Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function

AbstractOBJECTIVESThe purpose of this study was to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor imidapril and the calcium antagonist amlodipine on endothelial function before and after 2, 4, 8, 12, 24 and 48 weeks of treatment.BACKGROUNDThere are limited data on whether and how long endothelial function is improved after initiation of ACE inhibitor treatment and how the grade of endothelial function further progresses after improvement of endothelial dysfunction in patients with essential hypertension.METHODSThe forearm blood flow (FBF) was measured in 25 patients with essential hypertension and in 25 normotensive subjects by using strain-gauge plethysmography during reactive hyperemia (RH) (280 mm Hg for 5 min) and after sublingual administration of nitroglycerin (NTG, 0.3 mg).RESULTSThe FBF of patients with essential hypertension during RH was significantly less than that of normotensive subjects. The increase in FBF after sublingual NTG was similar in both groups. Both imidapril (n = 13) and amlodipine (n = 12) significantly reduced systolic blood pressure and diastolic after eight weeks of treatment from the pretreatment values. Forearm vascular resistance was significantly decreased after two weeks of treatment. Imidapril significantly augmented RH after 12 weeks of treatment from the pretreatment values (31.6 ± 5.7 to 38.2 ± 6.0 ml/min per 100 ml tissue, p < 0.05), whereas amlodipine did not alter RH for each treatment period. The ability of imidapril to improve RH was maintained throughout the 48-week treatment period. There was no significant difference in RH at 12, 24 and 48 weeks. The increase in FBF after sublingual administration of NTG was similar in all treatment periods for the two groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of RH in hypertensive patients treated with imidapril.CONCLUSIONSThese findings suggest that the ACE inhibitor imidapril augments RH after 12 weeks of treatment in patients with essential hypertension and that this ACE inhibitor-induced augmentation of RH may be due to an increase in NO

Gingival Nikolsky’s Sign: A Valuable Tool in Identifying Oral Manifestations of Mucous Membrane Pemphigoid and Pemphigus Vulgaris

Autoimmune bullous diseases are a group of rare, chronic blistering diseases that affects the skin and mucous membranes. Mucous membrane pemphigoid (MMP) is the most frequently occurring autoimmune bullous disease in the oral cavity, followed by pemphigus vulgaris (PV). Early diagnosis of MMP or PV is critical for proper management and prevention of potential serious complications. This study was based on a retrospective review of 39 cases that were classified as MMP (25 patients) or PV (14 patients). Nikolsky’s sign characterized by epithelial detachment as a result of slight pressure or rubbing the oral mucosa is a simple test that can confirm the existence of gingival desquamation. A positive reaction was confirmed in 38 patients (97.4%) at their first visit. This result indicates that patients showing positive Nikolsky’s sign should include MMP or PV in the differential diagnosis and, in that case, histopathological examination and direct immunofluorescence testing are critical to establish the final diagnosis. For the early diagnosis of autoimmune bullous disorders, oral healthcare providers should consider the use of the test for Nikolsky’s sign that may ultimately lead to the early diagnosis of MMP and PV or other diseases or disorders

Desquamative Gingivitis: Early Sign of Mucous Membrane Pemphigoid and Pemphigus Vulgaris

Early signs and symptoms of autoimmune bullous diseases such as mucous membrane pemphigoid (MMP) or pemphigus vulgaris (PV) develop in the oral cavity in almost all cases. Desquamative gingivitis (DG) is a clinical manifestation common to several diseases or disorders and is frequently associated with autoimmune bullous diseases. This is a retrospective study of 37 patients with MMP (24 cases) or PV (13 cases) including 10 males and 27 females with a mean age of 58.4 years. The study indicates that DG is an early sign of autoimmune bullous diseases such as MMP or PV. About 70.3% of the oral lesions were confined only to the gingiva, and DG was the only manifestation of the diseases. Since some lesions remain limited to the oral cavity for a long period of time, patients diagnosed with MMP or PV should be closely followed because they must be immediately referred to other experts when they develop lesions on parts of their body other than the oral cavity. The oral healthcare provider should collaborate with other healthcare experts including dermatologists, ophthalmologists, and otolaryngologists to evaluate and manage patients with autoimmune bullous diseases in the oral cavity

Low body mass index is a risk factor forimpaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress

AbstractObjectivesThe purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function.BackgroundEpidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease.MethodsThe forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese).ResultsPlasma concentrations of 8-hydroxy-2′-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups—but not in normal BMI group.ConclusionsThese findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO

Synergistic Formation of Radicals by Irradiation with Both Vacuum Ultraviolet and Atomic Hydrogen: A Real-Time In Situ Electron Spin Resonance Study

We report on the surface modification of polytetrafluoroethylene (PTFE) as an example of soft- and bio-materials that occur under plasma discharge by kinetics analysis of radical formation using in situ real-time electron spin resonance (ESR) measurements. During irradiation with hydrogen plasma, simultaneous measurements of the gas-phase ESR signals of atomic hydrogen and the carbon dangling bond (C-DB) on PTFE were performed. Dynamic changes of the C-DB density were observed in real time, where the rate of density change was accelerated during initial irradiation and then became constant over time. It is noteworthy that C-DBs were formed synergistically by irradiation with both vacuum ultraviolet (VUV) and atomic hydrogen. The in situ real-time ESR technique is useful to elucidate synergistic roles during plasma surface modification.Comment: 14 pages, 4 figure

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