Milos Gostimirovic

Background: Graft stenosis and graft failure remain frequent complications of coronary artery bypass grafting (CABG). People with type 2 diabetes mellitus (T2DM) represent a significant proportion of patients requiring CABG surgery, as T2DM induces vascular damage and impairs vasorelaxation. Resveratrol (RSV), a naturally occurring polyphenol with potent vasorelaxant properties, has emerged as a potential adjuvant for graft preservation solutions. While multiple pathways contribute to its effects, RSV-induced relaxation in endothelium-denuded segments is driven by direct action on vascular smooth muscle tissue, involving various voltage-dependent potassium (Kv) channels and sodium–calcium exchanger type 1 (NCX-1). Therefore, this study aimed to investigate the mechanism of RSV-induced relaxation in the human saphenous vein (HSV) from patients with and without T2DM, focusing on the roles of specific 4-AP-sensitive Kv channels, particularly margatoxin-sensitive (Kv1.2 and Kv1.3) and phrixotoxin-sensitive (Kv4.1-Kv4.3) subtypes, as well as the nickel-sensitive NCX-1. Methods: Samples of HSVs were taken after CABG surgery in two national cardiovascular clinics. Pharmacological experiments were conducted using isolated organ baths. To test the involvement of Kv1.2, Kv1.3, Kv4.1-Kv4.3, and the nickel-sensitive NCX-1 pathway in RSV-induced relaxation, the following blockers were utilized: 4-aminopyridine (4-AP), margatoxin (MgTox), phrixotoxin (PhTox), and nickel. Protein expression was investigated via Western blot. Results: A total of 112 HSV segments obtained from 49 patients (27 with T2DM; 22 non-diabetic controls (NDM)) were analyzed. RSV caused a concentration-dependent relaxation of the HSV, which was significantly less effective in the T2DM group than in the NDM group (pD₂ = 4.79 ± 0.05 vs. pD₂ = 5.04 ± 0.05, respectively, p = 0.001). 4-AP significantly antagonized RSV-induced relaxation of the HSV in both groups. MgTox did not block the relaxant response in either group, though a distinct variation in maximal efficacy (E_max) was noted in the T2DM group. Notably, PhTox and nickel significantly attenuated RSV-induced relaxation in the NDM group but exerted no significant effect in the T2DM group. Conclusions: RSV induces concentration-dependent relaxation in endothelium-denuded HSV segments from both NDM and T2DM patients. In non-diabetic patients, this relaxation is partially mediated by 4-AP-sensitive and PhTox-sensitive Kv channels, alongside nickel-sensitive pathways, likely corresponding to NCX-1. Conversely, these specific pathways appear compromised and do not contribute to RSV-induced relaxation in patients with T2DM. The involvement of alternative 4-AP-sensitive K channels, including other subtypes of Kv channels, cannot be ruled out in either patient group.

Potassium (K ⁺ ) channels are the most diverse group of ion channels and are required for many physiological functions such as cell excitability and insulin secretion. They are widely distributed throughout the body, but the majority of their subclasses are found in blood vessels, more specifically in the vascular smooth muscle cells (VSMCs) and in the endothelial cells (ECs). In blood vessels, they participate in the regulation of proper vascular tone. Certain diseases may impair the structure and function of vascular K ⁺ channels and decrease their expression in the blood vessels, causing improper blood flow through vital organs and vascular tone dysfunction. These changes lead to clinically significant diseases (hypotension, hypertension, atherosclerosis, cerebrovascular diseases, etc.), which increase total and cardiovascular mortality. Diabetes mellitus (DM) is a condition that significantly alters the structure and function of K ⁺ channels in the blood vessels. These changes contribute to the development of common DM-associated chronic macrovascular and microvascular complications, which further increases morbidity and mortality. These complications are especially prominent in diabetes mellitus type 2 (T2DM). Moreover, other concomitant pathophysiological processes impair K ⁺ channels, which accelerate the progression of DM. This profound bidirectional patophysiological connection between DM and vascular K ⁺ channels may redirect future antidiabetic therapy to novel mechanisms that include modulation of these channels. This up-to-date review summarizes the contribution of DM-induced vascular K ⁺ channel dysfunction to vascular complications of DM and future directions in the development of novel K ⁺ channels-targeted therapy for vascular disorders.

Background: The aims of this paper are to examine the impact of the COVID-19 pandemic on the non-rational use of antibiotics and potential alterations in the antibiotic resistance profiles of multi-drug resistant (MDR) isolates of Klebsiella pneumoniae (KPN), Pseudomonas aeruginosa (PAE), and Acinetobacter baumannii (ABA). Material and Methods: This study was conducted at the tertiary University Hospital “Dr Dragisa Misovic-Dedinje” (Belgrade, Serbia) and was divided into three periods: pre-pandemic (1.4.2019–31.3.2020, period I), COVID-19 pandemic (1.4.2020–31.3.2021, period II), and COVID-19 pandemic-second phase (1.4.2021–31.3.2022, period III). Cultures were taken from each patient with clinically suspected infection (symptoms, biochemical markers of infection). All departments of the hospital were included in this study. Based on the source, all microbiological specimens were divided into 1° blood, 2° respiratory tract (tracheal aspirate, bronchoalveolar lavage fluid, throat, sputum), 3° central-line catheter, 4° urine, 5° urinary catheter, 6° skin and soft tissue, and 6° other (peritoneal fluid, drainage sample, bioptate, bile, incisions, fistulas, and abscesses). After the isolation of bacterial strains from the samples, an antibiotic sensitivity test was performed for each individual isolate with the automated Vitek^® 2 COMPACT. Antibiotic consumption testing was performed by the WHO guideline equations (ATC/DDD). Results: A total of 2196 strains of KPN, PAE, and ABA from 41,144 hospitalized patients were isolated (23.6% of the number of total isolates). The number of ABA isolates statistically increased (p = 0.021), while the number of PAE isolates statistically decreased (p = 0.003) during the pandemic. An increase in the percentage of MDR strains was observed for KPN (p = 0.028) and PAE (p = 0.027). There has been an increase in the antibiotic resistance of KPN for piperacillin–tazobactam, the third and fourth generations of cephalosporins (ceftriaxone, ceftazidime, and cefepime), all carbapanems (imipenem, meropenem, and ertapenem), and levofloxacin; of PAE for imipenem; and of ABA for amikacin. Total antibiotic consumption increased (from 755 DBD to 1300 DBD, +72%), especially in the watch and reserve group of antibiotics. The highest increases were noted for vancomycin, levofloxacin, azithromycin, and meropenem. MV positively correlated with the increased occurrence of MDR KPN (r = 0.35, p = 0.009) and MDR PAE (r = 0.43, p = 0.009) but not for MDR ABA (r = 0.09, p = 0.614). There has been a statistically significant increase in the Candida sp. isolates, but the prevalence of Clostridium difficile infection remained unchanged. Conclusions: The COVID-19 pandemic has influenced the increase in total and MDR strains of KPN, ABA, and PAE and worsened their antibiotic resistance profiles. An increase in the consumption of both total and specific antibiotics was observed, mostly of fluoroquinolones and carbapenems. A positive correlation between the number of patients on MV and an increase in MDR KPN and MDR PAE strains was noted. It is necessary to adopt and demand the implementation of appropriate antimicrobial stewardship interventions to decrease the resistance of intrahospital pathogens to antibiotics.

Background: The aim of the study is to determine whether environmental and climatic factors (air quality, precipitation rates, and air temperatures) alongside specific public health measures (social distancing and vaccination) have influenced total number of SARS CoV-2 positive cases (TOTAL CASES) and deaths (TOTAL DEATHS) from COVID-19 infection in the Republic of Serbia (RS). Method: An observational, retrospective study was conducted, covering the following three-year period in the RS: I (1 March 2020–1 March 2021); II (1 March 2021–1 March 2022); and III (1 March 2022–1 March 2023). Air quality was expressed as the values of the air quality index (AQI) and the concentrations of particulate matter 2.5 µm (PM_2.5). Precipitation rates (PREC) were expressed as the average monthly amount of rainfall (mm), while average air temperatures (AIR TEMP) were expressed in °C. Data were collected from relevant official and publicly available national and international resources. Data regarding the COVID-19 pandemic were collected from the World Health Organization. Results: No differences between the periods were observed for the average values of AIR TEMP (11.2–12.2 °C), PREC (56.1–66.8 mm), and AQI (57.2–58.8), while the average values of PM_2.5 significantly decreased in the III period (21.2 compared to 25.2, p = 0.03). Both TOTAL CASES and TOTAL DEATHS from COVID-19 infection showed positive correlation with the AQI and PM_2.5 and a negative correlation with the AIR TEMP. The correlation coefficient was strongest between TOTAL DEATHS and the AIR TEMP in the II period (r = −0.7; p = 0.007). The extent of rainfall and vaccination rates did not affect any of the observed variables. No differences in TOTAL CASES and TOTAL DEATHS were observed between the periods of increased social measures and other months, while both statistically significantly increased during the vaccination period compared to months without the vaccination campaign (p < 0.02, for both). Conclusions: Air quality, more precisely AQI and PM_2.5 and average air temperatures, but no precipitation rates, influenced the number of TOTAL CASES and TOTAL DEATHS from COVID-19 infection. These were the highest during the vaccination period, but vaccination could be considered as a confounding factor since the intensive vaccination campaign was conducted during the most severe phase of the COVID-19 pandemic. Social distancing measures did not reduce the number of TOTAL CASES or TOTAL DEATHS during the COVID-19 pandemic.

Background: Hiking is a physical activity recommended for people of all ages. In an era of increased incidence of cardiovascular and psychiatric diseases, directing individuals to hiking can be very important from both public health and socioeconomic perspectives. Since the health status of recreational hikers and the general population in the Republic of Serbia has not been compared yet, our objectives are to compare the health-related characteristics of those two groups, including the prevalence of comorbidities, pharmacotherapy, and drug consumption. Methods: A descriptive epidemiological study was conducted. Research questions were asked via two specially prepared questionnaires distributed through the Google Forms platform. The means of the two groups were tested by a two-sample Student t-test for independent variables. Results: The sample consisted of 259 hikers and 292 people from the general population. A total of 199 hikers (76.8%) and 218 people from the general population group (74.7%) were declared as healthy. The statistically significant differences between the groups included age, sex, education level, and body mass index. In both groups, the majority of those with pre-existing medical conditions had at least one cardiovascular disease (23.5% of the hikers and 19.5% of the individuals in the general group). Pre-existing psychiatric diseases were noted in 6% of the hikers and in 12% of those in the general group. The average durations of the disease in the hiker and general population were 11.9 and 8.4 years, respectively (p < 0.05), whereas, there were no differences in drug consumption. Conclusions: This pilot study represents the comparison of the cardiovascular and mental health among hikers and the general population in the Republic of Serbia. Although psychiatric diseases were clearly less prevalent among hikers, the prevalence and burden of cardiovascular diseases must be interpreted with caution, due to big age difference between the respondents from both groups. However, our future studies will employ objective measurements and clinical parameters rather than self-reported surveys, so that the health benefits of hiking appear more clearly.

Here we have shown for the first time altered expression of the vascular smooth muscle (VSM) K_ATP channel subunits in segments of the human internal mammary artery (HIMA) in patients with type-2 diabetes mellitus (T2DM). Functional properties of vascular K_ATP channels in the presence of T2DM, and the interaction between its subunits and endogenous ligands known to relax this vessel, were tested using the potassium (K) channels opener, pinacidil. HIMA is the most commonly used vascular graft in cardiac surgery. Previously it was shown that pinacidil relaxes HIMA segments through interaction with K_ATP (SUR2B/Kir6.1) vascular channels, but it is unknown whether pinacidil sensitivity is changed in the presence of T2DM, considering diabetes-induced vascular complications commonly seen in patients undergoing coronary artery bypass graft surgery (CABG). K_ATP subunits were detected in HIMA segments using Western blot and immunohistochemistry analyses. An organ bath system was used to interrogate endothelium-independent vasorelaxation caused by pinacidil. In pharmacological experiments, pinacidil was able to relax HIMA from patients with T2DM, with sensitivity comparable to our previous results. All three K_ATP subunits (SUR2B, Kir6.1 and Kir6.2) were observed in HIMA from patients with and without T2DM. There were no differences in the expression of the SUR2B subunit. The expression of the Kir6.1 subunit was lower in HIMA from T2DM patients. In the same group, the expression of the Kir6.2 subunit was higher. Therefore, K_ATP channels might not be the only method of pinacidil-induced dilatation of T2DM HIMA. T2DM may decrease the level of Kir6.1, a dominant subunit in VSM of HIMA, altering the interaction between pinacidil and those channels.

Being in nature and numerous beneficial effects on health and disease prevention make hiking a physical activity recommended for all ages. However, this activity is not without absolute risk to health, considering that vast majority of mountaineering activities are organized at altitudes over 2000 m above sea level (highland), which can last for several days. In that case, risks caused by potentially inadequate psychophysical and ambient conditions (e.g. sprained joints, insect bites, frostbite/heat stroke, acute altitude sickness,...) must be considered, but also a dehydratation, especially in summertime. As a result of dehydration, serious health disorders can occur, which sometimes require immediate professional intervention. Therefore, it is recommended for every mountaineer who attend a physically and/or technically demanding mountaineering action, to know about the amount of water, its intake rate and factors that increase the need for water, as well as the general physiology and regulation of body fluids. More often, we see the youngest (even young infants) at the high-mountain activities, especially during the summer. The inclusion of children in mountaineering is affirmative, but it is also known that they are at greater risk for acute health disorders comparing to adults, including dehydration. The aim of this article is to give a general overview of the body fluids and provide useful practical tips for preventing dehydration of the youngest on the mountain, in order to fully express the psychophysical benefits of hiking, both for the child and for the parents.

The role of an imbalanced high-fat diet in the pathophysiology of common chronic noncommunicable diseases has been known for years. More recently, the concept of ‘gut microbiota’ and the interaction between their composition and gut metabolites produced from the intake of dietary products have gained the focus of researchers, mostly from the perspective of the prevention of cardiovascular and metabolic disorders, which are still the leading cause of death globally. The aim of this work is to highlight the health benefits of the interaction between resveratrol (RSV), red grape polyphenol, and gut microbiota, through aspects of their therapeutic and preventive potentials. Since changed microbiota (mostly as a consequence of antibiotic overuse) contribute to the persistence of post (‘long’)-COVID-19 symptoms, these aspects will be covered too. Data were obtained from the electronic databases (MedLine/PubMed), according to specific keywords regarding the protective role of resveratrol, the gut microbiota, and their synergy. RSV exerts beneficial properties in the modulation of cardiovascular, metabolic, and post-COVID-19-related disorders. In healthy individuals, it maintains an ergogenic capacity, prevents oxidative stress, and modulates the inflammatory response. Overall, it improves quality of life. The RSV–gut-microbiota interaction is beneficial in terms of maintaining human health. Along with physical activity, it is key for the prevention of chronic noncommunicable diseases.

Resveratrol (RSV), a plant-derived polyphenol, demonstrates broad-spectrum health benefits, including anti-proliferative, anti-inflammatory, antidiabetic, anti-ischemic and antioxidant effects. The aim of this review is to give an important heads-up regarding the influence of RSV as a phytoestrogen, RSV effects on most common pregnancy-related complications, as well as its impact on the embryogenesis, spermatogenesis, and women’s reproductive health. Considering the important implications of RSV on human reproductive health, this overview could provide a groundwork, encouraging more detailed research at the clinical level.

Regardless of the continuous improvement of diagnostic possibilities and the organizational structure of the healthcare system that contribute to the reduction of the complicated courses of diseases, modern socio-economic and environmental stressors, life habits and increased fluctuation in the psychological functioning of an individual still have a great influence on the overall burden of human diseases. At present, etiological factors and pathogenic mechanisms of numerous diseases are known, thus enabling their continuous and timely pharmacotherapy. However, for progressive diseases or those associated with numeorus complications, pharmacological treatment can lead to the side effects, and preventive measures are highlighted as the main strategy in the management of such diseases, especially in chronic non-communicable diseases such as cardiovascular diseases (CVDs). One of the preventive measures is timely and qualitative supplementation of the diet with beneficial micronutrients and oligoelements. Their main sources are represented in plant fibers that synthesize biologically active substances with a polyphenolic ring in their structure, called natural polyphenolic compounds (NPC). Decades of NPC research have brought new insights into the potential modification of existing pharmacotherapy of numeorus diseases. Currently, it is known that many polyphenols have an optimal pharmacological profile with cardioprotection and at the center of their overall effects. Research into the mechanisms of polyphenolic action is exhaustive, their interactions with numerous subcellular structures have been described, and they are refered as promising molecules, with the potential to modify key pathogenetic elements that lead to the progression of various diseases. So far, their numerous effects on endothelium, smooth muscle cells and lipid cells involved in the process of atherogenesis are known, their antidiabetic, antioxidant, anti-inflammatory and immunomodulatory properties have been proven, and the synergy with the intestinal microbial populations has recently been known to contribute to their beneficial effects. This paper has the aim to point out the most important mechanisms that NPC use to improve general functionality of the organism by stimulating its defense capacity, prolonging cell life and delaying its overall aging. As the most important cardioprotective nutrients, a special focus is given to their beneficial effects on cardiovascular and metabolic function.