Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

<p>Abstract</p> <p>Background</p> <p>Peripheral-type benzodiazepine receptor (PBR) expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL)-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB), p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-<it>Jun </it>N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT)3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect.</p> <p>Methods</p> <p>Cultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting.</p> <p>Results</p> <p>Midazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase), SP600125 (an inhibitor of SAPK/JNK), and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3). However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2). Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB.</p> <p>Conclusion</p> <p>These results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS.</p

Predictive scoring model of mortality after surgical or endovascular revascularization in patients with critical limb ischemia

ObjectiveThe latest guideline points to life expectancy of <2 years as the main determinant in revascularization modality selection (bypass surgery [BSX] or endovascular therapy [EVT]) in patients with critical limb ischemia (CLI). This study examined predictors and a predictive scoring model of 2-year mortality after revascularization.MethodsWe performed Cox proportional hazards regression analysis of data in a retrospective database, the Bypass and Endovascular therapy Against Critical limb ischemia from Hyogo (BEACH) registry, of 459 consecutive CLI patients who underwent revascularization (396 EVT and 63 BSX cases between January 2007 and December 2011) to determine predictors of 2-year mortality. The predictive performance of the score was assessed with the area under the time-dependent receiver operating characteristic curve.ResultsOf 459 CLI patients (mean age, 72 ± 10 years; 64% male; 49% nonambulatory status, 68% diabetes mellitus, 47% on regular dialysis, and 18% rest pain and 82% tissue loss as treatment indication), 84 died within 2 years after revascularization. In a multivariate model, age >75 years (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.85), nonambulatory status (HR, 5.32; 95% CI, 2.96-9.56), regular dialysis (HR, 1.90; 95% CI, 1.10-3.26), and ejection fraction <50% (HR, 2.49; 95% CI, 1.48-4.20) were independent predictors of 2-year mortality. The area under the time-dependent receiver operating characteristic curve for the developed predictive BEACH score was 0.81 (95% CI, 0.76-0.86).ConclusionsPredictors of 2-year mortality after EVT or BSX in CLI patients included age >75 years, nonambulatory status, regular dialysis, and ejection fraction <50%. The BEACH score derived from these predictors allows risk stratification of CLI patients undergoing revascularization

Clinical Management of Implant Prostheses in Patients with Bruxism

There is general agreement that excessive stress to the bone-implant interface may result in implant overload and failure. Early failure of the implant due to excessive loading occurs shortly after uncovering the implant. Excess load on a final restoration after successful implant integration can result in physical failure of the implant structure. Many clinicians believe that overload of dental implants is a risk factor for vertical peri-implant bone loss and/or may be detrimental for the suprastructure in implant prostheses. It has been documented that occlusal parafunction, such as, bruxism (tooth grinding and clenching) affects the outcome of implant prostheses, but there is no evidence for a causal relation between the failures and overload of dental implants. In spite of this lack of evidence, often metal restorations are preferred instead of porcelain for patients in whom bruxism is presumed on the basis of tooth wear. The purpose of this paper is to discuss the importance of the occlusal scheme used in implant restorations for implant longevity and to suggest a clinical approach and occlusal materials for implant prostheses in order to prevent complications related to bruxism

Integrated-gut-liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease

非アルコール性脂肪性肝疾患を再現した腸・肝連結臓器チップの開発. 京都大学プレスリリース. 2023-04-07.Two-organ chip to answer fatty liver questions. 京都大学プレスリリース. 2023-04-07.Non-alcoholic fatty liver disease (NAFLD) afflicts a significant percentage of the population; however, no effective treatments have yet been established because of the unsuitability of in vitro assays and animal experimental models. Here, we present an integrated-gut-liver-on-a-chip (iGLC) platform as an in vitro human model of the gut-liver axis (GLA) by co-culturing human gut and liver cell lines interconnected via microfluidics in a closed circulation loop, for the initiation and progression of NAFLD by treatment with free fatty acids (FFAs) for 1 and 7 days, respectively. Co-cultured Caco-2 gut-mimicking cells and HepG2 hepatocyte-like cells demonstrate the protective effects from apoptosis against FFAs treatment, whereas mono-cultured cells exhibit induced apoptosis. Phenotype and gene expression analyses reveal that the FFAs-treated gut and liver cells accumulated intracellular lipid droplets and show an increase in gene expression associated with a cellular response to copper ions and endoplasmic reticulum stress. As an in vitro human GLA model, the iGLC platform may serve as an alternative to animal experiments for investigating the mechanisms of NAFLD

Vessel Patency and Associated Factors of Drug-Coated Balloon for Femoropopliteal Lesion

Background Although clinical trials have reported favorable outcomes after drug-coated balloon (DCB) therapy for femoropopliteal lesions, their real-world performance and predictors have not been well evaluated. This study aimed to elucidate 1-year freedom from restenosis and to explore the associated factors after a DCB for femoropopliteal lesions in clinical settings. Methods and Results This multicenter, prospective cohort registered 3165 de novo or restenotic femoropopliteallesions (mean lesion length, 13.5±9.3 cm; chronic total occlusion, 25.9%; severe calcification, 14.6%) that underwent successful DCB (Lutonix [24.2%] and IN.PACT Admiral [75.8%]) treatment between March 2018 and December 2019. Patency was assessed at 12±2 months. The primary outcome measure was 1-year freedom from restenosis and its associated factors. Bailout stenting was performed in 3.5% of patients. The postprocedural slow flow phenomenon was observed in 3.9% of patients. During a median follow-up of 14.2 months, 811 patients experienced restenosis. The Kaplan-Meier estimate of freedom from restenosis was 84.5% at 12 months (79.7% at 14 months). Focal, tandem, diffuse, and occlusive restenosis accounted for 37.4%, 9.8%, 18.9%, and 33.9%, respectively. Freedom from target lesion revascularization was 91.5% at 12 months. Risk factors independently associated with 1-year restenosis were a history of revascularization, smaller distal reference vessel diameter, severe calcification, chronic total occlusion, low-dose DCB, and residual stenosis. Conclusions The 1-year clinical outcomes after DCB use for femoropopliteal lesions in real-world practice was favorable. The additive risk factors were associated with a lower rate of freedom from restenosis