日本におけるSUNCT/SUNAの臨床像 : クリニックベースの研究

Objectives:This study aimed to report the clinical profiles of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)/short-lasting unilateral neuralgiform headache attacks with cranial autonomic (SUNA) in a Japanese population by surveying those enrolled at a regional headache center in Japan.Methods:In this consecutive case series study, the clinical characteristics of patients with SUNCT (eight men, three women; mean age: 59.5 ± 20.5 years) and SUNA (five men, four women; mean age: 51.3 ± 18.4 years) who visited Tominaga Hospital from February 2011 to January 2017 were examined. Headaches were diagnosed according to the International Classification of Headache Disorders, Third edition (ICHD-3) guidelines.Results:Brief clusters of separate attacks were reported by all patients. The mean duration of attacks was 91.9 ± 87.9 s. Ipsilateral rhinorrhea was observed in 9 of 20 (45.0%) cases and facial sweating was observed in 1 of 20 (5.0%) cases. An eminent response to lamotrigine was observed in 9 of 9 (100%) patients; however, adverse events were only reported in 2 of 9 (22.2%) cases. An intravenous infusion of lidocaine was demonstrated to be completely successful for short-term prevention in 5 of 6 (83.3%) SUNCT cases.Conclusions:Lamotrigine can successfully treat most patients, and intravenous lidocaine is useful for the short-term preventive therapy of severe recalcitrant attacks in Japanese patients with SUNCT/SUNA.博士（医学）・乙第1437号・令和元年9月27日Copyright © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage)

CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes

Aims Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). Methods and results Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1+/+), and these effects were markedly attenuated in CB1 knockouts (CB1−/−). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX ± AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. Conclusion CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular disease

Novel ketone diet enhances physical and cognitive performance.

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.A.J.M. thanks the Research Councils UK for supporting his Academic Fellowship. This work was supported by the Defense Advanced Research Projects Agency.This is the final version of the article. It first appeared from FASEB at https://doi.org/10.1096/fj.201600773R

The “Great” Controlling Nucleotide Coenzymes

Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling energy metabolism through their shared potential energy, which is widely unobserved due to the paradox that the energy in the coenzyme pools cannot be determined from the concentration of the coenzyme couples. The potential energy of the nucleotide couples in the mitochondria or the cytoplasm is expressed in the enzyme reactions in which they take part. The energy in these couples, [NAD+]/[NADH], [NADP+]/[NADPH], [acetyl CoA]/[CoA], and [ATP]/[ADP]x[Pi], regulates energy metabolism. The energy contained in the couples can be altered by suppling energy equivalents in the form of ketones, such as, D-β-hydroxybutyrate to overcome insulin resistance, to restore antioxidants capacity, to form potential treatments for Alzheimer\u27s and Parkinson\u27s diseases, to enhance life span, and to increase physiological performance. © 2019 IUBMB Life, 71(5):565–579, 2019

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

Doxorubicin (DOX) is a potent available antitumor agent; however, its clinical use is limited because of its cardiotoxicity. Cell death is a key component in DOX-induced cardiotoxicity, but its mechanisms are elusive. Here, we explore the role of superoxide, nitric oxide (NO), and peroxynitrite in DOX-induced cell death using both in vivo and in vitro models of cardiotoxicity. Western blot analysis, real-time PCR, immunohistochemistry, flow cytometry, fluorescent microscopy, and biochemical assays were used to determine the markers of apoptosis/necrosis and sources of NO and superoxide and their production. Left ventricular function was measured by a pressure-volume system. We demonstrated increases in myocardial apoptosis (caspase-3 cleavage/activity, cytochrome c release, and TUNEL), inducible NO synthase (iNOS) expression, mitochondrial superoxide generation, 3-nitrotyrosine (NT) formation, matrix metalloproteinase (MMP)-2/MMP-9 gene expression, poly(ADP-ribose) polymerase activation [without major changes in NAD(P)H oxidase isoform 1, NAD(P)H oxidase isoform 2, p22phox, p40phox, p47phox, p67phox, xanthine oxidase, endothelial NOS, and neuronal NOS expression] and decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment to mice. All these effects of DOX were markedly attenuated by peroxynitrite scavengers. Doxorubicin dose dependently increased mitochondrial superoxide and NT generation and apoptosis/necrosis in cardiac-derived H9c2 cells. DOX- or peroxynitrite-induced apoptosis/necrosis positively correlated with intracellular NT formation and could be abolished by peroxynitrite scavengers. DOX-induced cell death and NT formation were also attenuated by selective iNOS inhibitors or in iNOS knockout mice. Various NO donors when coadministered with DOX but not alone dramatically enhanced DOX-induced cell death with concomitant increased NT formation. DOX-induced cell death was also attenuated by cell-permeable SOD but not by cell-permeable catalase, the xanthine oxidase inhibitor allopurinol, or the NADPH oxidase inhibitors apocynine or diphenylene iodonium. Thus, peroxynitrite is a major trigger of DOX-induced cell death both in vivo and in vivo, and the modulation of the pathways leading to its generation or its effective neutralization can be of significant therapeutic benefit

電気生理学的に経過を追跡しえたPost-treatment neuropathyの1例

雑誌掲載版28歳女.1年前より口渇・多飲・多尿・体重減少で近医に2型糖尿病と診断され入院した.インスリン治療が開始されたが,血糖値の急速な改善と頻回の低血糖とともに両下肢遠位に痺れ,異常感覚が出現し,精査目的で紹介入院した.神経学的には両下肢遠位に感覚障害を認め,神経伝導検査では両下肢に後脛骨神経運動神経伝導速度の軽度低下とF波最小潜時の軽度延長,腓骨神経運動神経伝導速度軽度低下と腓腹神経感覚神経活動電位振幅の低下を認めた.糖尿病性網膜症および糖尿病性腎症は認めなかった.時間の経過とともに症状,神経学的所見および神経伝導検査の改善を認め,6ヵ月後には症状の消失を認め,Post-treatment neuropathyが強く示唆された.神経障害症状のない患者でも血糖コントロールは慎重に行うべきで,同時にsubclinical neuropathyが存在するか否か電気生理学的検査も施行すべきと考えられ