Association of depressive symptomatology and dry-mouth feeling in relation to state of taking medicine in citizens from their 40s to 70s selected randomly from two cities in Hokkaido, Japan

Background: Troponin I (TnI) are highly specific to the myocardium, and measurement of the plasma TnI levels has been widely used to evaluate myocardial damage. This study was performed to ascertain the pathologic or perioperative variables that are significantly associated with the plasma cardiac TnI level. We also intended to provide reference range of TnI elevation after uncomplicated pediatric open heart surgery.Methods: One hundred fifty-one patients undergoing repair of atrial septal defects (ASDs) (n = 61), ventricular septal defects (VSDs) (n = 71), tetralogy of Fallot (TOF) (n = 14), or complete atrioventricular septal defects (CAVSDs) (n = 5) were included. The plasma TnI level was measured prior to surgery, on days 1 and 7 postoperatively. We analyzed the relationship between the TnI level and pathology, cardiopulmonary bypass, and other perioperative actors.Results: All patients underwent uncomplicated surgery and postoperative course. With all pathologies, the plasma TnI level peaked on postoperative day 1 and rapidly declined. The TnI level on postoperative day 1 was higher in VSD than ASD, and there was a further rise in TOF and CAVSD but no significant difference between them. The TnI level on postoperative day 1 was strongly correlated with the operative time, cardiopulmonary bypass time, and aortic cross-clamp (ACC) time. Multiple linear regression analysis showed that the operative time, ACC time, lowest rectal temperature, TOF lesion, and inotropic support period could influence the TnI level.Conclusions: Elevation of plasma TnI after pediatric open heart surgery for various congenital heart diseases is mainly associated with the condition of cardiopulmonary bypass (operative and ACC times) and is not affected with surgical procedures expect for ventricular muscle resection during repair of TOF. Level of TnI elevation confirmed in the study could provide reference range in uncomplicated open heart surgery for each four pathologies. (298 words

Association of depressive symptomatology and dry-mouth feeling in relation to state of taking medicine in citizens from their 40s to 70s selected randomly from two cities in Hokkaido, Japan

Background: Troponin I (TnI) are highly specific to the myocardium, and measurement of the plasma TnI levels has been widely used to evaluate myocardial damage. This study was performed to ascertain the pathologic or perioperative variables that are significantly associated with the plasma cardiac TnI level. We also intended to provide reference range of TnI elevation after uncomplicated pediatric open heart surgery.Methods: One hundred fifty-one patients undergoing repair of atrial septal defects (ASDs) (n = 61), ventricular septal defects (VSDs) (n = 71), tetralogy of Fallot (TOF) (n = 14), or complete atrioventricular septal defects (CAVSDs) (n = 5) were included. The plasma TnI level was measured prior to surgery, on days 1 and 7 postoperatively. We analyzed the relationship between the TnI level and pathology, cardiopulmonary bypass, and other perioperative actors.Results: All patients underwent uncomplicated surgery and postoperative course. With all pathologies, the plasma TnI level peaked on postoperative day 1 and rapidly declined. The TnI level on postoperative day 1 was higher in VSD than ASD, and there was a further rise in TOF and CAVSD but no significant difference between them. The TnI level on postoperative day 1 was strongly correlated with the operative time, cardiopulmonary bypass time, and aortic cross-clamp (ACC) time. Multiple linear regression analysis showed that the operative time, ACC time, lowest rectal temperature, TOF lesion, and inotropic support period could influence the TnI level.Conclusions: Elevation of plasma TnI after pediatric open heart surgery for various congenital heart diseases is mainly associated with the condition of cardiopulmonary bypass (operative and ACC times) and is not affected with surgical procedures expect for ventricular muscle resection during repair of TOF. Level of TnI elevation confirmed in the study could provide reference range in uncomplicated open heart surgery for each four pathologies. (298 words

A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E–Deficient Mice

ObjectivesThe aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).BackgroundThe new class of anti–type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.MethodsEndothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.ResultsDFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10−4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).ConclusionsA DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium

Direct cell–cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo

Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial–temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell–cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell–cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell–cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Protein kinase Cδ amplifies ceramide formation via mitochondrial signaling in prostate cancer cells

We studied the role of protein kinase C isoform PKCδ in ceramide (Cer) formation, as well as in the mitochondrial apoptosis pathway induced by anticancer drugs in prostate cancer (PC) cells. Etoposide and paclitaxel induced Cer formation and apoptosis in PKCδ-positive LNCaP and DU145 cells but not in PKCδ-negative LN-TPA or PC-3 cells. In contrast, these drugs induced mitotic cell cycle arrest in all PC cell lines. Treatment with Rottlerin, a specific PKCδ inhibitor, significantly inhibited drug-induced Cer formation and apoptosis in LNCaP cells, as did overexpression of dominant negative–type PKCδ. Overexpression of wild-type PKCδ had an opposite effect in PC-3 cells. Notably, etoposide induced biphasic Cer formation in LNCaP cells. The early and transient Cer increase resulted from de novo Cer synthesis, while the late and sustained Cer accumulation was derived from sphingomyelin hydrolysis by neutral sphingomyelinase (nSMase). Cer, in turn, induced mitochondrial translocation of PKCδ and stimulated the activity of this kinase, promoting cytochrome c release and caspase-9 activation. Furthermore, the specific caspase-9 inhibitor LEHD-fmk significantly inhibited etoposide-induced nSMase activation, Cer accumulation, and PKCδ mitochondrial translocation. These results indicate that PKCδ plays a crucial role in activating anticancer drug–induced apoptosis signaling by amplifying the Cer-mediated mitochondrial amplification loop