Dietary polyphenols have been associated with many beneficial cardiovascular effects. However, these effects are rather attributed to small phenolic metabolites formed by the gut microbiota, which reach sufficient concentrations in systemic circulation. 4-Methylcatechol (4-MC) is one such metabolite. As it is shown to possess considerable vasorelaxant effects, this study aimed to unravel its mechanism of action. To this end, experimental in vitro and in silico approaches were employed. In the first step, isometric tension recordings were performed on rat aortic rings. 4-MC potentiated the effect of cyclic nucleotides, but the effect was not mediated by either soluble guanylyl cyclase (sGC), modification of cyclic adenosine monophosphate levels, or protein kinase G. Hence, downstream targets such as calcium or potassium channels were considered. Inhibition of voltage-gated K+ channels (KV) markedly decreased the effect of 4-MC, and vasodilation was partly decreased by inhibition of the KV7 isoform. Contrarily, other types of K+ channels or L-type Ca2+ channels were not involved. In silico reverse docking confirmed that 4-MC binds to KV7.4 through hydrogen bonding and hydrophobic interactions. In particular, it interacts with two crucial residues for KV7.4 activation: Trp242 and Phe246. In summary, our findings suggested that 4-MC exerts vasorelaxation by opening KV channels with the involvement of KV7.4.

• MeSH
• aorta účinky léků   metabolismus   MeSH
• draslíkové kanály řízené napětím * metabolismus   MeSH
• katecholy * farmakologie   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• quercetin * farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vazodilatace * účinky léků   MeSH
• vazodilatancia farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The p53 family of proteins evolved from a common ancestor into three separate genes encoding proteins that act as transcription factors with distinct cellular roles. Isoforms of each member that lack specific regions or domains are suggested to result from alternative transcription start sites, alternative splicing or alternative translation initiation, and have the potential to exponentially increase the functional repertoire of each gene. However, evidence supporting the presence of individual protein variants at functional levels is often limited and is inferred by mRNA detection using highly sensitive amplification techniques. We provide a critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms. We conclude that despite the wealth of publications, several putative isoforms remain poorly established. Future research with improved technical approaches and the generation of isoform-specific protein detection reagents is required to establish the physiological relevance of p53-family isoforms in health and disease. In addition, our analyses suggest that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.

• MeSH
• alternativní sestřih * MeSH
• lidé MeSH
• messenger RNA metabolismus   genetika   MeSH
• molekulární evoluce MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   MeSH
• počátek transkripce MeSH
• protein - isoformy * genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The ribosome, owing to its exceptional conservation, harbours a remarkable molecular fossil known as the protoribosome. It surrounds the peptidyl transferase center (PTC), responsible for peptide bond formation. While previous studies have demonstrated the PTC activity in RNA alone, our investigation reveals the intricate roles of the ribosomal protein fragments (rPeptides) within the ribosomal core. This research highlights the significance of rPeptides in stability and coacervation of two distinct protoribosomal evolutionary stages. The 617nt 'big' protoribosome model, which associates with rPeptides specifically, exhibits a structurally defined and rigid nature, further stabilized by the peptides. In contrast, the 136nt 'small' model, previously linked to peptidyltransferase activity, displays greater structural flexibility. While this construct interacts with rPeptides with lower specificity, they induce coacervation of the 'small' protoribosome across a wide concentration range, which is concomitantly dependent on the RNA sequence and structure. Moreover, these conditions protect RNA from degradation. This phenomenon suggests a significant evolutionary advantage in the RNA-protein interaction at the early stages of ribosome evolution. The distinct properties of the two protoribosomal stages suggest that rPeptides initially provided compartmentalization and prevented RNA degradation, preceding the emergence of specific RNA-protein interactions crucial for the ribosomal structural integrity.

• MeSH
• konformace nukleové kyseliny MeSH
• molekulární modely MeSH
• peptidy chemie   metabolismus   MeSH
• peptidyltransferasy metabolismus   chemie   MeSH
• ribozomální proteiny * metabolismus   chemie   MeSH
• ribozomy * metabolismus   MeSH
• RNA metabolismus   chemie   MeSH
• stabilita RNA MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

• MeSH
• glukagonu podobné peptidy * MeSH
• kvalita života * MeSH
• lidé MeSH
• natriuretický peptid typu B MeSH
• obezita farmakoterapie   MeSH
• srdeční selhání * diagnóza   farmakoterapie   MeSH
• tepový objem MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

• MeSH
• antikoagulancia * škodlivé účinky   terapeutické užití   MeSH
• Aspirin * škodlivé účinky   terapeutické užití   MeSH
• cévní mozková příhoda * etiologie   prevence a kontrola   MeSH
• dvojitá slepá metoda MeSH
• embolie * etiologie   prevence a kontrola   MeSH
• fibrilace síní * komplikace   diagnóza   MeSH
• inhibitory faktoru Xa škodlivé účinky   terapeutické užití   MeSH
• krvácení chemicky indukované   MeSH
• lidé MeSH
• pyridony škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Kanada MeSH

Brožura informuje o novém českém online portálu, který se zaměřuje na zdravotnické informace. Určeno široké veřejnosti.

• MeSH
• informace pro uživatele zdravotní péče MeSH
• on-line systémy MeSH
• zdravotní gramotnost MeSH
• zdravotnické informační systémy MeSH
• Publikační typ
• populární práce MeSH
• Geografické názvy
• Česká republika MeSH

• Konspekt
• Teorie systémů. Automatické systémy. Informační systémy. Kybernetika
• NLK Obory
• knihovnictví, informační věda a muzeologie
• zdravotní výchova
• NLK Publikační typ
• brožury
• informační publikace

Sborník prací, které se zaměřují na terapii urologických nádorů pomocí přípravku enfortumab vedotin (Padcev). Určeno odborné veřejnosti.

• Klíčová slova
• enfortumab vedotin, Padcev,
• MeSH
• cílená molekulární terapie MeSH
• cytostatické látky MeSH
• humanizované monoklonální protilátky MeSH
• imunokonjugáty MeSH
• karcinom z přechodných buněk MeSH
• protinádorové látky imunologicky aktivní MeSH
• urologické nádory MeSH
• Publikační typ
• kazuistiky MeSH
• sborníky MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• farmakoterapie
• onkologie

Publikace se zaměřuje na bazální stimulaci v péči o pacienta v různých oborech. Určeno odborné veřejnosti.

• Klíčová slova
• bazální stimulace,
• MeSH
• fyzikální stimulace MeSH
• individualizovaná medicína MeSH
• péče o pacienta MeSH
• podprahová stimulace MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Fyziologie člověka a srovnávací fyziologie
• NLK Obory
• fyziologie
• lékařství

BACKGROUND: Maladaptive fear of movement in individuals with low back pain may be associated with worse clinical outcomes. OBJECTIVE: To explore beliefs about the perceived dangers regarding different spinal postures within the Czech Republic. DESIGN: Exploratory cross-sectional study including physiotherapists and members of the general public. METHODS: Self-reported perceived safety/danger of "straight" and "flexed" spinal postures regarding 1) sitting, 2) lifting of light and 3) heavy object from the floor based on three pairs of photographs was measured using numeric rating scales (0-10, safe to dangerous) without any given context and in the context of low back pain. The sum of differences between the ratings of flexed and straight postures were used to calculate Bending Safety Beliefs Thermometer (BSBThermometer) total score potentially ranging -60‒60 (higher values indicates evaluation of flexed spinal postures as more dangerous in comparison to straight postures). RESULTS: 760 participants were included in the analysis. The mean BSBThermometer total score was 31.1 (SD 16.1) and higher scores were positively associated with being women (b = 14.8, 95% CI [9.9-19.8]); non-medical profession (b = 24.7, 95% CI [15.2-34.2]); age (b = 0.38, 95% CI [0.16-0.6]; and their interactions. There was no significant association with current low back pain status or history of low back pain. CONCLUSIONS: On average, participants evaluated "flexed" spinal postures as significantly more dangerous when compared with "straight" spinal postures, with only subgroups of physiotherapists scoring lower than the general public. Clinically, these beliefs could be targeted by individualized education, exposure-based interventions and public campaigns; however, further research is required.

• MeSH
• dospělí MeSH
• fyzioterapeuti * psychologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lumbalgie * patofyziologie   psychologie   MeSH
• postura těla * fyziologie   MeSH
• průřezové studie MeSH
• senioři MeSH
• strach psychologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: The CONtrolled delivery For ImproveD outcomEs with cliNiCal Evidence registry was initiated to characterize the clinical safety and device performance from experienced transcatheter aortic valve implantation (TAVI) centers in Europe and Australia that use the Portico valve to treat patients with severe aortic stenosis. We herein report for the first time the valve performance at 30-day across all implanted valve sizes and the 1-year survival from this registry. METHODS: This was a prospective, multicenter, single-arm observational clinical investigation of patients clinically indicated for implantation of a Portico valve in experienced TAVI centers. Patients were treated with a commercially available valve (size 23, 25, 27, or 29 mm) using either the first-generation delivery system (DS) (n = 501) or the second-generation (FlexNav) DS (n = 500). Adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiographic outcomes were assessed at 30 days by an independent core laboratory, and a survival check was performed at 1 year. RESULTS: We enrolled 1001 patients (82.0 years, 62.5% female, 63.7% New York Heart Association functional class III/IV at baseline) from 27 clinical sites in 8 countries across Europe and one site in Australia. Implantation of a single valve was successful in 97.5% of subjects. Valve hemodynamics at 30 days were substantially improved relative to baseline, with large aortic valve areas and low mean gradients across all implanted valve sizes (aortic valve areas were 1.7 ± 0.4, 1.7 ± 0.5, 1.8 ± 0.5, and 2.0 ± 0.5 cm2, and mean gradients were 7.0 ± 2.7, 7.5 ± 4.7, 7.3 ± 3.3, and 6.4 ± 3.3 mmHg for 23, 25, 27, and 29 mm valve sizes, respectively). Across all implanted valve sizes, most patients (77.1%) had no patient-prosthesis mismatch. Death from any cause within 1 year occurred in 13.7% of the patients in the first-generation DS group as compared with 11.0% in the second-generation DS group (p = 0.2). CONCLUSIONS: The Portico valve demonstrated excellent hemodynamic performance across all valve sizes in a large cohort of subjects implanted in experienced TAVI centers. One-year survival rates were favorable when using both the first-generation and second-generation (FlexNav) DSs in this high-risk cohort. CLINICALTRIALSGOV IDENTIFIER: NCT03752866.

• Publikační typ
• časopisecké články MeSH