Unmutated Immunoglobulin M Can Protect Mice from Death by Influenza Virus Infection

To elucidate the role of class switch recombination (CSR) and somatic hypermutation (SHM) in virus infection, we have investigated the influence of the primary and secondary infections of influenza virus on mice deficient of activation-induced cytidine deaminase (AID), which is absolutely required for CSR and SHM. In the primary infection, AID deficiency caused no significant difference in mortality but did cause difference in morbidity. In the secondary infection with a lethal dose of influenza virus, both AID−/− and AID+/− mice survived completely. However, AID−/− mice could not completely block replication of the virus and their body weights decreased severely whereas AID+/− mice showed almost complete prevention from the reinfection. Depletion of CD8+ T cells by administration of an anti-CD8 monoclonal antibody caused slightly severer body weight loss but did not alter the survival rate of AID−/− mice in secondary infection. These results indicate that unmutated immunoglobulin (Ig)M alone is capable of protecting mice from death upon primary and secondary infections. Because the titers of virus-neutralizing antibodies were comparable between AID−/− and AID+/− mice at the time of the secondary infection, a defect of AID−/− mice in protection of morbidity might be due to the absence of either other Ig classes such as IgG, high affinity antibodies with SHM, or both

Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin: A Possible Role of HIF-1α Expression and Oxygen Metabolism

http://dx.doi.org/10.2337/db10-0655OBJECTIVE : Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1α. We assess here the effects of the biguanide, metformin, on the expression of HIF-1α in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats. RESEARCH DESIGN AND METHODS : We explored the effects of metformin on the expression of HIF-1α using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg/kg^/day^) or insulin. RESULTS : Metformin inhibited hypoxia-induced HIF-1α accumulation and the expression of HIF-1–targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP-activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1α expression. In addition, knockdown of AMPK-α did not abolish the inhibitory effects of metformin on HIF-1α expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1α accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1α expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1α expression and pimonidazole staining and ameliorated tubular injury in ZDF rats. CONCLUSIONS : Our data suggest that hypoxia-induced HIF-1α accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption

Studies of Multiple Endocrine Neoplasia Type 2A Syndrome: Linkage Analyses and Comparison of Constitutional and Tumor Genotypes

Linkage analyses were carried out in nine Japanese kindreds with multiple endocrine neoplasia type 2A (MEN-2A) using polymorphic classical markers and DNA markers. We excluded close linkage of the MEN-2A gene (MEN2A) locus with Gm, JK, PGMl, and a DNA segment, D20S5, which is assigned to band 12 of the short arm of chromosome 20 (20p12.2). Assuming that MEN2A is recessive at the cellular level as in retinoblastoma (RB) and Wilms\u27 tumor (WT). comparison of constitutional and tumor genotypes may be useful in the search for the MEN2A locus. When DNA samples from 12 patients with medullary thyroid carcinoma (MTC) were compared with 15 polymorphic DNA markers including two assigned to chromosome 20, the results were negative. Both the negative linkage data and the failure to find loss of heterozygosity in MTC with chromosome 20 probes suggest that MEN2A may not be at 20p12.2, which was previously suggested as the site of an inherited chromosomal deletion in MEN-2A

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

ダイキボ サイガイジ ニオケル ジチタイカン キョウリョク ヤ NPO/NGO ニヨル ジンテキ シエン ニ タイスル ヒサイ ジチタイ ノ ジュエンリョク ノ ケンキュウ : ヒガシニホン ダイシンサイ オ タイショウ トシテ

博士(社会学)同志社大学今後発生することが懸念されている大規模災害に備えて，より迅速で効果的な人的支援のあり方，特に人的支援に対する被災自治体の受援力の強化方策を検討するために，東日本大震災の初動期から応急対応期における人的支援について，自治体間協力や，単体としてのNPO/NGO，行政とNPO/NGOとから構成されるネットワーク組織という3つの組織形態別に，緊急社会システムを構成する組織の視点から実証分析を行う

An independent relation of atopic dermatitis to exercise-induced wheezing in asthmatic children

Background: Atopic dermatitis (AD) and exercise-induced asthma (EIA) are common in asthmatic children, and exercise is the most common trigger other than infection for acute onset asthma attack in children. We examined whether AD is related to exercise-induced wheezing (EIW), some proxy for EIA. Methods: Japanese version of the International Study of Asthma and Allergies in Childhood questionnaires were used. For 12,405 asthmatic school children, AD was defined as itchy rash coming and going for at least 6 months at any time in the last 12 months with affecting places of flexural parts of body, and severity of AD was rated according to frequency of being kept awake at night with the itch as follows: never in the past 12 months, less than one night per week and one or more nights per week. Results: Adjusted for frequency of asthma attack, odds ratios (OR) of children with current AD as compared to those without AD for having EIW were 1.32 (95% confidence interval = 1.15–1.52), 1.35 (1.14–1.68) and 1.10 (0.92–1.31) for primary school, junior high school and high school children, respectively. EIW was more likely observed in accordance with increasing severity of AD in the primary school children with ORs of 1.12, 1.59 and 1.54 (p for trend < 0.01), and in the junior high school ones with ORs of 1.18, 1.31, 2.03 (<0.01), respectively. Conclusions: AD may be possibly related to EIW. Further studies investigating effect of AD treatment on EIW may be required. Keywords: Asthma, Bronchoconstriction, Eczema, Epidemiology, Itchin

Exercise-Induced Wheezing among Japanese Pre-School Children and Pupils

Background: Exercise-induced wheezing (EIW) may be a symptom of asthma and is a predictor of exercise- induced bronchoconstriction, transient narrowing of the lower airway following exercise in the presence or absence of diagnosed asthma. Population-based studies with a large sample of EIW in relation to age, sex, current asthma severity and medication usage have been sparse. Methods: International Study of Asthma and Allergies in Childhood questionnaires were distributed at 885 nurseries, 535 primary schools, 321 junior high schools and 190 high schools, respectively, across Japan, and the corresponding data on 46,597, 41,216, 45,960 and 51,104 children were analyzed. Results: Prevalence of EIW was 4.8, 4.7, 17.9 and 15.4% for each of the four educational facility types, respectively. Among 24,103 current asthmatics, 20.9, 28.7, 76.1 and 73.6% of subjects for the 4 educational facility groups reported to have experienced EIW, respectively. Severity of current asthma was associated with the risk of EIW; odds ratio (95% confidence interval) of children with asthma attack every day for having EIW once a week or more, using intermittent asthmatics as reference group, were 24.48 (19.33 to 31.01) adjusted for other covariates. Among current asthmatic kindergartners, increase in risk for EIW due to ascending severity of current asthma was mitigated by daily use of leukotriene receptor antagonist (p for interaction=0.071). Conclusions: EIW was not rare among current asthmatic children. An increased risk for EIW was in accordance with increasing severity of current asthma and this relation was mitigated with leukotriene receptor antagonist daily use among kindergartners