アスペルガー障害患者の脳波研究

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1753号 , 学位授与年月日 : 平成18年3月22日, 学位授与大学 : 金沢大

Histochemical Nature of Eosinophilic Globules in Pheochromocytoma of Adrenal Medulla

Eosinophilic globules were observed in 7 out of 11 cases of pheochromocytoma of the adrenal medulla. All of these globules were present in the cytoplasm, and were round and eosinophilic, measuring 3 μm to 30 μm in diameter. These globules were periodic acid Schiff (PAS) -positive with and without diastase predigestion, phosphotungstic acid hematoxylin (PTAH) positive, acid fuchsin positive, and autofluorescent under ultraviolet illumination. These findings were very similar to the eosinophilic globules of yolk sac tumor, hepatocellular carcinoma, Kaposi\u27s sarcoma, and alpha-l-antitrypsin deficiency in light microscopy and histochemistry. They were not stained with Grimelius\u27s method for argyrophil reaction, and Fontana-Masson\u27s method for argentaffin reaction. It might be suggested that eosinophilic globules in pheochromocytoma of the adrenal medulla were not related to the chromaffin secretory granules and these globules were glycoprotein

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

A study of single nucleotide polymorphisms of the SLC19A1/RFC1 gene in subjects with autism spectrum disorder

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate-methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16-0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. © 2016 by the authors; licensee MDPI, Basel, Switzerland

Two genetic variants of CD38 in subjects with autism spectrum disorder and controls

金沢大学医薬保健研究域医学系The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p 70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD. © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society

Platinum-catalyzed reduction of amides with hydrosilanes bearing dual Si-H groups: a theoretical study of the reaction mechanism

A platinum-catalyzed amide reduction through hydrosilylation with 1,2-bis(dimethylsilyl) benzene (BDSB) was investigated on a theoretical basis. While the platinum-catalyzed hydrosilylation of alkenes is well known, that of carbonyl groups rarely occurs. The only exception involves the use of bifunctional hydrosilanes having dual, closely located Si-H groups, which accelerate the hydrosilylation of carbonyl groups, leading to successful reduction of amides to amines under mild conditions. In the present study, we determined through density functional theory calculations that the platinum-catalyzed hydrosilylation of the C=O bond proceeds via a Pt(IV)-disilyl-dihydride intermediate with an associated activation energy of 29.6 kcal mol(-1). Although it was believed that the hydrosilylation of carbonyl groups does not occur via the classical Chalk-Harrod cycle, the computational results support a mechanism involving the insertion of the amide CvO bond into a Pt-H bond. This insertion readily occurs because a Pt-H bond in the Pt(IV)-disilyl-dihydride intermediate is highly activated due to the strong s-donating interaction of the silyl groups. The modified Chalk-Harrod mechanism that occurs preferentially in rhodium-catalyzed hydrosilylation as well as the ionic outer sphere mechanism associated with iridium-catalyzed amide reduction were both safely ruled out as mechanisms for this platinum-catalyzed amide reduction, because of the unexpectedly large activation barrier (>40 kcal mol(-1)) for the Si-O bond formation