Yuki Bando

The strategy of immune globulin resistant Kawasaki disease: A comparative study of additional immune globulin and steroid pulse therapy

BACKGROUND We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with IVIG-resistant Kawasaki disease. METHODS We enrolled 164 patients with Kawasaki disease who were treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these patients were treated with additional IVIG therapy, and the other 13 patients were treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days). RESULTS Three patients in the group receiving additional IVIG treatment had coronary artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid pulse therapy group; the difference in the incidence of coronary artery aneurysm was not statistically significant. The duration of high fever after additional treatment in the steroid pulse therapy group (1 ± 1.3 days) was significantly shorter than that in the additional IVIG treatment group (3 ± 2.4 days; P < 0.05). The medical costs were significantly lower in the steroid pulse therapy group than in the additional IVIG treatment group. CONCLUSION Steroid pulse therapy was useful to reduce the fever duration and medical costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG treatment were not significantly different in terms of preventing the development of coronary artery aneurysm.

A Novel Strategy for Hemolytic Uremic Syndrome: Successful Treatment With Thrombomodulin α

Hemolytic uremic syndrome (HUS) is a life-threatening infectious disease in childhood for which there is no confirmed therapeutic strategy. Endothelial inflammation leading to microthrombosis formation via complement activation is the main pathology of HUS. Thrombomodulin is an endothelial membrane protein that has anticoagulation and anti-inflammatory effects, including the suppression of complement activity. Recombinant human soluble thrombomodulin (rTM) is a novel therapeutic medicine for disseminated intravascular coagulation. We administered rTM to 3 patients with HUS for 7 days and investigated the outcomes in view of the patients’ prognoses, changes in biochemical markers, complications, and adverse effects of rTM. Symptoms and laboratory data improved after initiation of rTM in all 3 patients. Abnormal activation of complements was also dramatically suppressed in 1 patient. The patients recovered without any complications or adverse effects of rTM. They were discharged having normal neurologic status and with no renal dysfunction. To our knowledge, this is the first report of rTM being used to treat HUS. These case reports show the positive effect of rTM in patients with HUS. Randomized controlled studies should be performed to assess the efficacy and safety of rTM for children with HUS.

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome

Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well‐characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS‐dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS‐like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS‐like phenotype. Methods Candidate genes associated with the ALPS‐like phenotype were screened by using whole‐exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF‐&agr;–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor &kgr;B pathway, was identified in one of the patients exhibiting the ALPS‐like phenotype. Increased activity of the nuclear factor &kgr;B pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia

AbstractCartilage-hair hypoplasia (CHH), or metaphyseal dysplasia, McKusick type, is an autosomal recessive disease with diverse clinical manifestations. CHH is caused by mutations in RMRP (ribonuclease mitochondrial RNA processing), the gene encoding the RNA component of the ribonucleoprotein complex RNase MRP. A common founder mutation, 70A>G has been reported in the Finnish and Amish populations. We screened 11 Japanese patients with CHH for RMRP mutations and identified mutations in five probands, including three novel mutations (16-bp dup at +1, 168G>A, and 217C>T). All patients were compound heterozygotes for an insertion or duplication in the promoter or 5′-transcribed regions and a point mutation in the transcribed region. Two recurrent mutations were unique to the Japanese population: a 17-bp duplication at +3 and 218A>G. Haplotype analysis revealed that the two mutations common in Japanese individuals were contained within distinct haplotypes. Through this analysis, we have identified a unique mutation spectrum and founder mutations in the Japanese population.

Kikuchi-Fujimoto disease developed into autoimmune disease : a report of two cases

We report herein the pathological findings and clinical courses of two cases of Kikuchi–Fujimoto disease (KFD) that developed into autoimmune diseases. The patients are currently undergoing treatment for a disease similar to Sjogren’s syndrome and systemic lupus erythematosus/mixed connective tissue disease. KFD is not an independent condition and most likely develops due to an autoimmune mechanism. Pediatricians should pay careful attention to KFD and encourage long-term follow-up in patients with this condition.

Abnormal fecal Lactobacillus flora and vitamin B12 deficiency in a patient with short bowel syndrome.

Lactobacillus overgrowth has been reported in patients with short bowel syndrome (SBS) (1–4). We previously reported D-lactic acidosis that Lactobacillus overgrowth caused in a male SBS patient (5). He had severe anemia related to vitamin B12 deficiency 9 years later. It has been generally accepted that B12 deficiency in SBS patients results from the inadequate absorption of B12 and/or the bacteria–host competition for uptake of B12 (6). In the present study, we suspected the recurrence of Lactobacillus overgrowth as a possible cause, because some lactobacilli require B12 for growth. Therefore, we analyzed the fecal flora and the B12 auxotrophy of Lactobacillus isolates.

Immunosuppressive Factors Detected during Convalescence in a Patient with Severe Serum Sickness Induced by Carbamazepine

We report on a patient with severe serum sickness induced by carbamazepine in whom anticarbamazepine IgG antibodies were detected in the serum. The T cells of the patient showed impairment of phytohemagglutinin-induced proliferation, and hypergammaglobulinemia was evident. The clinical features and immunological abnormalities were compatible with immunoblastic lymphadenopathy. Immunosuppressive factors were also detected in the patient. Their molecular weights ranged from 20,000 to 30,000 as evaluated by Sephadex G-200 gel filtration. Such immunosuppressive cytokines were not detected in other patients with carbamazepine allergy who did not develop the clinical manifestations of immunoblastic lymphadenopathy. These results suggest that the T cell functional deficiency of immunoblastic lymphadenopathy is induced by these immunosuppressive cytokines.

Enhanced efficiency of cell hybridization by neuraminidase treatment

Cell hybridization techniques have already been utilized, but the outcome is usually not very stable. In order to achieve high stability we tried to achieve closer intercellular contact. Neuraminidase treatment was used to remove sialic acid from the cell membrane, since sialic acid usually prevents close contact between B cells and myeloma cells. After neuraminidase treatment, not only mouse-mouse hybridization but also human-mouse hybridization produced significantly more clones. Our results indicate that neuraminidase treatment is a useful method for generating hybridomas efficiently.

An immunodominant haptenic epitope of carbamazepine detected in serum from patients given long-term treatment with carbamazepine without allergic reaction.

An anticarbamazepine antibody was detected in the serum of a patient with severe carbamazepine-induced serum sickness. We found that the patients T cells and IgG antibody recognized an epitope which appeared in subjects showing an allergic reaction, as well as that in subjects who showed no allergic reaction, after long-term carbamazepine therapy. These results show that an anti-carbamazepine immune response does not occur in the majority of subjects who undergo long-term carbamazepine therapy without developing allergic symptoms, although the immunodominant haptenic epitope of carbamazepine is present in their sera.

Changes in Neonatal Microbiota Distribution Influenced by the Environment of the Neonatal Intensive Care Unit in the First Month of Life

Commensal bacterial colonization is crucial for human health, and the early neonatal period is important for the establishment of microbial populations. However, studies on the developmental patterns of microbiota in early life, particularly in those exposed to the environment of the neonatal intensive care unit (NICU), are limited. Using a 16S ribosomal RNA polymerase chain reaction assay, this study aimed to evaluate the changes in the levels of representative microbiota in healthy term infants and infants who were admitted to the NICU during the first month of life. Compared with term infants, the NICU group showed lower levels of Bifidobacterium in the early days after birth but achieved the same levels as those of term infants after day 30 of probiotics use. In addition, we found that the presence of Staphylococcus aureus, including methicillin-resistant S. aureus, from fecal samples was not associated with disturbances in Bifidobacterium during the neonatal period. Clinical factors such as the mode of delivery, antibiotic therapy, and intubation for mechanical ventilation could change the neonatal distribution of microbiota, but the most important factor was insufficient enteral nutrition. This group, which had experienced poor general conditions and/or underwent surgery early in the neonatal period, showed are markable decrease in Bifidobacterium level at day 30. In conclusion, infants in the NICU developed similar microbiota composition as in the healthy term infants group in 1 month afterbirth; however, insufficient enteral nutrition could lead to disintegration of the microbiota distribution.