Comparisons of Therapeutic Effects of Allopurinol and Febuxostat in Chronic Hemodialysis Patients

More than few patients on maintenance hemodialysis present with hyperuricemia, and the control of serum uric acid level is an important issue in the long-term management. In addition to allopurinol, febuxostat can be used as a xanthine oxidase inhibitor in hemodialysis patients. In this study, the clinical effects of febuxostat were compared with allopurinol in chronic hemodialysis patients. Eligible hemodialysis patients taking allopurinol were randomly assigned to take 100 mg allopurinol（n＝26）or 20 mg febuxostat（n＝23）for 12 weeks. Serum uric acid was markedly lowered in the febuxostat group（0-week 6.7 mg/dL, 12-week 4.3 mg/dL, p＜0.001）as compared with the allopurinol group（0-week 6.0 mg/dL, 12-week 5.8 mg/dL）and systolic blood pressure was lowered by 5 mmHg（p＝0.036）at 4-week in the febuxostat group while blood pressure was not significantly changed in the allopurinol group throughout the study period. In addition, the dose of erythropoiesis stimulating agent was reduced（0-week 22.2 μg/wk, 12-week, 17.1 μg/wk, p＝0.012）and serum phosphate level was lowered（0-week 5.9 mg/dL, 12-week 5.1 mg/dL, p＝0.027）in the febuxostat group but not in the allopurinol group. It is concluded that febuxostat is more effective in lowering serum uric acid than allopurinol in hemodialysis patients. In addition, it is suggested that febuxostat has an advantage in the management of renal anemia and hyperphosphatemia as well as hyperuricemia

Comparisons of Increasing Calcium Channel Blocker dose and Adding Thiazide Diuretic in Hypertensive Patients Given Medium-dose Angiotensin II Receptor Blocker and Amlodipine

We compared the efficacies of 2 prescriptions, one of a medium-dose angiotensin II receptor blocker （ARB） with high-dose of calcium channel blocker （CCB） and another of medium-dose of ARB with medium-dose of CCB and a thiazide diuretic in 22 hypertensive patients who did not achieve the target blood pressure level with the combination of medium-dose of ARB and medium-dose of CCB. A randomized crossover study was performed giving a fixed combination of 100 mg irbesartan with 10 mg amlodipine or a fixed-dose combination of 100 mg irbesartan with 5 mg amlodipine added by 1 mg trichlormethiazide for 12-16 weeks each. The blood pressure measured in hospital was comparable between the high-dose CCB period （130/77 mmHg） and the thiazide period （130/79 mmHg）. The morning and the evening blood pressures measured at home were also comparable in the high-dose of CCB and the thiazide periods, while the evening heart rate was higher in the thiazide period than in the high-dose CCB period. As for the laboratory data, hemoglobin A1c （＋0.2％, p＝0.013）, serum nonHDL cholesterol （＋12 mg/dL, p＝0.047） and serum uric acid （＋0.8 mg/dL, p＝0.001） were significantly higher in the thiazide period than in the high-dose CCB period. On the other hand, urinary albumin excretion （－28.8％，p＝0.026） and estimated glomerular filtration rate （－5.8％，p＝0.012） were significantly lower in the thiazide period than in the high-dose CCB period. In the combination drug therapy of hypertension, the increase of CCB dose is preferable in preserving renal function and in avoiding adverse effects on metabolisms of glucose, lipid and uric acid

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

Relief of cardiac tamponade by a congenital partial left-sided pericardial defect in a patient with ruptured acute type A aortic dissection: a case report

Abstract Background Acute type A aortic dissections have an extremely poor prognosis, and cardiac tamponade is a major cause of death in these patients. Here, we describe a case where congenital partial pericardial defect relieved cardiac tamponade caused by ruptured type A aortic dissection. Case presentation A 79-year-old woman was hospitalized after experiencing chest pains and respiratory distress. She developed out-of-hospital cardiopulmonary arrest and was resuscitated with no sequelae 5 days before admission. Computed tomography confirmed pericardial and left pleural effusions, and type A aortic dissection was diagnosed. We began emergency ascending aortic replacement surgery under general anesthesia with propofol and remifentanil and incidentally discovered a congenital partial left-sided pericardial defect that allowed drainage of the hemopericardium and relieved cardiac tamponade. The surgery was successfully performed, and the patient recovered without complications. Conclusions We experienced an extremely rare case where a congenital partial pericardial defect relieved cardiac tamponade associated with aortic dissection and contributed to the patient’s survival

Juvenile Membranous Nephropathy Developed after Human Papillomavirus (HPV) Vaccination

A 16-year-old girl with no history of renal disease had a fever of 38 °C after her second HPV vaccination and was identified as positive for proteinuria. As she maintained urinary protein of 3.10 g/gCr and 5–9 urinary red blood cells/HPF, a renal biopsy was performed and small spikes on PAM staining with the granular deposition of IgG1++ and IgG3+ on the glomerular capillary wall were discovered by immunofluorescence, although PLA2R immunostaining was negative. Analysis by electron microscope showed electron density deposition in the form of fine particles under the epithelium. The diagnosis was secondary membranous nephropathy stage II. Immunostaining with the anti-p16 INK4a antibody was positive for glomerular cells, and Western blot analysis of urinary protein showed a positive band for p16 INK4a. However, laser-microdissection mass spectrometry analysis of a paraffin section of glomeruli failed to detect HPV proteins. It is possible that the patient was already infected with HPV and administration of the HPV vaccine may have caused secondary membranous nephropathy