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ObjectivesRoofless individuals represent the most severe category of homelessness. Their clinical characteristics and mortality patterns in Central and Eastern Europe are little known.MethodsA single-center retrospective case-control study at the internal medicine department in Bratislava, Slovakia was conducted. 5694 mortality records from 2010 to 2023 were screened, and 141 (118 men, 23 women) roofless individuals were identified. Patients were sex- and age-matched, with 141 patients from the cohort of non-homeless deceased patients.ResultsCompared to controls, roofless people had a higher incidence of immobility (p = 0.02) and hypothermia (p < 0.0001) at admission. 83% of the roofless people were men, and 59% of the roofless people died before reaching old age (60+). Homeless men died more often from infectious disease (p = 0.02), pneumonia being the most common one (60%). Men from the control group died more often from liver diseases (p = 0.03). There were no significant differences in the causes of mortality between women.ConclusionThese findings could help to reduce the invisibility of the issue of massive premature mortality amongst homeless populations and roofless individuals, in particular.

Abstract Background Quantitative RT-PCR is a valuable tool for assessing the gene expression in different human tissues, particularly due to its exceptional sensitivity, accuracy and reliability. However, the choice of adequate control for normalization is a crucial step, greatly affecting the results of all subsequent analyses. So far, only a few studies were focused on the selection of optimal reference genes in left ventricles of failing human hearts, leading to several disparities in experimental results focused on differential gene expression in this area. Therefore, the main objective of this study was to identify a set of suitable reference genes in normal and failing left ventricle tissues, which could increase the reliability of RT-qPCR-based studies in the future. Methods We analyzed the expression of 15 commonly used housekeeping genes (ACTB, B2M, GAPDH, GUSB, HMBS, HPRT1, IPO8, PGK1, POLR2A, PPIA, RPLP0, TBP, TFRC, UBC and YWHAZ) in left ventricles of normal and failed hearts with two-step approach. In the first step, we excluded genes which are variantly expressed using ANOVA-based statistical method. Afterwards, the remaining genes were analyzed using geNorm, NormFinder and BestKeeper algorithms, together with delta Cq method. Finally, the geometric mean of gene rankings across all methods was calculated. Results Our analysis identified IPO8 and POLR2A as the most stably expressed genes, whereas ACTB and B2M were found to be expressed variantly, suggesting a potential role of these genes in the pathophysiological processes in failing human hearts. Discussion/conclusion Using our two-step approach, we identified and validated two reference genes expressed invariantly in left ventricles of both healthy and failing human hearts, as well as provided a guideline for the selection of reference genes in studies comparing gene expression in these types of tissues.

Objectives: There is no consensus on specific serum 25-hydroxy vitamin D (25(OH) D) levels associated with higher risk of severe outcome in patients with coronavirus disease 2019 (COVID-19). According to the literature patients with serum 25(OH) D levels 12 ng/ml (p

Abstract Introduction Ibuprofen acid is poorly soluble in the stomach, thus reaching maximum plasma levels at approximately 90 min post-dose. Ibuprofen lysinate has been developed to accelerate absorption of ibuprofen to shorten the time to analgesic efficacy. This study compared analgesic efficacy and onset of effect of a single dose of ibuprofen lysinate or ibuprofen acid in patients undergoing third molar extraction. Methods Randomized, double-blind, placebo-controlled, multi-center, parallel-group single-dose study. Adults (18–60 years) undergoing extraction of ≥ 1 third molar were randomized 2:2:1 to ibuprofen lysinate, ibuprofen acid, or placebo postoperatively. Pain relief (PAR, 5-point scale, 0 = none to 4 = complete pain relief) and pain intensity (PI, 100 mm visual analog scale) were assessed between 15 and 360 min post-dose. The primary endpoint was the weighted sum of PAR scores at 6 h (TOTPAR). Time to onset of effect, global assessment of efficacy, and adverse events were also assessed. Results Overall, 351 patients received ibuprofen lysinate (N = 141), ibuprofen acid (N = 139), or placebo (N = 71). Both active treatments significantly reduced pain compared with placebo, from 15 min post-dose to 6 h (TOTPAR: ibuprofen lysinate: 19.57; ibuprofen acid: 19.96; placebo: 8.27). Ibuprofen lysinate was significantly more effective than placebo, but non-inferior to ibuprofen acid, at providing pain relief over 6 h. There was no significant difference between ibuprofen lysinate and ibuprofen acid for onset of analgesia. Both ibuprofen formulations were well tolerated; all adverse events were mild to moderate and considered unrelated to treatment. Conclusions A single dose of ibuprofen lysinate is non-inferior to ibuprofen acid in terms of analgesic efficacy, onset of action, and tolerability in patients who have recently undergone dental surgery. Trial Registration EudraCT No. 2006-006942-33. Plain Language Summary Plain language summary available for this article.

Aim: The safety and effectiveness of a preparation containing a mix of Cucurbita Pepo Seed extract, Equisetum arvense and Linum usitatissimum - Flax A (CELcomplex®) on stress urinary incontinence (SUI) was evaluated in female patients recruited from 20 urological and gynaecological outpatient clinics in Slovakia. Methods: A total of 86 women aged from 32 to 88 with SUI (grade 1 = 44, grade 2 = 42) were enrolled in the study and followed-up for six weeks (point 1) and twelve weeks (point 2). The primary outcome of the study was evaluated by changes in day-time and nocturnal urinary frequency (bathroom visits) and urinary incontinence episodes (leaks). Also, adverse events were quantified as well as the self-perceived effectiveness of the treatment. Research Ethics Board approval was obtained for this study. Results: After 12 weeks of treatment there was a 30% (grade 1 SUI, p

(1) Background: Autism, also known as autism-spectrum disorder, is a pervasive developmental disorder affecting social skills and psychological status in particular. The complex etiopathogenesis of autism limits efficient therapy, which leads to problems with the normal social integration of the individual and causes severe family distress. Injectable methylcobalamin was shown to improve the clinical status of patients via enhanced cell oxidative status and/or methylation capacity. Here we tested the efficiency of a syrup form of methylcobalamin in treating autism. (2) Methods: Methylcobalamin was administered daily at 500 µg dose to autistic children and young adults (n = 25) during a 200-day period. Clinical and psychological status was evaluated by parents and psychologists and plasma levels of reduced and oxidized glutathione, vitamin B12, homocysteine, and cysteine were determined before the treatment, and at day 100 and day 200 of the treatment. (3) Results: Good patient compliance was reported. Methylcobalamin treatment gradually improved the overall clinical and psychological status, with the highest impact in the social domain, followed by the cognitive, behavioral and communication characteristics. Changes in the clinical and psychological status were strongly associated with the changes in the level of reduced glutathione and reduced/oxidized glutathione ratio. (4) Conclusion: A high dose of methylcobalamin administered in syrup form ameliorates the clinical and psychological status of autistic individuals, probably due to the improved oxidative status.

Abstract Background Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF. Methods Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization. Results Elevated expression of RIP1 (receptor-interacting protein), pSer227-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr357-MLKL unlike pSer358-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr357-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis. Conclusions This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.

Background: Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence.Methods: The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study.Results: From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness.Conclusion: Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.

Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.

In recent years, the interstitial cells telocytes, formerly known as interstitial Cajal-like cells, have been described in almost all organs of the human body. Although telocytes were previously thought to be localized predominantly in the organs of the digestive system, as of 2018 they have also been described in the lymphoid tissue, skin, respiratory system, urinary system, meninges and the organs of the male and female genital tracts. Since the time of eminent German pathologist Rudolf Virchow, we have known that many pathological processes originate directly from cellular changes. Even though telocytes are not widely accepted by all scientists as an individual and morphologically and functionally distinct cell population, several articles regarding telocytes have already been published in such prestigious journals as Nature and Annals of the New York Academy of Sciences. The telocyte diversity extends beyond their morphology and functions, as they have a potential role in the etiopathogenesis of different diseases. The most commonly described telocyte-associated diseases (which may be best termed “telocytopathies„ in the future) are summarized in this critical review. It is difficult to imagine that a single cell population could be involved in the pathogenesis of such a wide spectrum of pathological conditions as extragastrointestinal stromal tumors (“telocytomas„), liver fibrosis, preeclampsia during pregnancy, tubal infertility, heart failure and psoriasis. In any case, future functional studies of telocytes in vivo will help to understand the mechanism by which telocytes contribute to tissue homeostasis in health and disease.

Systematic physical activity increases physical fitness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution profiles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs profiles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation.

Hyperuricemia is a pathologically increased concentration of uric acid in the blood and is a risk factor for gout and the development of other diseases. The prevalence of hyperuricemia has increased due to the increasing average age of the population, more frequent kidney diseases, increasing prevalence of obesity, changes in dietary habits, excessive use of diuretics or the influence of genetic factors. The study aims to analyse the therapy of hyperuricemia and gouty arthritis (arthritis uratica), joint involvement, and comorbidities in the patients. Of the patients with hyperuricemia (n = 14), most were male (79 %) and over 41 years old (64 %). Up to 50 % of patients reported involvement of the ankle joints and knee joints, 35 % involvement of the metatarsophalangeal joints and elbow joints, and 28 % of patients involvement of the metacarpophalangeal joints. Eight patients (57 %) reported a blood family history of rheumatological diseases. Seven patients (50 %) suffered from a gout attack once a year, three patients (21 %) had two episodes, one patient (7 %) had pain attacks three times, one patient (7 %) had more than three gout attacks, and two patients (14 %) did not report a single gout attack. Twenty-eight percent of patients sufferred from arterial hypertension, 21 % had hypercholesterolemia, 14 % were treated for DM type II, and one patient (7 %) sufferred from venous thrombosis. All patients were treated with allopurinol, and uricemia targets were achieved in 43 % of patients. [ABSTRACT FROM AUTHOR]

Stem cell transplantation represents a unique therapeutic tool in tissue engineering and regenerative medicine. However, it was shown that the post-injection survival of stem cells is poor, warranting a more comprehensive understanding of activated regenerative pathways. Numerous studies indicate that statins improve the therapeutic efficacy of stem cells in regenerative medicine. In the present study, we investigated the effect of the most widely prescribed statin, atorvastatin, on the characteristics and properties of bone-marrow-derived mesenchymal stem cells (BM-MSCs) cultured in vitro. We found that atorvastatin did not decrease the viability of BM-MSCs, nor did it change the expression of MSC cell surface markers. Atorvastatin upregulated the mRNA expression levels of VEGF-A and HGF, whereas the mRNA expression level of IGF-1 was decreased. In addition, the PI3K/AKT signaling pathway was modulated by atorvastatin as indicated by the high mRNA expression levels of PI3K and AKT. Moreover, our data revealed the upregulation of mTOR mRNA levels; however, no change was observed in the BAX and BCL-2 transcripts. We propose that atorvastatin benefits BM-MSC treatment due to its ability to upregulate angiogenesis-related genes expression and transcripts of the PI3K/AKT/mTOR pathway.

Background and Objectives: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. Materials and Methods: We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro, as well as their effects on the expression of angiogenic growth factors (VEGFA and HGF) and selected genes in apoptosis signalling pathways (BAX, BAK, CASP3, CASP9, and BCL2). Results: Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Conclusions: Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.

Background: The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with ”no-option“ critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment. Methods: In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation. Results: Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin. Conclusions: CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant.

Background and Objectives: Surgical revascularisation of patients with atherosclerosis of the ascending aorta remains a challenge. Different surgical strategies have been described in coronary surgical patients to offer alternative revascularisation strategies other than the conventional surgical revascularisation in patients unsuitable for it. The aim of this study is to compare the real-world outcomes between two groups of patients who underwent off-pump surgery (left internal mammary artery graft to the left anterior descending artery) or a hybrid with a percutaneous revascularisation procedure at a later stage. Materials and Methods: This is a single-centre retrospective observational study. Between the years 2010 and 2021, 91/6863 patients (1.33%) were diagnosed with severe atherosclerosis of the ascending aorta. All the patients were treated with off-pump revascularisation (91 patients), and the cardiologist would decide at a later stage whether the rest of the vessels would be treated with percutaneous revascularisation (25 patients). Results: There was no statistical difference in the various preoperative characteristics, except for coronary artery left main disease (30.30% vs. 64%; p = 0.0043). The two groups had no statistical differences in the perioperative characteristics and postoperative complications. The 1-, 5-, and 10-year mortality rates in the two groups were 6.1% vs. 0%, 59% vs. 80%, and 93.9% vs. 100%, respectively (off-pump vs. hybrid with percutaneous revascularisation procedure, p = 0.1958). Conclusions: Both strategies have high long-term comparable mortality. The off-pump surgery and the HCR procedure at a later stage may be solutions for these high-risk patients, but the target treatment should be complete HCR revascularisation during the index hospitalization.

Intercalated discs ensure mechanical and electrochemical coupling during contraction of the heart. Here, the authors show that loss of Xinβ results in cardiomyocyte proliferation defects and cardiomyopathy by influencing the Hippo-YAP signalling pathway, thus affecting cardiac development and function.

Background: Atrial fibrillation (AF) is associated with high risk of stroke preventable by timely initiation of anticoagulation. Currently available screening tools based on ECG are not optimal due to inconvenience and high costs. Aim of this study was to study the diagnostic value of apelin for AF in patients with high risk of stroke.Methods: We designed a multicenter, matched-cohort study. The population consisted of three study groups: a healthy control group (34 patients) and two matched groups of 60 patients with high risk of stroke (AF and non-AF group). Apelin levels were examined from peripheral blood.Results: Apelin was significantly lower in AF group compared to non-AF group (0.694 ± 0.148 vs. 0.975 ± 0.458 ng/ml, p = 0.001) and control group (0.982 ± 0.060 ng/ml, p < 0.001), respectively. Receiver operating characteristic (ROC) analysis of apelin as a predictor of AF scored area under the curve (AUC) of 0.658. Apelin's concentration of 0.969 [ng/ml] had sensitivity = 0.966 and specificity = 0.467. Logistic regression based on manual feature selection showed that only apelin and NT-proBNP were independent predictors of AF. Logistic regression based on selection from bivariate analysis showed that only apelin was an independent predictor of AF. A logistic regression model using repeated stratified K-Fold cross-validation strategy scored an AUC of 0.725 ± 0.131.Conclusions: Our results suggest that apelin might be used to rule out AF in patients with high risk of stroke.

The miR-17-92 cluster has been shown to regulate cardiomyocyte proliferation in vitro and in genetic mutation and overexpression models. Here the authors show that the cluster member miR-19a/19b regulates cardiomyocyte proliferation in vivo, and that delivery of miR-19a/19b to the heart leads to both short-term and long-term protective responses to myocardial infarction.

OBJECTIVE - Evaluation of the performance of the QRS voltage-duration product (VDP) for detection of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). METHODS - Orthogonal electrocardiograms (ECG) were recorded in male SHR at the age of 12 and 20 weeks, when systolic blood pressure (sBP) reached the average values of 165±3 mmHg and 195±12 mmHg, respectively. Age- and sex- matched normotensive Wistar Kyoto (WKY) rats were used as controls. VDP was calculated as a product of maximum QRS spatial vector magnitude and QRS duration. Left ventricular mass (LVM) was weighed after rats were sacrificed. RESULTS - LVM in SHR at 12 and 20 weeks of age (0.86±0.05 g and 1.05±0.07 g, respectively) was significantly higher as compared with that in WKY (0.65±0.07 g and 0.70±0.02 g). The increase in LVM closely correlated with the sBP increase. VDP did not reflect the increase in LVM in SHR. VDP was lower in SHR as compared with that in WKY, and the difference was significant at the age of 20 weeks (18.2mVms compared with 10.7mVms, p