Association of monoaminergic gene polymorphisms in chronic inflammatory pulmonary disease patients with successful smoking cessation.

BACKGROUND: Albeit smoking cessation has unequivocal health benefits, attempts to quit are not unanimous, even in patient populations at high risk for smoking-related diseases cessation. Allelic variations of enzymes involved in dopamine metabolism are being considered as candidates for nicotine addiction. We set out to assess whether rs4680 G/A and rs2235186 G/A polymorphisms of COMT and MAO-A, respectively are associated with the ability to quit smoking in chronic inflammatory pulmonary disease patients. METHODS: Patients managed for chronic inflammatory pulmonary disease by the Department of Pulmonology (University of Debrecen, Hungary), with a current or past smoking habit were included in the current analysis. The study was designed in line with the STROBE statement for cross-sectional studies and was approved by the National Center for Public Health, Hungary. Genomic DNA was extracted from peripheral blood specimens. SNPs were genotyped using TaqMan SNP genotyping assays. RESULTS: rs4680 COMT polymorphism showed significant effect for successful smoking cessation in patients with pulmonary disease. Accordingly, A/A subjects had lower odds for successful smoking cessation (odds ratio 0.37; 95% confidence interval 0.20-0.69, p = 0.002 (additive model). On the other hand, patients homozygous for the minor allele (A) at rs2235186 of MAO-A showed a non-significant trend toward increased odds for successful smoking cessation. CONCLUSIONS: The presence of the minor allele for rs4680 COMT was shown to decrease the odds for successful smoking cessation, a finding that may be interpreted in view of the altered balance between tonic and phasic dopamine release.

Mesocorticolimbic and Cardiometabolic Diseases-Two Faces of the Same Coin?

The risk behaviors underlying the most prevalent chronic noncommunicable diseases (NCDs) encompass alcohol misuse, unhealthy diets, smoking and sedentary lifestyle behaviors. These are all linked to the altered function of the mesocorticolimbic (MCL) system. As the mesocorticolimbic circuit is central to the reward pathway and is involved in risk behaviors and mental disorders, we set out to test the hypothesis that these pathologies may be approached therapeutically as a group. To address these questions, the identification of novel targets by exploiting knowledge-based, network-based and disease similarity algorithms in two major Thomson Reuters databases (MetaBase™, a database of manually annotated protein interactions and biological pathways, and IntegritySM, a unique knowledge solution integrating biological, chemical and pharmacological data) was performed. Each approach scored proteins from a particular approach-specific standpoint, followed by integration of the scores by machine learning techniques yielding an integrated score for final target prioritization. Machine learning identified characteristic patterns of the already known targets (control targets) with high accuracy (area under curve of the receiver operator curve was ~93%). The analysis resulted in a prioritized list of 250 targets for MCL disorders, many of which are well established targets for the mesocorticolimbic circuit e.g., dopamine receptors, monoamino oxidases and serotonin receptors, whereas emerging targets included DPP4, PPARG, NOS1, ACE, ARB1, CREB1, POMC and diverse voltage-gated Ca2+ channels. Our findings support the hypothesis that disorders involving the mesocorticolimbic circuit may share key molecular pathology aspects and may be causally linked to NCDs, yielding novel targets for drug repurposing and personalized medicine.

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far.

In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the "paradox" effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.

Acute stroke awareness of family physicians: translation of policy to practice.

BACKGROUND: Translating clinical guidelines into routine clinical practice is mandatory to achieve population level improvement of health. Emergence of specific therapy for acute stroke yielded the 'time is brain' concept introducing the need for emergency treatment, pointing to the need for increasing stroke awareness of the general population. General practitioners (GPs) manage chronic diseases and could hence catalyse stroke awareness. In our study, the knowledge of general practitioners toward accurate identification of acute stroke candidacy was investigated. METHODS: GPs and residents in training for family medicine participated in a survey on a voluntary basis using supervised self-administration between the 1st of February 2018 and 31st July 2018. Two clinical cases of acute stroke that differed only regarding the patient's eligibility for intravenous thrombolysis were presented. Participants answered two open-ended questions. Text analysis was performed using NVIVO software. RESULTS: Of the 127 respondents, 69 (54.3%) were female. The median age was 49 (34-62) years. The median time spent working after graduation was 14.5 (2-22.5) years. Board-certified GPs made up 77.2% of the sample. Qualitative analysis revealed stroke as the most frequent diagnosis for both cases. Territorial localization and possible aetiology were also established. Respondents properly identified eligibility for thrombolysis. Quantitative assessment showed that having the practice closer to the stroke centre increases the likelihood of adequate diagnosis for acute stroke. CONCLUSIONS: Our results show that GPs properly diagnose acute stroke and identify intravenous thrombolysis candidates. Moreover, we found that a vigorous acute stroke triage system facilitates the translation of theory into practice.

Socioeconomic Factors Predicting Depression Differ in the Acute Stage and at 1 year After Ischemic Stroke or TIA.

INTRODUCTION: Considerable depressive symptoms follow stroke in about one third of patients. Initial depressive symptoms may wane after the acute phase of stroke, but persisting depressive symptoms adversely affect rehabilitation and quality of life. We set forth to evaluate predictors of depressive symptoms with a focus on socioeconomic factors. METHODS: We evaluated clinical features and socioeconomic characteristics in 233 consecutive patients with acute ischemic stroke or TIA. Depressive symptoms could be evaluated in 168 subjects in the acute phase with a repeated testing after a mean of 14.7 months via telephone interview in 116 patients. Survival status, scores on the Center for Epidemiologic Studies-Depression Scale (CES-D), Beck Depression Inventory (BDI) and disability (modified Rankin scale, mRS) were recorded. RESULTS: In the acute phase, employment status (p = 0.037) and level of education (p = 0.048) whereas one year later dependency (mRS≥3, p = 0.002) and income (p = 0.012) were the significant predictors of the severity of depressive symptoms. A change from independent (mRS≤2) to dependent living predicted worsening depressive symptoms (p = 0.008), whereas improving to functional independence from an initially dependent condition was associated with diminishing depressive symptoms (p = 0.077 for CES-D and p = 0.044 for BDI) in the first year after an acute ischemic cerebrovascular event. CONCLUSIONS: Predictors of the severity of depressive symptoms differed in the acute phase and at follow-up. In addition to disability, education and employment status in the acute phase and income in the late phase predict the severity of depressive symptoms after ischemic stroke or TIA.

Altered irisin/BDNF axis parallels excessive daytime sleepiness in obstructive sleep apnea patients.

STUDY OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a sleep-related breathing disorder, characterized by excessive daytime sleepiness (EDS), paralleled by intermittent collapse of the upper airway. EDS may be the symptom of OSAHS per se but may also be due to the alteration of central circadian regulation. Irisin is a putative myokine and has been shown to induce BDNF expression in several sites of the brain. BDNF is a key factor regulating photic entrainment and consequent circadian alignment and adaptation to the environment. Therefore, we hypothesized that EDS accompanying OSAHS is reflected by alteration of irisin/BDNF axis. METHODS: Case history, routine laboratory parameters, serum irisin and BDNF levels, polysomnographic measures and Epworth Sleepiness Scale questionnaire (ESS) were performed in a cohort of OSAHS patients (n = 69). Simple and then multiple linear regression was used to evaluate data. RESULTS: We found that EDS reflected by the ESS is associated with higher serum irisin and BDNF levels; ß: 1.53; CI: 0.35, 6.15; p = 0.012 and ß: 0.014; CI: 0.0.005, 0.023; p = 0.02, respectively. Furthermore, influence of irisin and BDNF was significant even if the model accounted for their interaction (p = 0.006 for the terms serum irisin, serum BDNF and their interaction). Furthermore, a concentration-dependent effect of both serum irisin and BDNF was evidenced with respect to their influence on the ESS. CONCLUSIONS: These results suggest that the irisin-BDNF axis influences subjective daytime sleepiness in OSAS patients reflected by the ESS. These results further imply the possible disruption of the circadian regulation in OSAHS. Future interventional studies are needed to confirm this observation.

Accuracy and Precision of the Receptorial Responsiveness Method (RRM) in the Quantification of A1 Adenosine Receptor Agonists.

The receptorial responsiveness method (RRM) is a procedure that is based on a simple nonlinear regression while using a model with two variables (X, Y) and (at least) one parameter to be determined (cx). The model of RRM describes the co-action of two agonists that consume the same response capacity (due to the use of the same postreceptorial signaling in a biological system). While using RRM, uniquely, an acute increase in the concentration of an agonist (near the receptors) can be quantified (as cx), via evaluating E/c curves that were constructed with the same or another agonist in the same system. As this measurement is sensitive to the implementation of the curve fitting, the goal of the present study was to test RRM by combining different ways and setting options, namely: individual vs. global fitting, ordinary vs. robust fitting, and three weighting options (no weighting vs. weighting by 1/Y2 vs. weighting by 1/SD2). During the testing, RRM was used to estimate the known concentrations of stable synthetic A1 adenosine receptor agonists in isolated, paced guinea pig left atria. The estimates were then compared to the known agonist concentrations (to assess the accuracy of RRM); furthermore, the 95% confidence limits of the best-fit values were also considered (to evaluate the precision of RRM). It was found that, although the global fitting offered the most convenient way to perform RRM, the best estimates were provided by the individual fitting without any weighting, almost irrespective of the fact whether ordinary or robust fitting was chosen.

An Advanced In Silico Modelling of the Interaction between FSCPX, an Irreversible A1 Adenosine Receptor Antagonist, and NBTI, a Nucleoside Transport Inhibitor, in the Guinea Pig Atrium.

In earlier studies, we generated concentration-response (E/c) curves with CPA (N6-cyclopentyladenosine; a selective A1 adenosine receptor agonist) or adenosine, in the presence or absence of S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine (NBTI, a selective nucleoside transport inhibitor), and with or without a pretreatment with 8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)-benzoyloxy)propyl]-N1-propylxanthine (FSCPX, a chemical known as a selective, irreversible A1 adenosine receptor antagonist), in isolated, paced guinea pig left atria. Meanwhile, we observed a paradoxical phenomenon, i.e. the co-treatment with FSCPX and NBTI appeared to enhance the direct negative inotropic response to adenosine. In the present in silico study, we aimed to reproduce eight of these E/c curves. Four models (and two additional variants of the last model) were constructed, each one representing a set of assumptions, in order to find the model exhibiting the best fit to the ex vivo data, and to gain insight into the paradoxical phenomenon in question. We have obtained in silico evidence for an interference between effects of FSCPX and NBTI upon our ex vivo experimental setting. Regarding the mechanism of this interference, in silico evidence has been gained for the assumption that FSCPX inhibits the effect of NBTI on the level of endogenous (but not exogenous) adenosine. As an explanation, it may be hypothesized that FSCPX inhibits an enzyme participating in the interstitial adenosine formation. In addition, our results suggest that NBTI does not stop the inward adenosine flux in the guinea pig atrium completely.

FSCPX, a Chemical Widely Used as an Irreversible A1 Adenosine Receptor Antagonist, Modifies the Effect of NBTI, a Nucleoside Transport Inhibitor, by Reducing the Interstitial Adenosine Level in the Guinea Pig Atrium.

Based on in silico results, recently we have assumed that FSCPX, an irreversible A1 adenosine receptor antagonist, inhibits the action of NBTI that is apparent on E/c curves of adenosine receptor agonists. As a mechanism for this unexpected effect, we hypothesized that FSCPX might modify the equilibrative and NBTI-sensitive nucleoside transporter (ENT1) in a way that allows ENT1 to transport adenosine but impedes NBTI to inhibit this transport. This assumption implies that our method developed to estimate receptor reserve for agonists with short half-life such as adenosine, in its original form, overestimates the receptor reserve. In this study, therefore, our goals were to experimentally test our assumption on this effect of FSCPX, to improve our receptor reserve-estimating method and then to compare the original and improved forms of this method. Thus, we improved our method and assessed the receptor reserve for the direct negative inotropic effect of adenosine with both forms of this method in guinea pig atria. We have found that FSCPX inhibits the effects of NBTI that are mediated by increasing the interstitial concentration of adenosine of endogenous (but not exogenous) origin. As a mechanism for this action of FSCPX, inhibition of enzymes participating in the interstitial adenosine production can be hypothesized, while modification of ENT1 can be excluded. Furthermore, we have shown that, in comparison with the improved form, the original version of our method overestimates receptor reserve but only to a small extent. Nevertheless, use of the improved form is recommended in the future.

Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life.

The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation of a submaximal fraction of receptors can apparently elicit the maximal effect (in certain cases), provides an opportunity to assess the receptor reserve. However, determining receptor reserve is challenging for agonists with short half-lives, such as adenosine. Although adenosine metabolism can be inhibited several ways (in order to prevent the rapid elimination of adenosine administered to construct concentration-effect (E/c) curves for the determination), the consequent accumulation of endogenous adenosine biases the results. To address this problem, we previously proposed a method, by means of which this bias can be mathematically corrected (utilizing a traditional receptor theory-independent approach). In the present investigation, we have offered in silico validation of this method by simulating E/c curves with the use of the operational model of agonism and then by evaluating them using our method. We have found that our method is suitable to reliably assess the receptor reserve for adenosine in our recently published experimental setting, suggesting that it may be capable for a qualitative determination of receptor reserve for rapidly eliminating agonists in general. In addition, we have disclosed a possible interference between FSCPX (8-cyclopentyl-N³-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N¹-propylxanthine), an irreversible A1 adenosine receptor antagonist, and NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, i.e., FSCPX may blunt the effect of NBTI.

'Proactive' use of cue-context congruence for building reinforcement learning's reward function.

BACKGROUND: Reinforcement learning is a fundamental form of learning that may be formalized using the Bellman equation. Accordingly an agent determines the state value as the sum of immediate reward and of the discounted value of future states. Thus the value of state is determined by agent related attributes (action set, policy, discount factor) and the agent's knowledge of the environment embodied by the reward function and hidden environmental factors given by the transition probability. The central objective of reinforcement learning is to solve these two functions outside the agent's control either using, or not using a model. RESULTS: In the present paper, using the proactive model of reinforcement learning we offer insight on how the brain creates simplified representations of the environment, and how these representations are organized to support the identification of relevant stimuli and action. Furthermore, we identify neurobiological correlates of our model by suggesting that the reward and policy functions, attributes of the Bellman equitation, are built by the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), respectively. CONCLUSIONS: Based on this we propose that the OFC assesses cue-context congruence to activate the most context frame. Furthermore given the bidirectional neuroanatomical link between the OFC and model-free structures, we suggest that model-based input is incorporated into the reward prediction error (RPE) signal, and conversely RPE signal may be used to update the reward-related information of context frames and the policy underlying action selection in the OFC and ACC, respectively. Furthermore clinical implications for cognitive behavioral interventions are discussed.

[THE IMPORTANCE OF ANTICOAGULANT THERAPY IN PATIENTS WITH ARTIAL FIBRILLATION IN STROKE PREVENTION--SUMMARY OF INTERNATIONAL DATA AND NOVEL THERAPEUTIC MODALITIES]. / A PITVARFIBRILLÁLÓ BETEGEK ANTIKOAGULÁNS KEZELÉSÉNEK JELENTOSÉGE A STROKE MEGELOZÉSÉBEN--A NEMZETKÖZI ADATOK ÉS AZ ÚJABB TERÁPIÁS LEHETOSÉGEK ÁTTEKINTÉSE.

The most common cardiogenic cause of ischaemic stroke is atrial fibrillation which increases the probability of stroke five-fold and doubles case fatality. Based on international data the incidence of atrial fibrillation is approx. 2% however this rapidly increases with age. The necessity of using oral anticoagulants in the prevention of non-valvular atrial fibrillation related stroke is decided based on estimated stroke risk. The CHADS2 and the more predictive CHA2DS2-VASc scales are used for this purpose while the bleeding risk of patients treated with anticoagulant may be estimated by the HAS-BLED scoring scale. For decades oral anticoagulation meant using vitamin-K antagonists. Based on international data we can see that rate of anticoagulation is unacceptably low, furthermore most of the anticoagulated patients aren't within the therapeutic range of INR (INR: 2-3). A lot of disadvantages of vitamin-K antagonists are known (e.g. food-drug interaction, need for regular coagulation monitoring, increased risk of bleeding), therefore compounds with new therapeutic target have been developed. The novel oral anticoagulants (NOAC) can be divided in two major subgroups: direct thrombin inhibitors (dabigatran etexilate) and Xa-factor inhibitors (rivaroxaban, apixaban, edoxaban). These products are administered in fix doses, they less frequently interact with other medications or food, and regular coagulation monitoring is not needed when using these drugs. Moreover several studies have shown that they are at least as effective in the prevention of ischaemic stroke than the vitamin-K antagonists, with no more haemorrhagic complications.

Inhibition of TRPC6 by protein kinase C isoforms in cultured human podocytes.

Transient receptor potential canonical-6 (TRPC6) ion channels, expressed at high levels in podocytes of the filtration barrier, are recently implicated in the pathogenesis of various forms of proteinuric kidney diseases. Indeed, inherited or acquired up-regulation of TRPC6 activities are suggested to play a role in podocytopathies. Yet, we possess limited information about the regulation of TRPC6 in human podocytes. Therefore, in this study, we aimed at defining how the protein kinase C (PKC) system, one of the key intracellular signalling pathways, regulates TRPC6 function and expression. On human differentiated podocytes, we identified the molecular expressions of both TRPC6 and several PKC isoforms. We also showed that TRPC6 channels are functional since the TRPC6 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) induced Ca(2+) -influx to the cells. By assessing the regulatory roles of the PKCs, we found that inhibitors of the endogenous activities of classical and novel PKC isoforms markedly augmented TRPC6 activities. In contrast, activation of the PKC system by phorbol 12-myristate 13-acetate (PMA) exerted inhibitory actions on TRPC6 and suppressed its expression. Importantly, PMA treatment markedly down-regulated the expression levels of PKCα, PKCß, and PKCη reflecting their activation. Taken together, these results indicate that the PKC system exhibits a 'tonic' inhibition on TRPC6 activity in human podocytes suggesting that pathological conditions altering the expression and/or activation patterns of podocyte-expressed PKCs may influence TRPC6 activity and hence podocyte functions. Therefore, it is proposed that targeted manipulation of certain PKC isoforms might be beneficial in certain proteinuric kidney diseases with altered TRPC6 functions.

Operatic voices engage the default mode network in professional opera singers.

Extensive research with musicians has shown that instrumental musical training can have a profound impact on how acoustic features are processed in the brain. However, less is known about the influence of singing training on neural activity during voice perception, particularly in response to salient acoustic features, such as the vocal vibrato in operatic singing. To address this gap, the present study employed functional magnetic resonance imaging (fMRI) to measure brain responses in trained opera singers and musically untrained controls listening to recordings of opera singers performing in two distinct styles: a full operatic voice with vibrato, and a straight voice without vibrato. Results indicated that for opera singers, perception of operatic voice led to differential fMRI activations in bilateral auditory cortical regions and the default mode network. In contrast, musically untrained controls exhibited differences only in bilateral auditory cortex. These results suggest that operatic singing training triggers experience-dependent neural changes in the brain that activate self-referential networks, possibly through embodiment of acoustic features associated with one's own singing style.

The influence of the way of regression on the results obtained by the receptorial responsiveness method (RRM), a procedure to estimate a change in the concentration of a pharmacological agonist near the receptor.

The receptorial responsiveness method (RRM) enables the estimation of a change in concentration of an (even degradable) agonist, near its receptor, via curve fitting to (at least) two concentration-effect (E/c) curves of a stable agonist. One curve should be generated before this change, and the other afterwards, in the same system. It follows that RRM yields a surrogate parameter ("cx") as the concentration of the stable agonist being equieffective with the change in concentration of the other agonist. However, regression can be conducted several ways, which can affect the accuracy, precision and ease-of-use. This study utilized data of previous ex vivo investigations. Known concentrations of stable agonists were estimated with RRM by performing individual (local) or global fitting, this latter with one or two model(s), using a logarithmic (logcx) or a nonlogarithmic (cx) parameter (the latter in a complex or in a simplified equation), with ordinary least-squares or robust regression, and with an "all-at-once" or "pairwise" fitting manner. We found that the simplified model containing logcx was superior to all alternative models. The most complicated individual regression was the most accurate, followed closely by the moderately complicated two-model global regression and then by the easy-to-perform one-model global regression. The two-model global fitting was the most precise, followed by the individual fitting (closely) and by the one-model global fitting (from afar). Pairwise fitting (two E/c curves at once) improved the estimation. Thus, the two-model global fitting, performed pairwise, and the individual fitting are recommended for RRM, using the simplified model containing logcx.

The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine.

Although the A1 adenosine receptor (A1 receptor), the main adenosine receptor type in cardiac muscle, is involved in powerful cardioprotective processes such as ischemic preconditioning, the atrial A1 receptor reserve has not yet been quantified for the direct negative inotropic effect of adenosine. In the present study, adenosine concentration-effect (E/c) curves were constructed before and after pretreatment with FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 receptor antagonist, in isolated guinea pig atria. To prevent the intracellular elimination of the administered adenosine, NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, was used. As expected, NBTI alone and FSCPX-pretreatment alone shifted the adenosine E/c curve to the left and right, respectively. However, in the presence of NBTI, FSCPX-pretreatment appeared to increase the maximal response to adenosine. By means of the receptorial responsiveness method (RRM), our recently developed procedure, adenosine E/c curves generated in the presence of NBTI were corrected for the bias caused by the endogenous adenosine accumulated by NBTI. The corrected curves indicate a substantial A1 receptor reserve for the direct negative inotropy evoked by adenosine. In addition, our results suggest that accumulation of an endogenous agonist may bias the E/c curve constructed with the same or similar agonist that can lead to seemingly paradoxical results.

Thyroid hormones decrease the affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a competitive antagonist, for the guinea pig atrial A(1) adenosine receptor.

The aim of the present study was to investigate whether or not thyroxine (T(4)) treatment affects K(B), the equilibrium dissociation constant of the antagonist-receptor complex, for the interaction between CPX, a selective and competitive orthosteric antagonist, and the guinea pig atrial A1 adenosine receptor A1 receptor). The inotropic response to adenosine, a nonselective adenosine receptor agonist, or CPA, a selective A1 receptor agonist, was investigated in the absence or presence of CPX in paced left atria isolated from 8-day solvent- or T(4)-treated guinea pigs. To obtain K(B) values, adenosine and CPA concentration-response curves were evaluated by Schild analysis. CPA but not adenosine obeyed the requirements of the Schild analysis to provide correct K(B) values for CPX. According to the CPA concentration-response curves, affinity of CPX for the hyperthyroid guinea pig atrial A1 receptor (K(B) = 44.16 nM) was lower than that for the euthyroid one (K(B) = 16.63 nM). Regarding the intense reduction in the negative inotropic effect of adenosine and CPA in hyperthyroid atria, it is reasonable to assume that the moderate decrease in affinity of the guinea pig atrial A1 receptor is only in part responsible for the diminished A1 receptor-mediated effect in hyperthyroidism.

An Exploratory Assessment of Factors with Which Influenza Vaccine Uptake Is Associated in Hungarian Adults 65 Years Old and Older: Findings from European Health Interview Surveys.

Influenza vaccination is an imperative public health task for elderly people due to a higher risk of developing more severe complications. The main aim of our study was to determine the influencing factors of being vaccinated against influenza among subjects aged 65 and above. Data were from the Hungarian implementations of the European Health Interview Survey 2009, 2014 and 2019 studies with a final sample size of 3355. A multivariate logistic regression model with interactions was used to identify the possible factors associated with vaccination. Approximately 32% of the participants were vaccinated for the most recent influenza season. The most important factors were identified that contributed to influenza vaccination among individuals, which were the following: educational attainment, having a partner, the annual frequency of specialist and doctor visits, and having comorbidities. Respondents who thought that they could do a lot for their health had higher odds of being immunized. Being obese seemed to be a risk factor. According to our findings, the current influenza vaccination coverage was considered as low in Hungary; hence, the implementation of minor reformulations in the field of health policy is suggested.

The effect of a long-term treatment with cannabidiol-rich hemp extract oil on the adenosinergic system of the zucker diabetic fatty (ZDF) rat atrium.

Cannabidiol (CBD), the most extensively studied non-intoxicating phytocannabinoid, has been attracting a lot of interest worldwide owing to its numerous beneficial effects. The aim of this study was to explore the effect that CBD exerts on the adenosinergic system of paced left atria isolated from obese type Zucker Diabetic Fatty (ZDF) rats, maintained on diabetogenic rat chow, received 60 mg/kg/day CBD or vehicle via gavage for 4 weeks. We found that N6-cyclopentyladenosine (CPA), a relatively stable and poorly transported A1 adenosine receptor agonist, elicited a significantly weaker response in the CBD-treated group than in the vehicle-treated one. In contrast, adenosine, a quickly metabolized and transported adenosine receptor agonist, evoked a significantly stronger response in the CBD-treated group than in the vehicle-treated counterpart (excepting its highest concentrations). These results can be explained only with the adenosine transport inhibitory property of CBD (and not with its adenosine receptor agonist activity). If all the effects of CBD are attributed to the interstitial adenosine accumulation caused by CBD in the myocardium, then a significantly increased adenosinergic activation can be assumed during the long-term oral CBD treatment, suggesting a considerably enhanced adenosinergic protection in the heart. Considering that our results may have been influenced by A1 adenosine receptor downregulation due to the chronic interstitial adenosine accumulation, an adenosinergic activation smaller than it seemed cannot be excluded, but it was above the CBD-naïve level in every case. Additionally, this is the first study offering functional evidence about the adenosine transport inhibitory action of CBD in the myocardium.

Postischemic cardiac recovery in heme oxygenase-1 transgenic ischemic/reperfused mouse myocardium.

Heme oxygenase-1 (HO-1) transgenic mice (Tg) were created using a rat HO-1 genomic transgene. Transgene expression was detected by RT-PCR and Western blots in the left ventricle (LV), right ventricle (RV) and septum (S) in mouse hearts, and its function was demonstrated by the elevated HO enzyme activity. Tg and non-transgenic (NTg) mouse hearts were isolated and subjected to ischemia/reperfusion. Significant post-ischemic recovery in coronary flow (CF), aortic flow (AF), aortic pressure (AOP) and first derivative of AOP (AOPdp/dt) were detected in the HO-1 Tg group compared to the NTg values. In HO-1 Tg hearts treated with 50 µmol/kg of tin protoporphyrin IX (SnPPIX), an HO enzyme inhibitor, abolished the post-ischemic cardiac recovery. HO-1 related carbon monoxide (CO) production was detected in NTg, HO-1 Tg and HO-1 Tg + SnPPIX treated groups, and a substantial increase in CO production was observed in the HO-1 Tg hearts subjected to ischemia/reperfusion. Moreover, in ischemia/reperfusion-induced tissue Na(+) and Ca(2+) gains were reduced in HO-1 Tg group in comparison with the NTg and HO-1 Tg + SnPPIX treated groups; furthermore K(+) loss was reduced in the HO-1 Tg group. The infarct size was markedly reduced from its NTg control value of 37 ± 4% to 20 ± 6% (P < 0.05) in the HO-1 Tg group, and was increased to 47 ± 5% (P < 0.05) in the HO-1 knockout (KO) hearts. Parallel to the infarct size reduction, the incidence of total and sustained ventricular fibrillation were also reduced from their NTg control values of 92% and 83% to 25% (P < 0.05) and 8% (P < 0.05) in the HO-1 Tg group, and were increased to 100% and 100% in HO-1 KO(-/-) hearts. Immunohistochemical staining of HO-1 was intensified in HO-1 Tg compared to the NTg myocardium. Thus, the HO-1 Tg mouse model suggests a valuable therapeutic approach in the treatment of ischemic myocardium.