Yoshihiko Hidaka

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

Multiple sclerosis (MS) is a chronic demyelinating disease often displaying a relapsing-remitting course of neurological manifestations that is mimicked by experimental autoimmune encephalomyelitis (EAE) in animal models of MS. In particular, NOD mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 develop chronic relapsing-remitting EAE (CREAE). To elucidate the mechanisms that cause MS relapse, we investigated the histopathology and cytokine production of spleen cells and mRNA expression levels in the central nervous system (CNS) of CREAE mice. During the first attack, inflammatory cell infiltration around small vessels and in the subarachnoid space was observed in the spinal cord. Spleen cell production and mRNA expression in the CNS of several cytokines, including IFN-γ, TNF-α, IL-6, IL-17, and CC chemokine ligand 2 (CCL2), were higher in CREAE mice than in controls. Afterwards, parenchymal infiltration and demyelination were observed histologically in the spinal cord and corresponded with the more severe clinical symptoms of the first and second relapses. IL-17 and CCL2, but not IFN-γ, TNF-α, or IL-6, were also produced by spleen cells during recurrences. Our results suggested that the immune mechanisms in relapses were different from those in the first attack for CREAE. Further investigation of CREAE mechanisms may provide important insights into successful therapies for human relapsing-remitting MS.

Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society.

Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of approximately 25%, and with approximately 50% of cases resulting in end‐stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.

Clinical guides for atypical hemolytic uremic syndrome in Japan

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In 2013, we developed diagnostic criteria to enable early diagnosis and timely initiation of appropriate treatment for aHUS. Recent clinical and molecular findings have resulted in several proposed classifications and definitions of thrombotic microangiopathy and aHUS. Based on recent advances in this field and the emerging international consensus to exclude secondary TMAs from the definition of aHUS, we have redefined aHUS and proposed diagnostic algorithms, differential diagnosis, and therapeutic strategies for aHUS.

Successful treatment of fulminant Wilson's disease without liver transplantation

Fulminant Wilsons disease (WD) is life‐threatening. The revised WD prognostic index (RWPI) has been used to predict the severity of the disease, with a score ≥11 indicating fatal outcome without liver transplantation (LTx). We here report the case of a 10‐year‐old female patient with fulminant WD (RWPI, 16) who recovered fully after plasma exchange and continuous hemodiafiltration, followed by treatment with copper chelate agents. To the best of our knowledge, there have been five fulminant WD patients with RWPI ≥ 11 including the present patient, in whom LTx was not done. Based on the therapeutic modalities in these five cases, non‐surgical treatment (blood purification and copper chelate agents) may be able to avoid LTx in fulminant WD even with very high RWPI, although preparation for LTx is necessary.

Factors related to allergic transfusion reactions and febrile non-haemolytic transfusion reactions in children.

Allergic transfusion reactions (ATRs) and febrile non‐haemolytic transfusion reactions (FNHTRs) are the two major types of transfusion‐related adverse reactions (TRARs). Although prestorage leucocyte reduction and diversion of the first aliquot of blood (LR/D) could reduce FNHTRs and bacterial contamination in adult transfusion, ATRs are still problematic. In addition, there is little information about TRARs in paediatric population.

Factor H gene variants in Japanese: its relation to atypical hemolytic uremic syndrome.

Mutations and polymorphisms of factor H gene (FH1) are known to be closely involved in the development of atypical hemolytic uremic syndrome (aHUS). Several groups have identified disease risk mutations and polymorphisms of FH1 for the development of aHUS, and have investigated frequencies of aHUS in a number of ethnic groups. However, such studies on Japanese populations are limited. In the present study, we analyzed FH1 in Japanese aHUS patients and healthy volunteers, and examined whether those variants impacted on a tendency for the development of aHUS in Japanese populations. Similar to previous studies, we found that a high frequency of FH1 mutations, located in exon 23 of FH1, encodes short consensus repeat 20 in C-terminal end of factor H molecule in patients with aHUS (40%), but not in healthy volunteers. Interestingly, no significant differences in frequency of well-known disease risk polymorphisms for aHUS were observed between healthy volunteers and aHUS patients. Our results suggested that although FH1 mutations relates to the development of Japanese aHUS in accordance with other ethnic studies, other factor may be required for factor H polymorphism to be a risk factor of Japanese aHUS.

Critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis in acute lymphoblastic leukemia.

We report a pediatric case of critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis during acute lymphoblastic leukemia therapy. A 15-year-old boy developed B. cereus sepsis and multiple organ failure on the 19th day after initiation of chemotherapy, and multidisciplinary treatment was started. Treatment was effective and septic shock with multiple organ failure remitted. He was weaned from a respirator on day 23 after the onset of sepsis, but complete flaccid paralysis of the 4 extremities occurred. His compound muscle action potential and F-wave occurrence were reduced on a nerve conduction test. The number of motor units was markedly decreased, and the amplitude and duration of individual motor units were low and short, respectively, on electromyography. Cerebrospinal fluid was normal. On the basis of these findings, he was diagnosed with critical illness polyneuropathy/myopathy. He underwent intensive rehabilitation and recovered the ability to walk 3 months after onset. He was discharged 1 year after the initiation of chemotherapy, and remission has been maintained without inconvenience to daily living activities for 3 years since disease onset.

Polymyxin-direct hemoperfusion for sepsis-induced multiple organ failure†

We report a case of multiple organ failure caused by the Bacillus cereus infection during acute lymphoblastic leukemia therapy, who was treated successfully. A 15‐year‐old male developed (B. cereus) sepsis on the 19th day after chemotherapy initiation. Polymyxin‐direct hemoperfusion for septic shock was started, followed by continuous hemodiafiltration. His condition improved after starting the hemoperfusion. At the onset of sepsis, elevated levels of serum inflammatory cytokines, anti‐inflammatory cytokines, and plasminogen‐activator inhibitor complex‐1 were observed. Serum levels of these cytokines and bioactive substances decreased after blood purification therapy, which correlated with the improvement of clinical symptoms. Pediatr Blood Cancer 2010;55:202–205.

Effectiveness of vaccination and wearing masks on seasonal influenza in Matsumoto City, Japan, in the 2014/2015 season: An observational study among all elementary schoolchildren

Measures of seasonal influenza control are generally divided into two categories: pharmaceutical and non-pharmaceutical interventions. The effectiveness of these measures remains unclear, because of insufficient study sample size and/or differences in study settings. This observational epidemiological study involved all elementary schoolchildren in Matsumoto City, Japan, with seasonal influenza during the 2014/2015 season. Questionnaires, including experiences with influenza diagnosis and socio-demographic factors, were distributed to all 29 public elementary schools, involving 13,217 children, at the end of February 2015. Data were obtained from 10,524 children and analyzed with multivariate logistic regression analysis. The result showed that vaccination (odds ratio 0.866, 95% confidence interval 0.786–0.954) and wearing masks (0.859, 0.778–0.949) had significant protective association. Hand washing (1.447, 1.274–1.644) and gargling (1.319, 1.183–1.471), however, were not associated with protection. In the natural setting, hand washing and gargling showed a negative association, which may have been due to inappropriate infection control measures or aggregating infected and non-infected children to conduct those measures. These results may indicate a pathway for influenza transmission and explain why seasonal influenza control remains difficult in school settings. The overall effectiveness of vaccination and mask wearing was 9.9% and 8.6%, respectively. After dividing children into higher (grades 4–6) and lower (grade 1–3) grade groups, the effectiveness of vaccination became greater in the lower grade group, and the effectiveness of wearing masks became greater in the higher grade group. These results may provide valuable information about designing infection control measures that allocate resources among children.

Prospective epidemiological evaluation of seasonal influenza in all elementary schoolchildren in Matsumoto City, Japan, in 2014/2015.

Seasonal influenza is known to spread within and among educational organizations. Detailed understanding of the pattern of infection requires comprehensive prospective epidemiological studies, involving all schools within a community. This prospective survey evaluated 13,217 schoolchildren attending all of the 29 public elementary schools in Matsumoto City, Japan, in 2014/2015. Questionnaires were distributed to school nurses to obtain information about onset date and suspected route of transmission of influenza for all schoolchildren diagnosed with influenza virus at medical institutions. Responses were obtained for 2,548 infected schoolchildren, representing 96% of reported cases. Epidemic curves were plotted for each school by calculating the numbers of incident cases. Distance between schools was not associated with influenza spread over time. However, modeling showed that the occurrence of initial infection at each school and its spread over time could be fitted with a logistic curve. The transmission route for most children initially infected at each school was through a household member, whereas for most remaining schoolchildren it was through the school. These findings indicated that seasonal influenza was initially transmitted to schoolchildren by household members and then spread throughout the schools, with the initially infected child at each school fitting logistic curves over time.