Dual target ligands with 4-tert-butylphenoxy scaffold as histamine H3 receptor antagonists and monoamine oxidase B inhibitors

Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight

Tobacco smoking in Poland in the years from 2003 to 2014 : multi-centre National Population Health Examination Survey (WOBASZ)

The reduction of tobacco smoking remains a challenge for public health. The main purpose of this study was to evaluate changes in the prevalence and patterns of tobacco use in the adult population of Poles in the years from 2003 to 2014. Furthermore, changes in the smoking addiction, the declared reasons for smoking, as well as readiness and motivation to stop smoking were assessed. Based on data from the Polish studies WOBASZ and WOBASZ II, the analysis included 14 576 participants from the first study (6906 men and 7670 women) and 5696 participants from the second study (2578 men and 3118 women), aged between 20 and 74 years. According to the WOBASZ II study, 30% of men and 21% of women in Poland smoked, the rates being 9% and 4% lower for men and women, respectively, in comparison with the WOBASZ study (P <0.001). The average number of cigarettes smoked daily per smoker significantly decreased during the follow‑up period among men (from 17.9 to 15.8 cigarettes per day) and women (from 13.7 to 12.1 cigarettes per day). The percentage of men who never smoked increased from 29.8% to 36.1% (P <0.0001), while the proportion of women who never smoked did not change. However, the percentage of those expressing unwillingness to quit smoking nearly doubled in WOBASZ II in comparison with WOBASZ. Although the smoking rates in Poland have declined over the past decade, smoking remains prevalent among men and women. Therefore, it is necessary to optimize tobacco control in Poland, including fiscal policy, counseling and tobacco addiction treatment, as well as promotional and educational activities, with a special emphasis on the female population

The “athlete’s heart” features in amateur male marathon runners

Background: Training on a professional level can lead to cardiac structural adaptations called the “athlete’s heart”. As marathon participation requires intense physical preparation, the question arises whether the features of “athlete’s heart” can also develop in recreational runners.Methods: The study included 34 males (mean age 40 ± 8 years) who underwent physical examination, a cardiopulmonary exercise test and echocardiographic examination (ECHO) before a marathon. ECHO results were compared with the sedentary control group, reference values for an adult male population and those for highly-trained athletes. Runners with abnormalities revealed by ECHO were referred for cardiac magnetic resonance imaging (CMR).Results: The mean training distance was 56.5 ± 19.7 km/week, peak oxygen uptake was 53.7 ± 6.9 mL/kg/min and the marathon finishing time was 3.7 ± 0.4 h. Compared to sedentary controls, amateur athletes presented larger atria, increased left ventricular (LV) wall thickness, larger LV mass and basal right ventricular (RV) inflow diameter (p &lt; 0.05). When compared with ranges for the general adult population, 56% of participants showed increased left atrial volume, indexed to body surface area (LAVI), 56% right atrial area and interventricular septum thickness, while 47% had enlarged RV proximal outflow tract diameter. In 50% of cases, LAVI exceeded values reported for highly-trained athletes. Due to ECHO abnormalities, CMR was performed in 6 participants, which revealed hypertrophic cardiomyopathy in 1 runner.Conclusions: “Athlete’s heart” features occur in amateur marathon runners. In this group, ECHO reference values for highly-trained elite athletes should be considered, rather than those for the general population and even then LAVI can exceed the upper normal value

STAMINA: Bioinformatics Platform for Monitoring and Mitigating Pandemic Outbreaks

This paper presents the components and integrated outcome of a system that aims to achieve early detection, monitoring and mitigation of pandemic outbreaks. The architecture of the platform aims at providing a number of pandemic-response-related services, on a modular basis, that allows for the easy customization of the platform to address user’s needs per case. This customization is achieved through its ability to deploy only the necessary, loosely coupled services and tools for each case, and by providing a common authentication, data storage and data exchange infrastructure. This way, the platform can provide the necessary services without the burden of additional services that are not of use in the current deployment (e.g., predictive models for pathogens that are not endemic to the deployment area). All the decisions taken for the communication and integration of the tools that compose the platform adhere to this basic principle. The tools presented here as well as their integration is part of the project STAMINA

Precision Nutrition in Chronic Inflammation

The molecular foundation of chronic in fl ammatory diseases (CIDs) can differ markedly between individuals. As our understanding of the biochemical mechanisms underlying individual disease manifestations and progressions expands, new strategies to adjust treatments to the patient ’ s characteristics will continue to profoundly transform clinical practice. Nutrition has long been recognized as an important determinant of in fl ammatory disease phenotypes and treatment response. Yet empirical work demonstrating the therapeutic effectiveness of patient-tailored nutrition remains scarce. This is mainly due to the challenges presented by long-term effects of nutrition, variations in inter-individual gastrointestinal microbiota, the multiplicity of human metabolic pathways potentially affected by food ingredients, nutrition behavior, and the complexity of food composition. Historically, these challenges have been addressed in both human studies and experimental model laboratory studies primarily by using individual nutrition data collection in tandem with large- scale biomolecular data acquisition (e.g. genomics, metabolomics, etc.). This review highlights recent fi ndings in the fi eld of precision nutrition and their potential implications for the development of personalized treatment strategies for CIDs. It emphasizes the importance of computational approaches to integrate nutritional information into multi- omics data analysis and to predict which molecular mechanisms may explain how nutrients intersect with disease pathways. We conclude that recent fi ndings point towards the unexhausted potential of nutrition as part of personalized medicine in chronic in fl ammation

Pharmacotherapy of heart failure A.D. 2023. Expert opinion of Working Group on Cardiovascular Pharmacotherapy, Polish Cardiac Society

Heart failure (HF) remains one of the most common causes of hospitalization and mortality among Polish patients. The position of the Section of Cardiovascular Pharmacotherapy presents the currently applicable options for pharmacological treatment of HF based on the latest European and American guidelines from 2021–2022 in relation to Polish healthcare conditions. Treatment of HF varies depending on its clinical presentation (acute/chronic) or left ventricular ejection fraction. Initial treatment of symptomatic patients with features of volume overload is based on diuretics, especially loop drugs. Treatment aimed at reducing mortality and hospitalization should include drugs blocking the renin-angiotensin-aldosterone system, preferably angiotensin receptor antagonist/neprilysin inhibitor, i.e. sacubitril/valsartan, selected beta-blockers (no class effect — options include bisoprolol, metoprolol succinate, or vasodilatory beta-blockers — carvedilol and nebivolol), mineralocorticoid receptor antagonist, and sodium-glucose cotransporter type 2 inhibitor (flozin), constituting the 4 pillars of pharmacotherapy. Their effectiveness has been confirmed in numerous prospective randomized trials. The current HF treatment strategy is based on the fastest possible implementation of all four mentioned classes of drugs due to their independent additive action. It is also important to individualize therapy according to comorbidities, blood pressure, resting heart rate, or the presence of arrhythmias. This article emphasizes the cardio- and nephroprotective role of flozins in HF therapy, regardless of ejection fraction value. We propose practical guidelines for the use of medicines, profile of adverse reactions, drug interactions, as well as pharmacoeconomic aspects. The principles of treatment with ivabradine, digoxin, vericiguat, iron supplementation, or antiplatelet and anticoagulant therapy are also discussed, along with recent novel drugs including omecamtiv mecarbil, tolvaptan, or coenzyme Q10 as well as progress in the prevention and treatment of hyperkalemia. Based on the latest recommendations, treatment regimens for different types of HF are discussed

Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers

<p>Abstract</p> <p>Background</p> <p>Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERβ, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERα, ERβ, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated <it>BRCA1 </it>gene and in the control group.</p> <p>Methods</p> <p>The study group consisted of 48 women with <it>BRCA1 </it>gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERα, ERβ and PgR (progesterone receptor) was performed using monoclonal antibodies against ERα, PgR (DakoCytomation), and polyclonal antibody against ERβ (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998–99.</p> <p>Results</p> <p>The results of our investigation showed that <it>BRCA1 </it>mutation carriers were more likely to have ERα-negative breast cancer than those in the control group. Only 14.5% of <it>BRCA1</it>-related cancers were ERα-positive compared with 57.5% in the control group (<it>P </it>< 0.0001). On the contrary, the expression of ERβ protein was observed in 42% of <it>BRCA1</it>-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERα(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERβ.</p> <p>Conclusion</p> <p>In the case of <it>BRCA1</it>-associated tumors the expression of ERβ was significantly higher than the expression of ERα. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in <it>BRCA1 </it>mutation carriers.</p