1-Methyl-2-undecyl-4(1H)-quinolone, a derivative of quinolone alkaloid evocarpine, attenuates high phosphate-induced calcification of human aortic valve interstitial cells by inhibiting phosphate cotransporter PiT-1

AbstractAn abnormally high serum phosphate level induces calcific aortic stenosis (CAS), which is characterized by ectopic valve calcification and stenosis of the orifice area. Inhibition of ectopic calcification is a critical function of any internal medical therapy for CAS disease. The aim of the present study was to investigate the inhibitory effects of several derivatives of evocarpine, methanolic extracts from the fruits of Evodia rutaecarpa Bentham (Japanese name: Go-Shu-Yu) on the high phosphate-induced calcification of human aortic valve interstitial cells (HAVICs) obtained from patients with CAS. High phosphate (3.2 mM) concentrations significantly increased the calcification of HAVICs after 7 days of culture. This calcification was completely inhibited in the presence of sodium phosphonoformate (PFA), a selective inhibitor of the type III sodium-dependent phosphate cotransporter (PiT-1). PiT-1 contributes to phosphate uptake, resulting in calcification. 1-Methyl-2-undecyl-4(1H)-quinolone (MUQ; 30–300 nM), but not evocarpine or its derivatives dihydroevocarpine and 1-methyl-2-nonyl-4(1H)-quinolone, inhibited the high phosphate-induced HAVICs calcification in a concentration-dependent manner. Although all of the evocarpine derivatives attenuated alkaline phosphatase activity, only MUQ also decreased PiT-1 gene expression with cellular PiT-1 protein diminution. These results suggest that MUQ mitigated high phosphate-induced HAVICs calcification by inhibiting PiT-1 gene expression

ギノウ ・ テーマベツ コウギ ト モギ ジュギョウ ヲ トリ イレタ キョウジュホウ ジュギョウ -タコクセキ タンキ ケンシュウ 「 モジ ・ ゴイ シドウホウ 」 ヲ レイ ト シテ-

多国籍短期研修では、教授法授業に対する研修参加者のニーズ・レディネスや目標設定の多様性を前提として教授法のカリキュラムデザインをする必要がある。ここでは、2003年度冬短期と2004年度夏短期の比較的日本語運用力が高いBコースの教授法授業における、技能・テーマ別講義と模擬授業を取り入れた授業実践を報告する。前半に行われた技能・テーマ別講義では、教室活動や教材とそれらの背後にある理論のつながりを意識させることを目指した。前半講義の例として、「文字・語彙指導法」の授業の内容・方法と、研修参加者による事前のニーズ調査と事後の授業評価結果を報告する。また、後半の模擬授業の事例や模擬授業後の調査結果を紹介し、模擬授業が研修参加者自身による教授実践の振り返りにどう作用しているか、また前半の講義と後半の模擬授業が一つの流れとして機能しているか否かについて考察する。When designing the curriculum for the teaching methodology class of the Short-Term Courses for multinational Japanese language teachers, we need to give special consideration to the diversity of participantteacher needs, readiness and objectives. This paper reports a practice of teaching methodology class for teachers who are proficient in the Japanese language. This class includes lectures on teaching language skills and other related topics. Lectures in the first half of the class set its goal of raising awareness of association between classroom activities / teaching materials and background theories. We focus on a lecture, ‘Teaching Japanese Script and Vocabulary’, as an example, and report its contents and procedures and evaluation of this lesson from participant-teachers. Moreover, one lesson demonstration and teacher’s reflection notes are examined to see how a teacher intakes new pedagogical knowledge and applies it into their teaching context, and how the class works to promote the teacher’s reflection on their teaching practice

Psychiatric services in primary care settings: a survey of general practitioners in Thailand

BACKGROUND: General Practitioners (GPs) in Thailand play an important role in treating psychiatric disorders since there is a shortage of psychiatrists in the country. Our aim was to examine GP's perception of psychiatric problems, drug treatment and service problems encountered in primary care settings. METHODS: We distributed 1,193 postal questionnaires inquiring about psychiatric practices and service problems to doctors in primary care settings throughout Thailand. RESULTS: Four hundred and thirty-four questionnaires (36.4%) were returned. Sixty-seven of the respondents (15.4%) who had taken further special training in various fields were excluded from the analysis, giving a total of 367 GPs in this study. Fifty-six per cent of respondents were males and they had worked for 4.6 years on average (median = 3 years). 65.6% (SD = 19.3) of the total patients examined had physical problems, 10.7% (SD = 7.9) had psychiatric problems and 23.9% (SD = 16.0) had both problems. The most common psychiatric diagnoses were anxiety disorders (37.5%), alcohol and drugs abuse (28.1%), and depressive disorders (29.2%). Commonly prescribed psychotropic drugs were anxiolytics and antidepressants. The psychotropic drugs most frequently prescribed were diazepam among anti-anxiety drugs, amitriptyline among antidepressant drugs, and haloperidol among antipsychotic drugs. CONCLUSION: Most drugs available through primary care were the same as what existed 3 decades ago. There should be adequate supply of new and appropriate psychotropic drugs in primary care. Case-finding instruments for common mental disorders might be helpful for GPs whose quality of practice was limited by large numbers of patients. However, the service delivery system should be modified in order to maintain successful care for a large number of psychiatric patients

Diagnostic delay for giant cell arteritis – a systematic review and meta-analysis

Background Giant cell arteritis (GCA), if untreated, can lead to blindness and stroke. The study’s objectives were to (1) determine a new evidence-based benchmark of the extent of diagnostic delay for GCA and (2) examine the role of GCA-specific characteristics on diagnostic delay. Methods Medical literature databases were searched from inception to November 2015. Articles were included if reporting a time-period of diagnostic delay between onset of GCA symptoms and diagnosis. Two reviewers assessed the quality of the final articles and extracted data from these. Random-effects meta-analysis was used to pool the mean time-period (95% confidence interval (CI)) between GCA symptom onset and diagnosis, and the delay observed for GCA-specific characteristics. Heterogeneity was assessed by I 2 and by 95% prediction interval (PI). Results Of 4128 articles initially identified, 16 provided data for meta-analysis. Mean diagnostic delay was 9.0 weeks (95% CI, 6.5 to 11.4) between symptom onset and GCA diagnosis (I 2 = 96.0%; P < 0.001; 95% PI, 0 to 19.2 weeks). Patients with a cranial presentation of GCA received a diagnosis after 7.7 (95% CI, 2.7 to 12.8) weeks (I 2 = 98.4%; P < 0.001; 95% PI, 0 to 27.6 weeks) and those with non-cranial GCA after 17.6 (95% CI, 9.7 to 25.5) weeks (I 2 = 96.6%; P < 0.001; 95% PI, 0 to 46.1 weeks). Conclusions The mean delay from symptom onset to GCA diagnosis was 9 weeks, or longer when cranial symptoms were absent. Our research provides an evidence-based benchmark for diagnostic delay of GCA and supports the need for improved public awareness and fast-track diagnostic pathways

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Distribution of mammals on the offshore islands of Uwajima City, Shikoku, Japan

宇和海の4つの有人島: 九島, 嘉島, 戸島, 日振島(いずれも愛媛県宇和島市)において聞き取り調査とフィールドサイン調査を実施し, 野生哺乳類の分布を調べた. その結果, 九島ではタヌキ, イタチ類(イタチあるいはチョウセンイタチ), ハクビシン, イノシシ, ニホンノウサギ, 戸島ではニホンジネズミとイノシシ, 日振島ではイタチ類とイノシシの分布情報を得た. 嘉島では野生哺乳類の分布情報が得られなかった. 日振島に低密度で分布するイタチ類は, 1960年頃にドブネズミの天敵として愛媛県本土から導入された個体群の子孫であると考えられた. 同じ頃に嘉島と戸島へ導入されたイタチ類は絶滅した可能性が高い. 九島, 戸島, 日振島のイノシシは本土から近年新たに侵入した個体群であると考えられた. これらの島嶼ではイノシシによる農作物の被害が発生していた.We investigated the mammalian fauna of the four offshore islands (Hiburijima, Tojima, Kashima, and Kushima) of Uwajima City, Shikoku, Japan. As a result, six species: dsinezumi shrew Crocidura dsinezumi, raccoon dog Nyctereutes procyonoides, weasel Mustela sp., masked palm civet Paguma larvata, wild boar Sus scrofa, and Japanese hare Lepus brachyurus, were recorded. Weasels in Hiburijima are presumably descended from the population introduced from the mainland Ehime Prefecture around 1960. On the other hand, weasels introduced to Kashima and Tojima were probably extinct. Wild boars in Hiburijima, Tojima, and Kushima are presumably an invading population from the mainland. Agricultural damage by wild boar was found in the islands