Best anticoagulation strategy with and without appendage occlusion for stroke-prophylaxis in postablation atrial fibrillation patients with cardiac amyloidosis.

INTRODUCTION: Both atrial fibrillation (AF) and amyloidosis increase stroke risk. We evaluated the best anticoagulation strategy in AF patients with coexistent amyloidosis. METHODS: Consecutive AF patients with concomitant amyloidosis were divided into two groups based on the postablation stroke-prophylaxis approach; group 1: left atrial appendage occlusion (LAAO) in eligible patients and group 2: oral anticoagulation (OAC). Group 1 patients were further divided into Gr. 1A: LAAO + half-does NOAC (HD-NOAC) for 6 months followed by aspirin 81 mg/day and Gr. 1B: LAAO + HD-NOAC. In group 1 patients, with complete occlusion at the 45-day transesophageal echocardiogram, patients were switched to aspirin, 81 mg/day at 6 months. In case of leak, or dense "smoke" in the left atrium (LA) or enlarged LA, they were placed on long-term half-dose (HD) NOAC. Group 2 patients remained on full-dose NOAC during the whole study period. RESULTS: A total of 92 patients were included in the analysis; group 1: 56 and group 2: 36. After the 45-day TEE, 31 patients from group 1 remained on baby-aspirin and 25 on HD NOAC. At 1-year follow-up, four stroke, one TIA and six device-thrombus were reported in group 1A, compared to none in patients in group 1B (5/31 vs. 0/25, p = .03). No bleeding events were reported in group 1, whereas group 2 had five bleeding events (one subdural hematoma, one retinal hemorrhage, and four GI bleedings). Additionally, one stroke was reported in group 2 that happened during brief discontinuation of OAC. CONCLUSION: In patients with coexistent AF and amyloidosis, half-dose NOAC following LAAO was observed to be the safest stroke-prophylaxis strategy.

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations.

The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer's disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor ß (TGF-ß), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis.

Dynamic changes in physiologic oxygen are required for proper placenta development; yet, when low-oxygen levels persist, placental development is halted, culminating in preeclampsia (PE), a serious complication of pregnancy. Considering mitochondria's function is intimately linked to oxygen changes, we investigated the impact of oxygen on mitochondrial dynamics in placental mesenchymal stromal cells (pMSCs) that are vital for proper placental development. Transmission electron microscopy, proximity ligation assays for mitochondrial VDAC1 and endoplasmic reticulum IP3R, and immunoanalyses of p-DRP1 and OPA1, demonstrate that low-oxygen conditions in early 1st trimester and PE promote mitochondrial fission in pMSCs. Increased mitochondrial fission of mesenchymal cells was confirmed in whole PE placental tissue sections. Inhibition of DRP1 oligomerization with MDiVi-1 shows that low oxygen-induced mitochondrial fission is a direct consequence of DRP1 activation, likely via HIF1. Mitophagy, a downstream event prompted by mitochondrial fission, is a prominent outcome in PE, but not 1st trimester pMSCs. We also investigated whether mesenchymal-epithelial interactions affect mitochondrial dynamics of trophoblasts in PE placentae. Exposure of trophoblastic JEG3 cells to exosomes of preeclamptic pMSCs caused heightened mitochondrial fission in the cells via a sphingomyelin-dependent mechanism that was restored by MDiVi-1. Our data uncovered dichotomous regulation of mitochondrial fission and health in human placental mesenchymal cells under physiologic and pathologic hypoxic conditions and its impact on neighboring trophoblast cells.

Assessing the knee flexion range of motion after total knee arthroplasty: Technology versus senses.

INTRODUCTION: Following total knee arthroplasty surgery, attention should be paid to post-operative knee range of motion to achieve daily activities. Goniometer assessment is widely used to assess the range of motion in the post-operative period. This study aimed to determine the inter-rater ability of a smartphone application and visual estimation of the knee joint after total knee arthroplasty among different professions that commonly work together and compare whether any method is superior to another. METHOD: Range of motion measurements was performed by four clinicians as two physiotherapists and two orthopedic fellows. They utilized the Goniometer Reports application for smartphones, universal goniometer, and visual estimation to measure angles of knees which was operated. A two-way mixed model of intra-class correlation coefficient (ICC) with a 95% confidence level was used to assess inter-rater reliability. RESULTS: Thirteen patients (11 female) and 20 knees (10 right) were assessed. The ICCs were found excellent both for between methods and between raters. CONCLUSION: Our results show that technology seems a more accurate way to determine the knee range of motion after knee arthroplasty compared to senses. However, in lack of technological resources or time, or to avoid possible infection, visual estimation also could provide useful information.

MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Combination of photocatalytic and membrane distillation hybrid processes for reactive dyes treatment.

In this study, the degradation of azo dye solutions (Reactive Red 180 and Reactive Orange 16) of textile industry wastewater was investigated for using innovative hybrid process of photocatalytic and membrane distillation (MD) processes. Photocatalytic oxidation was conducted with semiconductor catalysts (ZnO and TiO2) and their mixture under UVA and UVC irradiation. More effective results were obtained under UVA at the initial stages of the reactions for both dye solutions. ZnO and TiO2 catalysts have given similar efficient results, but results with ZnO were better at initial stages. For the next stage, hybrid design of MD and photocatalytic processes was performed sequentially. Initially, the photocatalytic process was conducted for at least 1 h at initial values of 100 mg/L RR-180 dye solutions and 1 g/L ZnO catalyst loading under UVA irradiation and then treated solution was run through the distillation module at different temperatures (30°C and 40°C) and flow rates (210, 425, and 665 mL/min). Three types of membranes (polypropylene, polytetrafluoroethylene, and polyvinylidene fluoride) with different pore sizes (0.45 and 0.22 µm) were used in the module. Increasing temperature on the side of treated solution and decreasing the temperature on the other side has increased the distillate efficiency.