Endothelin-1 impairs skeletal muscle myogenesis and development via ETB receptors and p38 MAPK signaling pathway.

Myopenia is a condition marked by progressive decline of muscle mass and strength and is associated with aging or obesity. It poses the risk of falling, with potential bone fractures, thereby also increasing the burden on family and society. Skeletal muscle wasting is characterized by a reduced number of myoblasts, impaired muscle regeneration and increased muscle atrophy markers (Atrogin-1, MuRF-1). Endotheline-1 (ET-1) is a potent vasoconstrictor peptide. Increased circulating levels of ET-1 is noted with aging and is associated with muscular fibrosis and decline of strength. However, the regulatory mechanism controlling its effect on myogenesis and atrophy remains unknown. In the present study, the effects of ET-1 on myoblast proliferation, differentiation and development were investigated in C2C12 cells and in ET-1-infused mice. The results show that ET-1, acting via ETB receptors, reduced insulin-stimulated cell proliferation, and also reduced MyoD, MyoG and MyHC expression in the differentiation processes of C2C12 myoblasts. ET-1 inhibited myoblast differentiation through ETB receptors and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Additionally, ET-1 decreased MyHC expression in differentiated myotubes. Inhibition of proteasome activity by MG132 ameliorated the ET-1-stimulated protein degradation in differentiated C2C12 myotubes. Furthermore, chronic ET-1 infusion caused skeletal muscle atrophy and impaired exercise performance in mice. In conclusion, ET-1 inhibits insulin-induced cell proliferation, impairs myogenesis and induces muscle atrophy via ETB receptors and the p38 MAPK-dependent pathway.

NT-proBNP point-of-care testing for predicting mortality in end-stage renal disease: A survival analysis.

This study examines the predictive value of elevated N-terminal-pro brain natriuretic peptide (NT-pro BNP) levels for mortality among patients with end-stage renal disease (ESRD). Data from 768 ESRD patients, excluding those with cancer or lost follow-up, were analyzed using Kaplan-Meier curves and Cox proportional hazards models over three years. Results indicated that patients with very high NT-pro BNP levels had shorter average survival times and a significantly higher risk of mortality (hazard ratio 1.43). Advanced age, ICU admission, and comorbidities like cerebrovascular diseases and chronic obstructive pulmonary disease also contributed to increased mortality risks. Thus, elevated NT-pro BNP is an independent risk factor for mortality in ESRD patients.

High-performance monolayer MoS2nanosheet GAA transistor.

In this article, a 0.7 nm thick monolayer MoS2nanosheet gate-all-around field effect transistors (NS-GAAFETs) with conformal high-κmetal gate deposition are demonstrated. The device with 40 nm channel length exhibits a high on-state current density of ~410µAµm-1with a large on/off ratio of 6 × 108at drain voltage = 1 V. The extracted contact resistance is 0.48 ± 0.1 kΩµm in monolayer MoS2NS-GAAFETs, thereby showing the channel-dominated performance with the channel length scaling from 80 to 40 nm. The successful demonstration of device performance in this work verifies the integration potential of transition metal dichalcogenides for future logic transistor applications.

Quantitative two-dimensional phase-contrast magnetic resonance imaging characterization of lower extremity venous disease: venous reflux versus venous obstruction.

Background: Lower extremity venous disease (LEVD) is a complex disorder, and determining the etiology of LEVD is paramount for treatment selection. Two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) can provide an objective measure of hemodynamic status and may help differentiate between different etiologies of LEVD. A total of 271 participants, including 256 symptomatic patients with venous lower extremity disease and 15 healthy volunteers, were collected in this cohort study. Methods: It is a single-center prospective observational study using 2D PC-MRI analysis to assess the hemodynamic characteristics of patients with LEVD among participants recruited between April 2017 and October 2021 at a tertiary hospital. The approval institutional review board number for this study were 201802137B0, 201901058B0, 202100938B0, and 202102344B0. Participants were classified as venous reflux (VR) and venous obstruction (VO) by standard ultrasonography. 2D PC-MRI by 1.5 T scanner revealed stroke volume (SV), forward flow volume (FFV), absolute stroke volume (ASV), mean flux (MF), velocity time integral (VTI), and mean velocity (MV) for each selected venous segments. Results: 2D PC-MRI assessed 167 diseased legs from the 116 VR patients [mean age ± standard deviation (SD): 57.9±12.8 years; 39 males] and 113 diseased legs from the 95 VO patients (mean age ± SD: 66.4±12.8 years; 42 males). 2D PC-MRI analysis demonstrated discrimination ability to differentiate from VR to VO [SV, FFV, ASV, MF, VTI, and MV in the various venous segments, respectively, P≤0.001; area under the curve (AUC) =62-68.8%, P≤0.001 by Mann-Whitney U test]. The ratio data (morbid limb to normal limb) in the same individual with single-leg disease revealed differences between VR and VO (SV, FFV, ASV, and MF in the various venous segments, respectively; P<0.05; AUC =60.2-68.7%, P≤0.05 by Mann-Whitney U test). The most favorable differentiating variables of ratios were FFV in the great saphenous veins [AUC =68.7%, 95% confidence interval (CI): 59.8-77.6%] and ASV in the external iliac veins (AUC =67.4%, 95% CI: 58.7-76.2%). Conclusions: Quantitative 2D PC-MRI analysis is capable of differentiating VR from VO. It also provides an important diagnostic capability for preoperative evaluation.

Neutrophil-Lymphocyte Ratio as a Predictor of Cerebral Small Vessel Disease in a Geriatric Community: The I-Lan Longitudinal Aging Study.

Cerebral Small Vessel Disease (CSVD) frequently affects the elderly, with inflammation playing a crucial role in related health complications, including dementia, stroke, and SVD. Studies, including animal experiments, indicate a strong link between inflammation and SVD progression. The Neutrophil-Lymphocyte Ratio (NLR) serves as a possible biomarker for ongoing inflammatory risks. A total of 720 adults aged 50 years or older from the community-based I-Lan Longitudinal Aging Study were included in this study. General linear regression and ordinally logistic regression analyses were performed to evaluate the association between NLR and CSVD. We further examined the presence of lacune, microbleed, and white matter hyperintensity (WMH) on brain MRI, which were used to construct a combined CSVD score. The NLR was positively associated with WMH (adjusted r = 0.109, p = 0.003), microbleed (adjusted r = 0.102, p = 0.006), and lacune (adjusted r = 0.100, p = 0.008). After adjustments for smoking, drinking, and physical activity in the ordinal logistic regression analysis, age, gender, brachial Systolic Blood Pressure (SBP), fasting glucose, LDL-cholesterol, and Hs-CRP were compared among subjects with low tertile (T1), medium tertile (T2) and high tertile (T3) NLR. The results showed that T2 vs. T1 had an odds ratio of 1.23 (0.86-1.77); and T3 vs. T1 had an odds ratio of 1.87 (1.29-2.71) of CSVD scores in four groups (zero (reference group), one, two, and three or more). NLR could be used to assess the state of inflammation in cerebral vessels. A significant and positive correlation between NLR and CSVD was verified in this study. However, the practical clinical application of NLR in CSVD patients and prognosis prediction should be validated through more scientific attempts.

Cysteine-cysteine Chemokine Receptor Type 5 Plays a Critical Role in Exercise Performance by Regulating Mitochondrial Content in Skeletal Muscle.

Cysteine-cysteine chemokine receptor type 5 (CCR5) is thought to play an important role in the trafficking of lymphoid cells but has recently also been associated with AMPK signaling pathways that are implicated in energy metabolism in skeletal muscle. We hypothesized that genetic deletions of CCR5 would alter mitochondria content and exercise performance in mice. CCR5-/- and wild-type mice with the same genetic background were subjected to endurance exercise and grip strength tests. The soleus muscle was stained with immunofluorescence for myosin heavy chain 7 (MYH7) and succinate dehydrogenase (SDH) analysis as well as the expression of genes associated with muscle atrophy and mitochondrial oxidative phosphorylation were measured using qPCR. Although there were no differences in the weight of the soleus muscle between the CCR5-/- group and the wild-type mice, the CCR5-/- mice showed the following muscular dysfunctions: (i) decreased MYH7 percentage and cross-section area, (ii) higher myostatin and atrogin-1 mRNA levels, (iii) dropped expression of mitochondrial DNA-encoded electron respiratory chain genes (cytochrome B, cytochrome c oxidase subunit III, and ATP synthase subunit 6) as well as mitochondrial generation genes (PPARγ and PGC-1α), and (iv) lower SDH activity and exercise performance when compared with wild-type mice. In addition, genes associated with mitochondrial biogenesis (PGC-1α, PPARγ, and MFN2) and mitochondrial complex (ND4 and Cytb) were upregulated when the skeletal muscle cell line C2C12 was exposed to cysteine-cysteine chemokine ligand 4 (a ligand of CCR5) in vitro. These findings suggested that attenuation of endurance exercise performance is related to the loss of mitochondrial content and lower SDH activity of soleus muscle in CCR5 knockout mice. The present study provides evidence indicating that the chemokine receptor CCR5 might modulate the skeletal muscle metabolic energy system during exercise.

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration. Methods: Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients (N = 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150 × 109/l, lactate dehydrogenase ≥1.5 × upper limit of normal, hemoglobin ≤ lower limit of normal, serum creatinine ≥ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. Conclusion: APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.

Detecting microstructural alterations of cerebral white matter associated with breast cancer and chemotherapy revealed by generalized q-sampling MRI.

Objective: Previous studies have discussed the impact of chemotherapy on the brain microstructure. There is no evidence of the impact regarding cancer-related psychiatric comorbidity on cancer survivors. We aimed to evaluate the impact of both chemotherapy and mental health problem on brain microstructural alterations and consequent cognitive dysfunction in breast cancer survivors. Methods: In this cross-sectional study conducted in a tertiary center, data from 125 female breast cancer survivors who had not received chemotherapy (BB = 65; 49.86 ± 8.23 years) and had received chemotherapy (BA = 60; 49.82 ± 7.89 years) as well as from 71 age-matched healthy controls (47.18 ± 8.08 years) was collected. Chemotherapeutic agents used were docetaxel and epirubicin. We used neuropsychological testing and questionnaire to evaluate psychiatric comorbidity, cognitive dysfunction as well as generalized sampling imaging (GQI) and graph theoretical analysis (GTA) to detect microstructural alterations in the brain. Findings: Cross-comparison between groups revealed that neurotoxicity caused by chemotherapy and cancer-related psychiatric comorbidity may affect the corpus callosum and middle frontal gyrus. In addition, GQI indices were correlated with the testing scores of cognitive function, quality of life, anxiety, and depression. Furthermore, weaker connections between brain regions and lower segregated ability were found in the post-treatment group. Conclusion: This study suggests that chemotherapy and cancer-related mental health problem both play an important role in the development of white matter alterations and cognitive dysfunction.

Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy-associated genes: A subgroup analysis of the PARADIGM-HF trial.

AIMS: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. METHODS AND RESULTS: This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj ] = 4 × 10-3 ), leaner (27.8 kg/m2 vs. 29.4 kg/m2 ; padj = 3.2 × 10-3 ), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10-3 ), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10-4 ). CONCLUSION: Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.

Noncontrast MRI in assessing venous reflux of legs using QFlow analysis and radial basis function neural network technique.

Since venous reflux is difficult to quantify, triggered angiography non-contrast-enhanced (TRANCE)-magnetic resonance imaging (MRI) is a novel tool for objectively evaluating venous diseases in the lower extremities without using contrast media. This study included 26 pre-intervention patients with superficial venous reflux in the lower extremities and 15 healthy volunteers. The quantitative flow (QFlow) analyzed the phase shift information from the pixels within the region of interest from MRI. The fast and simple radial basis function neural network (RBFNN) learning model is constructed by determining the parameters of the radial basis function and the weights of the neural network. The input parameters were the variables generated through QFlow, while the output variables were morbid limbs with venous reflux and normal limb classification. The stroke volume, forward flow volume, absolute stroke volume, mean flux, stroke distance, and mean velocity of greater saphenous veins from QFlow analysis could be used to discriminate the morbid limbs of pre-intervention patients and normal limbs of healthy controls. The neural network successfully classified the morbid and normal limbs with an accuracy of 90.24% in the training stage. The classification of venous reflux using the RBFNN model may assist physicians in clinical settings.

Venous Segmental Flow Changes after Superficial Venous Intervention Demonstrating by Quantitative Phase-Contrast Magnetic Resonance Analysis: Preliminary Data from a Longitudinal Cohort Study.

The effects of superficial venous intervention on hemodynamics can be quantified using two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI). Twelve patients received pre- and postintervention 2D PC-MRI analysis using quantitative hemodynamic parameters. Fifteen healthy volunteers served as controls. The 2D PC-MRI results of the target limbs (limbs scheduled for intervention for venous reflux) differed from those of the controls in terms of stroke volume (SV), forward flow volume (FFV), absolute stroke volume (ASV), and mean flux (MF) in all venous segments. The velocity time integral (VTI) and mean velocity (MV) of the popliteal vein (PV) segments were similar between the target limbs and controls preoperatively. After intervention, the target limbs exhibited an increase in VTI and MV in the femoral vein (FV) and PV segments. We compared the target and nontreated limbs of the individual patients preoperatively and postoperatively to minimalize individual bias. All QFlow parameter ratios in the FV segment increased after venous intervention (VTI, p = 0.025; MV, p = 0.024). In the PV segment, FFV and ASV increased significantly (p = 0.035 and 0.024, respectively). After interventions, the volume (FFV and ASV) of the PV segment and the efficiency (VTI and MV) of the FV segment significantly increased.

Isotonic and Isometric Exercise Interventions Improve the Hamstring Muscles' Strength and Flexibility: A Narrative Review.

BACKGROUND: Hamstring weakness has been associated with an increased risk of hamstring strain, a common sports injury that occurs when athletes perform actions such as quick sprints. The hamstring complex comprises three distinct muscles: the long and short heads of the bicep femoris, the semimembranosus, and the semitendinosus. METHODS: The researchers collected the data from different electronic databases: PubMed, Google Scholar, and the Web of Science. RESULTS: Many studies have been conducted on the numerous benefits of hamstring strength, in terms of athletic performance and injury prevention. Isotonic and isometric exercises are commonly used to improve hamstring strength, with each exercise type having a unique effect on the hamstring muscles. Isotonic exercise improves the muscles' strength, increasing their ability to resist any force, while isometric training increases strength and the muscles' ability to produce power by changing the muscle length. CONCLUSIONS: These exercises, when performed at low intensity, but with high repetition, can be used by the healthy general population to prepare for training and daily exercise. This can improve hamstring muscle strength and flexibility, leading to enhanced performance and reduced injury risk.

Nitric Oxide Mobilizes Intracellular Zn2+ via the GC/cGMP/PKG Signaling Pathway and Stimulates Adipocyte Differentiation.

Plasma and tissue zinc ion levels are associated with the development of obesity. Previous studies have suggested that zinc ions may regulate adipocyte metabolism and that nitric oxide (NO) plays a pivotal role in the regulation of adipocyte physiology. Our previous study showed that chronic NO deficiency causes a significant decrease in adipose tissue mass in rats. Studies also suggested that zinc ions play an important modulatory role in regulating NO function. This study aims to explore the role of zinc ions in NO-regulated adipocyte differentiation. We hypothesized that NO could increase intracellular Zn2+ level and then stimulate adipocyte differentiation. ZnCl2 and the NO donor, NONOate, were used to explore the effects of Zn2+ and NO on adipocyte differentiation. Regulatory mechanisms of NO on intracellular Zn2+ mobilization were determined by detection. Then, Zn2+-selective chelator TPEN was used to clarify the role of intracellular Zn2+ on NO-regulated adipocyte differentiation. Furthermore, the relationship between adipocyte size, Zn2+ level, and NOS expression in human subcutaneous fat tissue was elucidated. Results showed that both ZnCl2 and NO stimulated adipocyte differentiation in a dose-dependent manner. NO stimulated intracellular Zn2+ mobilization in adipocytes through the guanylate cyclase (GC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, and NO-stimulated adipocyte differentiation was Zn2+-dependent. In human subcutaneous adipose tissue, adipocyte size was negatively correlated with expression of eNOS. In conclusion, NO treatment stimulates intracellular Zn2+ mobilization through the GC/cGMP/PKG pathway, subsequently stimulating adipocyte differentiation.

A case of acquired hemophilia A and bullous pemphigoid following SARS-CoV-2 mRNA vaccination.

Acquired hemophilia is a rare disease resulting from autoantibodies against endogenous factor VIII (FVIII), which associates with bleeding and a high mortality rate. The pathophysiology is still unclear. Recent studies suggest genetic and environmental factors trigger the breakdown of immune tolerance. We report a 77-year-old Taiwanese man presented with multiple ecchymoses and some hemorrhagic blisters three weeks after SARS-CoV-2 mRNA (Moderna) vaccination. Isolated activated partial thromboplastin time (aPTT) prolongation was found. Acquired hemophilia A (AHA) was confirmed by low factor VIII (FVIII) activity and high titer of FVIII inhibitor. The pathohistology of skin biopsy further supported the concomitant diagnosis of bullous pemphigoid. To date, 6 cases of acquired hemophilia A following SARS-CoV-2 mRNA vaccination were reported worldwide. We reviewed and summarized the characteristics of these cases. We also discussed the rare finding of concomitant acquired hemophilia A and bullous pemphigoid. Bullous pemphigoid results from autoantibody against epithelial basement membrane zone of skin. In this article, we proposed possibility of SARS-CoV-2 mRNA vaccine associated autoimmunity against FVIII and epithelial basement membrane zone.

Blood Flow Analysis of the Great Saphenous Vein in the Su-Pine Position in Clinical Manifestations of Varicose Veins of Different Severities: Application of Phase-Contrast Magnetic Resonance Imaging Data.

The progression of clinical manifestations of lower-limb varicose veins remains unclear. This study investigated changes in lower-limb venous blood flow using phase-contrast magnetic resonance angiography. Data were collected on veins from 141 legs. We compared legs with and without varicose veins and related symptoms and examined varying levels of varicose vein symptom severity. Legs without varicose veins exhibited a lower absolute stroke volume (ASV, p < 0.01) and mean flux (MF, p = 0.03) for the great saphenous vein (GSV) compared with legs with symptomatic varicose veins. Legs with asymptomatic varicose veins exhibited lower MF for the GSV (p = 0.02) compared with legs with symptomatic varicose veins. Among legs with varicose veins, asymptomatic legs exhibited lower ASV (p = 0.03) and MF (p = 0.046) for the GSV compared with legs that exhibited skin changes or ulcers; however, no significant differences were observed between legs presenting with discomfort or edema and legs with skin changes or ulcers, and between legs presenting with discomfort or edema and asymptomatic legs. In conclusion, in the supine position, increased blood flow rate and blood flow volume in the GSV were associated with symptomatic varicose veins and increased symptom severity.

Wearable hydrogel patch with noninvasive, electrochemical glucose sensor for natural sweat detection.

Recent advances in microelectronics and electrochemical sensing platforms have preceded the development of devices for personal monitoring and managing physiological and metabolic information that exploit sweat as a noninvasive, convenient approach for providing information about underlying health conditions, such as glucose level monitoring. Although most sweat glucose sensors have targeted applications during exercise and other active stimulation induced-sweat, natural sweating offers an attractive alternative with minimal effect on users that can be accessed during routine and sedentary activities without impeding personal lifestyle and preserves the correlation between blood and sweat glucose. Here, we present a noninvasive sweat glucose sensor with convenient hydrogel patches for rapid sampling of natural perspiration without external activities that stimulate sweating. The wearable hydrogel patch rapidly takes up natural sweat from the hand and serves as a medium for electrochemical sensing. A prussian blue-doped poly(3,4-ethylenedioxythiophene nanocomposite (PB-PEDOT NC) electrode provides cost-effective, stable and excellent electrocatalytic activity in sweat glucose measurements. We demonstrated sweat glucose sensor functionality by long-term measurements of glucose in sweat from human subjects consuming food and drinks. By enabling the analysis of sweat glucose during routine and sedentary activities, the sweat glucose sensor shows great promise for clinical-grade glucose management and enlarges the scope of next-generation noninvasive sensing systems.