Antigenicity of chlorpromazine and clozapine to rabbits

Antigenicity of clozapine was studied in rabbits, comparing with that of chlorpromazine as control. The results indicate that chlorpromazine produces antibody in rabbit as revealed by passive hemagglutination test, giving the titer of 1 : 2, 000 or higher in all the five cases observed, though specific precipitin lines has not been obtained and PCA test proves to be negative. Clozapine failed to produce anti.clozapine antibody giving negative passive hemagglutination test, passive cutaneous anaphylaxis and precipitin reaction, in all forms tested. Some remarks were made on the possible close relation between the antigenicity of the drug and its affinity to protein.</p

Physical analysis of the energy transducing reaction in mitochondria

As is generally known, the energy transducing reaction in mitochondria is of highly complicated one. Free energy produced by transferring electrons from substrate to oxygen, where many dehydrogenases and respiratory chain of mitochondria are concerned, is transduced to ATP formation or utilized for the ion accmulation reaction, synthesis of various substances, reversal electron transport and the mechanochemical changes of mitochondria. The mechanism of these energy trasducing reactions which is supposed to be closely related with each other, has not yet been clarified. The authors tried to solve these biological energy transducing mechnism by applying physical circuit theory in electronics and elucidate that the energy transduction occurring in mitochondria can be explained theoretically. And some unknown but possible reaction have been postulated from such a physical consideration.</p

Studies on the mechanism of phagocytosis. I. Effect of metabolic inhibitors on the phagocytosis of iron colloid particles by ascites macrophages

For the purpose to clarify the mechanism of phagocytosis or pinocytosis, the observations on the tumor ascites, including the macrophages as well as the tumor cells, were carried out by incubating with the iron colloid with or without pretreatment by several inhibibitors of glycolysis, oxidative phosphorylation and respiration, or under hypotonic or cold environments. The results have demonstrated that there are three steps in the phagocytosis. The first step is the adhesion of the substance to the cell surface, which is not an energy-requiring process. The second step is the engulfing which proceeds by using the energy supplied by glycolysis. The third is the accumulation of the substance into the vesicles through the canaliculi connecting the cell surface with the vesicles. The discussion was made on the existence of the active site on the cell surface to which the substance can be adhered, and the accumulation mechanism of the material into the phagocytic vesicles by the membrane flow, the flowing movement of the outer lipid layer of a unit membrane through the canaliculi which connect the cell surface to the phagocytic vesicles.</p

Loosening of the cytomembrane of Ehrlich ascites tumor cell by unsaturated fatty acid

Ehrlich ascites tumor cells affected by oleic and linoleic acids lose their cytomembrane followed by the leak out of ribosomes. Some cells survived through this treatment when they were transplanted into mouse peritoneal cavity, but they changed their characteristics showing wider and less basophilic cytoplasm and smaller nuclei with dense nuclear chromatin and ambiguous nucleoli. In spite of many attempts, no qualitative changes have been found between normal and cancer cells. Recently, Ishikawa found the specific antigenicity of cancer cell membrane which was common to several strains of canccr cells. Grobstein and coworkers have clarified that pancreatic cells can differentiate in association with neighboring mesenchymal cells, probably getting some information. Their works suggest that the cell differentiation will be induced by mutual association of cells by which the cell will receive some substance acting as the information for differentiation. Taking the works of Ishikawa and his collabolators into consideration, it seems that cancer cells may be unable to differentiate by their defective or incomplete cell membrane through which they cannot associate with neighboring cells and fail to get the information. Almost all of the biological characteristics of cancer cells, immaturity, autonomic growth, invasive and metastatic properties independent from the neighboring cell groups, are well explained or consistent with this view. Recently, we found that the cell membrane can be loosened by some unsaturated fatty acids resulting in the leak-out of ribosomes. In this paper it is demonstrated how the Ehrlich ascites tumor cell affected by fatty acids lose their cytomembrane and the ribosomes and how the cells survived through this treatment show different characteristics from the original ones, taking the appearance more matured cells.</p

Leukemia autopsies in Japan

For the purpose to know whether the annual increase of leukemia incidence in Japan is due to some leukemogenic factors or due to the increased detection rate, the authors made some statistical survey of autopsy cases in which the diagnosis is reliable and not any type of leukemias escape the detection. The results showed that acute leukemias, which are found mostly in younger age, is actually increasing. In addition, it has been deduced that among the suspected factors the increase in ionizing radiation will be one of the most probable factors for the increase in leukemia incidence</p

Rare Concurrence of Apical Hypertrophic Cardiomyopathy and Effusive Constrictive Pericarditis

A 78-year-old man with a history of pulmonary tuberculosis was referred for preoperative evaluation of cardiac function. Echocardiography and cardiac cine magnetic resonance imaging (MRI) indicated apical hypertrophic cardiomyopathy (HCM), a thickened visceral pericardium, and a large pericardial effusion. Cardiac late gadolinium-enhanced MRI revealed pericardial inflammation or fibrosis. Apical HCM with concurrent effusive constrictive pericarditis was diagnosed. Further studies are required to elucidate the pathophysiology of this condition

急性心不全における退院時の尿素窒素分画排泄率の予後判定への有用性

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long-term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post-discharge all-cause death. Patients were divided into two groups according to a FEUN cut-off value of 35%, commonly used in pre-renal failure. The FEUN <35% (low-FEUN) group included 224 patients (48.1%), and the all-cause mortality rate for the total cohort was 37.1%. The log-rank test revealed that the low-FEUN group had a significantly higher rate of all-cause death compared to the FEUN equal to or greater than 35% (high-FEUN) group (P<0.001). Multivariate Cox proportional hazards model analysis revealed that low-FEUN was associated with post-discharge all-cause death, independently of other heart failure risk factors (hazard ratio, 1.467; 95% CI, 1.030-2.088, P=0.033). The risk of low-FEUN compared to high-FEUN in post-discharge all-cause death was consistent across all subgroups; however, the effects tended to be modified by renal function (threshold: 60 mL/min/1.73 m2, interaction P=0.069). Conclusions Our study suggests that FEUN may be a novel surrogate marker of volume status in patients with ADHF requiring diuretics.博士（医学）・甲第814号・令和4年3月15日Copyright © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made

再灌流後急性心筋梗塞患者におけるリバースリモデリングと非造影T1低信号梗塞コア

Background: Non-contrast T1 hypointense infarct cores (ICs) within infarcted myocardium detected using cardiac magnetic resonance imaging (CMR) T1 mapping may help assess the severity of left ventricular (LV) injury. However, because the relationship of ICs with chronic LV reverse remodeling (LVRR) is unknown, this study aimed to clarify it. Methods and Results: We enrolled patients with reperfused AMI who underwent baseline CMR on day-7 post-primary percutaneous coronary intervention (n=109) and 12-month follow-up CMR (n=94). Correlations between ICs and chronic LVRR (end-systolic volume decrease ≥15% at 12-month follow-up from baseline CMR) were investigated. We detected 52 (47.7%) ICs on baseline CMR by non-contrast-T1 mapping. LVRR was found in 52.1% of patients with reperfused AMI at 12-month follow-up. Patients with ICs demonstrated higher peak creatine kinase levels, higher B-type natriuretic peptide levels at discharge, lower LV ejection fraction at discharge, and lower incidence of LVRR than those without ICs (26.5% vs. 73.3%, P<0.001) at follow-up. Multivariate logistic regression analysis showed that the presence of ICs was an independent and the strongest negative predictor for LVRR at 12-month followup (hazard ratio: 0.087, 95% confidence interval: 0.017–0.459, P=0.004). Peak creatine kinase levels, native T1 values at myocardial edema, and myocardial salvaged indices also correlated with ICs. Conclusions: ICs detected by non-contrast-T1 mapping with 3.0-T CMR were an independent negative predictor of LVRR in patients with reperfused AMI.博士（医学）・乙第1529号・令和5年3月15

可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.博士（医学）・乙第1384号・平成28年11月24日© 2016 American Heart Association, Inc.The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371

慢性腎臓病では血中可溶型fms様チロシンキナーゼ-1産生の減少が動脈硬化症を悪化させる

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.博士（医学）・甲614号・平成26年3月17