Correction of a Severe Poliomyelitic Equinocavovarus Foot Using an Adjustable External Fixation Frame

One-stage surgical correction of severe equinocavovarus deformity can result in complications ranging from skin necrosis to tibial nerve palsy. Fewer complications have been reported when severe deformities were treated by gradual correction using external frames such as the Ilizarov external fixator or the Taylor Spatial FrameTM. We describe a case of a 64-year-old female patient with severe poliomyelitic equinocavovarus whose deformity required her to ambulate using the dorsum of her right foot as a weightbearing surface. We treated the deformity with gradual correction using a Taylor Spatial FrameTM, followed by ankle arthrodesis. At the most recent postoperative evaluation, 20 months after the initial surgery, the patient was pain free and ambulating on the sole of her right foot. © 2014 American College of Foot and Ankle Surgeons

Over 10-year follow-up of functional outcome in patients with bone tumors reconstructed using distraction osteogenesis

Background: The aim of this study was to investigate the long-term functional capabilities of patients who underwent bone distraction for the treatment of bone defects caused by bone tumor excision. Methods: Bone distraction was indicated for patients with stage IIB malignant bone tumors when chemotherapy was judged to be effective and an epiphysis could be preserved or for patients with low-grade or aggressive benign bone tumors. Twenty-two patients who underwent reconstruction with bone distraction and were followed up for at least 10 years were retrospectively investigated. Patients included 8 males and 14 females, with a mean age of 25.3 years. Tumor types included seven osteosarcomas, two osteofibrous dysplasias, one Ewing\u27s sarcoma, five low-grade osteosarcomas, two adamantinomas, and five giant cell tumors. Chemotherapy was performed during bone distraction in 8 cases. Bone transport was used in 17 cases, while shortening distraction was used in 5 cases. Results: The mean distraction length was 8.1 cm, and the mean external fixation period was 301 days. The average Musculoskeletal Tumor Society score (used to measure functional outcome) was 91.5 % at mean follow-up of 202 months. Fourteen patients were able to play sports without any difficulty. Conclusions: Epiphyseal preservation and reconstruction by bone distraction require both time and effort, but can provide excellent long-term outcomes, resulting in a stable reconstruction that functionally restores the natural limb. © 2012 The Japanese Orthopaedic Association

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

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

Positive correlation between blood pressure or heart rate and chymase-dependent angiotensin II-forming activity in circulating mononuclear leukocytes measured by new ELISA

The aim of the present study was to establish a convenient clinically applicable assay method for chymase-dependent angiotensin II forming activity of circulating mononuclear leukocytes (CML), which was potentially a marker of tissue chymase activity. Using this method, association between CML chymase activity and clinical parameters was determined. Cardiovascular outpatients (n = 170) without taking antihypertensive medication were recruited. An ELISA for chymase-dependent angiotensin II-forming activity in CML was established using Nma /Dnp-modified angiotensin I. Logistic regression analysis revealed that age and male gender were significant independent determinants of the increased CML chymase activity. After adjustment by age and gender, the CML chymase activity was positively correlated with systolic blood pressure, pulse rate, and the brain natriuretic peptide level. The relation between blood pressure and CML chymase activity suggests that it might reflect that increased tissue chymase activity contributes to systemic high blood pressure and heart rate because plasma chymase is inactive due to inhibitory plasma inhibitors

Efficacy and safety of a combination antihypertensive drug (olmesartan plus azelnidipine): “Issues with hypertension studies in real-world practice”

Background: This study investigated whether a combination drug containing an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) could provide effective antihypertensive therapy. Methods: A multicenter, prospective, open-label study was conducted at the clinics of Clinical Research Network. The subjects had uncontrolled blood pressure (BP) despite ARB or CCB monotherapy. The effect on both office and home BP was examined after patients switched to a combination drug (REZ: containing 20 mg of olmesartan [OL] and 16 mg of azelnidipine [AZ]). Results: A total of 78 patients were enrolled. After switching to REZ, a significant and sustained reduction of office BP was observed. The proportion of patients who achieved the target for both office and home BP was an increase from 0% to 55%. Switching from amlodipine to REZ resulted in a significant and sustained decrease of office and home BP. There was also a significant decrease of home pulse rate (PR), but office PR was unchanged. To determine the accuracy of the BP and PR values reported by patients, the frequency of each number as the first digit was determined. The frequency of “0” was extremely high for both office and home BP values, and the same was noted for home PR values. Conclusion: The results of this study suggested that switching from a single drug to combination therapy with REZ could achieve a stronger antihypertensive effect. However, concern was raised regarding the methods of BP and PR measurement and recording in this clinical trial involving general practitioners

Add-on aliskiren treatment can decrease blood pressure but requires attention to risks of renal impairment and hyperkalemia Chikushi Anti-Hypertension Trial-Rasilez® (CHAT-Ras)

Background Renin is the starting point of the renin angiotensin (RA) system cycle. Aliskiren (AL), which is a direct renin inhibitor, suppressed the entire RA cycle. In the present study, the efficacy of add-on of AL treatment in patients with essential hypertension (HT) was investigated. Methods This study was a multi-center, open-label, prospective, observational study. Study subjects were patients with essential HT and poor blood pressure (BP) control, who had received calcium channel blocker monotherapy or angiotensin II receptor blocker monotherapy or had not received any BP lowering drugs. Following add-on of AL for 12 months, BP and additional laboratory findings were analyzed. Results A total of 150 subjects were enrolled. There were 50 dropout subjects including discontinuation. Dropouts were the highest in the ARB combination therapy group at 9 subjects due to adverse events, and 3 of them were due to hyperkalemia. A significantly higher number of patients with chronic kidney disease (CKD) dropped out compared to patients without CKD (φ = 0.166, p < .05). BP before add-on of AL was 155/88 mmHg. After add-on of AL, BP was significantly improved and this lowering was sustained for 3 months (136/78 mmHg, p < .001), 6 months (136/77 mmHg, p < .001) and 12 months (134/78 mmHg, p < .001). In contrast, add-on of AL increased the potassium level and decreased the estimated glomerular filtration rate. Conclusion While add-on AL treatment achieved a favorable and sustained decrease of BP in this study, caution is necessary with regard to elevation of potassium levels and renal impairment