Earthquake-Induced Potentiation of Acute Risk Factors in Hypertensive Elderly Patients: Possible Triggering of Cardiovascular Events After a Major Earthquake

AbstractObjectives. We sought to investigate the potentiation of acute risk factors after the Hanshin-Awaji earthquake (7.2 on the Richter scale).Background. The frequency of cardiovascular events increases just after a major earthquake, but the causative factors have not been fully investigated.Methods. We studied the changes in cardiovascular risk factors in 42 elderly outpatients with well-controlled hypertension living near the epicenter (Awaji-Hokudan districts) 7 to 14 days after the earthquake when the major felt-aftershocks persisted. They all experienced the highest stress grading of 6 (catastrophic stress) according to the DSM-III-R. To study the hemostatic profile and endothelial cell state, we measured the blood pressure (BP), hematocrit and lipid profiles as well as fibrinogen, a marker of fibrin turnover (d-dimer), fibrinolytic factors (plasmin-alpha2–plasmin inhibitor complex [PIC], tissue-type plasminogen activator [t-PA] antigen and t-PA inhibitor [PAI] activity) and an endothelial cell-derived marker (von Willebrand factor [vWF]).Results. Systolic and diastolic blood pressures and other variables increased after the earthquake. Before and after the earthquake, the median (25th to 75th percentiles) systolic BP was 152 (range 142 to 164) and 170 mm Hg (range 161 to 178), respectively (p < 0.0001), and the diastolic BP was 83 (range 79 to 88) and 91 mm Hg (range 84 to 96), respectively (p < 0.0001). Of blood viscosity determinants, hematocrit was 38.1% (range 40.7% to 35.9%) and 39.7% (range 42.9% to 38.3%), respectively (p < 0.001), and fibrinogen 316 (range 272 to 360) and 335 mg/dl (range 307 to 391), respectively (p < 0.05). Von Willebrand factor was 128% (range 74% to 148%) and 148% (range 100% to 178%), respectively (p < 0.01); d-dimer was 410 (range 285 to 633) and 560 ng/ml (range 391 to 888), respectively (p < 0.0001); and PIC was 0.74 (range 0.58 to 0.91) and 0.75 μg/ml (range 0.58 to 1.1), respectively (p < 0.05). In contrast, lipid profiles did not change after the quake. When the patients were classified into the high stress and moderate stress groups according to the degrees of damage to their house and injury to family members, the levels of fibrinogen, vWF, PIC and t-PA antigen were increased only in the former group, whereas BP, hematocrit and d-dimer levels were increased in both groups. These abnormalities of acute risk factors, except for vWF, were transient and decreased to prequake levels by 4 to 6 months after the quake.Conclusions. Earthquake-induced stress seems to induce transient increases in BP, blood viscosity determinants and fibrin turnover and to prolong endothelial cell stimulation. The potentiation of these acute risk factors might contribute to the occurrence of cardiovascular events just after a major earthquake in elderly subjects with hypertension.(J Am Coll Cardiol 1997;29:926–33)© 1997 by the American College of Cardiolog

Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus : A randomized, crossover trial

Aims: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. Methods: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). Results: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). Conclusions: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM

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

Dose-response Relationship of Thymic and Non-thymic Lymphomas Induction by Gamma Radiation in SCID Mice

SCID mice which have the defect of DNA-dependent protein kinase catalytic subunit, exhibit the limited activities of repair from DNA double strand breaks and are sensitive to ionizing radiation. In order to study the relationship between repair capacity for DNA double strand breaks and carcinogenesis, and the responsibitily at the low dose of gamma rays, the effects of ionizing radiation on tumor induction were studied using scid homozygote (scid/scid), and C.B-17(+/+)mice. Carcinogenesis experiments showed the significant increase of the incidence of thymic lymphomas at 25cGy to sublethal dose. At very low dose(5 and 10cGy), non-thymic B or T cell lymphomas were incuced in scid mice, whereas there was no induction of these lymphomas in wild-type mice. No tumors other than lymphomas were observed, because of the life shortning effect by the induction of thymic lymphomas. Thus scid mice is highly sensitive to the induction of non-thymic lymphomas at very low doses.放射線影響学会第４６回大

Existence of a threshold-like dose for gamma-ray induction of thymic lymphomas and no susceptibility to radiation-induced solid tumors in SCID mice

Severe combined immune deficiency (SCID) mice exhibit limited repair of DNA double-strand breaks and are sensitive to ionizing radiation due to a mutation of the DNA-dependent protein kinase catalytic subunit gene. To elucidate the effects of deficient DNA double-strand break repair on radiation-induced carcinogenesis, the dose-response relationship for the induction of all tumor types was examined in wild-type and SCID mice. In wild-type mice, the incidence of thymic lymphomas at gamma-ray doses up to 1 Gy was almost equal to the background level, increased gradually above 1 Gy, and reached a maximum of 12.5% at 5 Gy, which is indicative of a threshold dose of less than 1 Gy. SCID mice were extremely susceptible to the induction of spontaneous and radiation-induced thymic lymphomas. The incidence of thymic lymphomas in SCID mice irradiated with 0.1 Gy or less was similar to the background level; that is, it increased markedly from 31.7% at 0.1 Gy to 51.4% at 0.25 Gy, and reached a maximum of 80.6% at 2 Gy, suggesting the presence of a threshold-like dose at low gamma-ray doses, even in radiosensitive SCID mice. As the average latency for the induction of thymic lymphomas at 0.1 Gy was significantly shortened, the effect of 0.1 Gy gamma-rays on thymic lymphoma induction was marginal. The high susceptibility of SCID mice to develop thymic lymphomas indicates that thymic lymphomas are induced by a defect in DNA double-strand break repair or V(D)J recombination. Excessive development of tumors other than thymic and nonthymic lymphomas was not observed in SCID mice. Furthermore, our data suggest that the defective double-strand break repair in SCID mice is not a major determinant for the induction of nonlymphoid tumors

Pharmacokinetics of 6-shogaol, a pungent ingredient of Zingiberis Rhizoma, and the anti-inflammatory activity of its metabolite, 6-paradol

金沢大学医薬保健研究域薬学系Zingiberis Rhizoma の辛味成分である 6-shogaol およびその代謝物 6-paradol の体内動態および薬理活性について， 検討した。 6-shogaol （10 mg/kg） をラットに経口投与した際の血漿中 6-shogaol および 6-paradol 濃度を LC/MS/MSを用いて測定したところ， ともに投与 5 分後で Cmax に到達し， 投与 2 時間後までに速やかに血漿中から消失した。 代謝物である血漿中 6-paradol 濃度はいずれの採血時間においても， 6-shogaol 濃度に比べて約 4 倍高い値を示した。 次に， 6-shogaol および6-paradolの薬理活性について検討したところ， in vitro 実験において 6-paradol は 6-shogaol に比べ約 6 倍強い COX-2 阻害活性を示し， in vivo 実験においても 6-paradol が 6-shogaol より有意に強い抗炎症作用， 鎮痛作用および解熱作用を示した。 このことから， Zingiberis Rhizoma 中の 6-shogaol は体内で速やかに 6-paradol に代謝されること， また代謝物である 6-paradol が抗炎症作用を示すメイン化合物であることが示唆された。This study examined the pharmacokinetics and pharmacological activities of 6-shoganol, a pungent ingredient of Zingiberis Rhizoma, and its metabolite, 6-paradol. The concentrations of 6-shogaol and 6-paradol in rat plasma determined by LC/MS/MS reached their maximum values (Cmax) at 5 minutes after oral administration of 6-shogaol (10 mg/kg). Both 6-shogaol and 6-paradol were eliminated from the plasma within 2 hours after injection. The plasma concentration of 6-paradol, the metabolite, was about 4 times higher than that of 6-shogaol at all points during blood sampling. Next, pharmacological activities of 6-shogaol and 6-paradol were studied. In vitro experiment revealed that the cyclooxygenase-2-inhibitory activity of 6-paradol was about 6 times stronger than that of 6-shogaol. In vivo experiments, 6-paradol demonstrated significantly stronger anti-inflammatory, analgesic, and antipyretic activities compared to 6-shogaol. These results suggest that 6-shogaol in Zingiberis Rhizoma is metabolized rapidly to 6-paradol and that 6-paradol is the main compound having anti-inflammatory activity. © 2013, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved

Effects of changes in polycyclic aromatic hydrocarbons (PAHs) emissions and degradation on their concentrations in Tokyo from 2007 and 2016

The concentrations of polycyclic aromatic hydrocarbons (PAHs) in aerosol were measured in Shinjuku, which is central Tokyo, Japan, for 10 years from 2007 to 2016. The effects of changes in emission sources and their degradation by reaction with ozone were assessed in this study. There was no significant increasing or decreasing trend of the PAH concentrations during 10 years (P > 0.05). The average selected seven the PAH concentrations (0.88 ng m−3) during 10 years was lower than those in New York and Paris. However, the trend of ozone concentrations is increasing in central Tokyo. This inconsistency raises a question. Did the fact that the ozone concentration was higher than the PAH concentrations promote PAH degradation? To apportion the PAH sources, we used PAH concentration profiles and positive matrix factorization analysis. The contribution of vehicle emissions to the PAHs ranged from 40 to 80%. Ozone concentrations increased by 3.70%/year during 10 years. The theoretical degradation rates of PAHs by ozone, which were calculated using a pseudo-first-order rate equation, suggested that the lifetimes of benzo[a]pyrene (BaP) decreased by 1 min from 2007 to 2016. We investigated the aging of BaP using the profile of the isomer ratios. We found that the aging of BaP at the urban and roadside sites were nearly identical indicating aging regardless of the season. Although the decomposition of BaP is promoted by the photochemical oxidation reaction, this result suggests that a certain threshold value exists as the degree of the decomposition. This degradation of PAH can improve chemical loss processes in air quality model