Phosphoramidon inhibits the generation of endothelin-1 from exogenously applied big endothelin-1 in cultured vascular endothelial cells and smooth muscle cells

AbstractWhen cultured porcine aortic endothelial cells (ECs) were incubated with porcine big endothelin-1 (bit ET-I1–39), there was a time-dependent increase in immunoreactive (IR)-ET in the culture supernatant, in addition to an endogenous IR-ET release fron the cells. Reverse-phase HPLC of the culture supernatant revealed one major IR-ET component corresponding to the elution position of synthetic ET-1, thereby indicating that the additional increase in IR-ET was due to the conversion of big ET-1 to mature ET-11–21. Phosphoramidon, a metalloproteinase inhibitor, strongly suppressed this increase in IR-ET as well as the endogenous IR-ET release. Cultured vascular smooth muscle cells (VSMCs) also released IR-ET. The apparent conversion of exogenously applied big ET-1 to ET-1 and its inhibition by phosphoramidon were observed using cultured VSMCs, although the enzyme inhibitor did not influence the basal secretion of IR-ET from VSMCs. These results suggest that both cultured ECs and VSMCs can generate ET-1 from exogenously applied big ET-1 via action of the same type of phosphoramidon-sensitive metalloproteinase, which is also involved in the endogenous ET-1 generation in ECs

第4-5腰椎変性疾患に対する椎間cageのみでの低侵襲前方固定術(mini-ALIF)の臨床成績と放射線学的検討

Surgical treatment for degenerative spinal disorders is controversial, although lumbar fusion is considered an acceptable option for disabling lower back pain. Patients underwent instrumented minimally invasive anterior lumbar interbody fusion (mini-ALIF) using a retroperitoneal approach except for requiring multilevel fusions, severe spinal canal stenosis, high-grade spondylolisthesis, and a adjacent segments disorders. We retrospectively reviewed the clinical records and radiographs of 142 patients who received mini-ALIF for L4-5 degenerative lumbar disorders between 1998 and 2010. We compared preoperative and postoperative clinical data and radiographic measurements, including the modified Japanese Orthopaedic Association (JOA) score, visual analog scale (VAS) score for back and leg pain, disc height (DH), whole lumbar lordosis (WL), and vertebral wedge angle (WA). The mean follow-up period was 76 months. The solid fusion rate was 90.1% (128/142 patients). The average length of hospital stay was 6.9 days (range, 3-21 days). The mean blood loss was 63.7 ml (range, 10-456 ml). The mean operation time was 155.5 min (range, 96-280 min). The postoperative JOA and VAS scores for back and leg pain were improved compared with the preoperative scores. Radiological analysis showed significant postoperative improvements in DH, WL, and WA, and the functional and radiographical outcomes improved significantly after 2 years. The 2.8% complication rate included cases of wound infection, liquorrhea, vertebral body fractures, and a misplaced cage that required revision. Mini-ALIF was found to be associated with improved clinical results and radiographic findings for L4-5 disorders. A retroperitoneal approach might therefore be a valuable treatment option.博士（医学）・乙第1338号・平成26年5月28日Copyright © 日本脳神経外科学会 | The Japan Neurosurgical Society / 学会誌名（Neurologia medico-chirurgica）とJ-STAGEからの出典であ

Use of iGlarLixi for Management of Type 2 Diabetes in Japanese Clinical Practice : SPARTA Japan, a Retrospective Observational Study

Introduction: Many individuals with type 2 diabetes (T2D) experience suboptimal glycemic control. Treatment intensification options include fixed-ratio combination products containing a basal insulin and a glucagon-like peptide-1 receptor agonist, such as iGlarLixi (insulin glargine 100 U/mL and lixisenatide). This study aimed to provide real-world evidence of the effect of iGlarLixi in Japanese clinical practice. Methods: SPARTA Japan was a non-comparative, observational study conducted at 27 institutions in Japan. Anonymized individual-level data from adults with T2D receiving iGlarLixi in routine clinical practice were retrospectively collected. The primary study objective was to assess the impact of iGlarLixi on the change in glycated hemoglobin (HbA1c) at 6 months’ post-treatment initiation, with preplanned subanalyses to determine the influence of baseline characteristics. Secondary and exploratory endpoints included assessment of the proportion of individuals achieving HbA1c targets, change in body weight, and incidence and severity of hypoglycemia and gastrointestinal events. Results: The full analysis set included 432 individuals, with data available at 6 months for 426. Of the 432 individuals, the mean (SD) age at baseline was 61.6 (12.8) years and the majority had a T2D duration of ≥ 10 years [mean (SD) 13.3 (10.4) years]. At 6 months, HbA1c had significantly decreased versus baseline ( –0.85%; P < 0.0001), with a greater decrease in those aged < 65 years, with a shorter duration of T2D and higher baseline HbA1c. A significant increase in the proportion of participants achieving age-specific HbA1c versus baseline was observed. Mean body weight decreased by 0.5 kg (P = 0.0034 versus baseline). There were few hypoglycemia and gastrointestinal events (in individuals with HbA1c data); no severe hypoglycemic events were reported. Conclusions: The results of this real-world study indicate that iGlarLixi may improve glycemic control without serious adverse events in Japanese individuals with T2D who have suboptimal glycemic control on current treatment regimens and switch to iGlarLixi

Use of iGlarLixi for the Management of Type 2 Diabetes in Japanese Clinical Practice : Prior Treatment Subgroup Analysis of the SPARTA Japan Study

Introduction: iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, is one option for treatment intensification in individuals with type 2 diabetes (T2D) who are unable to achieve targeted glycaemic control with their current glucose-lowering agent. Real-world data on the impact of prior treatment on the effectiveness and safety of iGlarLixi may be useful to guide individualised treatment decisions. Methods: This analysis of the 6-month, retrospective, observational SPARTA Japan study compared glycated haemoglobin (HbA1c), body weight and safety for pre-specified subgroups defined by prior treatment: post oral antidiabetic agent (OAD), GLP-1 RA, basal insulin (BI) + OADs (BOT), GLP-1 RA + BI or multiple daily injections (MDI). The post BOT and MDI subgroups were further divided on the basis of prior dipeptidyl peptidase 4 inhibitor (DPP-4i) use, and the post MDI group was divided on the basis of whether participants continued bolus insulin. Results: Of the 432 participants in the full analysis set (FAS), 337 were included in this subgroup analysis. Across subgroups, mean baseline HbA1c ranged from 8.49% to 9.18%. iGlarLixi significantly (p < 0.05) reduced mean HbA1c from baseline in all but the post GLP-1 RA + BI group. At 6 months, these significant reductions ranged from 0.47% to 1.27%. Prior DPP-4i exposure had no impact on the HbA1c-lowering effect of iGlarLixi. Mean body weight decreased significantly in the FAS (0.5 kg) and the post BOT (1.2 kg) and MDI (1.5 and 1.9 kg) subgroups but increased in the post GLP-1 RA subgroup (1.3 kg). iGlarLixi treatment was generally well tolerated, with very few participants discontinuing because of hypoglycaemia or gastrointestinal events. Conclusion: In participants with suboptimal glycaemic control on various regimens, 6 months of iGlarLixi treatment improved HbA1c in all but one prior treatment subgroup (GLP-1 RA + BI), and was generally well tolerated

Lewis Acid and Fluoroalcohol Mediated Nucleophilic Addition to the C2 Position of Indoles

Indole readily undergoes nucleophilic substitution at the C3 site, and many indole derivatives have been functionalized using this property. Indole also forms indolium, which allows electrophilic addition in acidic conditions, but current examples have been limited to intramolecular reactions. C2 site-selective nucleophilic addition to indole derivatives using fluoroalcohol and a Lewis acid was developed

Is central repair with coronary artery bypass grafting enough for multi-organ malperfusion in acute type A aortic dissection with coronary malperfusion?

Objectives: Acute type A aortic dissection with coronary malperfusion syndrome is rare but associated with high mortality. Multi-organ malperfusion is an independent predictor of acute type A aortic dissection. Coronary malperfusion requires treatment, but it is not feasible to treat all malperfusions. The adequacy of "central repair and coronary artery bypass grafting" for patients with coronary and other organ malperfusion is unknown. Methods: Of the 299 patients who underwent surgery between 2008 and 2018, 21 patients with coronary malperfusion, who received cental repair with coronary artery graft bypass, were analyzed retrospectively. They were divided; into Group M (n = 13, coronary and other organ malperfusion) and Group O (n = 8, coronary malperfusion only). The patient background, surgical content, details of malperfusion, surgical mortality and morbidity, and long-term outcome were compared. Results: There was no difference in operation time (205 ± 30 vs. 266 ± 88, p = 0.49), but the time from arrival to circulatory arrest tended to be shorter in Group M (81 vs. 134, p = 0.05). Among Group M, cerebral malperfusion was the most common at 92%. Two of the three cases with mesenteric malperfusion died. The mortality of Group M and Group O was 13% and 15% (P = 0.85), respectively. There was no difference in long-term mortality (p = 0.62). Conclusions: Central repair and coronary artery bypass grafting is a sufficiently acceptable treatment for patients with acute type A aortic dissection and multi-organ malperfusion, including coronary malperfusion.journal articl

Significant association between high serum CCL5 levels and better disease‐free survival of patients with early breast cancer

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C-C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead-based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease-free survival (DFS) of patients with high CCL5 levels (cut-off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10- 0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis