Monoclonal antibody against bacterial lipopolysaccharide cross-reacts with DNA-histone

（1）目　的　　自己抗体の産生機構を明らかにするため、リポポリサッカライド（LPS）に対する単クローン抗体と核抗原との反応性を検討した。（2）研究方法　単クローン性抗LPS抗体は、Salmonella Minnesota Re595株由来のLPSを抗原としてハイブリドーマを作製して得た。抗核抗体の検出には、ラット肝を基質として蛍光抗体法を用い、さらに二重免疫抗散法に基づき、精製核抗原との反応性を確認した。なお、抗LPS抗体は酸素免疫測定法により、LPSのエンドトキシンはリムルスを基質に用いて測定した。（3）結　果１）抗LPSモノクロナール抗体（RSO１）の抗核抗体活性　LPS免疫マウスより得た140ウエルのハイブリドーマのうち、抗LPS抗体活性をもち、びまん型の強い抗核抗体活性を有するハイブリドーマRSO１株を確立した。本抗体は１gM　Kappaで、その抗核抗体活性はDNA-ヒストンにより完全に吸収された。さらに核材の塩酸処理およびヒストン再添加後の反応および二重免疫拡散法によるDNAーヒストンとの沈降線形成などの結果より抗DNA-ヒストン抗体活性を有することを確認した。またRSO１抗体は、in vitroでLE体形成能を有していた。２）RSO１の抗LPS抗体活性　RSO１と各種細菌由来のLPSとの反応性を検討した結果、Salmonella M.Re595株由来のLPSとのみ特異的に反応することが示された。３）RSO１のLPSと核抗原との交差反応性　RSO１をSalmonella M.Re株で吸収すると抗核抗体活性は消失した。またRSO１の抗LPS抗体活性は、DNA-ヒストンの添加により競合的に阻害され、RSO１が核成分であるDNA-ヒストンとLPSの両者に特異的抗体活性を有することが示された。（4）考　察　細菌固有のLPSを用いて免疫することにより、抗DNA-ヒストン抗体が産生されることを明らかにした。この成績は、抗核抗体のなかには外来性抗原によって生ずるものがあり、それが自己抗原と交差反応する可能性を示唆する。　抗DNA-ヒストン抗体は全身性エリテマトーデス（SLE）に特異性の高い自己抗体であるので、SLEの発症に関与する一要因としてLPSの果たす役割に注目し、さらに追求する必要性が示された。Thesis--University of Tsukuba, D.M.S.(B), no. 346, 1986.11.3

Combined Therapy for Anti-N-methyl D-aspartate Receptor Encephalitis

Background Anti-N-methyl- d-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune neurological disorder that usually occurs as a paraneoplastic syndrome and is particularly associated with ovarian teratoma. Standard therapy for severe cases is not established and the prognosis in patients who do not respond to first-line treatment is poor. Case Report An 11-year-old boy complained psychiatric symptoms and rapidly lost consciousness. CT scan revealed mediastinal teratoma and serum/spinal fluid was positive for anti-NMDAR antibody. He kept comatose and his brain stem function was profoundly disturbed. His symptoms were refractory to first-line therapy, which involved tumor resection, methylprednisolone (mPSL) pulse, Intravenous immunoglobulin (IVIG), and plasma exchange. We administered a combination therapy of rituximab and cyclophosphamide as second-line therapy and achieved complete recovery without adverse effects related to treatment. Conclusion  We consider early intensive treatment with a combination of rituximab and cyclophosphamide to be a safe and effective option for severe cases of anti-NMDAR encephalitis

Hospital-based care utilization of children with medical complexity in Japan

BackgroundFew studies have investigated the hospital‐based care utilization of children with medical complexity (CMC) in Japan. This study examined the frequency and differences in hospital‐based care utilization for CMC according to the level of medical complexity (moderate and severe).MethodsMedical records of three pediatric tertiary hospitals in one prefecture were examined in 2014. We examined the number of outpatient visits and of admissions to the hospital for CMC in the 5 years after the introduction of home medical care.ResultsOf 92 CMC, 55 had medical complexity that was moderate (CMC‐moderate) and 37 had medical complexity that was severe (CMC‐severe). The number of CMC who had medical care introduced at home had increased year by year, especially that of CMC <2 years old; the number of older CMC (i.e. 7–17 years old) had also increased in 2010–2014. The median total outpatient visits was 20 (IQR, 13–29 visits) for CMC‐moderate and 20 (IQR, 17–26 visits) for CMC‐severe in the first year. CMC‐severe had significantly longer length of admissions in the 5 years than CMC‐moderate. The number of total visits and admissions during the subsequent 4 years (from the second to the fifth year) was slightly decreased compared with the first year, but this was not significantly different.ConclusionsCMC had high utilization of hospital‐based care, and consistently utilized hospital‐based care in the 5 years after the introduction of home medical care. Further study is needed to examine both hospital‐based and home/community‐based services use

Hypophosphataemia among Severely-malnourished Children: Case Series

Phosphorus is an essential substance in our body, and hypophosphataemia (HP) is well-described in rickets, refeeding syndrome, diabetic ketoacidosis (DKA), and in chronic alcohol-abuse. However, to our knowledge, HP among severely-malnourished children has not been studied in detail, and information on prevalence, severity, and treatment is scarce. Currently, there are only a few published case reports of HP. This case series describes three cases of HP that presented to Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Our first case required mechanical ventilation for respiratory distress associated with severe hypokalaemia (K 1.1 mmol/L) and moderate hypophosphataemia (P 2.1 mg/dL). The second case presented with severe sepsis which was associated with symptomatic hypocalcaemia (Ca 1.68 mmol/L), hypokalaemia (K 1.82 mmol/L), and severe hypophosphataemia (P 0.9 mg/dL). The third case presented with pneumonia and sepsis which were complicated by hypokalaemia (K 2.05 mmol/L) and severe hypophosphataemia (P 1.1 mg/dL). Marked lethargy and severe hypotonia were associated with HP in all of these cases. Manifestations of HP are diverse and can occur in association with other electrolyte imbalances, especially among malnourished children. Malnutrition, combined with sepsis, is one of the major killers of children younger than 5 years of age, and both malnutrition and sepsis can cause HP. It is concluded that the underlying causes of morbidity, including HP, should be actively sought and treated to reduce the mortality of children aged below five years

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

Background & aimsGenetic 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.MethodsWe 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.ResultsHLA-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.ConclusionHLA-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

Mental Health of Parents as Caregivers of Children with Disabilities: Based on Japanese Nationwide Survey.

The number of children with disability is increasing gradually in Japan. Previous researches in other countries have reported that parents as caregivers (CGs) of children with disability have mental health problems, but the actual situation has not been examined nationwide in Japan so far. The aim of this study was to evaluate the association between mental health of CGs who had children with disability and characteristics of children, CGs, and household based on the nation-wide survey. This study utilized data from 2010 Comprehensive Survey of the Living Conditions, and defined children with disability aged 6 to 17. Individual data of children and CGs were linked, and 549 pairs of them were extracted. The Japanese version of Kessler 6 (K6) was used to assess mental health status of caregiver, scored 5 and over represented to general psychological distress. Logistic regression was used to evaluate the associations of interest. The almost half (44.4%) of CGs had psychological distress (k6 score; 5 +) in nationwide, and 8.9% of CGs might have serious mental illness (K6 score; 13 +). After adjusting covariates of child, CG, and household factors, CG having a current symptom (OR, 95% CI: 3.26, 1.97-5.39), CG's activity restriction (OR, 95% CI: 2.95, 1.38-6.32), low social support (OR, 95%CI: 9.31, 1.85-46.8), three generation family (OR, 95% CI: 0.49, 0.26-0.92), and lower 25% tile group of monthly household expenditure (OR, 95% CI:1.92, 1.05-3.54), were significantly associated with psychological distress of CGs. This study encourages health care providers to pay more attentions toward parent's mental health, especially for in case of having low social support, and lower income family. Further research should examine the detailed information of child's disease and disability, medical service use, and quality and quantity of social support in nationwide to straighten the system for supporting services of both children with disabilities and their CGs

The Partial Duplication of the 5′ Segment of KMT2A Revealed KMT2A-MLLT10 Rearrangement in a Boy with Acute Myeloid Leukemia

The duplication of 5′ segment of KMT2A is a rare molecular event in childhood leukemia, and the influence on prognosis is unknown. Here, we report on a boy who developed acute monocytic leukemia. Fluorescence in situ hybridization revealed the duplication of the 5′ segment with 2 normal alleles at KMT2A which was eventually found to be fused with MLLT10. Chemotherapy promptly induced the first complete remission in the patient at our facility, and the patient remained in first complete remission with negative minimal residual disease at 3.5 years from diagnosis. Our case is similar to two previously reported patients who had partial duplication of the 5′ segment of KMT2A with a KMT2A-MLLT10 rearrangement. Further studies and experience with this cryptic translocation may shed more light on the management of acute myeloid leukemia