El Tao del Islam

Abstract not availabl

Unexpected Instability of Family of Repeats (FR), the Critical cis-Acting Sequence Required for EBV Latent Infection, in EBV-BAC Systems

A group of repetitive sequences, known as the Family of Repeats (FR), is a critical cis-acting sequence required for EBV latent infection. The FR sequences are heterogeneous among EBV strains, and they are sometimes subject to partial deletion when subcloned in E. coli-based cloning vectors. However, the FR stability in EBV-BAC (bacterial artificial chromosome) system has never been investigated. We found that the full length FR of the Akata strain EBV was not stably maintained in a BAC vector. By contrast, newly obtained BAC clones of the B95-8 strain of EBV stably maintained the full length FR during recombinant virus production and B-cell transformation. Investigation of primary DNA sequences of Akata–derived EBV-BAC clones indicates that the FR instability is most likely due to a putative secondary structure of the FR region. We conclude that the FR instability in EBV-BAC clones can be a pitfall in E. coli-mediated EBV genetics

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

京大開発の薬剤「KUS121」の変形性膝関節症への効果を確認 --外傷性変形性関節症の治療薬として臨床応用へ--. 京都大学プレスリリース. 2020-12-17.Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA

Roles of Protease-Activated Receptor-2 in Atherogenesis

Background: The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X (FXa), are expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. Methods: We generated apolipoprotein E-deficient (ApoE-/-) mice lacking systemic PAR-2 expression (PAR-2-/-ApoE-/-). ApoE-/- mice which lack or express PAR-2 only in bone-marrow (BM) cells were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a western-type diet (WTD) by histological analyses, quantitative RT-PCR, and western blotting. In vitro experiments using BM-derived macrophages were performed to confirm pro-inflammatory roles of PAR-2. The association between plasma FXa level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. Results: PAR-2-/-ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch (P<0.05) along with features of stabilized atherosclerotic plaques such as less lipid deposition (P<0.05), collagen loss (P<0.01), macrophage accumulation (P<0.05), and inflammatory molecule expression (P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/- mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that FXa or a specific peptide agonist of PAR-2 significantly increased expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of NF-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma FXa level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score (P<0.05) and plaque volume (P<0.01). Conclusions: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans

肥満によって遊離する脂肪細胞由来のDNA断片が脂肪組織の炎症とインスリン抵抗性を引き起こす

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance

Acceleration of small bowel motility after oral administration of dai-kenchu-to (TJ-100) assessed by cine magnetic resonance imaging.

Dai-kenchu-to (TJ-100) is an herbal medicine used to shorten the duration of intestinal transit by accelerating intestinal movement. However, intestinal movement in itself has not been evaluated in healthy volunteers using radiography, fluoroscopy, and radioisotopes because of exposure to ionizing radiation. The purpose of this study was to evaluate the effect of TJ-100 on intestinal motility using cinematic magnetic resonance imaging (cine MRI) with a steady-state free precession sequence. Ten healthy male volunteers received 5 g of either TJ-100 or lactose without disclosure of the identity of the substance. Each volunteer underwent two MRI examinations after taking the substances (TJ-100 and lactose) on separate days. They drank 1200 mL of tap water and underwent cine MRI after 10 min. A steady-state free precession sequence was used for imaging, which was performed thrice at 0, 10, 20, 30, 40, and 50 min. The bowel contraction frequency and distention score were assessed. Wilcoxon signed-rank test was used, and differences were considered significant at a P-value <0.05. The bowel contraction frequency tended to be greater in the TJ-100 group and was significantly different in the ileum at 20 (TJ-100, 8.95 ± 2.88; lactose, 4.80 ± 2.92; P < 0.05) and 50 min (TJ-100, 9.45 ± 4.49; lactose, 4.45 ± 2.65; P < 0.05) between the groups. No significant differences were observed in the bowel distention scores. Cine MRI demonstrated that TJ-100 activated intestinal motility without dependence on ileum distention

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow (BM) transplantation is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BM or peripheral blood stem cell (PBSC) transplantations from an HLA-matched sibling for leukemia were eligible. BM was used in 13% and 53% of Caucasian and Japanese patients, respectively. In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grades III–IV acute GVHD was significantly lower in Japanese than in Caucasian patients (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57–0.96), which resulted in lower risk of non-relapse mortality in Japanese patients (HR 0.69, 95% CI 0.54–0.89). The risk of relapse was also lower in this group. Lower risk of non-relapse mortality and relapse resulted in lower overall mortality rates among Japanese patients. In conclusion, irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, which results in lower risk of non-relapse mortality

A Prospective Multicenter Observational Study of Venous Thromboembolism after Gastric Cancer Surgery (SHISA-1601).

Introduction:This study aimed to clarify the frequency and risk factors of intercurrent venous thromboembolism (VTE) in patients undergoing major curative gastric cancer surgery.Methods:This prospective, multicenter, observational study included patients with gastric cancer who underwent radical gastrectomy at 5 hospitals between June 2016 and May 2018. Patients who were preoperatively administered anticoagulants were excluded.Results:A total of 126 patients were eligible to participate. VTE occurred within 9 days postoperatively in 5 cases (4.0%; 2 symptomatic and 3 asymptomatic). Postoperative day (POD) 1 plasma D-dimer and soluble fibrin (SF) levels were significantly higher in the VTE group than in the non-VTE group. Receiver-operating characteristic curve (ROC) analysis indicated a statistically significant ability of POD 1 D-dimer and SF levels to predict postoperative VTE development after gastrectomy; this finding was reflected by an area under the curve (AUC) of 0.97 (95% CI 0.92-1.0) and 0.87 (95% CI 0.74-1.0), respectively. Cutoff values of D-dimer (24.6 µg/mL) and SF (64.1 µg/mL) were determined. Intraoperative blood transfusion (odds ratio [OR] 7.86), POD 1 D-dimer ≥24.6 µg/mL (OR 17.35), and POD 1 SF ≥64.1 µg/mL (OR 19.5) were independent predictive factors for postoperative VTE (p < 0.05).Conclusion:VTE occurred in 4.0% patients (1.6% symptomatic and 2.4% asymptomatic) after gastric cancer surgery; however, with an early diagnosis and anticoagulant therapy, no patients experienced progression. Careful observation of patients with a high risk for VTE, including intraoperative blood transfusion and high POD 1 D-dimer or SF levels, would contribute to the early detection of VTE

ショクドウ ソウカン ニヨル フンゴウブ カンゼン リカイ オ カイケッチョウ サイケン デ シュウフクシタ ショクドウ セツジョ ノ 1レイ

症例は60 歳代, 男性. 身長162.6 cm, 体重40.0 kg, Body Mass Index（BMI）15.1 kg / m2であり, 既往歴に慢性閉塞性肺疾患（COPD）を認めた. 胸部上部食道癌 T1b N0 M0 Stage Iに対して食道亜全摘, 3領域リンパ節郭清, 胸骨後胃管再建を施行した.術当日に抜管したが, 術後肺炎に伴う呼吸不全のため, 術後6日目に気管内挿管を試みたが、食道挿管となった．再挿管, 人工呼吸管理の後に軽快し術後13日目に抜管となったが, 術後透視で吻合部周囲に造影剤漏出を認めた. 2ヶ月間の保存的加療で造影剤漏出は消失したが吻合部に長径4 cmの高度狭窄を認めた．内視鏡的拡張術での改善は困難であり, 術後243日目に消化管再建術を施行した. 手術所見として, 第2肋間より頭側の胸骨を切除したところ, 胃管の口側断端は第2肋間の高さの胸骨後面に位置していた.食道断端までは肉芽で置換されていた.胸骨前経路回結腸再建を施行し, 再建術後 8日目に食事を開始し, 合併症なく再建術後30日目に退院となった. 回結腸再建後2年経過後も食道癌の再発は認めず, 通過障害なく経口摂取のみでの生活が可能となっている．A 60s-year-old man underwent endoscopic screening during which a tumor was detected in the upper thoracic esophagus, which was diagnosed as T1bN0M0 Stage I esophageal squamous cell carcinoma. He had a history of chronic obstructive pulmonary disease. He underwent subtotal esophagectomy with 3 field lymph node dissection. Reconstruction was performed by gastric tube through the posterior sternal route. Extubation was performed on the day of surgery. Respiratory failure by postoperative pneumonia occurred, and ventilatory management was performed on the sixth postoperative day. However, the intubation was put into the esophagus. He became well and extubation was performed on the 13th postoperative day. Postoperative fluoroscopy showed contrast leakage around the anastomotic site. After 2 months of conservative treatment, the contrast leak disappeared, but there was a severe stenosis of 4 cm in length at the anastomosis. Endoscopic dilatation was not sufficient to improve the stenosis. Gastrointestinal reconstruction was performed on the 243rd postoperative day. The cephalic sternum was resected, and the gastrointestinal canal opening margin was located on the posterior surface of the sternum, at the level of the second intercostal space. The segment was replaced by a granulation. The patient underwent anterior sternal ileocolic reconstruction. Oral intake started on the 8th day after the reconstruction, and hospital discharge was on the 30 th day after the reconstruction without any complications. Two years after ileocolic reconstruction, there has been no cancer recurrence, and he lives well on oral intake only

トウイン ニオケル キョウクウ キョウカ ショクドウ セツジョ ノ ドウニュウ ト タンキ チリョウ セイセキ ノ ケントウ

【背景】食道癌に対する胸腔鏡手術は本邦で広く行われており、施設ごとに手術手技の定型化がなされている.胸腔鏡下手術の利点として拡大視効果や緻密な手術操作が可能となることが挙げられるが、当院でも2016年より腹臥位胸腔鏡下食道手術を導入し、出血の少ない安全かつ確実な郭清を目指し、定型化に向けてその手技を刷新している.【対象と方法】】2016年4月から2019年4月までに当院で施行した胸腔鏡下食道切除38例につき、その短期成績を検討した.【結果】男:女＝32:6、年齢中央値 66歳(41-76)、cStage I / II / III / IVa: 17 / 6 / 13 / 2であった.胸腔内出血量中央値は10ml(0-53)、胸部操作時間中央値は192分(97-478)、胸腔内郭清リンパ節個数中央値は17個(1-42)であった.術後合併症は、縫合不全3例(7.9％)、反回神経麻痺7例(18.4％)、肺炎12例(31.6％)であった.術後在院日数中央値は19日(11-38)であった.導入期からの前半19例では反回神経麻痺を6例(31.6％)に認めたが、後半19例では１例(5.2％)であった(p=0.036).【結語】当院における胸腔鏡下食道切除術は安全に導入、施行可能であった.手術手技が定型化されることで反回神経麻痺を少なくする郭清が可能になると考えられた.Background: Thoracoscopic esophagectomy (TE) is increasingly being used worldwide in patients with esophageal cancer. In this study, we investigated the clinical short-term outcomes of TE performed in patients placed in the prone position. Method: We investigated the surgical and clinical outcomes in 38 patients with esophageal cancer who underwent TE at our hospital between April 2016 and April 2019. Results: Of the 39 patients investigated, 32 were men. Median patient age was 66 (range 41–76) years, the median intraoperative blood loss was 10 (0–53) mL, and the median operation time for thoracoscopy was 192 (97–478) min. The mean operation time for thoracoscopy in the latter group was significantly shorter than that in the former group (188 min vs. 232 min, p=0.013). The following postoperative complications were observed: 7 (18.4%) cases of recurrent nerve palsy, 3 (7.9%) cases of anastomotic leakage, 12 (31.6%) cases of pneumonia, and 0 (0%) cases of chylothorax. The incidence of recurrent nerve palsy was lower in the latter group than in the former group (5.2% vs. 31.6%, p=0.036). Conclusions: TE in the prone position is safe and feasible. As experience performing the procedure increases, the performance of the procedure stabilizes