Ryo Sumazaki

The Association of the Delayed Introduction of Cow's Milk with IgE-Mediated Cow's Milk Allergies

BACKGROUNDnAlthough exclusive breastfeeding at least 4 to 6 months has been recommended to prevent IgE-mediated cows milk allergy (IgE-CMA), early introduction of food allergens has received a lot of attention in recent years for the prevention of food allergies.nnnOBJECTIVESnWe aimed to determine whether IgE-CMA is associated with a feeding pattern in early infancy.nnnMETHODSnIn a case-control study, we retrospectively compared the patient background, past history of atopic dermatitis, bronchial asthma, family history of allergic diseases, feeding patterns in early infancy, and the reason for choosing early infancy feeding patterns of patients with IgE-CMA with age- and sex-matched healthy controls using a questionnaire completed by their mothers. To minimize the influence of confounders, we also compared patients with IgE-CMA with those with IgE-mediated egg allergy (IgE-EA).nnnRESULTSnA total of 51 patients with IgE-CMA were compared with 102 controls (1:2 matching) and 32 unmatched patients with IgE-EA. In a multivariable logistic regression analysis, the adjusted odds ratio of delayed (started more than 1 month after birth) or no regular cows milk formula (less than once daily) was 23.74 (95% CI, 5.39-104.52) comparing the CMA group with the Control group, and 10.16 (95% CI, 2.48-41.64) comparing the CMA group with the EA group. Only 3 (6.5%), 2 (4.8%), and 3 (14.3%) mothers in the CMA group, the Control group, and the EA group chose To prevent allergic disease as a reason for choosing exclusive or almost exclusive breastfeeding in the first month of life, respectively.nnnCONCLUSIONSnThe early introduction of cows milk formula is associated with lower incidence of IgE-CMA.

Serum dipeptidyl peptidase 4 activity in children with type 1 diabetes mellitus.

Abstract Background: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). Aim: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. Methods: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. Results: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57±0.99 vs. 2.67±0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA1c, blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=–0.35, p<0.05). Conclusions: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children.

Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response

BACKGROUND & AIMSnGenetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine.nnnMETHODSnWe performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies.nnnRESULTSnHLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses.nnnCONCLUSIONnHLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.

Drug-induced QT-interval prolongation and recurrent torsade de pointes in a child with heterotaxy syndrome and KCNE1 D85N polymorphism.

We present a child case of heterotaxy syndrome (asplenia syndrome) after Fontan procedure that showed extreme prolongation of QT interval and torsade de pointes (TdP) after administration of sodium channel blockers for paroxysmal atrial tachycardia. Despite low serum concentration of the drugs, QT prolongation persisted and TdP attacks with unconsciousness recurred, possibly in association with junctional bradycardia and myocardial damage although he had never experienced QT prolongation during bradycardia before. Temporal cardiac pacing via a venous route to exclude possible implication of bradycardia in induction of TdP was difficult to apply due to total cavopulmonary connection (TCPC) circulation. Continuous intravenous administration of low-dose isoproterenol was started but an appropriate heart rate for prevention of TdP was difficult to obtain. Finally, we were urged to conduct implantation of a DDD pacemaker combined with ICD surgically with epicardial leads, resulting in successful suppression of TdP and syncope. Screening of the genotype disclosed the KCNE1 D85N polymorphism, which is known as one of the typical disease-causing gene variants in long-QT syndrome (LQTS).

High Dose Octreotide for the Treatment of Chylothorax in Three Neonates

Chylothorax is an abnormal condition of lymphatic fluid collection in theax80x80pleural space, and the somatostatin analog octreotide is thought to have a beneficial effect on chylothorax. However, the octreotide dosage and administration route for chylothorax have been inconsistent to date. We report three neonatal cases of persistent chylothorax successfully treated with high-dose octreotide infusion therapy (20 μg/kg/h). Case 1 was congenital chylothorax, Case 2 was secondary chylothorax after an operation for congenital diaphragmatic hernia, and Case 3 was chylothorax after a cardiac operation. In all cases, the chylothorax was not decreased by a low-dose octreotide infusion, but after a high-dose octreotide infusion, the chylothorax decreased and eventually vanished, with no side effects. nConclusion: We suggest that the dose of octreotide in neonatal chylothorax can be safely increased to a maximum of 20 µg/kg/h.

Continuous regional arterial infusion effective for children with acute necrotizing pancreatitis even under neutropenia

Severe acute pancreatitis is one of the critical conditions that may develop in children with cancer. The leading cause of death due to acute pancreatitis is infectious pancreatitis or circulation collapse. Therefore, patients who develop acute pancreatitis while undergoing chemotherapy or after hematopoietic transplantation are at risk for a life‐threatening and fatal course. We treated 140 patients with malignancy from April 2002 to March 2009 at our hospital and encountered 3 patients under neutropenia who developed severe acute pancreatitis. Two of them were successfully treated with continuous regional arterial infusion of a protease inhibitor and antibiotic even under agranulocytosis. Another patient was treated with conventional therapy with intravenous antibiotics plus a protease inhibitor and total or partial parenteral nutrition. Even though the two patients treated with continuous regional arterial infusion presented much more severe conditions, their symptoms resolved earlier. In conclusion, acute pancreatitis is one of the severe complications of childhood malignancy. Even under agranulocytosis, continuous regional arterial infusion of a protease inhibitor and antibiotic was well tolerated and effective among our cases and might reduce early death due to pancreatitis.

An infant with life‐threatening hemangioma successfully treated with low‐dose cyclophosphamide

promyelocytic-like leukaemia. Hum. Mol. Genet. 1999; 8: 1741–9. 12 Song X, Gong S, Chen J, Gao L, Yang J, Wang J. ATRA is effective to an acute promyelocytic leukemia patient without RARA gene rearrangement. Leuk. Res. 2010; 34: e190–e193. 13 Wang HP, Xu H, Chen ZM, Tong XM, Qian WB, Jin J. t(X;17) as the sole karyotypic anomaly in a case of M3r subtype of acute promyelocytic leukemia without RARalpha rearrangement. Leuk. Res. 2010; 34: e55–e57.

Significant associations between hemostatic/fibrinolytic systems and accumulation of cardiovascular risk factors in Japanese elementary schoolchildren.

The aim of this study was to establish the reference values of hemostatic/fibrinolytic markers and investigate their relationship with physical constitution and cardiovascular risk factors in a normal schoolchildren population. This study comprised 148 healthy Japanese children aged 9–10 years (males 73; females 75). We performed laboratory tests including blood levels of leptin, high-sensitive C-reactive protein (hs-CRP), hemostatic and fibrinolytic markers [plasminogen activator inhibitor 1 (PAI-1), coagulation factor VII (FVII), coagulation factor X (FX), fibrinogen (Fbg), protein C, protein S], as well as common biochemical markers in the morning after an overnight fast. We investigated the mean, 10th, 50th and 90th percentile values of these markers. All parameters were compared between two groups, that is those with body mass index (BMI) 90th percentile or higher and BMI less than 90th percentile, and between subgroups based on the number of cardiovascular risk factors. Multiple-linear regression was used to assess associations between these hematological parameters and the components related to metabolic syndrome (MetS). Alanine aminotransferase (ALT), uric acid, leptin, hs-CRP, and all hemostatic/fibrinolytic markers (PAI-1, FVII, FX, Fbg, protein C, protein S) tested were significantly higher in the group with BMI 90th percentile or higher, and increased with accumulation of cardiovascular risk factors. Multiple-linear regression analysis showed that these values were associated with one or more components related to MetS. Reference values of hemostatic/fibrinolytic markers in Japanese schoolchildren were obtained. Many hemostatic/fibrinolytic markers showed significant association with BMI and accumulation of cardiovascular risk factors in normal Japanese schoolchildren.

Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old

Maturity‐onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19‐month‐old Japanese boy with a family history of young‐onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young‐onset diabetes and should perform molecular investigations.

Persistent low level Epstein-Barr virus DNAemia in childhood cancer survivors.

Background: Clinical observation of Epstein-Barr virus (EBV) status has not documented in childhood cancer survivors (CCSs) sustaining long-term remission of malignant diseases. Thus, the aim of this study was to evaluate the EBV status in children with various malignant diseases after they completed their treatments. Patients and Methods: Thirty consecutive children with various malignant diseases previously received treatment at the University of Tsukuba Hospital. Nine cases had acute lymphoblastic leukemia (ALL), 10 had solid tumors, 4 had lymphoma, 4 had CNS tumors, and 3 had acute myeloid leukemia (AML). EBV DNA in 328 whole blood samples were monitored by real-time QPCR for all cases after treatment. Clinical records and laboratory data were also reviewed. Results: There were 6/30 (20%) cases with continuous detection of EBV DNA while there were 24/30 (80%) cases without continuous EBV DNA. EBV DNAemia was persistently observed in 4/9 (44.4%) cases with ALL and in 2/4 (50%) cases with lymphoma. Persistent EBV DNAemia can be observed for >5 years without any EBV associated symptoms or diseases. Conclusions: Childhood cancer survivors have persistent EBV DNAemia more frequently, which is thought to be observed in cases with ALL and lymphoma with higher tendency for >5 years after treatment. Persistent EBV DNAemia is frequent in CCSs aged 5–10 years. Any immunological alteration is speculative in a pathophysiology of persistent EBV DNAemia.