Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)

Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)­(2,4′-bipyridin-3-yl)­methanone, IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies

ガンカンジャサン ノ エイヨウ カンリ オ ササエル エイヨウ サポート チーム

Several hospitals have recently established a nutrition support team（NST）for the nutritional management of inpatients. The NST includes medical doctors, nurses, dietitians, and pharmacists. The aims of the NST are to improve the nutritional condition and the quality of life（QOL）of patients. In Tokushima University Hospital, a NST was established in２００２. Our team comprises physicians, surgeons, dentists, nurses, dietitians, pharmacists, dental hygienists, and physical therapists. Overall, ７０％ of patients undergoing a NST intervention have cancer. Nutritional management in patients with cancer plays an important role in the supportive care during cancer treatment（surgery, chemotherapy, and radiotherapy）. It is focused on the improvement of undernutrition, return to oral feeding, and an improvement in QOL in palliative care. Recently, cancer cachexia has received a lot of attention, with various studies reporting on the nutritional care in patients with cancer. Malnutrition negatively impacts a patient’s response to therapy, leading to an increase in the incidence of treatment-related side effects, and impairment in muscle function, performance status, immune function, and QOL. Recently, it has been reported that NST improves the treatment outcome in patients with cancer because nutritional status is an important part of cancer treatment. Therefore, nutritional management by a NST in patients with cancer has played a crucial role in cancer therapy

Quantum flavor oscillations extended to the Dirac theory

This report deals with the quantum theory of flavor oscillations in vacuum, extended to fermionic particles in the several subtle aspects of the first and second quantization theories. In this scenario, the use of the Dirac equation is required for a satisfactory evolution of fermionic mass-eigenstates since in the standard treatment of oscillations the mass-eigenstates are implicitly assumed to be scalars and, consequently, the spinorial form of neutrino wave functions is not included in the calculations. Within first quantized theories, besides flavor oscillations, chiral oscillations automatically appear when we set the dynamic equations for a fermionic Dirac-type particle. The left-handed chiral nature of created and detected neutrinos can be implemented in the first quantized Dirac theory in presence of mixing; the probability loss due to the changing of initially left-handed neutrinos to the undetected right-handed neutrinos can be obtained in analytic form. In the context of a causal relativistic theory of a free particle, one of the two effects should be present in flavor oscillations: (a) rapid oscillations or (b) initial flavor violation. Concerning second quantized approaches, a simple second quantized treatment exhibits a tiny but inevitable initial flavor violation without the possibility of rapid oscillations. Such effect is a consequence of an intrinsically indefinite but approximately well defined neutrino flavor. The violation effects are shown to be much larger than loop induced lepton flavor violation processes, already present in the standard model in the presence of massive neutrinos with mixing. The conclusions of this report lead to lessons concerning flavor mixing, chiral oscillations, interference between positive and negative frequency components of Dirac equation solutions, and the field formulation of quantum oscillations.Comment: 116 pages, 10 figures (The abstract was suppressed due to online title limitations of the abstract field. See the manuscript for obtaining the complete abstract

Autonomic function measurements for evaluating fatigue and quality of life in patients with breast cancer undergoing radiation therapy: a prospective longitudinal study

Background: Fatigue during radiation therapy in women with breast cancer can decrease quality of life (QOL), yet it is often underestimated and needs to be evaluated objectively. This longitudinal study aimed to evaluate fatigue and QOL of women with breast cancer undergoing radiotherapy with a simple autonomic function measurement. Methods: Women with breast cancer who underwent postoperative radiotherapy in eight cancer care hospitals in Chubu and Kinki regions in Japan were recruited between October 2021 and June 2022. The women underwent a self-administered questionnaire that included the Cancer Fatigue Scale (CFS) and the Short Form-8 Health Survey (SF-8) and an autonomic nervous function measurement using a simple, non-invasive device before (T0, baseline), mid (T1), and at the end (T2) of treatment. Results: The 57 women showed similar trends, with CFS scores and log LF/HF ratio being the highest at T0 and significantly decreasing at T1 (both p < 0.05). The log LF/HF trends differed between those with high and low baseline log LF/HF values. Women with mental component summary (MCS) score improvement (T0 to T2) had the highest log LF/HF ratio at T0 and had significantly lower log LF/HF values at T1 and T2 than at T0 (p < 0.01 and p < 0.05, respectively). The change of (⊿) MCS from T0 to T1 was negatively correlated with ⊿log LF/HF from T0 to T1 (r = − 0.36, p < 0.01). Conclusions: Measurement of autonomic nerve function with a simple device is useful for objective fatigue assessment during radiotherapy. Psychological support is important as improvement in mental health helps improve autonomic nerve function and, in turn, fatigue.Aoki M., Kuratsune H., Yamamoto S., et al. Autonomic function measurements for evaluating fatigue and quality of life in patients with breast cancer undergoing radiation therapy: a prospective longitudinal study. Radiation Oncology 18, 171 (2023); https://doi.org/10.1186/S13014-023-02362-W

Secondary Torsion of Vermiform Appendix with Mucinous Cystadenoma

Torsion of the vermiform appendix is a rare disorder, which causes abdominal symptoms indistinguishable from acute appendicitis. We report a case (a 34-year-old male) of secondary torsion of the vermiform appendix with mucinous cystadenoma. This case was characterized by mild inflammatory responses, pentazocine-resistant abdominal pain, and appendiceal tumor, which was not enhanced by the contrast medium on computed tomography presumably because of reduced blood flow by the torsion. These findings may be helpful for the preoperative diagnosis of secondary appendiceal torsion

Reliability and validity of the Japanese version of the Resilience Scale and its short version

<p>Abstract</p> <p>Background</p> <p>The clinical relevance of resilience has received considerable attention in recent years. The aim of this study is to demonstrate the reliability and validity of the Japanese version of the Resilience Scale (RS) and short version of the RS (RS-14).</p> <p>Findings</p> <p>The original English version of RS was translated to Japanese and the Japanese version was confirmed by back-translation. Participants were 430 nursing and university psychology students. The RS, Center for Epidemiologic Studies Depression Scale (CES-D), Rosenberg Self-Esteem Scale (RSES), Social Support Questionnaire (SSQ), Perceived Stress Scale (PSS), and Sheehan Disability Scale (SDS) were administered. Internal consistency, convergent validity and factor loadings were assessed at initial assessment. Test-retest reliability was assessed using data collected from 107 students at 3 months after baseline. Mean score on the RS was 111.19. Cronbach's alpha coefficients for the RS and RS-14 were 0.90 and 0.88, respectively. The test-retest correlation coefficients for the RS and RS-14 were 0.83 and 0.84, respectively. Both the RS and RS-14 were negatively correlated with the CES-D and SDS, and positively correlated with the RSES, SSQ and PSS (all p < 0.05), although the correlation between the RS and CES-D was somewhat lower than that in previous studies. Factor analyses indicated a one-factor solution for RS-14, but as for RS, the result was not consistent with previous studies.</p> <p>Conclusions</p> <p>This study demonstrates that the Japanese version of RS has psychometric properties with high degrees of internal consistency, high test-retest reliability, and relatively low concurrent validity. RS-14 was equivalent to the RS in internal consistency, test-retest reliability, and concurrent validity. Low scores on the RS, a positive correlation between the RS and perceived stress, and a relatively low correlation between the RS and depressive symptoms in this study suggest that validity of the Japanese version of the RS might be relatively low compared with the original English version.</p

Study on the way of educational practical training of special needs education in at the special needs class in the affiliated school, Hiroshima Univerisity

本研究は，附属学校の特別支援学級における教育実習において，実習終了後に行う公立特別支援学校での教育実習のさらなる充実を図り，学部の教育と附属の実習，公立特別支援学校での実習の連続性整備のためにプログラムの見直しや改善を図ると共に，そのあり方について検討する。附属東雲小学校・中学校は大学の特別支援教育学講座と連携し，教育実習の内容の検討や改善に向けての提言を受ける他，具体的な大学における取り組みとも連動するようにした。さらに，特別支援教育実習協議会を通して特別支援学校との連携を図り，実習校と学生へのアンケート調査によって課題を明らかにした。また，全国の附属学校特別支援学級の連絡協議会を活用し，教育実習における実情や課題を情報交換することで、情報の共有化を図り新たな知見も得た。このような取り組みを進めていく中で，実習の事前指導にあたり，公立特別支援学校との連携が不足していたことが課題としてあげられた。この課題を解決していくために，教育実習に対しての附属学校としての取り組みを改善すると共に，より具体的かつ実用的な指導や評価を行い，内容を引き継ぐシステムの構築が必要であることが明らかとなった。The purpose of this research is to improve the teaching practice at the public special support school which is carried out after completion of the educational practice of the attached school special support class and to improve the educational practice of the undergraduate school and the special special support school We reviewed the contents of teaching practice and examined improvement. Attached Shinonome Elementary School and Junior High School have a special support education course lecture of the Graduate school of pedagogy and a public education practice meeting with the public special support school, and from the questionnaire survey to each school and the student, lack of cooperation with the public special support school It was made clear that it was. In order to solve the problem, it is necessary to instruct teacher interns more practical guidance and evaluation, and to inherit the contents to the public special support school