastrointestinal bleeding, anemia, feeding difficulties, respiratory compromise, and rarely, spontaneous rupture and malignant transformation to angiosarcoma. IHHE has also been reported to be associated with fulminant hepatic failure and associated biliary atresia11), deletion of chromosome 6q14), heterotopic liver with diaphragmatic hernia15), trisomy 21, transposition of the great arteries, and extranumerary digits11).

rupture and malignant transformation to angiosarcoma. IHHE has also been reported to be associated with fulminant hepatic failure and associated biliary atresia11), deletion of chromosome 6q14), heterotopic liver with diaphragmatic hernia15), trisomy 21, transposition of the great arteries, and extranumerary digits11). Of our 23 patients, 14 presented with asymptomatic abdominal masses at the time of diagnosis, whereas 5 (22%) were diagnosed incidentally without suspicious symptoms. The main complaints at presentation were heart failure, skin hemangioma, hepatomegaly, and abnormal LFT results. Physical examination revealed hepatomegaly in 10 (43%) patients. Detailed physical examination is usually needed for accurate assessment. About half of our patients with IHHE had high output heart failure, considered a leading cause of death, along with consumptive coagulopathy. In addition, increased serum TSH concentrations were observed in two of the nine patients tested. Clinically significant hypothyroidism may be due to thyroid hormone catabolism by the tumor16), indicating the need for thyroid function tests in patients suspected of having IHHE. We found, however, that the incidences of hepatosplenomegaly and abdominal mass, previously reported to be the most common presenting signs in patients with IHHE, were lower than previously reported. In contrast to previous reports however, tumors in many of our patients were detected by fetal sonography and few had clinically severe conditions. Thus, high proportion of the patients with incidentally detected IHHE may explain the reduced incidence of patients with clinically severe IHHE.

r than previously reported. In contrast to previous reports however, tumors in many of our patients were detected by fetal sonography and few had clinically severe conditions. Thus, high proportion of the patients with incidentally detected IHHE may explain the reduced incidence of patients with clinically severe IHHE. In addition, because more patients may be diagnosed prenatally, further studies may be needed to assess the natural history and treatment strategy of IHHE during the neonatal period. Radiological evaluation is useful for patient diagnosis, with sonography often being the initial diagnostic modality. On sonography, IHHE is characterized by discrete, hypoechoic lesions (either solitary or multiple) within the liver that may have calcifications or shunting on Doppler evaluation.

In addition, because more patients may be diagnosed prenatally, further studies may be needed to assess the natural history and treatment strategy of IHHE during the neonatal period. Radiological evaluation is useful for patient diagnosis, with sonography often being the initial diagnostic modality. On sonography, IHHE is characterized by discrete, hypoechoic lesions (either solitary or multiple) within the liver that may have calcifications or shunting on Doppler evaluation. Of our 23 patients, 22 were diagnosed by sonography including 7 who were diagnosed by fetal sonography. Compared with sonography, CT shows a more variable enhancement pattern, although it offers several advantages, including more precise anatomical localization, tissue enhancement and characterization17,18). MRI generally shows well-defined spherical lesions, hypointense to the liver on T1 sequences and hyperintense on T2, with flow-voids and centripetal enhancement after the administration of gadolinium17,19). However, it may be difficult to establish a definite diagnosis based on imaging modalities alone. Histopathologically, IHHEs are usually composed of vascular channels lined by a single continuous layer of plump endothelial cells in a supporting fibrous stroma that may contain well-preserved bile ducts. Hematopoietic activity is a specific characteristic of these tumors. Thrombosis with infarction, followed by fibrosis and even calcification, can occur in the centers of large tumors8,20).

by a single continuous layer of plump endothelial cells in a supporting fibrous stroma that may contain well-preserved bile ducts. Hematopoietic activity is a specific characteristic of these tumors. Thrombosis with infarction, followed by fibrosis and even calcification, can occur in the centers of large tumors8,20). Serum AFP is an important tumor marker for the evaluation of pediatric hepatic masses. Serum AFP concentrations decrease rapidly after birth and reach adult levels by 8 months of age. Increased serum AFP concentrations are rarely observed in patients with IHHE, with one study reporting that clinical symptoms, age at presentation, tumor size and AFP concentration were not significantly related to time required for complete tumor regression21-23). Similarly, only three of our patients had increased concentrations of AFP, with all three having multiple tumors; despite receiving different treatment modalities, all three showed nearly complete tumor resolution. We found, however, that increased AFP was not directly related to treatment outcome. The etiology of increased serum AFP in IHHE is unclear, but it may be secreted by morphologically normal hepatic cells in response to the tumor5,22). AFP was shown to be expressed by hepatocytes near or trapped within the tumor, but not by tumor cells23). The most important prognostic factors are the presence of a symptomatic mass, congestive heart failure, jaundice, and multiple tumor nodules, and the absence of cavernous differentiation3-5,7).

Serum AFP is an important tumor marker for the evaluation of pediatric hepatic masses. Serum AFP concentrations decrease rapidly after birth and reach adult levels by 8 months of age. Increased serum AFP concentrations are rarely observed in patients with IHHE, with one study reporting that clinical symptoms, age at presentation, tumor size and AFP concentration were not significantly related to time required for complete tumor regression21-23). Similarly, only three of our patients had increased concentrations of AFP, with all three having multiple tumors; despite receiving different treatment modalities, all three showed nearly complete tumor resolution. We found, however, that increased AFP was not directly related to treatment outcome. The etiology of increased serum AFP in IHHE is unclear, but it may be secreted by morphologically normal hepatic cells in response to the tumor5,22). AFP was shown to be expressed by hepatocytes near or trapped within the tumor, but not by tumor cells23). The most important prognostic factors are the presence of a symptomatic mass, congestive heart failure, jaundice, and multiple tumor nodules, and the absence of cavernous differentiation3-5,7). Not all patients with IHHE require treatment. These tumors tend to grow during the first year of life then spontaneously regress without treatment, probably due to thrombosis and scar formation. The decision not to treat asymptomatic patients is not a strict rule. Each patient should be evaluated individually. Indications for therapy may include cardiac insufficiency, respiratory distress, coagulopathy, abdominal compartment syndrome and deterioration in hepatic function tests. If therapy is needed, first-line medical treatment is recommended, followed in some patients by invasive or surgical procedures3,5,7,9).

ndividually. Indications for therapy may include cardiac insufficiency, respiratory distress, coagulopathy, abdominal compartment syndrome and deterioration in hepatic function tests. If therapy is needed, first-line medical treatment is recommended, followed in some patients by invasive or surgical procedures3,5,7,9). Among the medical treatments for these tumors are corticosteroids, cytotoxic agents, INF-α, and irradiation. Patients who do not respond to medical treatment may undergo radical interventions, such as hepatic artery ligation, transcatheter hepatic artery embolization, surgical resection, and even liver transplantation24). Surgical resection is recommended to remove huge masses with a low potential for spontaneous regression and masses for which a diagnosis of malignancy cannot be excluded clinically and/or radiologically25-27).

ry ligation, transcatheter hepatic artery embolization, surgical resection, and even liver transplantation24). Surgical resection is recommended to remove huge masses with a low potential for spontaneous regression and masses for which a diagnosis of malignancy cannot be excluded clinically and/or radiologically25-27). Spontaneous resolution occurred in 2 of 6 asymptomatic patients without specific therapy (33%), and 8 (67%) of 12 patients were successfully treated with corticosteroids and/or INF-α. Of patients treated with corticosteroids alone, 50% achieved resolution of the lesion, similar to previously reported response rates as high as 45% in symptomatic patients8). Responses often occurred within 1 or 2 weeks and a median time to complete resolution by medical treatment was approximately 30 months (range, 0 to 43 months). Although the precise mechanism of action is unclear, corticosteroids may cause vasoconstriction of the rapidly proliferating immature endothelial cells that line the vascular channels of the lesion3). Moreover, the antiangiogenic agent INF-α, which inhibits endothelial cell migration and proliferation, may also be helpful in causing early regression of hemangioendotheliomas resistant to corticosteroids28). We also found that INF-α yielded satisfactory results, either alone or in combination with steroids. Embolization was effective in three patients who had inoperable, symptomatic, and solitary lesions, but was not successful in one patient despite additional therapy (corticosteroids, INF-α) (Table 4). We found that 48% of patients with IHHE could be managed successfully with or without treatment, with tumor regression observed in an additional 43%.

three patients who had inoperable, symptomatic, and solitary lesions, but was not successful in one patient despite additional therapy (corticosteroids, INF-α) (Table 4). We found that 48% of patients with IHHE could be managed successfully with or without treatment, with tumor regression observed in an additional 43%. Based on our experience and the current literature, we propose the following algorithm for the treatment of children with IHEE (Fig. 1). Once the diagnosis is suggested, either by patient symptomatology or as an incidental finding, prompt diagnostic evaluation is mandatory. Asymptomatic unilobar lesions may be observed for regression. However, both asymptomatic, but progressive lesion and symptomatic lesions should be treated with corticosteroids and/or INF-α. If, despite medical treatment, symptoms progress over several weeks or develop in patients with asymptomatic lesions, interventional modalities should be used immediately. If the lesion is accessible to surgical resection, partial hepatectomy should be performed as definitive therapy. Patients with inoperable tumors should undergo embolization followed by medical therapy, either to attempt a definitive cure or as a temporary measure while the patient is evaluated and listed for cadaveric orthotopic liver transplantation or until a suitable living, related donor is identified.

as definitive therapy. Patients with inoperable tumors should undergo embolization followed by medical therapy, either to attempt a definitive cure or as a temporary measure while the patient is evaluated and listed for cadaveric orthotopic liver transplantation or until a suitable living, related donor is identified. Given the malignant potential of IHHEs, we recommend long-term monitoring of patients with presumed or confirmed IHHE, at least until complete resolution of the hepatic lesion. Monitoring is probably best accomplished by serial clinical examinations and imaging with sonography or CT. Serum AFP concentration should also be monitored if it was increased at the time of diagnosis. Patients with IHHE usually have an excellent prognosis, especially because the rates of spontaneous regression after the first year of life and long-term survival are about 70%. A multidisciplinary approach that involves pediatric oncologists, radiologists and surgeons is the best treatment option for these patients, increasing their survival. Fig. 1 Management strategy for patients with infantile hepatic hemangioendothelioma (IHHE). Dx, diagnosis; Op, operation. Table 1 Patient Demographic and Clinical Characteristics at Diagnosis (n=23) Values are presented as median (range), number (%), or number. HFT, hepatic function tests; TSH, thyroid-stimulating hormone; CT, computed tomography; MRI, magnetic resonance imaging; Rt, right; Lt, left. Table 2 Tumor Extent and Other Clinical Factors in Three Patients Who Had Increased Concentration of Alpha-Fetoprotein (AFP)

Values are presented as median (range), number (%), or number. HFT, hepatic function tests; TSH, thyroid-stimulating hormone; CT, computed tomography; MRI, magnetic resonance imaging; Rt, right; Lt, left. Table 2 Tumor Extent and Other Clinical Factors in Three Patients Who Had Increased Concentration of Alpha-Fetoprotein (AFP) Tx, treatment; F/U, follow-up; US, ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; Bx, biopsy; PD, prednisolone; IFN, interferon. Table 3 Clinical Characteristics and Treatment Results of Patients with Infantile Hepatic Hemangioendothelioma Sx, symptoms; Tx, treatment; F/U, follow-up; Rt, right; Lt, left; HFT, hepatic function test; CHF, congestive heart failure; KMS, Kasabach Merritt syndrome; PD, prednisolone; IFN-α, interferon-alpha; Emb, embolization; NA, not available. *Tx duration: full dose / tapering. †Progression to coagulopathy, liver failure and sepsis despite embolization in 1 patient. Table 4 Outcomes Relative to Management in Patients with Infantile Hepatic Hemangioendothelioma (n=23) IFN, interferon; Op, operation.

Introduction Distal trisomy, or duplication of 15q, is an extremely rare chromosomal disorder in which the end portion of the long arm of the 15th chromosome (15q) appears three times (trisomy), rather than twice, in cells of the body. Since Fujimoto et al.1) reported on duplication of distal 15q in 1974, at least 50 cases of duplication of regions 15q21-15q26.3 have been identified. The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q. However, there are consistent and recognizable clinical phenotypes with partial duplication for distal 15q, which are characterized by minor craniofacial anomalies, congenital heart disease, mental retardation, and genital anomalies, particularly in affected males2). Most reported cases have resulted from unbalanced translocations or deletions involving chromosome 15 and another chromosome3). We report on a girl with a de novo duplication, 15q24-qter, with breakpoints that differ from those that have been described previously and did not result from unbalanced translocation or deletion. Bacterial artificial chromosome (BAC) clone-based-array comparative genomic hybridization (aCGH) analysis revealed a gain of 42 clones on 15q24-qter. Thus, the patient was diagnosed as having de novo duplication of chromosome 15; 15q24-q26.3. This case represents the only reported patient in Korea with a 15q24-qter duplication or trisomy that did not result from an unbalanced translocation and did not have a concomitant deletion.

d a gain of 42 clones on 15q24-qter. Thus, the patient was diagnosed as having de novo duplication of chromosome 15; 15q24-q26.3. This case represents the only reported patient in Korea with a 15q24-qter duplication or trisomy that did not result from an unbalanced translocation and did not have a concomitant deletion. Case report A female infant was born at 37+3 weeks of gestation following a repeat caesarean section performed in a local obstetrics clinic. She was the second child of healthy, phenotypically normal, and non consanguineous Korean parents. Her mother was 34 years old, and her father was 33 years old. There were no reported drug or teratogenic exposures during pregnancy and normal fetal activity was reported. The patient's Apgar scores were 5 and 8 at 1 and 5 minutes. She weighed 3,940 g (>90 percentile), was 52 cm long (>90 percentile), and had a head circumference of 36 cm (>90 percentile) at birth. She had cyanosis and irregular respiration, as well as peculiar facial morphology, and multiple anomalies, including craniofacial limbs, were detected after birth. Thus, she was transferred to the Neonatal Intensive Care Unit of Pusan Paik Hospital, Inje University College of Medicine.

36 cm (>90 percentile) at birth. She had cyanosis and irregular respiration, as well as peculiar facial morphology, and multiple anomalies, including craniofacial limbs, were detected after birth. Thus, she was transferred to the Neonatal Intensive Care Unit of Pusan Paik Hospital, Inje University College of Medicine. She had a large anterior fontanel with wide sutures, a narrow, asymmetric face, with down-slanting palpebral fissures, and a large, prominent nose, pointed chin, and micrognathia, low set dysmorphic ears with poorly formed helices (Fig. 1); she also had long, tapering fingers, and slender hands, with a drumstick appearance of the terminal phalanges, and narrow feet, with broad big toes (Fig. 2). A grade II systolic murmur on the left sternal border and coarse breath sounds were heard. Chest radiograph showed atelectasis and ground glass opacities in both lung fields. Patent ductus arteriosus and atrial septal defects were detected on echocardiogram. Abdominal ultrasound examination showed bilateral hydronephrosis and hydroureter. 1. Cytogenetic analysis Standard chromosomal analysis of peripheral blood by Giemsatrypsin banding showed additional chromosomal material on the long arm of one chromosome 15 and in all cells examined. Results from propositus demonstrated 46,XX,inv(9)(p12q13),dup(15) (q24q26.3). The karyotype of the father was normal, 46, XY, while that of the mother showed 46,XX,inv(9)(p12q13) (Fig. 3).

ood by Giemsatrypsin banding showed additional chromosomal material on the long arm of one chromosome 15 and in all cells examined. Results from propositus demonstrated 46,XX,inv(9)(p12q13),dup(15) (q24q26.3). The karyotype of the father was normal, 46, XY, while that of the mother showed 46,XX,inv(9)(p12q13) (Fig. 3). 2. aCGH analysis We have developed a microarray for comparative genomic hybridization utilizing genomic clones from chromosome 15q for characterization of genomic rearrangements. The array accurately localized all breakpoints associated with gains or losses on 15q. We used the MAC Array Karyo 4000 (Macrogen Inc., Seoul, Korea) spotted with 4,030 human (BAC) clones, which covered the entire human genome at an average interval of 0.83 Mb. These BAC clones were selected from genome databases archived at the gene ontology website (http://www.geneontology.org). Array-based CGH was performed as reported. Images (16-bit) of fluorescence intensity for spots were captured from each array slide with a Gene Pix 4000A scanner and the ratio value was calculated using MAC viewer software (Macrogen Inc.). Average log2 Cy3/Cy5 signal ratios of triplicate BAC clones were calculated for each sample, and ±0.25 log2 ratio was used as a threshold for defining copy number increases (gains) and decreases (losses). BAC clone-based-aCGH analysis revealed a gain of 42 clones on 15q24-q26.3. Thus, the patient was diagnosed as having de novo duplication 15 q24-q26.3 (Fig. 4).

cate BAC clones were calculated for each sample, and ±0.25 log2 ratio was used as a threshold for defining copy number increases (gains) and decreases (losses). BAC clone-based-aCGH analysis revealed a gain of 42 clones on 15q24-q26.3. Thus, the patient was diagnosed as having de novo duplication 15 q24-q26.3 (Fig. 4). Discussion Partial trisomy, or duplication of the long arm of chromosome 15, represents a very rare and heterogenous group of chromosomal aberrations, which were first described by Fujimoto et al.1) in 1974. Common phenotypic findings in the distal duplication 15q syndrome are consistent and are characterized by down slanting palpebral fissures, a large, prominent nose, facial asymmetry, ptosis, micrognathia, congenital heart disease, severe mental deficiency, and genital anomalies, including cryptorchidism and hypogonadism (in affected male), and hand anomalies (arachnodactyly and camptodactyly)2,4). In the majority of patients, duplication of 15q is concomitant with translocation or deletion. Breakpoints in distal 15q trisomy occur most often between bands 15q21 and 15q235,6). Van Allen et al.7) reported on families with breakpoints at 15q15 and 15q26, respectively. In contrast to the above cases, our patient has a duplication of the mid-distal part of the long arm of chromosome 15. Zollino et al.8) reviewed the most detailed reports on a total of 32 patients with the 15q duplication and divided them into two groups, based on their trisomic extent: one group (26 patients) had trisomy for 15q21-qter, and the other group (6 patients) had trisomy for 15q25qter. They compared and described the clinical phenotypes between duplication 15q21-24 and duplication 15q25-26qter. Both groups shared mental retardation, a prominent nose, a long, narrow, and asymmetric face, severe scoliosis with chest deformity, a pointed chin, and micrognatia, hypotonia, congenital heart defects, and renal abnormalities. Clinical features typical for trisomy for 15q25-qter included tall stature (in 4 of 6 patients), macrocephaly, craniosynostosis, and broad thumbs/big toes. Clinical features specific for duplication of 15q21-24 included microcephaly and normal prenatal growth2). The present report provides further evidence for a specific phenotype related to duplication of 15q25 or 26-qter with macrosomia at birth; overgrowth, macrocephaly, and broad thumbs and big toes, but craniosynostosis. Over growth is rarely associated with chromosomal anomalies.

icrocephaly and normal prenatal growth2). The present report provides further evidence for a specific phenotype related to duplication of 15q25 or 26-qter with macrosomia at birth; overgrowth, macrocephaly, and broad thumbs and big toes, but craniosynostosis. Over growth is rarely associated with chromosomal anomalies. Overgrowth has been reported as well in association with duplication of distal 15q. The cause of overgrowth and tall stature has been thought to be the triplication of the insulin-like growth factor 1 receptor (IGF1R) gene located on 15q26.3. Insulin-like growth factors (IGF) and their receptors have been implicated in pre- and postnatal growth. IGF1R is a transmembrane heterotetramer, located on 15q25-q26.3, which mediates the mitogenic effect of IGF1 and IGF29). Faivre et al.10) suggested that overgrowth might be causally related to a dosage excess of the IGF1R gene. Of particular interest, overgrowth has also been reported in patients with tetrasomy of chromosome 15q25-qter, as well as in some patients with larger trisomy 15q22qter. Also, a gene for macrocephaly is likely to be located in this region. Of particular interest, a large family with autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facial features has been recently reported, and a gene locus was identified on 15q26.2411).

er trisomy 15q22qter. Also, a gene for macrocephaly is likely to be located in this region. Of particular interest, a large family with autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facial features has been recently reported, and a gene locus was identified on 15q26.2411). In contrast, patients with 15q-monosomy, including a deletion of distal 15q and a ring chromosome 15, showed some distinct clinical findings. Most of these patients had intrauterine growth retardation (IUGR), microcephaly, abnormal face and ears, micrognathia, a highly arched palate, renal abnormalities, lung hypoplasia, failure to thrive, and developmental/mental retardation12). Roback et al.13) reported on an infant with del(15)(q26.1qter) and a girl with r(15) (p12q26.3), respectively; both patients had IUGR that was associated with loss of an allele of the (IGF1R) gene.

a highly arched palate, renal abnormalities, lung hypoplasia, failure to thrive, and developmental/mental retardation12). Roback et al.13) reported on an infant with del(15)(q26.1qter) and a girl with r(15) (p12q26.3), respectively; both patients had IUGR that was associated with loss of an allele of the (IGF1R) gene. Most cases of partial trisomy, or duplication of a segment of distal 15q, were the result of unbalanced translocations. The second chromosome involved in the reciprocal translocation has varied; chromosomes 2, 7, 8, 11, 13, 15 (Robertsonian translocation), and 21 have been reported6). Other cases of 15q duplication have been the result of direct or inverted duplication14,15). However, in this case, there were no concomitant translocations or deletions. This case represents the only reported patient with a de novo 15q24-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component in Korea. In our case, BAC clone-based-aCGH analysis revealed a gain of 42 clones on 15q24-qter. Thus, the patient was diagnosed as having de novo 46,XX,inv(9)(p12q13),dup(15)(q24q26.3) chromosome complement. Microarray-based CGH using large-insert clones is useful for detection of deletions or duplications that are greater than about 10 kb, but below the level of detection by karyotype analysis. Microarray CGH enables assessment of hundreds or even thousands of sites in a single hybridization, thus providing a whole-genome scan for rearrangements. Array CGH has been used for detection of constitutional chromosomal abnormalities. Recent studies utilizing chromosome 15-specific BAC microarrays of varying resolution have provided more detailed molecular characterization of chromosome 15 rearrangements16).

tion, thus providing a whole-genome scan for rearrangements. Array CGH has been used for detection of constitutional chromosomal abnormalities. Recent studies utilizing chromosome 15-specific BAC microarrays of varying resolution have provided more detailed molecular characterization of chromosome 15 rearrangements16). The majority of idic(15q) chromosomes are comprised of symmetrical arms with four copies of the breakpoint 1 to breakpoint 5 region. Patients with less common breakpoints that are not distinguished by routine cytogenetic methods have been more accurately characterized by array analysis. This microarray provides a detailed characterization for chromosomal abnormalities involving 15q and is useful for more precise genotype-phenotype correlations17).

. Patients with less common breakpoints that are not distinguished by routine cytogenetic methods have been more accurately characterized by array analysis. This microarray provides a detailed characterization for chromosomal abnormalities involving 15q and is useful for more precise genotype-phenotype correlations17). We have developed a microarray for comparative genomic hybridization utilizing genomic clones from chromosome 15q for characterization of abnormal regions. The array accurately localized all breakpoints associated with gains or losses on 15q. The results confirmed the location of breakpoints associated with interstitial duplications. Partial duplication of distal 15q due to de novo pure duplication is very rare18). This case represents the only reported patient in Korea with a 15q24-qter duplication or trisomy that did not result from an unbalanced translocation and did not have a concomitant monosomic component. Cytogenetic analysis of the parents demonstrated that no other chromosomal aberrations, except for inv(9)(p12q13), were present in the mother, who was phenotypically normal. Inversion of chromosome 9; inv(9)(p12q13) was demonstrated in both the patient and the mother. Pericentric inversion of chromosme 9 is one of the most common structurally balanced chromosomal variations and has been found in normal populations, and does not appear to be pathogenic with regard to congenital anomalies19). The present case necessitates the continuing delineation of phenotype-karyotype correlations and phenotypic consequences of chromosome 15q abnormalities.

on structurally balanced chromosomal variations and has been found in normal populations, and does not appear to be pathogenic with regard to congenital anomalies19). The present case necessitates the continuing delineation of phenotype-karyotype correlations and phenotypic consequences of chromosome 15q abnormalities. Fig. 1 Photographs of the Face. (A) Narrow asymmetric face with down-slanting palpebral fissures, and large prominent nose, pointed chin and micrognathia are shown in the photograph of the face. (B) Low set dysmorphic ears with poorly formed helices, micrognathia and retrognathia are shown in lateral view of patient's face. Fig. 2 Photographs of hand and foot. (A) Arachnocamptodactyly; long tapering fingers, and slender hand with drumstick appearance of the terminal phalanges are shown. (B) Narrow foot with broad big toe. Fig. 3 GTG banded Karyotypes of the lymphocytes from the patient. (A) The Result of karyotyping was 46,XX,inv(9) (p12q13),dup(15)(q24q26.3). The arrows indicate the abnormal chromosomes. Duplication of the distal chromosome 15q with inversion of chromosome 9 were detected. (B) Chromosome 15 ideogram and partial karyotype of the patient indicating the extent of duplicated region (q24->q26.3) (arrow). The abnormal chromosome is on the right.

up(15)(q24q26.3). The arrows indicate the abnormal chromosomes. Duplication of the distal chromosome 15q with inversion of chromosome 9 were detected. (B) Chromosome 15 ideogram and partial karyotype of the patient indicating the extent of duplicated region (q24->q26.3) (arrow). The abnormal chromosome is on the right. Fig. 4 The ratio plots from array comparative genomic hybridization. Normalized data in which the test sample was labeled with cyanine 3 are shown in blue, while that in which the test sample was labeled with cyanine 5 are shown in red. A gain of a particular clone is manifested as a positive (upward) deviation of the blue signal from modal value 0.25 and a negative (downward) deviation of the red signal from -0.25 for same clone. Conversely, a loss of a clone shows the opposite pattern. A forty two - clone gain on 15q24-q26.3 (between arrows) are found.

Introduction Loeys-Dietz syndrome (LDS) is a recently recognized genetic aortic aneurysm syndrome characterized by the triad of hypertelorism, bifid uvula or cleft palate, and generalized arterial tortuosity with aneurysms and dissections throughout the arterial tree1). LDS is associated with mutations in the transforming growth factor beta receptor type I (TGFBR1) and type II (TGFBR2) genes1,2). These mutations cause increment of downstream TGFB signaling in the aortic media and subsequent overproduction of collagen, disarrayed elastic fiber and loss of elastin content in extracellular matrix1-3). Therefore, patients with LDS usually show aggressive and rapid progression of aortic dilatation and regurgitation, and have a high risk of aortic dissection or rupture, even though the patients are young in age and had smaller aortic diameters than other aortic aneurysm syndromes. We report a child who was diagnosed as LDS with specific, characterized phenotype and two novel gene missense mutations in TGFBR2 gene, and underwent surgical repair for aortic root aneurysm. Case report A 7-year-old girl was consulted from another department because of an abnormal electrocardiogram (ECG) pattern of severe left axis deviation and tall R in V5-6, and cardiomegaly (cardiothoracic ratio 0.62) in a chest X-ray. In physical examinations, she had ocular hypertelorism, bifid uvula (Fig. 1A) and high arched palate, strabismus, pectus excarvatum, arachnodactyly, calcaneus eversion and metatarsus adductus (Fig. 1B, C). Weight and height were in the 30th and >97th percentile, respectively.

Case report A 7-year-old girl was consulted from another department because of an abnormal electrocardiogram (ECG) pattern of severe left axis deviation and tall R in V5-6, and cardiomegaly (cardiothoracic ratio 0.62) in a chest X-ray. In physical examinations, she had ocular hypertelorism, bifid uvula (Fig. 1A) and high arched palate, strabismus, pectus excarvatum, arachnodactyly, calcaneus eversion and metatarsus adductus (Fig. 1B, C). Weight and height were in the 30th and >97th percentile, respectively. In past history, she was born at term to a 30-year-old mother and a 30-year-old unrelated father. Her mother's obstetric history was gravida 4, para 1, abortion 3 and was unremarkable. She was referred to our neonatal intensive care unit on day 1 of life for additional evaluation of a genetic syndrome in the setting of diffuse hypotonia and musculoskeletal abnormalities. All growth parameters including height, weight and head circumference were within normal limits. Family history was unremarkable. Investigations included chromosomal study, skeletal imaging, ultrasonogram of the head, and echocardiography. Although she had abnormal skeletal morphology, her chromosome was normal. She had no intracranial abnormalities. A small patent ductus arteriosus without aneurysm and a small atrial septal were defected on echocardiography.

s included chromosomal study, skeletal imaging, ultrasonogram of the head, and echocardiography. Although she had abnormal skeletal morphology, her chromosome was normal. She had no intracranial abnormalities. A small patent ductus arteriosus without aneurysm and a small atrial septal were defected on echocardiography. She underwent serial orthopedic surgical intervention for correction for lower-extremity abnormalities at neonatal and childhood period and had done regular follow-up at the orthopedic department. The patient was subsequently lost to the cardiology department follow-up until cardiology consult was performed because of cardiomegaly and abnormal ECG findings for ophthalmologic intervention due to strabismus. When she was consulted for abnormal ECG, subsequent echocardiography was performed and revealed marked dilated aortic annulus and root4), which measured 23 to 24 mm and 33 to 35 mm, respectively (Z-value >2, body surface area =0.83), with grade II aortic regurgitation, dilated pulmonary annulus (24 to 25 mm, Z-value >2), and small cone shaped patent ductus arteriosus. Computed tomography (CT) angiography showed arterial tortuosity at the common carotid artery (Fig. 2). Based on above findings, the suspicion of LDS rather than Marfan syndrome (MFS) was raised because she had all of the typical triad of LDS, such as facial abnormalities (hypertelorism and bifid uvula), markedly dilated aortic annulus and root in spite of young age and arterial tortuosity of the neck vessels. Moreover she did not have ectopia lentis or myopia which is the frequent findings in MFS.

was raised because she had all of the typical triad of LDS, such as facial abnormalities (hypertelorism and bifid uvula), markedly dilated aortic annulus and root in spite of young age and arterial tortuosity of the neck vessels. Moreover she did not have ectopia lentis or myopia which is the frequent findings in MFS. To confirm our clinical diagnosis of LDS, we performed molecular genetic testing of the TGFBR1 and TGFBR2 genes. Informed consent of the parents was obtained prior to genetic testing.

was raised because she had all of the typical triad of LDS, such as facial abnormalities (hypertelorism and bifid uvula), markedly dilated aortic annulus and root in spite of young age and arterial tortuosity of the neck vessels. Moreover she did not have ectopia lentis or myopia which is the frequent findings in MFS. To confirm our clinical diagnosis of LDS, we performed molecular genetic testing of the TGFBR1 and TGFBR2 genes. Informed consent of the parents was obtained prior to genetic testing. All coding exons and flanking intron regions of the TGFBR1 and TGFBR2 genes were amplified and sequenced using primer sets designed in our laboratory. In TGFBR1 gene, we could not detect any variations, whereas we identified one synonymous, one intronic and two missense variations in the TGFBR2 gene (Table 1). Of these, one intronic (c.263+7A>G, rs1155705) and one synonymous (c.1167C>T, rs2228048) variations were inherited from one of parents and known-polymorphisms listed in the single nucleotide polymorphism database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/). However, the two heterozygous missense variations (c.1526G>T c.1528A>T) were novel variations which have not been described in any previous literatures. These two missense variations were not detected in the proband's parents suggesting as de novo (Fig. 3). These variations are located in exon 7 and are included in the highly conserved serine/threonine kinase domain XI of TGFBR2. Furthermore, when we checked the influence of these variations to the function of protein using sorting intolerant from tolerant algorithm, both of those variations are expected to affect protein function. When we used the polymorphism phenotyping (PolyPhen) algorithm, Gly509Val was expected as 'probably damaging variation' and Ile510Phe was expected as benign one.

hese variations to the function of protein using sorting intolerant from tolerant algorithm, both of those variations are expected to affect protein function. When we used the polymorphism phenotyping (PolyPhen) algorithm, Gly509Val was expected as 'probably damaging variation' and Ile510Phe was expected as benign one. Medication of angiotensin receptor II antagonist (losartan, 0.5 mg/kg/day) was started and prophylactic surgical repair for aortic root aneurysm such as valve sparing root replacement was performed. So far, surgical intervention was successful, she has had a medical checkup at regular intervals with losartan medication and CT angiography every year. Discussion Loeys et al.2) first reported six families who had phenotype characterized by typical cardiovascular (generalized arterial tortuosity and aneurysms with dissection throughout the arterial tree), craniofacial (hypertelorism, bifid uvula and/or cleft palate), and skeletal (pectus excarvatum, dolichostenomelia, arachnodactyly and metatarsus adductus) manifestations, and heterozygous mutations in the genes encoding TGFBR I or II. They described this phenotype as LDS, a new aortic aneurysm syndrome. So far, more than 80 LDS patients including some pediatric patients have been described in previous papers, and many TGFBR1 or TGFBR2 gene mutations have been also reported in those patients2,5-7).

ygous mutations in the genes encoding TGFBR I or II. They described this phenotype as LDS, a new aortic aneurysm syndrome. So far, more than 80 LDS patients including some pediatric patients have been described in previous papers, and many TGFBR1 or TGFBR2 gene mutations have been also reported in those patients2,5-7). TGFBR2 gene, which is located chromosome 3p22.5, consists of seven exons and six introns, and encodes the human TGFBR II8). This receptor regulates cellular proliferation, differentiation, motility, organization, apoptosis, and formation of extracellular matrix, especially in the cardiovascular system9,10). Mutations of TGFBR2 gene are associated with increased downstream TGFB signaling in the aortic media, overproduction and deposition of collagen, organization of elastic fiber and loss of elastin content in extracellular matrix1-3). Excessive collagen deposition results in weakness of aortic vascular bed, dilatation and dissection of the aorta.

are associated with increased downstream TGFB signaling in the aortic media, overproduction and deposition of collagen, organization of elastic fiber and loss of elastin content in extracellular matrix1-3). Excessive collagen deposition results in weakness of aortic vascular bed, dilatation and dissection of the aorta. The LDS phenotype may resemble that of the MFS. MFS is characterized by skeletal, ocular, cardiovascular, pulmonary, skin findings, and dural ectasia. Among of these findings for MFS, specific ocular finding, bilateral ectopia lentis occurs in about 40 to 56% of patients with MFS11) and does not occur in LDS1). In comparison to MFS, LDS patients show typical characteristics such as facial dysmorphology (hypertelorism, bifid uvula and/or cleft palate), aortic root aneurysm, aneurysm of other vessels and widespread arterial tortuosity1,2,12). If the patient has typical characteristics for LDS and does not have ectopia lentis, the patient can be diagnosed with LDS and gene testing for LDS should be performed.

morphology (hypertelorism, bifid uvula and/or cleft palate), aortic root aneurysm, aneurysm of other vessels and widespread arterial tortuosity1,2,12). If the patient has typical characteristics for LDS and does not have ectopia lentis, the patient can be diagnosed with LDS and gene testing for LDS should be performed. In respect to specific genotype, LDS patients show TGFBR1 or TGFBR2 gene mutations but do not show mutations in the gene encoding fibrillin-1 (FBN1). On the other hand, most of MFS patients show mutations in the gene encoding FBN1 although some of MFS patients have been reported to have TGFBR mutations without FBN1 mutations5). LDS patients have arterial tortuosity and aneurysms throughout the arterial tree, whereas the main target vessel in MFS is the ascending aorta and aortic root1,2,12). Therefore, the initial evaluation of patients with a presentation similar to that of MFS requires a multi-disciplinary approach including clinical genetics, cardiology, ophthalmology and radiology.

eurysms throughout the arterial tree, whereas the main target vessel in MFS is the ascending aorta and aortic root1,2,12). Therefore, the initial evaluation of patients with a presentation similar to that of MFS requires a multi-disciplinary approach including clinical genetics, cardiology, ophthalmology and radiology. The most important finding of LDS is the aggressive and rapid progression of aortic pathology even though the patients are young in age and shorter median survival due to occurrence of dissections at smaller diameters than in other connective-tissue disorders1,13). The median survival was 37 years among patients with LDS1), 48 years among patients with vascular Ehlers-Danlos syndrome14) and 70 years among patients with MFS who underwent treatment15). In previous report, mean age of operation was 9.2+5.7 years (range, 0.5 to 17 years) in pediatric patients undergoing aortic surgery13). Among 14 pediatric patients, 3 patients aged younger than 10 years had fatal aortic dissection and intracerebral hemorrhage, and these findings occurred in patients who had a smaller aortic root diameter than in MFS patients13). Our patient also showed marked aortic root dilatation and progressive aortic regurgitation when she was 7-year-old, so we considered early surgical intervention.

fatal aortic dissection and intracerebral hemorrhage, and these findings occurred in patients who had a smaller aortic root diameter than in MFS patients13). Our patient also showed marked aortic root dilatation and progressive aortic regurgitation when she was 7-year-old, so we considered early surgical intervention. In conclusion, patients with distinct phenotypic characteristics, marked aortic dilatation and aneurysm at early age should be suspected to be affected by LDS and could benefit from rapid TGFBR1 or TGFBR2 gene analysis. Early genetic diagnosis is the essential tool to make adequate management for LDS patients. If clinical diagnosis is confirmed by molecular genetic testing of the TGFBR genes, according to guideline13), medical checkup and clinical assessments using echocardiography, CT or magnetic resonance imaging angiography at regular intervals, and early, prophylactic surgical intervention of abnormal aortic dilation and aneurysm such as valve sparing root replacement, must be done to prevent future vascular events. Fig. 1 The patient had (A) bifid uvula (B,C) metatarsus adductus. Fig. 2 Computed tomography angiography showed arterial tortuosity at common carotid artery. Fig. 3 DNA chromatograms from the patient and parents are shown. In patient, G to T and A to T transitions are shown at nucleotide position 1526 and 1528, respectively. These variations substituted a Gly for a Val and an Ile for a Phe at codon 509 and 510, repectively. In parents, any of these variations are not found. Table 1 Genetic Variations Identified in the TGFBR2 Gene in the Patient

Fig. 3 DNA chromatograms from the patient and parents are shown. In patient, G to T and A to T transitions are shown at nucleotide position 1526 and 1528, respectively. These variations substituted a Gly for a Val and an Ile for a Phe at codon 509 and 510, repectively. In parents, any of these variations are not found. Table 1 Genetic Variations Identified in the TGFBR2 Gene in the Patient dbSNP, single nucleotide polymorphism database.

Introduction During last 40 years, the Korean population has been increasing steadily, and reached 47.99 million in 2010. However, due to a decline in birth rate and total number of births, the fertility rate between 2005 and 2010 was the lowest in the world. In addition, the Korean population has been aging rapidly and is the highest in the world, resulting in adramatic demographic transition1). In 2000, Korea was labeled as an aging society and is expected to become an aged society by 2018 and a "super-aged" society in 20262). Average maternal age and advanced maternal age have been increased along with a decreasing average birth rate and an increasing low birth weight infants3-7). Thus, it is important to develop appropriate policies to the variety of issues addressed. This study researched the changes in maternal and infant characteristics associated with birth outcomes during the past four decades are based on Korean birth data from the Statistics Korea (Korea National Statistical Office)8), Organization for Economic Cooperation and Development (OECD) Family database9) and studies of birth outcomes in Korea and abroad. Ultimately, this study aims to identify necessary information infrastructures to effective countermeasures the decrease in birth rate and increase in prevalence of low birth weight infants in Korea.

tion for Economic Cooperation and Development (OECD) Family database9) and studies of birth outcomes in Korea and abroad. Ultimately, this study aims to identify necessary information infrastructures to effective countermeasures the decrease in birth rate and increase in prevalence of low birth weight infants in Korea. Changes in birth statistics in Korea 1. Changes in the population, marriages, and birth rate in Korea, 1970 to 2010 The Korean population increased from 31.43 million in 1970 to 47.99 million in 2010. The elderly population ≥65 years increased more than tripled, from 3.31% in 1970 to 11.30% in 2010; however, the population of children less than 15 years old decreased, from 42.12% in 1970 to 16.23% in 2010. The aged-child ratio, a ratio based on the proportion of elderly to young, increased from 34.98 in 2000 to 69.66 in 2010. An aging society is defined as a society with an aged-child ratio of >30; thus, Korea was classified as an aging society in 2000, because its aged-child ratio was >30. In addition, the number of marriages per year has been gradually decreased, thereby resulting in a decreasing crude marriage rate from 9.2 in 1970 to 6.5 in 2010. Live births declined from 1,006,654 in 1970 to 435,031 in 2005-the lowest number of live births recorded-and then rose to 470,171 in 2010. The crude birth rate and total fertility rate decreased consistently, reaching their lowest in 2005, and then increasing slightly to 9.4 and 1.23 in 2010, respectively (Table 1)1).

Live births declined from 1,006,654 in 1970 to 435,031 in 2005-the lowest number of live births recorded-and then rose to 470,171 in 2010. The crude birth rate and total fertility rate decreased consistently, reaching their lowest in 2005, and then increasing slightly to 9.4 and 1.23 in 2010, respectively (Table 1)1). Compared to the total fertility rate of OECD member countries, Korea was higher than the OECD average before 1984; however, the average rate declined continuously after 1984. In 2009, the average for the 34 member countries of the OECD was 1.74, and the average for Korea was 1.15 which was the lowest overall9). 2. Birth outcomes of infants born in Korea, 1993 to 2010 As the number of live births has decreased, so has the average birth weight: from 3.31 kg in 1993 to 3.22 kg in 2010; males were 100 g heavier than females. The rate of very low birth weight infants (VLBWIs, <1,500 g) increased from 0.13 in 1993 to 0.6% in 2010, and the rate of low birth weight infants (LBWIs, <2,500 g) increased from 2.63 to 5.02%. The rate of preterm births before 32 weeks increased from 0.28 in 1995 to 0.75% in 2010, and the rate of preterm birthsbefore 37 weeks increased from 2.56 to 5.94%. The multiple birth rate increased steadily from 1.13 in 1993 to 2.76% in 2010, and among these births, the rate of LBWIs increased from 49.20 in 2000 to 54.50% in 2010, and the rate of preterm births before 37 weeks increased from 24.15 in 1995 to 53.70% in 2010 (Table 2).

sbefore 37 weeks increased from 2.56 to 5.94%. The multiple birth rate increased steadily from 1.13 in 1993 to 2.76% in 2010, and among these births, the rate of LBWIs increased from 49.20 in 2000 to 54.50% in 2010, and the rate of preterm births before 37 weeks increased from 24.15 in 1995 to 53.70% in 2010 (Table 2). Maternal factors that could influence the gestational age and birth weight of newborns were investigated. The average maternal age of first delivery increased from 27.6 years in 1993 to 31.3 years in 2010. The group aged 20 to 24 has increased continuously since 1970, was the highest at 40.5% in 1984, but decreased to 5.2% in 2010. The group aged 25 to 29 decreased from its highest at 54.6 in 1970 to 31.4% in 2010. The group aged 30 to 34 was the lowest at 8.5% in 1984 but increased to 45.7% in 2010. The >35-year group was 1.9% in 1988 and increased to 17.1% in 2010. The <20-year group has decreased from 3.0 in 1970 to 1.6% in 2010 (Fig. 1). The mean age of Korean women at the birth of their first child at 29.6 years was ranked 5th among OECD member countries. The United Kingdom ranked the highest with 30.09). The mean age of Korean women at the birth of their first child increase to 30.1 years in 2010.

decreased from 3.0 in 1970 to 1.6% in 2010 (Fig. 1). The mean age of Korean women at the birth of their first child at 29.6 years was ranked 5th among OECD member countries. The United Kingdom ranked the highest with 30.09). The mean age of Korean women at the birth of their first child increase to 30.1 years in 2010. The number of mothers who graduated high school increased from 87.0 in 1993 to 97.8% in 2010, and the number of mothers who graduated college or had a higher level of education, increased from 6.1 in 1973 to 27.6 in 1993 and to 67.3% in 2010. The rate of delivery after legal marriage was 98.9% in 1981 and 97.9% in 2010. However, the rate of births out of wedlock has been increased gradually from 1.1 to 2.1%10). The proportion of births out of wedlock in 2008 in OECD countries, rated from lowest to highest, was Korea (1.8%), Japan (2.0%), OECD average (36.3%), United States (US) (38.5%), and Iceland (64.1%)9). 3. Distribution of infant birth weight groups in relation to maternal age in Korea, 1993 to 2010 From 1993 to 2010, average infant birth weight decreased by 90 g. When maternal age was divided according to five-year intervals, mothers <20 years and >40 years had infants with the lower average birth weight (Table 3).

The number of mothers who graduated high school increased from 87.0 in 1993 to 97.8% in 2010, and the number of mothers who graduated college or had a higher level of education, increased from 6.1 in 1973 to 27.6 in 1993 and to 67.3% in 2010. The rate of delivery after legal marriage was 98.9% in 1981 and 97.9% in 2010. However, the rate of births out of wedlock has been increased gradually from 1.1 to 2.1%10). The proportion of births out of wedlock in 2008 in OECD countries, rated from lowest to highest, was Korea (1.8%), Japan (2.0%), OECD average (36.3%), United States (US) (38.5%), and Iceland (64.1%)9). 3. Distribution of infant birth weight groups in relation to maternal age in Korea, 1993 to 2010 From 1993 to 2010, average infant birth weight decreased by 90 g. When maternal age was divided according to five-year intervals, mothers <20 years and >40 years had infants with the lower average birth weight (Table 3). The birth rate of VLBWIs has increased at least three times in the last 17 years, and the maternal group <20 years and >35 years had higher risk pregnancies. In addition, the rate of LBWIs has increased at least 1.5 times in the last 17 years. The birth rate of normal birth weight infants (2.5 to 3.9 kg) increased <1%, and the rate of birth weights ≥4.0 kg decreased >3%. The rate of overweight newborns became lower as maternal age became younger (Table 4).

risk pregnancies. In addition, the rate of LBWIs has increased at least 1.5 times in the last 17 years. The birth rate of normal birth weight infants (2.5 to 3.9 kg) increased <1%, and the rate of birth weights ≥4.0 kg decreased >3%. The rate of overweight newborns became lower as maternal age became younger (Table 4). Notably, the VLBWIs group has increased at least two times more than the LBWIs group. This suggests that with advance in neonatal care in Korea there may have been an increase in the reporting of live births, such as would be the case in very small birth weights or extremely low gestational age, as opposed to what would have been reported as stillbirths11). In Korea, the low average birth weight is closely related to a mixture of an increase in low birth weight newborns (+2.39%), a decrease in over-weight newborns (-3.18%), and a slight increase (+0.75%) in normal weight newborns.

Notably, the VLBWIs group has increased at least two times more than the LBWIs group. This suggests that with advance in neonatal care in Korea there may have been an increase in the reporting of live births, such as would be the case in very small birth weights or extremely low gestational age, as opposed to what would have been reported as stillbirths11). In Korea, the low average birth weight is closely related to a mixture of an increase in low birth weight newborns (+2.39%), a decrease in over-weight newborns (-3.18%), and a slight increase (+0.75%) in normal weight newborns. It has been reported that the mother's sociodemographic factors are closely associated with birth outcomes. These include maternal education, age, place of birth, parity, marital status, smoking, alcohol use, prenatal care status, and medical and obstetric complications12-15). Lim et al.11) examined birth outcomes of Korean infants in the US between 1995 and 2004. Decreased parity, unmarried status, smoking during pregnancy, inadequate prenatal care, and obstetric complications-all increased the risk of a low birth weight. The risk factors that can cause low birth weight are also partially caused by the increased use of in vitro fertilization technologies and delivery management techniques such as induction and Cesarean section16,17). Kim et al.18) analyzed the birth rate of LBWIs in Korea between 1995 and 2007 and indicated that the birth rate of LBWIs is related to prematurity, multiple births, female gender, unmarried mother, and mother more than 35 years old.

logies and delivery management techniques such as induction and Cesarean section16,17). Kim et al.18) analyzed the birth rate of LBWIs in Korea between 1995 and 2007 and indicated that the birth rate of LBWIs is related to prematurity, multiple births, female gender, unmarried mother, and mother more than 35 years old. Although the percentage of LBWIs has increased in Korea, it is still remarkably low in comparison to other countries. Compared to OECD countries in 2008, Korea (4.9%) was lower than Japan (9.6%), the US (8.2%), the OECD average (6.6%), and higher than Iceland (3.8)9). The risk of overweight newborns is related to the mother having a history of overweight-newborn deliveries, having a substantial weight gain, gestational diabetes mellitus, and obesity19,20). Park et al.21) reported that macrosomia is related to an increase in gestational age, the male gender, a maternal age of 30 to 39 years, mothers with a high-school diploma, and birth during the spring, autumn, or winter. The reasons for the decrease in overweight newborns in Korea are considered to be the development of antenatal care for postmature babies, diabetes mellitus, and obesity as well as a decrease in high-risk pregnancies through an increased number of Cesarean sections, a decreased rate of three or more children, which decreases the total fertility rate, and a decrease in the preference for a son rather than a daughter.

f antenatal care for postmature babies, diabetes mellitus, and obesity as well as a decrease in high-risk pregnancies through an increased number of Cesarean sections, a decreased rate of three or more children, which decreases the total fertility rate, and a decrease in the preference for a son rather than a daughter. 4. Distribution of mean maternal ages by birth order, 1981 to 2010 According to the distributions of birth order between 1981 and 2010, the rate at which women delivered third (16.4%→9.4%) and fourth (9.1%→1.3%) child were decreased extremely, but there were no change in therate at which women delivered first and second child (Table 5). The mean maternal ages by birth order in Korea between 1993 and 2010 had increased in every birth order, and that the average maternal age for a first delivery was 30.1 years in 2010. Ten years ago, average maternal age for women with more than three deliveries was >30 years; however, in 2010, theaverage maternal age for a woman's first delivery was >30 years (Fig. 2). 5. The sex ratio of live births by birth order in Korea, 1981 to 2010 The sex ratio at birth in 1970 was imbalanced at 109.5, recovered to 106.2 (normal ratio, 103 to 107) in 2007, and was 106.9 in 2010. Compared with birth order, contrary to first and second sex ratio at birth was relatively balanced, third or more sex ratio had a severe imbalance. However, the imbalance in the sex ratio of the third (111.1) and fourth (109.8) child was significantly improved in 2010. This suggests that a parent's notion of preferring a son has changed (Fig. 3).

ontrary to first and second sex ratio at birth was relatively balanced, third or more sex ratio had a severe imbalance. However, the imbalance in the sex ratio of the third (111.1) and fourth (109.8) child was significantly improved in 2010. This suggests that a parent's notion of preferring a son has changed (Fig. 3). 6. The multiple birth rate Despite the total number of newborns in 2010 was lower than in 1991, the number of multiple gestations increased from 7,066 in 1991 to 12,841 in 2010, and the multiple birth rate increased 2.5 times from 11.3 to 27.2 in 2008. Comparing maternal age and the multiple birth rate, the multiple birth rate was high at 37.4 in the group of 35 to 39-year old, and 30.3 in the group of 30 to 34-year old. Mothers ≥40-year old were generally more prevalent than those <30-year old (Table 6). Advanced maternal age and the use of advanced reproductive technology (ART) procedures are significant factors associated with the increasing trend in multiple births5). Similar trends have been reported in other countries. Choi and his associates indicated that the increasing multiple birth rate is due to an increase in maternal age and the use of ART16,22).

nced reproductive technology (ART) procedures are significant factors associated with the increasing trend in multiple births5). Similar trends have been reported in other countries. Choi and his associates indicated that the increasing multiple birth rate is due to an increase in maternal age and the use of ART16,22). 7. Congenital anomalies According to the congenital anomaly survey and statistics in 2005 to 2006 by The Korea Institute for Health and Social Affairs23), the prevalence of congenital anomalies in newborns was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In 2006, the prevalence per 100,000-rated from highest to lowest-was cardiopulmonary (141.40, 44.9%), musculoskeletal (55.96, 18.8%), gastrointestinal (34.30, 10.9%), and urological systems (30.99, 9.8%). The prevalence of the ten major congenital anomalies were atrial septal defect (73.39), ventricular septal defect (40.57), congenital hydronephrosis (18.72), patent ductusarteriosus (15.82), undescended testis (12.29), polydactyly (11.76), hip dislocation (8.64), cleft palate (7.50), syndactyly (5.73), and cleft lip (5.27). The prevalence of atrial and ventricular septal defects was over two times higher than other congenital anomalies.

), congenital hydronephrosis (18.72), patent ductusarteriosus (15.82), undescended testis (12.29), polydactyly (11.76), hip dislocation (8.64), cleft palate (7.50), syndactyly (5.73), and cleft lip (5.27). The prevalence of atrial and ventricular septal defects was over two times higher than other congenital anomalies. In 2006, the prevalence of anomalies (968.11) in premature births was 3.7 times higher than in term-births (260.37). The prevalence of anomalies in multiples (531.26) was 1.8 times higher than in singletons (289.35). Low birth weight infants (1,057.84) were four times more prevalent than in normal birth weight infants, and infants of mothers ≥35-year (339.28) were more prevalent than in infants of mothers <35-year. Compared to the prevalence of congenital anomalies in OECD countries, transposition of the great arteries, reduction defects of the limbs, spina bifida, and Down syndrome were lower in Korea. The number of congenital anomalies is expected to increase due to advanced maternal age4). Korea only has national statistical data for congenital anomalies during 2005 and 2006.Therefore, it is required to collect national data every year.

tion defects of the limbs, spina bifida, and Down syndrome were lower in Korea. The number of congenital anomalies is expected to increase due to advanced maternal age4). Korea only has national statistical data for congenital anomalies during 2005 and 2006.Therefore, it is required to collect national data every year. 8. Rate of international marriages Marriages to foreigners have been more than 10% of all marriages since 2004. The total number of marriages was 326,104 in 2010, and the number of marriages to foreigners decreased slightly to 34,235 (10.5%) from 10.8% in 2009. Among these, there were 26,274 marriages between a Korean man and a foreign woman and 7,961 marriages between a Korean woman and a foreign man. The major nationalities of the foreign women were Chinese (36.6%), Vietnamese (36.6%), and Pilipino (7.3%). The major nationalities of the foreign men were Chinese (28.8%), Japanese (26.3%), and American (19.0%). The average age difference between Korean men and foreign women was 12.1 years10).

woman and a foreign man. The major nationalities of the foreign women were Chinese (36.6%), Vietnamese (36.6%), and Pilipino (7.3%). The major nationalities of the foreign men were Chinese (28.8%), Japanese (26.3%), and American (19.0%). The average age difference between Korean men and foreign women was 12.1 years10). The number of newborns born in a multiracial family is expected to increase steadily; however, the national statistics is insufficient. Newborn birth weight is highly related to parents' ethnicity, particularly the mother's. Along with the increased number of marriages to foreigners, both maternal ethnicity and the acculturation process influence the birth weight of Korean newborns24). Lim et al.11) compared the birth weights of Asian infants born in the US and classified them into six groups by parent ethnicity, which indicated that the birth weight of a newborn in Korea is the highest, followed by China and the Philippines. A study on birth outcomes of international marriages is important. Moreover, it is likely that a continuous national plan of growth, development, and adjustment to society will be needed.

parent ethnicity, which indicated that the birth weight of a newborn in Korea is the highest, followed by China and the Philippines. A study on birth outcomes of international marriages is important. Moreover, it is likely that a continuous national plan of growth, development, and adjustment to society will be needed. Summary and Perspectives Korea has one of the lowest total fertility rates in the world due to the decrease in the number of married couples, advanced maternal age, and a declining birth rate. The prevalence of low birth weight infants and multiple births has increased as compared to the decrease in birth rate25). This trend reduces human capital, and also increase aged-child ratio. Socio-economic and individual factors that have had a negative influence on fertility, include increase in uncertainty for the future due to high unemployment among young population, unstable job security, increasing economical burden of child-rearing including costs for private education of children, incompatibility between works and home, lack of infrastructure for child-care, etc. These factors have also interactive impact on people's attitudes on marriage and child. Therefore, it needs to provide the youth with employment opportunities with stable status as well as to put an emphasis on values in favor of marriage and children from their early ages under school and social education system26).

. These factors have also interactive impact on people's attitudes on marriage and child. Therefore, it needs to provide the youth with employment opportunities with stable status as well as to put an emphasis on values in favor of marriage and children from their early ages under school and social education system26). In June 2006, the Presidential Committee on Aging Society and Population Policy promulgated the basic plan for low fertility and aged society: 1) The first basic plan (2006 to 2010) aims to foster environments in favor of child-rearing, to establish a base for improving the quality of life in the aged society. 2) The second basic plan (2011 to 2015) aims to steady the recovery of fertility rate, and consolidate the social system for the aged society. 3) The third plan (2016 to 2020) aims to increase the fertility rate to the average level of OECD countries, and foster successful adaption for the aged society. It is notable that the number of children increased from 435,031 in 2005 to 470,171 in 2010. Further, the crude birth rate and total fertility rate increased slightly from 8.9 and 1.08 to 9.4 and 1.23. Such an increase is worthwhile, but more precise access on its further trends should be required.

In June 2006, the Presidential Committee on Aging Society and Population Policy promulgated the basic plan for low fertility and aged society: 1) The first basic plan (2006 to 2010) aims to foster environments in favor of child-rearing, to establish a base for improving the quality of life in the aged society. 2) The second basic plan (2011 to 2015) aims to steady the recovery of fertility rate, and consolidate the social system for the aged society. 3) The third plan (2016 to 2020) aims to increase the fertility rate to the average level of OECD countries, and foster successful adaption for the aged society. It is notable that the number of children increased from 435,031 in 2005 to 470,171 in 2010. Further, the crude birth rate and total fertility rate increased slightly from 8.9 and 1.08 to 9.4 and 1.23. Such an increase is worthwhile, but more precise access on its further trends should be required. Medical field can contribute to increase human capital by reducing morbidity and mortality of LBWIs being born. Recent advances in neonatal medicine have been attributed to reducing morbidity and mortality of infants, but yet a lot more improvement is needed, which can be made by diffusing medical knowledge and technology of newborn care from the major city centers to throughout the country. And also Governmental comprehensive supports for neonatal intensive care unit are required.

ted to reducing morbidity and mortality of infants, but yet a lot more improvement is needed, which can be made by diffusing medical knowledge and technology of newborn care from the major city centers to throughout the country. And also Governmental comprehensive supports for neonatal intensive care unit are required. Compared to the Asian average birth weight, the Korean average birth weight is the highest in Asia. Moreover, the rate of low birth weight infants is low, and infant mortality is similarly low across Asia. The maternal education level is high, the single-mother birth rate is low, and the gender imbalance has been lessened. The number of overweight babies has decreased due to the increased adequate prenatal care. The number of congenital anomalies and multiple births is expected to increase due to advanced maternal age. In addition, the number of interracial children is expected to increase due to the rise in the number of international marriages. Therefore, it will be necessary to collect data on congenital anomalies, babies from international marriages, artificial abortion, and artificial reproductive therapies, due to the lack of domestic statistical materials.

erracial children is expected to increase due to the rise in the number of international marriages. Therefore, it will be necessary to collect data on congenital anomalies, babies from international marriages, artificial abortion, and artificial reproductive therapies, due to the lack of domestic statistical materials. Accurate and detailed national birth outcome data is needed to consider how best to deal with the low fertility and the aged Society. Birth outcome data from the Korea National Statistical Office lacked detailed information, particularly for parental race, prenatal care status, and maternal medical and obstetric complications. In addition, it is necessary to collect accurate detail data of very low birth weight infants; therefore, data should be collected in various ways through medical institutions (Obstetrics or Pediatrics) and the National Health Insurance Corporation, and should include birth registration. Acknowledgements I would like to express my sincere gratitude to Kwang-sun Lee, MD, Chang Gi Park, PhD (Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, Illinois, USA), and Chong Woo Bae, MD (Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea) for their generous cooperation. Fig. 1 Live births by grouping of age of mother in five-year intervals and total fertility rate in Korea, 1970 to 2010. The group excludes foreigners. Total fertility rate; the average number of children that would be born to a woman over her lifetime.

Acknowledgements I would like to express my sincere gratitude to Kwang-sun Lee, MD, Chang Gi Park, PhD (Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, Illinois, USA), and Chong Woo Bae, MD (Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea) for their generous cooperation. Fig. 1 Live births by grouping of age of mother in five-year intervals and total fertility rate in Korea, 1970 to 2010. The group excludes foreigners. Total fertility rate; the average number of children that would be born to a woman over her lifetime. Fig. 2 Mean maternal ages at delivery by birth order in Korea, 1993 to 2010. Fig. 3 Sex ratio at birth by birth order in Korea, 1981 to 2010. Sex ratio is the ratio of males to every 100 females in a population. The natural sex ratio at birth was estimated to be close to 103 to 107 males/100 females. Table 1 Total Population and Number of Marriages and Live Births in Korea, 1970 to 2010 *Foreigners are excluded. †Per 1,000 persons. Table 2 Birth Outcomes of Infants Born in Korea, 1993 to 2010 Table 3 Distribution of Infants Birth Weight Group in Relation to Maternal Age in Korea, 1995 to 2010 Table 4 Percentage of Births of Very Low Birth, Low Birth, Normal Birth, and Excessive Birth Weight by Maternal Age in Korea, 1995 to 2010 Table 5 Percentage of Births by Birth Order in Korea, 1981 to 2010 Table 6 Change of Multiple Birth Rate by Maternal Age in Korea, 2000 to 2010

Introduction Body size is known to change in response to socioeconomic changes1). Many historical approaches in anthropometry, performed mainly in Western countries, have clearly shown that the height and weight of children and adolescents had changed a great deal during the last centuries. An anthropometric survey is one of the most important approaches used to evaluate the health status of individual children and to provide information for public purposes2). In Korea, a series of periodic surveys was performed in 1967, 1975, 1985, 1997, and 2005 by the Korean Pediatric Society and Korea Ministry of Health and Welfare3-7). These surveys were developed at teaching hospitals, selected based on regional allocation, and were non-randomized. Data under 2 years of age was gathered mostly by hospitals and after around 2 years of age was by community based survey. Recently, the Ministry of Education, Science, and Technology, with the support of the Korean Pediatric Society, revised school health examinations to reflect modern statistics, such as adopting updated growth references and stratified random sampling. In addition, the Korea National Health and Nutrition Examination Surveys were ongoing since 1998 under the supervision of Korea Centers for Disease Control and Prevention8,9). These recent surveys can be the resources to study about the body measurements in children. The goal of this article was to provide an overview about the secular trend in Korean children's growth by briefly reviewing past data and comparing the data to the updated surveys.

enters for Disease Control and Prevention8,9). These recent surveys can be the resources to study about the body measurements in children. The goal of this article was to provide an overview about the secular trend in Korean children's growth by briefly reviewing past data and comparing the data to the updated surveys. Age adjustment and analysis There are many data with anthropometric information; however, few have proved useful in making scientific comparisons. Many of them lack the exact age of children. As a result, in this review, only previously published data and raw data with exact ages were compared. To make exact comparisons, ages were adjusted. Data from recent surveys with ages rounded to the year generally needed to be recalculated because old reports, to which recent surveys were to be compared, generally rounded ages down to the nearest age. It was the previous standard to make groups based on the closest year of age because most nationwide surveys that were to be used to make growth charts were made in an era without personal computers10,11). In this article, statistical software Stata ver. 12 (Stata Co., College Station, TX, USA) and MS Excel (Microsoft Inc., Seattle, WA, USA) were used to generate the new results.

st year of age because most nationwide surveys that were to be used to make growth charts were made in an era without personal computers10,11). In this article, statistical software Stata ver. 12 (Stata Co., College Station, TX, USA) and MS Excel (Microsoft Inc., Seattle, WA, USA) were used to generate the new results. Rapid secular trends of body sizes in Korea 1. Dramatic incremental changes in height and weight in accordance with a rapid socioeconomic transition 1) Height According to the 2005 survey report performed by the Korean Pediatric Society, in association with the government12), the mean height of boys was 50.4 cm at birth, 77.3 cm at 12 months, and 174.3 cm at 20 years. The mean height of girls was 49.9 cm at birth, 76.4 cm at 12 months, and 161.2 cm at 20 years. To demonstrate the secular trend, in 1965, the mean height of boys was 74.8 cm at 12 months, and in 2005, the mean height was 77.3 cm (2.5 cm gain). In 1965, the mean height of girls at 12 months was 72.8 cm, and, in 2005, the mean height was 76.4 cm (3.6 cm gain). In 1965, the mean height of boys at 7 years was 112.5 cm, and in 2005, it was 124.9 cm (12.4 cm gain). In 1965, the mean height of boys at 20 years was 168.9 cm; in 1997, it was 173.4 cm; and in 2005, it was 174.3 cm (4.5 cm, 0.9 cm gain, respectively). In 1965, the mean height of girls at 7 years was 112.0 cm, and in 2005, it was 123.7 cm (11.7 cm gain). In 1965, the mean height of girls at 20 years was 155.9 cm; in 1997, it was 160.4 cm; and in 2005, it was 161.2 cm (4.5 cm, 0.8 cm gain, respectively). Compared to 2010 school health examination data8), there was almost no change in the final height of late adolescents in 2005 (173.5 cm in boys, 160.6 cm in girls). In summary, there were great secular changes in height from 1965 to 1997; nevertheless, there were few changes in the final height after 1997. As for growth acceleration in puberty, during the past decades it seemed quite pronounced; however, the rate now seems much slower (Fig. 1, 2).

5 cm in boys, 160.6 cm in girls). In summary, there were great secular changes in height from 1965 to 1997; nevertheless, there were few changes in the final height after 1997. As for growth acceleration in puberty, during the past decades it seemed quite pronounced; however, the rate now seems much slower (Fig. 1, 2). 2) Weight The mean weight of boys was 3.3 kg at birth, 10.3 kg at 12 months, and 70.9 kg at 20 years. The mean weight of girls was 3.2 kg at birth, 9.8 kg at 12 months, and 55.1 kg at 20 years. To illustrate the secular trend, in 1965, the mean weight of boys at 12 months was 8.9 kg; in 1985 it was 10.3 kg, and in 2005, it was also 10.3 kg. In 1965, the mean weight of girls was 8.3 kg, and in 2005, it was 9.8 kg. In 1965, the mean weight of boys at 7 years was 19.1 kg; in 1985, it was 22.3 kg, and in 2005, it was 26.8 kg. In 1965, the mean weight of boys at 20 years was 58.2 kg; in 1985, it was 61.9 kg, and in 2005, it was 70.9 kg. In 1965, the mean weight of girls at 7 years was 19.1 kg; in 1985, it was 21.2 kg, and in 2005, it was 25.5 kg. In 1965, the mean weight of girls at 20 years was 51.5 kg; in 1985, it was 51.8 kg, and in 2005, it was 51.5 kg in 2005. Weight also has changed dramatically during the past decades and there seemed no stagnation in the secular trend. Recent school examination data showed that there seemed little change in weight across age ranges during the last few years.

years was 51.5 kg; in 1985, it was 51.8 kg, and in 2005, it was 51.5 kg in 2005. Weight also has changed dramatically during the past decades and there seemed no stagnation in the secular trend. Recent school examination data showed that there seemed little change in weight across age ranges during the last few years. 3) Head circumference The mean head circumference (HC) of boys was 34.5 cm at birth and 46.3 cm at 12 months. The mean HC of girls was 34.1 cm at birth and 45.4 cm at 12 months. To demonstrate the secular trend, in 1965, the mean HC of boys at 12 months was 45.8 cm; in 1985, it was 46.5 cm, and in 2005, it was 46.3 cm. In 1965, the mean HC of girls was 44.8 cm, and in 2005, it was 45.4 cm.

cm at birth and 46.3 cm at 12 months. The mean HC of girls was 34.1 cm at birth and 45.4 cm at 12 months. To demonstrate the secular trend, in 1965, the mean HC of boys at 12 months was 45.8 cm; in 1985, it was 46.5 cm, and in 2005, it was 46.3 cm. In 1965, the mean HC of girls was 44.8 cm, and in 2005, it was 45.4 cm. 4) Chest circumference The mean chest circumference (CC) of boys at birth was 33.0 cm; at 12 months it was 47.5 cm, and at 17 years it was 77.5 cm. The mean CC of girls at birth was 32.7 cm; at 12 month, it 46.6 cm, and at 17 years it was 77.5 cm. To demonstrate the secular trend, in 1965, the mean CC of boys at 12 months was 46.4 cm; in 1985, it was 47.2 cm, and in 2005, it was 47.5 cm. In 1965, the mean CC of girls at 12 months was 45.3 cm, and in 2005, it was 46.6 cm. In 1965, the mean CC of boys at 7 years was 56.8 cm; in 1985, it was 57.6 cm, and in 2005, it was 61.6 cm. In 1965, the mean CC of boys at 17 years was 83.3 cm; in 1985, it was 82.3 cm, and in 2005, it was 77.5 cm. In 1965, the mean CC of girls at 7 years was 55.9 cm; in 1985, it was 55.8 cm, and in 2005, it was 59.6 cm. In 1965, the mean CC of girls at 17 years was 75.8 cm; in 1985, it was 76.2 cm, and in 2005, it was 77.6 cm. Detailed data of body measurements are summarized in Table 1.

was 82.3 cm, and in 2005, it was 77.5 cm. In 1965, the mean CC of girls at 7 years was 55.9 cm; in 1985, it was 55.8 cm, and in 2005, it was 59.6 cm. In 1965, the mean CC of girls at 17 years was 75.8 cm; in 1985, it was 76.2 cm, and in 2005, it was 77.6 cm. Detailed data of body measurements are summarized in Table 1. 2. Obesity epidemic, ongoing Problem According to the 2005 survey, in 1997, the mean body mass index (BMI) of boys at 12 months was 17.2 kg/m2, and in 2005, it was 17.2 kg/m2. In 1997, the mean BMI of girls at 12 months was 16.9 kg/m2, and in 2005, it was 16.7 kg/m2. In 1997, the mean BMI of boys at 7 years was 16.4 kg/m2, and in 2005, it was 17.1 kg/m2. In 1997, the mean BMI of boys at 20 years was 22.1 kg/m2, and in 2005, it was 23.3 kg/m2. In 1997, the mean BMI of girls at 7 years was 16.0 kg/m2, and in 2005, it was 16.5 kg/m2. In 1997, the mean BMI of girls at 20 years was 21.5 kg/m2, and in 2005, it was 21.1 kg/m2. The prevalence of obesity increased significantly during the period. In 2005, 9.7% (11.3% for boys, 8.0% for girls) of Korean children and adolescents were obese, and 19.0% (19.7% for boys, 18.2% for girls) were overweight or obese. The prevalence of obesity increased from 5.8% in 1997 to 9.7% in 200513). In 2010, the prevalence of overweight or obesity was still high-approximately 20% in high school boys and over 17% in girls (Table 2).