Defect of Adaptation to Hypoxia in Patients With COPD Due to Reduction of Histone Deacetylase 7

BackgroundHypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7.MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO2, and 94% N2) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting.ResultsHIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells.ConclusionsHDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD

Early Diagnosis of Pancreatic Cancer Report of Five Cases of the Small Pancreatic Cancer

Eighty-nine cases of pancreatic cancers were experienced during the last 12 years. Among them, 5 cases (5.6%) were small pancreatic cancer (below 2cm in diameter); 3 cases were pancreas head cancer, 1 case body cancer and 1 case tail cancer. These cancers were all resectable. The patient of the small pancreatic cancers were survived comparatively long; the average period was 18 months. All of the 3 cases of pancreas head cancers were started with jaundice, 1 case of body cancer was started with elevation of urinary amylase output and 1 case of tail cancer was started with continuously high level of serum amylase value indolently. In this report, the 5 cases of small pancreatic cancers as well as the positive rate of laboratory data are first outlined. The clue for diagnosis and the details are stated herewith, and regarding a patient of body cancer (2.0X1.5 cm) who survived comparatively long for 36.3 months after surgery and also a patient of tail cancer (0.7X0.6 cm) who, 45 months after surgery, is still survived without relapse

Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia

AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone.MethodsThe study included 5 CPVT patients with a mutation in RYR2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone.ResultsBoth β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living.ConclusionFlecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities

Mechanistic insights into intramembrane proteolysis by E. coli site-2 protease homolog RseP

細胞膜の中ではたらく特殊なタンパク質分解酵素の構造を解明 --細菌感染症の新たな治療法の開発へ期待--. 京都大学プレスリリース. 2022-08-25.Site-2 proteases are a conserved family of intramembrane proteases that cleave transmembrane substrates to regulate signal transduction and maintain proteostasis. Here, we elucidated crystal structures of inhibitor-bound forms of bacterial site-2 proteases including Escherichia coli RseP. Structure-based chemical modification and cross-linking experiments indicated that the RseP domains surrounding the active center undergo conformational changes to expose the substrate-binding site, suggesting that RseP has a gating mechanism to regulate substrate entry. Furthermore, mutational analysis suggests that a conserved electrostatic linkage between the transmembrane and peripheral membrane-associated domains mediates the conformational changes. In vivo cleavage assays also support that the substrate transmembrane helix is unwound by strand addition to the intramembrane β sheet of RseP and is clamped by a conserved asparagine residue at the active center for efficient cleavage. This mechanism underlying the substrate binding, i.e., unwinding and clamping, appears common across distinct families of intramembrane proteases that cleave transmembrane segments

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

Algorithmic Versus Expert Human Interpretation of Instantaneous Wave-Free Ratio Coronary Pressure-Wire Pull Back Data

Objectives The aim of this study was to investigate whether algorithmic interpretation (AI) of instantaneous wave-free ratio (iFR) pressure-wire pull back data would be noninferior to expert human interpretation. Background Interpretation of iFR pressure-wire pull back data can be complex and is subjective. Methods Fifteen human experts interpreted 1,008 iFR pull back traces (691 unique, 317 duplicate). For each trace, experts determined the hemodynamic appropriateness for percutaneous coronary intervention (PCI) and, in such cases, the optimal physiological strategy for PCI. The heart team (HT) interpretation was determined by consensus of the individual expert opinions. The same 1,008 pull back traces were also interpreted algorithmically. The coprimary hypotheses of this study were that AI would be noninferior to the interpretation of the median expert human in determining: 1) the hemodynamic appropriateness for PCI; and 2) the physiological strategy for PCI. Results Regarding the hemodynamic appropriateness for PCI, the median expert human demonstrated 89.3% agreement with the HT in comparison with 89.4% for AI (p < 0.01 for noninferiority). Across the 372 cases judged as hemodynamically appropriate for PCI according to the HT, the median expert human demonstrated 88.8% agreement with the HT in comparison with 89.7% for AI (p < 0.0001 for noninferiority). On reproducibility testing, the HT opinion itself changed 1 in 10 times for both the appropriateness for PCI and the physiological PCI strategy. In contrast, AI showed no change. Conclusions AI of iFR pressure-wire pull back data was noninferior to expert human interpretation in determining both the hemodynamic appropriateness for PCI and the optimal physiological strategy for PCI

Productivity and Cost of Retention Harvesting Operation in Conifer Plantations

Retention forestry is a harvesting system that intentionally retains important forest structures at harvest time. We examined the effect of dispersed retention on the productivity and cost of harvesting operations in a large-scale field experiment in conifer plantations in Hokkaido, Japan. For dispersed retention, we retained broad-leaved trees in three levels (10, 50, or 100 trees/ha). We used daily operator reports and investigated time consumption (h/m3) of felling and pre-hauling operations and the total cost to roadside. Compared with clearcutting, mean felling time was 7% and 17% longer, and mean pre-hauling time was 20% and 19% longer in 50 and 100 retained trees/ha, respectively. The other operations were not affected by tree retention because they were conducted at pre-existed strip roads or landings where no trees were retained. Increased time consumption caused an increased cost of felling and pre-hauling. Compared with clearcutting, the combined cost of felling and pre-hauling was 14% and 18% higher in 50 and 100 retained trees/ha, respectively. However, the total cost to roadside increased only by 3% compared with clearcutting because these two operations in total occupied 19% of the overall cost, and the cost of the other operations was not affected by tree retention. This suggests that the impact of tree retention on the total cost was small and that the harvesting system used in the present study can reduce cost increment due to tree retention unless trees are not retained on strip roads