Efficacy and duration of analgesia from a sustained-release lidocaine sheet in humans

BACKGROUNDWe have synthesized a sustained-releaselidocaine sheet (SRLS) and injectable sustained-release lidocaine particles(SRLP) using biodegradable polymers. In the present study, we performed anexploratory first clinical trial of the SRLS in healthy volunteers as a preludeto patient administration. This trial is meant as an initial intervention inultimately developing and refining the SRLP. METHODSWe evaluated the intensity and duration ofanalgesia of the SRLS compared with 8% lidocaine spray. In Protocol 1, weapplied the SRLS piece to the mucous membrane of the nasal vestibule. Weexamined the local pain threshold over 72 h after administration, and removedthe SRLS after 72 h. Individuals that finished Protocol 1 underwent Protocol 2,in which we applied 8% lidocaine spray. RESULTSTwelve volunteers were enrolled and seven ofthese volunteers finished Protocol 1. All seven individuals who completedProtocol 1 also completed Protocol 2. The mean pain thresholds were 32 g, 78 g,90 g, 90 g, 87 g, and 87 g at pre-administration and 4 h, 10 h, 24 h, 48 h, and72 h after administration, respectively, in Protocol 1, and 36 g, 85 g, 49 g,and 33 g at pre-administration and 15 min, 2 h, and 4 h, respectively, inProtocol 2. CONCLUSIONA sustained-release lidocaine usingbiodegradable polymers was applied as a sheet in humans for the first time inthe world. It maintained significant analgesia for 72 h without majortoxicities. Furthermore, degree of analgesia provided by the SRLS throughoutthe entire study was similar to that provided by the 8% lidocaine spray. It may suitable for management ofpostoperative pain especially in outpatients

Association of the malate dehydrogenase‑citrate synthase metabolon is modulated by intermediates of the Krebs tricarboxylic acid cycle

Mitochondrial malate dehydrogenase (MDH)-citrate synthase (CS) multi-enzyme complex is a part of the Krebs tricarboxylic acid (TCA) cycle ‘metabolon’ which is enzyme machinery catalyzing sequential reactions without diffusion of reaction intermediates into a bulk matrix. This complex is assumed to be a dynamic structure involved in the regulation of the cycle by enhancing metabolic flux. Microscale Thermophoresis analysis of the porcine heart MDH-CS complex revealed that substrates of the MDH and CS reactions, NAD+ and acetyl-CoA, enhance complex association while products of the reactions, NADH and citrate, weaken the affinity of the complex. Oxaloacetate enhanced the interaction only when it was present together with acetyl-CoA. Structural modeling using published CS structures suggested that the binding of these substrates can stabilize the closed format of CS which favors the MDH-CS association. Two other TCA cycle intermediates, ATP, and low pH also enhanced the association of the complex. These results suggest that dynamic formation of the MDH-CS multienzyme complex is modulated by metabolic factors responding to respiratory metabolism, and it may function in the feedback regulation of the cycle and adjacent metabolic pathways

Notable underlying mechanism for pancreatic β-cell dysfunction and atherosclerosis: Pleiotropic roles of incretin and insulin signaling

Under healthy conditions, pancreatic β-cells produce and secrete the insulin hormone in response to blood glucose levels. Under diabetic conditions, however, β-cells are compelled to continuously secrete larger amounts of insulin to reduce blood glucose levels, and thereby, the β-cell function is debilitated in the long run. In the diabetic state, expression levels of insulin gene transcription factors and incretin receptors are downregulated, which we think is closely associated with β-cell failure. These data also suggest that it would be better to use incretin-based drugs at an early stage of diabetes when incretin receptor expression is preserved. Indeed, it was shown that incretin-based drugs exerted more protective effects on β-cells at an early stage. Furthermore, it was shown recently that endothelial cell dysfunction was also associated with pancreatic β-cell dysfunction. After ablation of insulin signaling in endothelial cells, the β-cell function and mass were substantially reduced, which was also accompanied by reduced expression of insulin gene transcription factors and incretin receptors in β-cells. On the other hand, it has been drawing much attention that incretin plays a protective role against the development of atherosclerosis. Many basic and clinical data have underscored the importance of incretin in arteries. Furthermore, it was shown recently that incretin receptor expression was downregulated in arteries under diabetic conditions, which likely diminishes the protective effects of incretin against atherosclerosis. Furthermore, a series of large-scale clinical trials (SPAED-A, SPIKE, LEADER, SUSTAIN-6, REWIND, PIONEER trials) have shown that various incretin-related drugs have beneficial effects against atherosclerosis and subsequent cardiovascular events. These data strengthen the hypothesis that incretin plays an important role in the arteries of humans, as well as rodents.Kaneto, H.; Obata, A.; Kimura, T.; Shimoda, M.; Sanada, J.; Fushimi, Y.; Katakami, N.; Matsuoka, T.; Kaku, K. Notable Underlying Mechanism for Pancreatic β-Cell Dysfunction and Atherosclerosis: Pleiotropic Roles of Incretin and Insulin Signaling. Int. J. Mol. Sci. 2020, 21, 9444

NBRP databases: databases of biological resources in Japan

The National BioResource Project (NBRP) is a Japanese project that aims to establish a system for collecting, preserving and providing bioresources for use as experimental materials for life science research. It is promoted by 27 core resource facilities, each concerned with a particular group of organisms, and by one information center. The NBRP database is a product of this project. Thirty databases and an integrated database-retrieval system (BioResource World: BRW) have been created and made available through the NBRP home page (http://www.nbrp.jp). The 30 independent databases have individual features which directly reflect the data maintained by each resource facility. The BRW is designed for users who need to search across several resources without moving from one database to another. BRW provides access to a collection of 4.5-million records on bioresources including wild species, inbred lines, mutants, genetically engineered lines, DNA clones and so on. BRW supports summary browsing, keyword searching, and searching by DNA sequences or gene ontology. The results of searches provide links to online requests for distribution of research materials. A circulation system allows users to submit details of papers published on research conducted using NBRP resources

Development of an extremely soft x-ray generator

The development of an extremely soft x-ray generator with a tungsten-target tube and its applications including radiography are described. This generator consists of a high-voltage transformer, a filament power supply, and an x-ray tube. Negative high voltages are applied to the cathode electrode in the x-ray tube, and the tube voltage and current are regulated by the input voltage of the transformer and the filament voltage, respectively. The x-ray tube is a glass-enclosed double-focus diode with a tungsten target and a 0.2 mm-thick beryllium window. The maximum tube voltage and the electric power were 60 kV and 400 W, respectively. The focal-spot sizes were 4×4 (large) and 1×1 mm (small), respectively. Radiography was performed with a computed radiography system. In angiography using iodine-based microspheres, we observed fine blood vessels of about 50 μm or less with high contrasts. Using this generator, we designed an experimental setup for disinfection achieved with extremely soft x rays

Quasi-monochromatic x-ray irradiation from weakly ionized linear nickel plasma

In the plasma flash x-ray generator, a high-voltage main condenser of approximately 200 nF is charged up to 50 kV by a power supply, and electric charges in the condenser are discharged to an x-ray tube after triggering the cathode electrode. Flash x rays are then produced. The x-ray tube is a demountable triode connected to a turbo molecular pump with a pressure of approximately 1 mPa. As electrons from the cathode electrode are roughly focused onto a rod nickel target of 3.0 mm in diameter by the electric field in the x-ray tube, a weakly ionized linear plasma consisting of nickel ions and electrons forms by target evaporation. At a charging voltage of 50 kV, the maximum tube voltage was almost equal to the charging voltage of the main condenser, and the peak current was about 17 kA. When the charging voltage was increased, the linear plasma formed, and the intensities of K-series characteristic x rays increased. The K-series lines were quite sharp and intense, and hardly any bremsstrahlung rays were detected. The x-ray pulse widths were approximately 700 ns, and the time-integrated x-ray intensity had a value of approximately 30 μC/kg at 1.0 m from the x-ray source at a charging voltage of 50 kV

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