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Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and strokes because of their ability to promote endogenous angiogenesis and neurogenesis via a variety of secreted factors. MSCs found in the Wharton's jelly of the human umbilical cord are easily obtained and are capable of transplantation without rejection. We isolated MSCs from Wharton's jelly and bone marrow (WJ-MSCs and BM-MSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology.

Background: Atrial fibrillation (AF) is related to a variety of chronic diseases and life-threatening complications. It is estimated that by 2050, there will be 72 million patients with AF in Asia, of which 2.9 million will have AF-associated stroke. AF has become a major issue for health care systems. Objective: We aimed to evaluate the effects of a web-based integrated management program on improving coping strategies, medication adherence, and health-related quality of life (HRQoL) in patients with AF, and to detect the effect on decreasing readmission events. Methods: The parallel-group, single-blind, prospective randomized controlled trial recruited patients with AF from a medical center in northern Taiwan and divided them randomly into intervention and control groups. Patients in the intervention group received the web-based integrated management program, whereas those in the control group received usual care. The measurement tools included the Brief Coping Orientation to Problems Experienced (COPE) scale, Medication Adherence Rating Scale (MARS), the three-level version of the EuroQoL five-dimension self-report questionnaire (EQ-5D-3L), and readmission events 2 years after initiating the intervention. Data were collected at 4 instances (baseline, 1 month, 3 months, and 6 months after initiating the intervention), and analyzed with generalized estimating equations (GEEs). Results: A total of 231 patients were recruited and allocated into an intervention (n=115) or control (n=116) group. The mean age of participants was 73.08 (SD 11.71) years. Most participants were diagnosed with paroxysmal AF (171/231, 74%), and the most frequent comorbidity was hypertension (162/231, 70.1%). Compared with the control group, the intervention group showed significantly greater improvement in approach coping strategies, medication adherence, and HRQoL at 1, 3, and 6 months (all P<.05). In addition, the intervention group showed significantly fewer readmission events within 2 years (OR 0.406, P=.03), compared with the control group. Conclusions: The web-based integrated management program can significantly improve patients' coping strategy and medication adherence. Therefore, it can empower patients to maintain disease stability, which is a major factor in improving their HRQoL and reducing readmission events within 2 years. Trial Registration: ClinicalTrials.gov NCT04813094; https://clinicaltrials.gov/ct2/show/NCT04813094.

The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.

Uncertainty in illness is regarded as a source of stress in many chronic diseases and is negatively related to health-related quality of life (HRQoL). However, studies on the relationship between uncertainty and HRQoL in patients with heart failure are limited. This study used Mishel's theory of uncertainty in illness to investigate the mediating role of uncertainty in illness and depressive symptoms between symptom distress and HRQoL in patients with heart failure. This study used a cross-sectional correlation design. Participants were recruited by convenience sampling from outpatient services and medical wards of cardiology departments of a medical center in northern Taiwan. Data were collected for uncertainty, depressive symptoms, symptoms distress of heart failure, and HRQoL using self-report questionnaires. Demographics and clinical characteristics were analyzed with descriptive statistics. The mutual effects of disease characteristics, symptom distress, uncertainty in illness, depressive symptoms and HRQoL, as well as the overall model fitness, were analyzed by with structural equation modeling. We collected 147 qualified questionnaires. The mean score for the Mishel Uncertainty in Illness Scale for patients with heart failure was 73.5 (SD = 18.55); 65.3% of participants had a score of ≧13 on the Beck Depressive Inventory-II, indicating mild depression. Uncertainty, depressive symptoms, and HRQoL were directly related to symptom distress. Symptom distress and depressive symptoms were both mediators between uncertainty and depressive symptoms. Depressive symptoms also mediated emotional support and HRQoL. Uncertainty and depressive symptoms were important factors in the pathway between symptom distress and HRQoL for heart failure patients. We suggest providing heart failure patients with tailored interventions for effective self-management of symptoms based on Mishel's theory of uncertainty in illness, which could help control disease symptoms, alleviate uncertainty and depression as well as improve HRQoL.

Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3'-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.

Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.

PurposeThis study evaluated the association between ischaemic stroke (IS) and heart failure (HF) in the absence of atrial fibrillation (AF) or atrial flutter (AFL) using a population-based nation-wide cohort database.MethodNewly diagnosed patients with HF without previous stroke and acute myocardial infarction (AMI) were enrolled. Based on the propensity scores matching age, sex and all comorbidities, our studies comprised 12 179 patients with HF and 12 179 patients without HF. Cox proportion hazard regression models and competing-risk regression models were used to evaluate the risk of IS among patients with HF without AF or AFL.ResultsIn the multivariable analysis, older age (adjusted HR (95% CI)=1.05 (1.04 to 1.05)), male sex (adjusted HR (95% CI)=1.36 (1.24 to 1.50)), diabetes (adjusted HR (95% CI)=2.22 (1.97 to 2.49)) and hypertension (adjusted HR (95% CI)=1.60 (1.41 to 1.82)) were markedly associated with IS in patients with HF. The HF group had a markedly higher risk of IS than did the non-HF group (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66) and AMI (SHR=3.40, 95% CI: 2.71 to 4.28). Additionally, according to the Kaplan-Meier analysis, patients with HF were at a significantly higher risk of cumulative incidence of IS and AMI than did patients with non-HF (p value of log-rank test <0.001).ConclusionThis study indicated that HF is a strong independent risk factor for IS, even in the absence of AF or AFL. Clinical physicians should investigate IS through routine screening and careful monitoring of patients with HF.

Pre-capillary pulmonary hypertension (PH) is a progressive and incurable disease characterized by high morbidity, frequent emergency department (ED) visits, and persistently poor survival despite targeted therapies. Web-based symptom monitoring programs offer a promising, non-invasive approach to support self-management and enable the early detection of decompensation. This study aimed to evaluate the effects of a web-based symptom-monitoring program on symptom interference, physical activity, and ED readmission in patients with pre-capillary PH. This parallel-group, single-blind, randomized controlled trial recruited patients with precapillary PH from a cardiology outpatient department in northern Taiwan. Patients were included if they had been diagnosed with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension and had a mean pulmonary arterial pressure of >20 mmHg confirmed via right heart catheterization. Participants were randomized into 2 groups: an intervention group (n=26), which received a 6-month symptom monitoring program delivered via a web-based application, or a control group (n=25), which received standard care. Outcomes were assessed by comparing measures at baseline (enrollment) with measures at 3, 6, and 9 months postintervention. The primary outcome was symptom interference, and the secondary outcomes included physical activity based on the 6-minute walk test, hemodynamic data, and readmissions to the ED. Changes in baseline measurements were analyzed using generalized estimating equations. The mean age of the 51 participants was 59.6 (SD 13.6) years. Most patients were diagnosed with connective tissue disease-associated pulmonary arterial hypertension (39.2%), with a mean duration of PH since diagnosis of 3.38 (SD 2.55) years. The patient characteristics did not differ significantly between the groups. Compared with the control group, the intervention group experienced greater reduction in symptom interference, and over the 9-month intervention period, the intervention group showed a significantly greater improvement in the 6-minute walk test, with the distance increasing by an average of 9.8 meters every 3 months (β=9.81; 95% CI 0.93 to 18.70; P=.03). Additionally, generalized estimating equations analysis demonstrated that, compared to the control group, the intervention group had a 65% decrease (β=-1.03; OR=0.35; P=.04) in the likelihood of ED readmissions for every 3-month interval during the 9-month study period. A web-based symptom monitoring program effectively reduced symptom interference, improved physical activity, and decreased ED visits in patients with pre-capillary PH.

Background Lifestyle modification is an essential component of prevention and management of hypertension. Existing instruments in Taiwan focus on assessing lifestyle modifications by evaluating medication adherence or confidence in controlling blood pressure. However, other self-care activities, such as diet, physical activity, weight management, smoking, and alcohol consumption are also important. The Hypertension Self-Care Activity Level Effects (H-SCALE) is one such instrument, but there are no similar tools available in Taiwan. Aim This study aimed to translate the H-SCALE into Chinese and test its validity, and reliability in a sample of adults with hypertension. Methods The English version of the 31-item H-SCALE was translated into Chinese using the forward-backward method. The content validity index (CVI) of the translated scale was determined by five experts in hypertension. Item analysis was conducted with a pilot sample of 20 patients with hypertension. Cronbach’s α was used to establish the internal consistency reliability for the Chinese version of the H-SCALE (H-SCALE-C). Exploratory factor analysis (EFA) explored the structure of the H-SCALE-C. Additionally, construct validity was examined with confirmatory factor analysis (CFA). Patients with hypertension were recruited by convenience sampling from a cardiovascular outpatient clinic of a medical center in northern Taiwan. A total of 318 patients met the inclusion criteria and participated in factor analysis in the study. Results Pilot testing of the scale items indicated most patients could not accurately estimate the number of days of alcohol consumption for the previous week. Therefore, three alcohol-related items were removed. The adaptation resulted in a 28-item H-SCALE-C. EFA revealed a 4-factor solution with 13 items that explained 63.93% of the total variance. CFA indicated a good fit for a 4-factor model and construct validity was acceptable. Internal consistency reliability was acceptable (Cronbach’s alpha for the four subscales ranged from 0.65 to 0.94). Convergent validity was acceptable, and discriminant validity was significant. Conclusions The H-SCALE-C is a valid, reliable tool for promptly assessing life-style activities for patients with hypertension in Taiwan. The instrument is suitable for assisting healthcare providers in evaluating self-care activities, which could be used to facilitate lifestyle modifications for patients with hypertension.

Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment for DM. Detection of miR-134 expression in FIR-treated ECFCs should help us to explore further the effectiveness of FIR therapy.