Yoko Yamakawa

Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis

Background:  Serum pro‐inflammatory cytokine levels are frequently elevated in the acute phase of pediatric inflammatory bowel disease (IBD). Because the role of pro‐inflammatory cytokine in the acute phase of pediatric IBD has not been well investigated, the serum levels of pro‐inflammatory cytokines and the expression of Th1 and Th2 signaling molecules in mucosa from the acute phase of pediatric IBD were examined.

ω-3 fatty acids attenuate mucosal inflammation in premature rat pups.

BACKGROUND Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although ω-3 fatty acids are known to have antiinflammatory effects, their effect against NEC remains unclear. METHODS Mother rats fed a soybean-based, docosahexaenoic acid (DHA)- or eicosapentaenoic acid (EPA)-enriched diet from days 7 to 20 of gestation were examined. On day 20, the rat pups were delivered by abdominal incision, their intestines were removed, and messenger RNA was extracted. A rat NEC model was used to confirm the effects of ω-3 fatty acids on the inflamed intestine (n = 20-28). The expression of inflammatory molecules was analyzed by real-time polymerase chain reaction (n = 11-14). RESULTS The concentrations of DHA and EPA in the intestine were significantly increased in the DHA and EPA groups (P < .01). The expression of the antiinflammatory prostaglandin E2 receptor EP3 was increased in the DHA (P < .05) and EPA groups (P < .01). In the NEC model, the reduced incidence of colitis was confirmed in the DHA and EPA groups. The expression of peroxisome proliferator-activated receptor γ was increased (P < .05), and the inhibitor of nuclear factor-κB α/β decreased in both the DHA (P < .01) and EPA groups (P < .05). CONCLUSION Our findings indicate that ω-3 fatty acids are beneficial for protecting the premature intestine from inflammation by regulating eicosanoid- and nuclear factor-κB-related metabolite expression.

Lissencephaly with marked ventricular dilation, agenesis of corpus callosum, and cerebellar hypoplasia caused by TUBA1A mutation

We described the clinical course and pathological findings in a child with TUBA1A mutation. MRI revealed marked ventricular dilation with thin cortex, poorly differentiated basal ganglia, agenesis of corpus callosum, cerebellar hypoplasia with preserved vermis at 2 months of age. No gain of developmental milestones was observed until she died with respiratory failure at 23 months of age. A de novo missense mutation of c.1096G>A (G366R) was identified in TUBA1A gene. Pathological findings included a lack in lamination in the cerebral cortex, absent corpus callosum without Probst bundle, blurred demarcation among the striatum, internal capsule and globus pallidus in association with irregular running of myelinated fibers, cerebellar hypoplasia with irregular undulation in the dentate nucleus and inferior olivary nucleus, absent olfactory bulbs and tracts, and pyramidal tract hypoplasia. These findings are consistent with previous reports and will be a clue to diagnosis of TUBA1A mutation.

Microarray analysis of mucosal biopsy specimens in neonates with rectal bleeding: is it really an allergic disease?

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Monitoring 6-thioguanine nucleotide concentrations in Japanese children and adolescents with inflammatory bowel disease.

Background and Aim:  6‐Mercaptopurine (6‐MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6‐thioguanine nucleotide (6‐TGN) concentrations in Japanese children with IBD have not been reported.

A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting γ-aminobutyric acid degradation. We describe here a boy with a severe phenotype of SSADH deficiency. He was referred because of a developmental delay at 4 months of age. At the age of 8 months, severe seizures developed. The diagnosis of SSADH deficiency was confirmed by an increase in 4-hydroxybutyric acid and heteroallelic mutation in the ALDH5A1 gene. His seizures were successfully treated with high-dose phenobarbital, and the electroencephalogram (EEG) abnormalities were ameliorated. However, the patient showed a degenerative clinical course with severe neurological deficits. A magnetic resonance imaging (MRI) scan revealed abnormal high intensities in the putamina and caudate nuclei on T2-weighted images, followed by marked atrophic changes. The clinical manifestation of our patient indicates the wide variety of SSADH deficiency phenotypes.

Overfeeding Can Cause NEC-Like Enterocolitis in Premature Rat Pups

Background: Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. The mortality rate associated with NEC is quite high and in most reports ranges from 20 to 30%. Despite extensive studies, the pathogenesis of NEC remains poorly understood. Objectives: To investigate the mechanisms of NEC in terms of inflammatory signaling in the intestine. Methods: A new enterocolitis model was established and examined the expression of inflammatory and anti-inflammatory signals in the intestines of rat pups. The premature rat pups, delivered by abdominal incision on day 20 of gestation (day 21 is considered as full term), were divided into three groups, and they were given a single administration of 0.05, 0.1, and 0.15 ml of formula milk via an orogastric catheter. After 24 h, the development of enterocolitis was evaluated by the presence of hemorrhagic enterocolitis, and the expression of signaling molecules, inhibitor of nuclear factor-ĸB (IĸB)-α/β and peroxisome proliferator-activated receptor (PPAR)-γ mRNA was examined by reverse transcription-polymerase chain reaction from inflamed and non-inflamed intestinal samples. Results: The incidence of enterocolitis increased with the volume of milk, and 50% of rat pups showed enterocolitis with a volume of 0.15 ml of milk. Expression of IĸB-α/β and PPAR-γ mRNA increased in inflamed intestine. Conclusions: Increased expression of IĸB-α/β suggested that the inflammatory mediator nuclear factor-ĸB is deeply involved in the pathogenesis of enterocolitis that can be easily introduced by overfeeding of milk ingestion in premature rat pups which mimic those seen in NEC. Increased expression of PPAR-γ may possibly regulate further development of enterocolitis in this system.

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

AbstractBackground: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear. Objective: To investigate the efficacy of LTRAs in children with food allergy. Methods: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14±9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups. Results: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosin-ophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (−273 ± 232 vs -595 ± 295/μL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 ± 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 ± 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 ± 31.0 to 27.3 ± 10.1 pg/mL), IL-5 (6.7 ± 5.2 to 5.0 ± 0.4 pg/mL), and ECP (45.4 ± 15.0 to 15.0 ± 9.8 μg/L) levels (p < 0.05 for each). Conclusion: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development.

Acute encephalopathy with biphasic seizures and late reduced diffusion associated with hemophagocytic syndrome

We reported a girl with HHV-6 infection associated with both acute encephalopathy with biphasic seizures and late reduced diffusion, and hemophagocytic syndrome. She had a prolonged convulsion after a one-day history of febrile illness. Cerebrospinal fluid or brain CT showed no abnormalities on admission and her consciousness was recovered on the next day. However, a prolonged seizure and deterioration of consciousness appeared on the sixth day of illness. Diffusion-weighted images revealed marked reduction of water diffusion in the bilateral frontal areas. HHV-6 infection was virologically proven by polymerase chain reaction. She was treated with gamma-globulin, steroid pulse therapy, and brain hypothermia. In addition, decrease in white blood cells and platelet counts, and elevation of liver enzymes and ferritin were noted on the fourth day of illness. Hemophagocytic macrophages were revealed by bone marrow aspiration on the sixth day. Her hematological and blood chemistry abnormalities recovered gradually after steroid pulse therapy. An elevation of interleukin-6, -8, and -10, and tumor necrosis factor in the serum and that of interleukin-4, -6, and-8 in the cerebrospinal fluid were observed at the onset of a late seizure. These facts suggested that hypercytokinemia will be related to the pathogenesis of acute encephalopathy of our patient.

Enhanced differentiation of intraepithelial lymphocytes in the intestine of polymeric immunoglobulin receptor-deficient mice

To clarify the effect of secretory IgA (sIgA) deficiency on gut homeostasis, we examined intraepithelial lymphocytes (IELs) in the small intestine (SI) of polymeric immunoglobulin receptor‐deficient (pIgR−/−) mice. The pIgR−/− mice exhibited the accumulation of CD8αβ+ T‐cell receptor (TCR)‐αβ+ IELs (CD8αβ+αβ‐IELs) after weaning, but no increase of CD8αβ+γδ‐IELs was detected in pIgR−/− TCR‐β−/− mice compared with pIgR+/+ TCR‐β−/− mice. When 5‐bromo‐2′‐deoxyuridine (BrdU) was given for 14 days, the proportion of BrdU‐labelled cells in SI‐IELs was not different between pIgR+/+ mice and pIgR−/− mice. However, the proportion of BrdU‐labelled CD8αβ+‐IELs became higher in pIgR−/− mice than pIgR+/+ mice 10 days after discontinuing BrdU‐labelling. Intravenously transferred splenic T cells migrated into the intraepithelial compartments of pIgR+/+ TCR‐β−/− mice and pIgR−/− TCR‐β−/− mice to a similar extent. In contrast, in the case of injection of immature bone marrow cells, CD8αβ+αβ‐IELs increased much more in the SI of pIgR−/− TCR‐β−/− mice than pIgR+/+ TCR‐β−/− mice 8 weeks after the transfer. αβ‐IELs from pIgR−/− mice could produce more interferon‐γ and interleukin‐17 than those of pIgR+/+ mice, and intestinal permeability tended to increase in the SI of pIgR−/− mice with aging. Taken together, these results indicate that activated CD8αβ+αβ‐IELs preferentially accumulate in pIgR−/− mice through the enhanced differentiation of immature haematopoietic precursor cells, which may subsequently result in the disruption of epithelial integrity.