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

穿孔性十二指腸潰瘍におけるHelicobacter pylori感染の関与に関する病理学的検討

現在,十二指腸潰瘍とHelicobacter pylori (H. pylori)の関連が明らかにされているが,十二指腸潰瘍の穿孔に対するH. pyloriの関与については議論が分かれている.そこで,1981年1月～1989年3月に当院第二外科で行われた179例の穿孔性十二指腸潰瘍に対する胃切除手術症例のうち,潰瘍穿孔部と幽門腺領域の標本が存在する89例につき,病理形態学的所見とH. pyloriとの関連について検討した.ヘマトキシリン・エオジン染色,マッソン・トリクローム染色を行い,病理形態学的所見により急性潰瘍穿孔型(A群)と慢性潰瘍穿孔型(C群)に分け,臨床的背景を検討した.また,免疫組織化学染色により,潰瘍穿孔部周辺のH. pyloriの有無,幽門腺領域のH. pylori感染を定性的に評価し,病理形態学的所見との関連を検討した.C群は60例,A群は29例であった.臨床的背景では,潰瘍の既往,1週間以上の穿孔前症状,手術時の肉眼所見で両群に有意差を認めた.潰瘍穿孔部周辺にH. pyloriは観察されず,幽門腺領域では81例に感染を認め,レベル1が20例,レベル2が35例,レベル3が26例であった.H. pylori感染と病理形態学的所見の関連では,線維化や瘢痕形成,潰瘍周辺部の動脈璧の肥厚や線維化,好中球優位の炎症細胞浸潤,粘膜の炎症,浮腫,毛細管性出血について有意差が認められた.A群の55%がレベル1で,レベル2,3は28%であったが,C群は88%がレベル2,3であり,A群に比べ,有意にH. pyloriの感染レベルが高かった.両群は臨床的背景だけでなくH. pyloriの感染レベルも有意に異なっていた.潰瘍形成から穿孔に至る機序は,急性型と慢性型で異なると推測され,特に急性潰瘍穿孔症例は,H. pylori以外にも穿孔要因があることが示唆された.There is controversy concerning the contribution of Helicobacter pylori (H. pylori) to perforation by duodenal ulcers. We therefore investigated the association between the pathological findings and H. pylori infection in the 89 operated cases. We performed hematoxylin and eosin staining, Masson trichrome staining, and to observe the presence of H. pylori by immunohistochemical staining. We divided the cases into an acute ulcer perforation type (A group) and a chronic ulcer perforation type (C group). There were 60 cases in the C group and 29 cases in the A group. Infection was observed in the pyloric gland region in 81 cases without detection of H. pylori around the site of ulcer perforation. In the A group, 55% of the cases had up to 20 bacteria/gastric pit present in a few of gastric pits. However in the C group, 88% were almost all of or many gastric pits with more than 20 bacteria/gastric pits. Thus the infection was significantly higher in the C group than in the A group. The two groups differed significantly in level of H. pylori infection. The results suggested that the acute type and the chronic type differed in the mechanism that led from ulcer formation to perforation

β-Arrestin-Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate

The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca2+ channels through angiotensin type 1 receptor (AT1R) and β-arrestin. TRV027, a β-arrestin-biased AT1R agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the AT1R/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the AT1R/β-arrestin/L-type Ca2+ channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.ArticleJACC. Basic to translational science 5(11) : 1057-1069(2020)journal articl

バルーン下逆行性経静脈的塞栓術で治療した十二指腸静脈瘤の1例

十二指腸静脈瘤はまれであるが,致死的な出血を来す.近年,種々の治療法が行われている.肝硬変を有する46歳の男性が,重症の貧血のため入院した.血液検査ではヘマトクリット8.9%,血色素量2.3g/dlであった.内視鏡および造影CT検査により十二指腸水平脚に静脈瘤を認めた.第4病日にバルーン下逆行性経静脈的塞栓術を行い,治療に成功した.第4週の造影CT,MRIと内視鏡検査で十二指腸静脈瘤は消失していた.止血している十二指腸静脈瘤では,バルーン下逆行性経静脈的塞栓術が有効であると考えられた.Duodenal varices are a rare and fatal condition. Treatment options for duodenal varices have been more variety in recent years. A 46-year-old man with liver cirrhosis was admitted because of severe anemia. Laboratory findings showed extremely low values for hematocrit (8.9%) and hemoglobin (2.3 g/dl). Upon endoscopic examination and contrast-enhanced computed tomography, duodenal varices were evident on the third portion of the duodenum. On the 4th day, he was successfully treated by balloon-occluded retrograde transvenous obliteration (BRTO). Contrast-enhanced computed tomography, magnetic resonance imaging and endoscopy on the 4th week showed that the varices had diminished. In cases of duodenal varices when hemostasis, we support the use of BRTO