A Japanese Patient with Gastric Cancer and Dihydropyrimidine Dehydrogenase Deficiency Presenting with DPYD Variants

A 63-year-old Japanese male with stomach adenocarcinoma received oral 5-fluorouracil derivative, cisplatin and trastuzumab chemotherapy. On day 8, severe diarrhea and mucositis developed; chemotherapy was stopped. On day 14, the patient developed renal dysfunction and febrile neutropenia. He also suffered from pneumonia due to Candida albicans. Systemic symptoms improved after intensive conservative treatment. Best supportive care was continued until the patient died from gastric cancer. The dihydropyrimidine dehydroge-nase protein level was low at 3.18 U/mg protein. The result of DPYD genotyping revealed three variants at posi-tions 1615 (G > A), 1627 (A > G), and 1896 (T > C) in exons 13, 13, and 14, respectively

21セイキ ノ カンドウミャク インターベンション

Coronary intervention has come to achieve good results with the use of new devices, such as Rotablator (ROTA), new directional coronary atherectomy (DCA), and a special guide wire, even for lesions in which good results were not obtained with plain old balloon angioplasty. In the present study, we evaluated the initial results in patients who underwent ROTA procedures, coronary intervention for chronic total occlusion (CTO), and new DCA procedures in our hospital between January and December 2001. (1) There were 99 patients who underwent ROTA, with an average age of 68±12 years, a lesion length of 15.9±9.9 mm, a reference vessel diameter of 2.7±0.6 mm, and a success rate of 98%. Among these 99 patients, there were 82 patients (83%) with B2 or C type lesion, which is difficult to treat. (2) There were 61 patients with CTO who underwent coronary intervention, with an average age of 63±9 years, an occlusion length of 22.8±13.3 mm, a reference vessel diameter of 2.6±0.7 mm, and a success rate of 82%. (3) There were 5 patients who underwent DCA for ostial lesion of left anterior desending artery and the target lesion was successfully dilated in all these patients. These results indicated that new devices for coronary intervention have made it possible to treat a wider range of lesions, but restenosis still remains to be solved. In Europe and the U.S.A., restenosis is reported to have been drastically reduced by drug eluting stents, which are expected to be introduced in Japan in the future

ジンソクナ バイスタンダー シンパイ ソセイホウ ニヨリ トツゼンシ オ マヌガレ シャカイ フッキ デキタ コウコウセイ ノ 2 ショウレイ

Bystander CPR means that people who find cardiopulmonary arrest perform cardiopulmonary resuscitation on the spot. Quick CPR contributes to increase in the rate of returning to the society as well as one-month survival rate and neurological prognosis. We report our experience with two high school students who underwent quick Bystander CPR, avoided sudden death, and returned to the society. ［Case 1］ Eighteen-year-old man : He collapsed suddenly in his home. Bystander CPR was performed by his family until emergency crews arrived there. Automated external defibrillator （AED） worked twice and his heartbeat started again. In electrocardiogram, coved type ST elevation in lead V1 was observed, and he was diagnosed as Brugada syndrome. We implanted an implantable cardioverter-defibrillator. Since his condition was stable, he was discharged on the 19th day. ［Case 2］ Seventeen-year-old woman : She collapsed suddenly walking with her family. Her father confirmed that she had no response, and started Bystander CPR. Her father got AED quickly and AED worked once, and she started to breathe again. She was admitted to our hospital for a work-up. Torsades de pointes （TdP） was observed in monitor electrocardiogram, and her QTc time was 513 msec in 12‐lead electrocardiogram. She was diagnosed as congenital long QT syndrome because genetic test showed that she had LQT2. Her QTc time was improved （approximately 350 msec） by medication, and she was discharged on the 25th day. Utstein-style statistics in Japan shows that the rate of returning to the society can be doubled by performing Bystander CPR on patients with cardiopulmonary arrest. However, performing rate of Bystander CPR is less than 50％ in Japan. In order to increase survival rate of patients with cardiopulmonary arrest for the future, it is important to inform people about CPR and to promote CPR, and in fact, we have been promoting CPR

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

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study

IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS

Year‐long effects of COVID‐19 restrictions on glycemic control and body composition in patients with glucose intolerance in Japan: A single‐center retrospective study

ABSTRACT Aims/Instruction During the coronavirus disease 2019 (COVID‐19) pandemic, the lockdowns in Europe raised concerns about negative effects on glycemic control and body composition in patients with diabetes. In Japan, voluntary‐based restrictions were imposed as the declaration of a state of emergency (DSE), whose metabolic consequences have not been fully investigated. We carried out a single‐center retrospective study to evaluate changes in glycemic control and body composition in outpatients with glucose intolerance after the DSE. Materials and Methods We enrolled outpatients with glucose intolerance: (i) for whom longitudinal data about body composition were available; (ii) who participated in dietary follow up with nutritionists; and (iii) whose laboratory data included glycated hemoglobin (HbA1c) levels before and after the DSE. Results Among 415 patients, we found no significant changes in HbA1c overall after the DSE. Bodyweight and fat mass increased significantly, whereas skeletal mass decreased significantly. HbA1c changes after the DSE were significantly correlated with changes in bodyweight and fat mass. In 128 patients whose HbA1c levels increased ≥0.3%, changes in bodyweight and fat mass were significantly larger than those in the other 287 patients. With regard to lifestyle changes, increased snacking was likely to worsen glycemic control (odds ratio 1.76, P = 0.036). Conclusions COVID‐19 restrictions in Japan had unfavorable metabolic consequences for patients with glucose intolerance, highlighted by increased bodyweight and body fat, and decreased skeletal muscle. In addition, lifestyle changes, such as increased snacking, might worsen glycemic control. Clinical attention and interventions are required to prevent such metabolic changes

A case of severe paraquat poisoning treated by continuous hemodiafiltration without sequelae

Background In a suicide attempt, a 49‐year‐old male ingested pesticides. He arrived at the hospital restless and vomiting blue liquid. Case Presentation The patient was diagnosed with paraquat poisoning at a lethal dose and experienced renal dysfunction during treatment. He underwent continuous hemodiafiltration (CHDF). Hemodialysis was temporarily initiated and found to improve renal function. He was discharged on day 36 in good condition. He remains well with only mild renal impairment and no pulmonary fibrosis, 240 days after the incident. The fatality rate of paraquat poisoning is approximately 80%, regardless of the treatment. Early hemodialysis combined with CHDF within 4 h has been reported to be effective. In this case, CHDF was initiated approximately 3 h after paraquat administration and showed a successful outcome. Conclusion CHDF should be performed as soon as possible to treat paraquat poisoning