Possible retinotoxicity of long-term vardenafil treatment.

Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.

Preliminary validation of the Mental Health Test in a psychiatric sample.

To assist psychiatrists and clinical psychologists to assess their patients' psychological immune competence-based capacities and resources, depending on the mental health disorder diagnosis and the severity of the symptoms, the present study examined the psychometric properties of the Mental Health Test in a psychiatric sample. The research was carried out in four Hungarian healthcare facilities using a cross-sectional design. A total of 331 patients (140 male, 188 female, and 3 who preferred not to disclose their gender) completed the Mental Health Test, six well-being and mental health measures, and the Symptom Checklist-90. Psychiatrists and clinical psychologists reported the mental disorder status of each participant. Confirmatory factor analysis showed a good fit of the five-factor model to the data for the clinical version of the Mental Health Test (CFI = 0.972, RMSEA = 0.034). High internal consistency coefficients (α: 0.70-0.84; ω: 0.71-0.85) and excellent external and content validity were reported. The test is not sensitive to sociodemographic indicators but is sensitive to the correlates of well-being and to the symptoms of different types of mental disorders. Our preliminary findings suggest that the Mental Health Test is a suitable measure for assessing mental health capacities and resources in psychiatric samples.

Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release.

Fluoxetine is a safe antidepressant with remarkable anti-inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic-polycytidylic acid (p(I:C))-induced inflammatory model. We found that a non-cytotoxic concentration (MTT-assay, CyQUANT-assay) of fluoxetine significantly suppressed p(I:C)-induced expression and release of several pro-inflammatory cytokines (Q-PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF-κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)-induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3-kinase (PI3K) pathway. Importantly, the PI3K-inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q-PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell-free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA-Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)-treatment, and exerted an overall anti-inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti-inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.

Effect of pharmacological selectivity of SGLT2 inhibitors on cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetic (T2DM) patients. Pharmacological selectivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clinical relevance. Genetically reduced SGLT1-but not SGLT2-activity correlates with lower risk of heart failure and mortality, therefore additional non-selective SGLT1 inhibition might be beneficial. In this prespecified meta-analysis, we included 6 randomized, placebo-controlled cardiovascular outcome trials of SGLT2 inhibitors assessing MACE in 57,553 patients with T2DM. Mixed-effects meta-regression revealed that pharmacological selectivity of SGLT2 inhibitors (either as continuous or dichotomized variable) had no significant impact on most outcomes. However, lower SGLT2 selectivity correlated with significantly lower risk of stroke (pseudo-R2 = 78%; p = 0.011). Indeed, dual SGLT1/2 inhibitors significantly reduced the risk of stroke (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.94), unlike selective agents (p for interaction = 0.018). The risk of diabetic ketoacidosis and genital infections was higher in both pharmacological groups versus placebo. However, hypotension occurred more often with non-selective SGLT2 inhibitors (odds ratio [OR], 1.87; 95% CI, 1.20-2.92) compared with selective agents (p for interaction = 0.044). In conclusion, dual SGLT1/2 inhibition reduces stroke in high-risk T2DM patients but has limited additional effect on other clinical outcomes.

Corrigendum: A new complex mental health test in a positive psychological framework.

[This corrects the article DOI: 10.3389/fpsyg.2022.775622.].

Mannich-type modifications of (-)-cannabidiol and (-)-cannabigerol leading to new, bioactive derivatives.

(-)-Cannabidiol (CBD) and (-)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound.

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation.

Introduction: Extracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear. Methods: Our research aimed to investigate the effects of CBD, CBN, and THCV on human DCs differentiated from monocytes (moDCs). moDCs were treated with up to 10 µM of each phytocannabinoid, and their effects on viability, differentiation, and maturation were assessed both alone, and in conjunction with TLR agonists. The effects of CBD on cytokine production, T cell activation and polarization as well as the transcriptome of moDCs was also determined. Results: Phytocannabinoids did not influence the viability of moDCs up to 10 µM, and only CBD had effects on maturational markers of moDCs, and neither compound influenced LPS-induced activation at 10 µM. Since only CBD had measurable effects on moDCs, in our subsequent experiments we tested the effect only of that pCB. On moDCs differentiated in the presence of CBD subsequent activation by LPS induced a markedly different, much more tolerogenic response. CBD-treated moDCs also produced significantly more interleukin (IL)-6, TNFα and, importantly, IL-10 in response to LPS, which shows a shift toward anti-inflammatory signaling, as well as a more robust secretory response in general. To rule out the possibility that these effects of CBD are specific to TLR4 signaling, we determined the effect of CBD on TLR7/8-induced maturation as well, and saw similar, although less marked responses. CBD-treated moDCs were also less efficient at activating naïve T cells after LPS stimulation, further supporting the tolerogenic effect of this phytocannabinoid on moDCs. Reactome pathway analysis showed an inflammatory response to LPS in moDCs, and to a lesser extent to CBD as well. In contrast CBD-treated moDCs responded to LPS with a shift towards a more tolerogenic phenotype, as IL-10 signaling was the most prominently induced pathway in this group. Discussion: Our results show that CBD achieves an anti-inflammatory effect on adaptive immune responses only in the presence of an activating stimuli on moDCs by reprogramming cells during long-term treatment, and not through acute, short-term effects.

Pressure overload-induced systolic heart failure is associated with characteristic myocardial microRNA expression signature and post-transcriptional gene regulation in male rats.

Although systolic function characteristically shows gradual impairment in pressure overload (PO)-evoked left ventricular (LV) hypertrophy (LVH), rapid progression to congestive heart failure (HF) occurs in distinct cases. The molecular mechanisms for the differences in maladaptation are unknown. Here, we examined microRNA (miRNA) expression and miRNA-driven posttranscriptional gene regulation in the two forms of PO-induced LVH (with/without systolic HF). PO was induced by aortic banding (AB) in male Sprague-Dawley rats. Sham-operated animals were controls. The majority of AB animals demonstrated concentric LVH and slightly decreased systolic function (termed as ABLVH). In contrast, in some AB rats severely reduced ejection fraction, LV dilatation and increased lung weight-to-tibial length ratio was noted (referred to as ABHF). Global LV miRNA sequencing revealed fifty differentially regulated miRNAs in ABHF compared to ABLVH. Network theoretical miRNA-target analysis predicted more than three thousand genes with miRNA-driven dysregulation between the two groups. Seventeen genes with high node strength value were selected for target validation, of which five (Fmr1, Zfpm2, Wasl, Ets1, Atg16l1) showed decreased mRNA expression in ABHF by PCR. PO-evoked systolic HF is associated with unique miRNA alterations, which negatively regulate the mRNA expression of Fmr1, Zfmp2, Wasl, Ets1 and Atg16l1.

[Myocardial bridge: morphological factors which influence symptoms]. / Myocardialis izomhíd: a tüneteket befolyásoló morfológiai faktorok vizsgálata.

INTRODUCTION: Myocardial bridge is a frequently detected congenital coronary anomaly which is kept benign. It is unique because it can cause a dynamic compression during systole. OBJECTIVE: In this article, we focus on the detection and evaluation of morphological parameters that can determine the symptomatic bridges. METHOD: We summarize the invasive and noninvasive modalities regarding this topic. We also present our retrospective research when we studied the morphological features of the left anterior descendent bridges with coronarography which led to angina pectoris. We compared the prognosis of patients where only myocardial bridge was found to those where atherosclerosis also had been presented. RESULTS: Intravascular ultrasound can be adapted for the visualization of myocardial bridge and for measuring the severity of compression. Intracoronary Doppler- and fractional flow reserve allow the appreciation of functional significance. Stress echocardiography is the most used non-invasive imaging modality in this field. According to our results, the group where only myocardial bridge was presented has more severe morphological features. The shortening of the tunneled segment was more expressed. The mortality during long term (appr. 10 years) follow-up was low. Meanwhile, our results have demonstrated that none of the morphological parameters influence mortality. CONCLUSION: There is an essential discrepancy between the phenomenon's high prevalence, the good prognosis, and the numerous case reports where the authors report about severe complications. Today we possess those invasive and non-invasive techniques which can help us to design prospective trials clarify the morphological features' functional significance. Orv Hetil. 2023; 164(14): 563-570.

The impact of the first wave of COVID-19 on students' attainment, analysed by IRT modelling method.

Universities around the world were closed for several months to slow down the spread of the COVID-19 pandemic. During this crisis, a tremendous amount of effort was made to use online education to support the teaching and learning process. The COVID-19 pandemic gave us a profound insight into how online education can radically affect students and how students adapt to new challenges. The question is how switching to online education affected dropout? This study shows the results of a research project clarifying the impact of the transition to online courses on dropouts. The data analysed are from a large public university in Europe where online education was introduced in March 2020. This study compares the academic progress of students newly enroled in 2018 and 2019 using IRT modelling. The results show that (1) this period did not contribute significantly to the increase in dropout, and we managed to retain our students.(2) Subjects became more achievable during online education, and students with less ability were also able to pass their exams. (3) Students who participated in online education reported lower average grade points than those who participated in on-campus education. Consequently, on-campus students could win better scholarships because of better grades than students who participated in online education. Analysing students' results could help (1) resolve management issues regarding scholarship problems and (2) administrators develop programmes to increase retention in online education.

Impact of Sex and Exercise on Femoral Artery Function: More Favorable Adaptation in Male Rats.

Blood flow increases in arteries of the skeletal muscles involved in active work. Our aim was to investigate the gender differences as a result of adaptation to sport in the femoral arteries. Vascular reactivity and histology of animals were compared following a 12-week swimming training. Animals were divided into sedentary male (MS), trained male (MTr), sedentary female (FS), and trained female (FTr) groups. Isolated femoral artery rings were examined by wire myography. Contraction induced by phenylephrine (Phe) did not differ between the four groups. The contractile ability in the presence of indomethacin (INDO) was decreased in both sedentary groups. However, we found a specific cyclooxygenase-2 (COX-2) role only in FS rats. After exercise training, we observed increased vasoconstriction in both sexes, when nitro-L-arginine methyl ester (L-NAME) was present. The COX-dependent vasoconstriction effect disappeared in MTr animals, and the COX-2-dependent vasoconstriction effect disappeared in FTr ones. Relaxation was reduced significantly, when L-NAME was present in MTr animals compared to in FTr rats. The training was associated with greater endothelial nitric oxide synthase (eNOS) protein expression in males, but not in females. The present study proves that there are gender differences regarding adaptation mechanisms of musculocutaneous arteries to sports training. In males, relaxation reserve capacity was markedly elevated compared to in females.

Survival of Myocardial Infarction Patients with Diabetes Mellitus at the Invasive Era (Results from the Városmajor Myocardial Infarction Registry).

Due to the lifelong nature of diabetes mellitus (DM), it has been demonstrated to have significant effects on patients' morbidity and mortality. The present study aimed to assess the effects of DM on the clinical outcome and survival in patients who underwent percutaneous coronary intervention (PCI) due to myocardial infarction (MI) and to examine the relationship of DM to the type of the MI and to left ventricular (LV) and renal functions. A total of 12,270 patients with ST-elevation MI (STEMI) or non-ST-elevation MI (NSTEMI) were revascularized at our Institution between 2005 and 2013. In this pool of patients, 4388 subjects had DM, while 7018 cases had no DM. In both STEMI and NSTEMI, the 30-day and 1-year survival were worse in diabetic patients as compared to non-diabetic cases. In the patients with DM, NSTEMI showed worse prognosis within 1-year than STEMI similarly to non-diabetic subjects. Regarding survival, the presence of DM seemed to be more important than the type of MI. Regardless of the presence of DM, reduced LV function was a maleficent prognostic sign and DM significantly reduced the prognosis both in case of reduced and normal LV function. Survival is primarily affected by LV function, rather than DM. Worse renal function is associated with worse 30-day and 1-year survival in both cases with and without DM. Considering different renal functions, the presence of DM worsens both short- and long-term survival. Survival is primarily affected by renal function, rather than DM. The results from a high-volume PCI center confirm significant the negative prognostic impact of DM on survival in MI patients. DM is a more important prognostic factor than the type of the MI. However, survival is primarily affected by LV and renal functions, rather than DM. These results could highlight our attention on the importance of recent DM treatment with new drugs including SGLT-2 inhibitors and GLP-1 antagonists with beneficial effects on survival.

TRPV4 Activation Increases the Expression of CD207 (Langerin) of Monocyte-Derived Langerhans Cells without Affecting their Maturation.

Langerhans cells (LCs) are the sole professional antigen-presenting cell normally found in the human epidermal compartment. Research into their physiological role is hindered by the fact that they are invariably activated during isolation from the skin. To overcome this challenge, we turned to a monocyte-derived LC (moLC) model, which we characterized with RNA sequencing, and compared the transcriptome of moLCs with that of donor-matched immature dendritic cells. We found that moLCs express markers characteristic of LC2 cells as well as TRPV4. TRPV4 is especially important in the skin because it has been linked to the conservation of the skin barrier, immunological responses, as well as acute and chronic itch, but we know little about its function on LCs. Our results show that TRPV4 activation increased the expression of Langerin and led to increased intracellular calcium concentration in moLCs. Regarding the functionality of moLCs, we found that TRPV4 agonism had a mitigating effect on their inflammatory responses because it decreased their cytokine production and T-cell activating capability. Because TRPV4 has emerged as a potential therapeutic target in dermatological conditions, it is important to highlight LCs as, to our knowledge, a previously unreported target of these therapies.

Emlorák hasüregi áttétei - Egy szokatlan entitás klinikopatológiai jellemzoi.

Case report: A sixty-five-year-old female patient underwent surgery for severe gastrointestinal symptoms, following an alarming CT image. Laparotomy revealed irresectable gastric cancer and peritoneal carcinosis. Palliative gastro-jejunostomy and ileo-descendostomy were performed. The endoscopic diagnosis - linitis plastica - and the intraoperative macroscopic appearance matched and agreed on the histologically presumed shigillocellular carcinoma. Three years following the initial abdominal symptoms, histological samples taken from newly detected cutaneous metastases which developed during oncological palliative treatment verified occult lobular breast carcinoma. Histological revision of the sample taken from abdominal exploration confirmed the latter diagnosis. The hormone receptor positive, human epidermal growth factor receptor-2 negative malignancy showed very good regression for the palliative hormone treatment. Discussion: About ten percent of breast cancer cases are lobular carcinomas, which are more often multicentric, bilateral, occult and have a propensity to metastasize to serous membranes, abdominal and pelvic viscera. Due to the increasing survival of breast cancer patients, the number of abdominal metastases of breast cancer is expected to increase. Histological confirmation is indispensable even in case of advanced abdominal malignancies, especially in the case of an unusual medical history. The currently rare case demonstrates the need for multidisciplinary cooperation in all diagnostic and therapeutic fields of breast cancer.

The wellbeing paradox in Hungarian local sustainable agriculture: a health psychology approach.

BACKGROUND: The literature suggests that farmers' work involves a number of operational difficulties. Although alternative food networks address the majority of their problems, they can potentially generate new hardships. The aim of this study is to examine the situational and engagement-related work difficulties associated with the everyday world of Community Supported Agriculture (CSA) farmers. METHODS: This study used the health psychology approach, namely interpretive phenomenology, to understand the social determinants of farmers' working lives in CSA and to explore mental health challenges within the practices of local sustainable farming. To collect data, semi-structured, in-person interviews were conducted with CSA farmers in Hungary. RESULTS: Our study shows that new modes of consumer-producer connectivity create novel situations and issues which farmers are forced to address. Three personal experiential themes emerge from the data to describe CSA farmers' work difficulties: (1) Conflicted autonomy; (2) The pressure of boxes; (3) Social overload. The difficulties for CSA farmers seem to be rooted in the economic characteristics of alternative agriculture where farmers organize food production for the satisfaction of consumer needs. In addition, structural conditions require several different CSA farmer roles, which could even be conflicting. CONCLUSION: This study provides participants' perspectives on the health and wellbeing costs of sustainable farming. Newer producer-consumer connections require both time and experience and involve extra effort or skills, but farmers often lack these abilities. The results show how perceptions of work processes relate to the general framework of CSA, which necessitates a distinct strategy for farm management.

Seeds that bloom on stony ground - Concept paper of the future perspectives of the unexploited capacities of positive clinical psychology in Hungary.

Positive psychology has fully examined the flourishing among healthy people but neglected to understand how "optimal human functioning" can apply to the life experiences of a vulnerable person. Considering methodological issues, this article gives a brief overview on how the conceptualization of mental health and mental disorders affects the consideration of strengths along with the presence of dysfunction with the emergence of positive psychology. First, we summarize the shortcomings of the applicability of clinical positive psychology, focusing especially on Hungarian clinical practice. Second, we discuss the problems with the conceptualization of mental health in positive psychological framework. Third, we propose a model, the Maintainable Positive Mental Health Theory based on capacities and competences. Finally, we conclude with methodological questions and present a research protocol. The key finding of our review is that the opportunity exists for psychiatrists and psychologists to embrace disability as part of human experiences and to show how people with vulnerabilities can be supported to recover. (Neuropsychopharmacol Hung 2022; 24(3): 113-119).

Admission lactate level and the GRACE 2.0 score are independent and additive predictors of 30-day mortality of STEMI patients treated with primary PCI-Results of a real-world registry.

BACKGROUND: In many of the risk estimation algorithms for patients with ST-elevation myocardial infarction (STEMI), heart rate and systolic blood pressure are key predictors. Yet, these parameters may also be altered by the applied medical treatment / circulatory support without concomitant improvement in microcirculation. Therefore, we aimed to investigate whether venous lactate level, a well-known marker of microcirculatory failure, may have an added prognostic value on top of the conventional variables of the "Global Registry of Acute Coronary Events" (GRACE) 2.0 model for predicting 30-day all-cause mortality of STEMI patients treated with primary percutaneous coronary intervention (PCI). METHODS: In a prospective single-center registry study conducted from May 2020 through April 2021, we analyzed data of 323 cases. Venous blood gas analysis was performed in all patients at admission. Nested logistic regression models were built using the GRACE 2.0 score alone (base model) and with the addition of venous lactate level (expanded model) with 30-day all-cause mortality as primary outcome measure. Difference in model performance was analyzed by the likelihood ratio (LR) test and the integrated discrimination improvement (IDI). Independence of the predictors was evaluated by the variance inflation factor (VIF). Discrimination and calibration was characterized by the c-statistic and calibration intercept / slope, respectively. RESULTS: Addition of lactate level to the GRACE 2.0 score improved the predictions of 30-day mortality significantly as assessed by both LR test (LR Chi-square = 8.7967, p = 0.0030) and IDI (IDI = 0.0685, p = 0.0402), suggesting that the expanded model may have better predictive ability than the GRACE 2.0 score. Furthermore, the VIF was 1.1203, indicating that the measured lactate values were independent of the calculated GRACE 2.0 scores. CONCLUSIONS: Our results suggest that admission venous lactate level and the GRACE 2.0 score may be independent and additive predictors of 30-day all-cause mortality of STEMI patients treated with primary PCI.