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The pharmaceutical medicine course at the Semmelweis University of Budapest, Hungary, was initiated as part of the Innovative Medicines Initiative (IMI is the main program, IMI-PharmaTrain is one of the IMI projects) Pharmaceutical Medicine Training Programs (16 IMI Call 2008/1/16). The aim was to extend training in the development of pharmaceutical medicine to those EU member states where no such education was present. The final program envisaged the development of a cooperative education supported by universities located in Central and Eastern Europe. It was considered to be the economically and scientifically most viable approach to combine the expertise from these countries to form a united teaching staff and provide education jointly for young professionals of the region. Semmelweis University was selected to manage this coordinated program. In this report, we describe the organization and functioning of this international university-based pharmaceutical medicine education project called the Cooperative European Medicines Development Course (CEMDC) and evaluate its successes and shortcomings. During the pandemic, the educational course was interrupted. The follow-on program is reorganized as a postgraduate MSc course named “Semmelweis Pharma MBA” and will be started in 2025. It will continue the established PharmaTrain educational tradition. However, it will deal in more detail with the transition from basic pharmacological to industrial research, as well as biopharmaceutical formulation and manufacturing and marketing aspects of medicines development.

Introduction: Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. Methods: A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Results: Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Conclusions: Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction.

In this study, our focus was on developing and investigating nanoparticle-filled polypropylene-based single polymer composite foams. These composites had porous and nanotube-reinforced matrices, with plain woven polypropylene (PP) fabric as reinforcement. Our main objective was to enhance the energy absorption and stiffness of the single polymer composites (SPCs) by modifying their matrices. We produced SPCs with two different matrices: one of amorphous poly-alpha-olefin (APAO) and one of thermoplastic elastomer (TPE) blended with APAO. We observed that the APAO matrix exhibited better impregnation of the fabric due to its low viscosity, while the composites with the TPE matrix showed significantly better tensile properties. The foaming process applied to the matrices resulted in a substantial increase in energy absorption for the SPCs, while preserving their tensile properties relative to their density. Scanning electron microscope images confirmed that foaming of the APAO matrix was notably more effective, primarily due to its low viscosity. Furthermore, we successfully enhanced the stiffness and tensile properties of the SPCs by nano-reinforcing the matrices with multi-wall carbon nanotubes (MWCNTs). Due to the size of the nanotubes, this reinforcement did not compromise the impact properties of the SPCs. Scanning electron microscope images also demonstrated improved dispersion of the nanotubes within the APAO matrices.

Abstract Aims Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression. Methods and results Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO‐induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age‐matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4‐ and 8‐month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated. Results The model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4‐ and 8‐month, which indicates VO‐induced hypertrophy. In addition, 8‐months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity‐time index compared with their age‐matched controls. These changes were accompanied by increased Ca2+ sensitivity and titin‐based cardiomyocyte stiffness in 8‐month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8‐month VO rats compared with age‐matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca2+ sensitivity and titin‐based cardiomyocyte stiffness and perhaps the development of hypertrophy. Conclusions Our findings showed VO‐induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy.

Abstract Background The concept of frailty provides an age-independent, easy-to-use tool for risk stratification. We aimed to summarize the evidence on the efficacy of frailty tools in risk assessment in COVID-19 patients. Methods The protocol was registered (CRD42021241544). Studies reporting on frailty in COVID-19 patients were eligible. The main outcomes were mortality, length of hospital stay (LOH) and intensive care unit (ICU) admission in frail and non-frail COVID-19 patients. Frailty was also compared in survivors and non-survivors. Five databases were searched up to 24th September 2021. The QUIPS tool was used for the risk of bias assessment. Odds ratios (OR) and weighted mean differences (WMD) were calculated with 95% confidence intervals (CI) using a random effect model. Heterogeneity was assessed using the I 2 and χ 2 tests. Results From 3640 records identified, 54 were included in the qualitative and 42 in the quantitative synthesis. Clinical Frailty Scale (CFS) was used in 46 studies, the Hospital Frailty Risk Score (HFRS) by 4, the Multidimensional Prognostic Index (MPI) by 3 and three studies used other scores. We found that patients with frailty (CFS 4–9 or HFRS ≥ 5) have a higher risk of mortality (CFS: OR: 3.12; CI 2.56–3.81; HFRS OR: 1.98; CI 1.89–2.07). Patients with frailty (CFS 4–9) were less likely to be admitted to ICU (OR 0.28, CI 0.12–0.64). Quantitative synthesis for LOH was not feasible. Most studies carried a high risk of bias. Conclusions As determined by CFS, frailty is strongly associated with mortality; hence, frailty-based patient management should be included in international COVID-19 treatment guidelines. Future studies investigating the role of frailty assessment on deciding ICU admission are strongly warranted.

Az 1953-ban útjára indult, immáron hetvenéves Belügyi Szemle tudományos folyóirat jubileumi „70 év, 70 gondolat” című kiadványában megjelent tanulmány olvasható a felkért szerzőktől.

Introduction: Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. Methods: A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Results: Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Conclusions: Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Background Helicobacter pylori (H. pylori) infection affects ≈4.4 billion people worldwide. Several studies suggest that this pathogen impacts the digestive system, causing diverse and severe conditions, and results in extragastrointestinal disorders like vascular diseases. Our study aims to examine the association between H. pylori infection and carotid intima‐media thickness. Methods and Results Electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, and Scopus) were searched for studies, comparing the thickness of the carotid intima‐media in H. pylori–infected and noninfected individuals listed until October 20, 2020. Statistical analyses were performed using the random effects meta‐analysis of model of weighted mean differences with the corresponding 95% CI using the DerSimonian and Laird method. The protocol was registered in advance in PROSPERO (International Prospective Register of Systematic Reviews; CRD42021224485). Thirteen studies were found meeting inclusion criteria for our systematic review and meta‐analysis, presenting data on the thickness of the carotid intima‐media considering the presence of H. pylori infection. Altogether, 2298 individuals’ data were included (1360 H. pylori positive, 938 negative). The overall carotid intima‐media thickness was significantly larger among infected patients compared with uninfected participants (weighted mean difference: 0.07 mm; 95% CI, 0.02–0.12; P=0.004; I2=91.1%; P

Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope®in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.

Magyarország részese a nemzetközi (humán) migrációnak, amely már elnevezése alapján is határokon átívelő, szupranacionális jelenség. Ebben a folyamatban az ország államhatárán változó intenzitással és számmal, de a világ szinte valamennyi országából érkezők megjelennek. Reguláris (normakövető) vagy akár irreguláris (meg nem engedett) módon lépnek át, az ország területén tartózkodnak vagy átutaznak azon. Kutatók vagyunk, akik belülről ismerik a rendőrség és a menekültügyi hatóság működését, a rendőrség állományába tartoznak, akikkel a tisztviselők nyitottak voltak és megvitatták érzelmeiket a külföldiek hatáskörbe rendelt ellenőrzése kapcsán. Elfogadjuk azt a minimum követelményt, amely szerint az emberi alapjogok biztosítására a külföldi határátlépő személyek ellenőrzését olyan tisztviselőknek kell végrehajtani, akik célzott felkészítést kaptak az érkezőkre jellemző multikulturális jellemzők kezelésére. A jogszerű, szakszerű intézkedéseket az ügyintézőknek a hivatali esküjüknek és a nemzetközi, nemzeti jogszabályoknak, szakmai rendelkezéseknek megfelelve úgy kell objektíven és a méltányossági elveket is képviselve végrehajtaniuk, hogy a társadalom tagjaként eközben őket is olyan hatások érik, amelyek befolyást gyakorolhatnak eseti döntésükre. A tanulmány összehasonlító elemzéssel vizsgálja a hivatalnokokat is magában foglaló magyar társadalom egészére jellemző idegenellenességet, valamint annak a hatáskörrel rendelkező határrendész tisztviselőkre gyakorolt hatását 2010. és 2016. években. Ajánlásokat is megfogalmaz a rendészeti intézkedések humánusságának növelését célzó képzésekre vonatkozóan.

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Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.

Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, the mechanism of this potential cardiotoxicity is unclear. We aimed to establish a cellular platform to investigate DPP4 inhibition and the role of its neuropeptide substrates substance P (SP) and neuropeptide Y (NPY), and to determine the expression of DDP4 and its neuropeptide substrates in the human heart. Western blot, radio-, enzyme-linked immuno-, and RNA scope assays were performed to investigate the expression of DPP4 and its substrates in human hearts. Calcein-based viability measurements and scratch assays were used to test the potential toxicity of DPP4 inhibitors. Cardiac expression of DPP4 and NPY decreased in heart failure patients. In human hearts, DPP4 mRNA is detectable mainly in cardiomyocytes and endothelium. Treatment with DPP4 inhibitors alone/in combination with neuropeptides did not affect viability but in scratch assays neuropeptides decreased, while saxagliptin co-administration increased fibroblast migration in isolated neonatal rat cardiomyocyte-fibroblast co-culture. Decreased DPP4 activity takes part in the pathophysiology of end-stage heart failure. DPP4 compensates against the elevated sympathetic activity and altered neuropeptide tone. Its inhibition decreases this adaptive mechanism, thereby exacerbating myocardial damage.

BackgroundThe prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.ObjectivesWe aimed to assess sex-specific differences in the expression of inflammatory and fibrotic genes, as well as in cholesterol metabolism, focusing on the expression of Pcsk9 in several tissues in a mouse model of NASH that shows the typical features of the human condition.Methods and ResultsWe fed 10-months-old male and female C57Bl/6J mice with a NASH-inducing CDAA or corresponding control diet for 8 weeks. We found that, compared to the control male mice baseline, hepatic Pcsk9 expression as well as serum PCSK9 level was significantly higher in females, and both circulating PCSK9 level and the hepatic Pcsk9 gene were markedly decreased in female mice during NASH development. Histological analysis revealed that male and female mice develop a similar degree of steatosis; however, fibrosis was more pronounced in males upon CDAA diet feeding. Strikingly, female mice have higher hepatic expression of the pro-inflammatory cytokines (Il1b, Ifng), and increased IL-1β cleavage by the NLRP3 inflammasome, and a decrease in Clec4f+ resident Kupffer cell population in comparison to males in the CDAA-fed groups.ConclusionThis is the first demonstration that there are critical sex-specific differences during NASH development in middle-aged mice regarding inflammation, fibrosis, and cholesterol metabolism and that changes in PCSK9 and IL-1β are likely important contributors to sex-specific changes during the transition to NASH.

IntroductionThe use of comorbidity models is crucial in cardioprotective drug development. Hypercholesterolemia causes endothelial and myocardial dysfunction, as well as aggravates ischemia/reperfusion (I/R)-induced myocardial injury. Endogenous cardioprotective mechanisms against I/R are impaired in hyperlipidemic and hyperglycemic in vivo animal models. Therefore, our aim was to develop a medium throughput comorbidity cell-based test system of myocardial I/R injury, hypercholesterolemia and hyperglycemia that mimics comorbidity conditions.MethodsCardiac myocytes isolated from neonatal or adult rat hearts were cultured in control or in three different hypercholesterolemic media with increasing cholesterol content (hiChol) or hiChol + hyperglycemic medium, respectively. Each group was then subjected to simulated ischemia/reperfusion (SI/R) or corresponding normoxic condition, respectively. Cholesterol uptake was tested by Filipin staining in neonatal cardiac myocytes. Cell viability, total cell count and oxidative stress, i.e., total reactive oxygen species (ROS) and superoxide level were measured by fluorescent assays.ResultsNeonatal cardiac myocytes took up cholesterol from the different hiChol media at a concentration-dependent manner. In normoxia, viability of hiChol neonatal cardiac myocytes was not significantly changed, however, superoxide levels were increased as compared to vehicle. After SI/R, the viability of hiChol neonatal cardiac myocytes was decreased and total ROS level was increased as compared to vehicle. HiChol combined with hyperglycemia further aggravated cell death and oxidative stress in normoxic as well as in SI/R conditions. Viability of hiChol adult cardiac myocytes was significantly decreased and superoxide level was increased in normoxia and these changes were further aggravated by SI/R. HiChol combined with hyperglycemia further aggravated cell death, however level of oxidative stress increased only in normoxic condition.ConclusionHiChol rat cardiac myocytes showed reduction of cell viability and increased oxidative stress, which were further aggravated by SI/R and with additional hyperglycemia. This is the first demonstration that the combination of the current hypercholesterolemic medium and SI/R in cardiac myocytes mimics the cardiac pathology of the comorbid heart with I/R and hypercholesterolemia.

Influenza infection may lead to serious complications in the postpartum period, therefore, oseltamivir treatment in these patients and their breastfed infants is of great importance. However, the pharmacokinetics of oseltamivir in postpartum lactating women with acute influenza infection, and the consequent infant exposure to oseltamivir are still unknown, and these data would help in assessing risk and the need for dose adjustment in breastfed infants. Six lactating women with influenza‐like symptoms, at a standard dose of 75 mg oral oseltamivir twice daily for 5 days, were recruited in this phase IV clinical study during the 2011/2012 H1N1 pandemic seasons. Breast milk/colostrum and venous blood samples were taken at multiple timepoints, maternal urine samples were obtained from total output within the 12‐hour observational period following the seventh dose of oseltamivir. Oseltamivir phosphate (OP) reached a maximum 69.5 ± 29.4 ng/mL concentration in breast milk, higher than that found in the plasma, and showed elimination within ~ 8 hours. Oseltamivir carboxylate (active metabolite of OP) showed a lower, nearly steady‐state concentration in breast milk during the observational period (maximum plasma concentration (Cmax) = 38.4 ± 12.9 ng/mL). Based on estimated daily milk consumption of exclusively breastfed infants, their calculated daily exposure is < 0.1% of the infant dose of oseltamivir for treatment of influenza as per marketing authorization. Here, we provide the first maternal breast milk pharmacokinetic data for oral multiple‐dose oseltamivir in lactating patients with influenza and showed that its concentration in the breast milk is not sufficient to reach a therapeutic dose for breastfed infants. [ABSTRACT FROM AUTHOR]