The intersection of genome, epigenome and social experience in autism spectrum disorder: Exploring modifiable pathways for intervention.

The number of children diagnosed with autism spectrum disorder (ASD) has increased substantially over the past two decades. Current research suggests that both genetic and environmental risk factors are involved in the etiology of ASD. The goal of this paper is to examine how one specific environmental factor, early social experience, may be correlated with DNA methylation (DNAm) changes in genes associated with ASD. We present an innovative model which proposes that polygenic risk and changes in DNAm due to social experience may both contribute to the symptoms of ASD. Previous research on genetic and environmental factors implicated in the etiology of ASD will be reviewed, with an emphasis on the oxytocin receptor gene, which may be epigenetically altered by early social experience, and which plays a crucial role in social and cognitive development. Identifying an environmental risk factor for ASD (e.g., social experience) that could be modified via early intervention and which results in epigenetic (DNAm) changes, could transform our understanding of this condition, facilitate earlier identification of ASD, and guide early intervention efforts.

[Art and equality: Budapest Art Brut Gallery and PsychArt® 24 Art Marathon].

In our society, the perception of psychiatric patients is not favourable, and negative prejudices do not promote the social reintegration of the persons concerned. Many covert and overt stigmatisations and discriminations in the public mood, as in the public discourse and in the functioning of institutions repeatedly affect people with psychiatric illnesses, those involved in psychiatric treatment and psychiatric institutions. In 2009, the Moravcsik Foundation established the Budapest Art Brut Gallery (BAB Gallery) which provides a showcase for art brut and outsider artists, art therapy workshops and contemporary artists. The mission of the gallery is to contribute to a positive change in the social attitudes and prejudices towards people with mental illnesses and marginalised people, and to create equal opportunities in the cultural and artistic life. Another important mission of the gallery is to showcase and promote the works of art created by people with mental illnesses. The basic idea behind the creation of PsychArt® 24 is to bring participants closer together through joint creative work, using the language and expressive means of art, and to get to know each other's perspectives, thoughts and ways of seeing. The creative session which lasts for 24 hours in a shared space and the spontaneous unconditional communication create opportunities and help individuals with mental illnesses to distinguish between themselves and their illnesses with confidence, strengthen their social relationships and increase their self-esteem. Through the community of PsychArt® 24, opportunity, support and security are not only offered to people with a psychiatric illness, but also for the other participants who create with them and can experience the uplifting experience of being together and the removal of their prejudices and fears. The PsychArt® 24 Art Marathon anti-stigma programme helps to reduce prejudice against people with psychosocial disabilities and to create cultural equality through raising awareness.

The Best Approach for Patients with Stable Coronary Disease: The Importance of a Multidisciplinary Heart Team.

Background: A multidisciplinary Heart Team (HT) is nowadays considered to be of great importance for a complete and accurate assessment of patients with stable coronary disease (CAD). This study evaluates the role of the HT approach in the selection of best therapeutic strategies for patients with stable CAD. Methods: The study included 200 patients with stable coronary artery disease. The weekly HT meetings consisted of open discussion taking into consideration the latest recommended therapies. HT outcome options included medical therapy (MT), percutaneous coronary intervention (PCI), or surgical intervention (CABG). Following HT implementation, the 1-, 3-, and 6-month outcomes in addition to the distribution of baseline characteristics were assessed. Results: The following HT strategies were implemented: PCI - 46%, CABG - 10% and MT - 44% of patients. Patients selected for surgical treatment were more likely to have multi-vessel coronary disease (p=0.011). The survival rates at 6 months according to HT strategy were 96.8% for PCI, 95% for CABG, and 94.2% for MT. Conclusions: The HT multidisciplinary decision is mandatory for optimal patient care and can prevent specialty biases. Tertiary care institutions should develop and implement interdisciplinary protocols for common CAD cases.

The lack of aspirin resistance in patients with coronary artery disease.

BACKGROUND: Aspirin resistance established by different laboratory methods is still a debated problem. Using COX1 specific methods no aspirin resistance was detected among healthy volunteers. Here we tested the effect of chronic aspirin treatment on platelets from patients with stable coronary artery disease. The expression of COX2 mRNA in platelets and its influences on the effect of aspirin was also investigated. METHODS: One hundred and forty four patients were enrolled in the study. The direct measurement of COX1 acetylation was carried out by monoclonal antibodies specific to acetylated and non-acetylated COX1 (acCOX1 and nacCOX1) using Western blotting technique. Arachidonic acid (AA) induced TXB2 production by platelets was measured by competitive immunoassay. AA induced platelet aggregation, ATP secretion and VerifyNow Aspirin Assay were also performed. COX2 and COX1 mRNA expression in platelets were measured in 56 patients by RT-qPCR. RESULTS: In 138 patients only acCOX1 was detected, in the remaining six patients nacCOX1 disappeared after a compliance period. AA induced TXB2 production by platelets was very low in all patients including the 6 patients after compliance. AA induced platelet aggregation, secretion and with a few exceptions the VerifyNow Assay also demonstrated the effect of aspirin. Smoking, diabetes mellitus and inflammatory conditions did not influence the results. The very low amount of COX2 mRNA detected in 39 % of the investigated platelets did not influence the effect of aspirin. CONCLUSIONS: No aspirin resistance was detected among patients with stable coronary artery disease. COX2 expression in platelets did not influence the effect of aspirin.

How to test the effect of aspirin and clopidogrel in patients on dual antiplatelet therapy?

Dual antiplatelet therapy with clopidogrel and aspirin is frequently used for the prevention of recurrent ischemic events. Various laboratory methods are used to detect the effect of these drugs administered in monotherapy, however their value in dual therapy has not been explored. Here, we determined which methods used for testing the effect of clopidogrel or aspirin are influenced by the other antiplatelet agent. One arm of the study included 53 ischemic stroke patients being on clopidogrel monotherapy showing effective inhibition of the P2Y12 ADP receptor. Laboratory tests routinely used for the detection of aspirin resistance (arachidonic acid (AA)-induced platelet aggregation/secretion, AA-induced thromboxane B2 (TXB2) production in platelet-rich plasma and VerifyNow Aspirin assay) were carried out on samples obtained from these patients. The other arm of the study involved 52 patients with coronary artery disease being on aspirin monotherapy. Methods used for testing the effect of clopidogrel (ADP-induced platelet aggregation and secretion, flow cytometric analysis of vasodilator-stimulated phosphoprotein (VASP) phosphorylation and a newly developed P2Y12-specific platelet aggregation (ADP[PGE1] test)) were performed on samples obtained from these patients. Clopidogrel monotherapy significantly inhibited AA-induced platelet aggregation and secretion, moreover, AA-induced TXB2 production was also significantly decreased. VASP phosphorylation and AA-induced platelet aggregation showed fair correlation in patients taking clopidogrel only. Clopidogrel did not inhibit the VerifyNow Aspirin test significantly. Aspirin monotherapy influenced ADP-induced platelet aggregation and secretion, but did not have an effect on VASP phosphorylation and on the ADP[PGE1] platelet aggregation test.

[The role of art therapy in the rehabilitation of psycho-socially disabled people]. / A mövészetterápia szerepe a pszichoszociális fogyatékkal élok rehabilitációjában.

The present review focuses on the generally accepted and applied community psychiatry based models of psycho-social rehabilitation. The basics of the Strenghts model and the Recovery based model are introduced in this paper. Both models can be assisted by art therapy in various ways. The forms and the therapeutic factors of art therapy are also discussed, as well as the effects of the creating experience during the art therapy sessions. The authors introduce the good practice of the Moravcsik Foundation with highlights in two special areas that are beyond the generally applied art therapy work and representing important support in reaching the goals set during the rehabilitation process. Further, the authors describe the Budapest Art Brut Gallery and the PsychArt24 art marathon project in details.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Opening a portal to pleasure based sexual and reproductive health around the globe; a qualitative analysis and best practice development study.

Pleasure is often left out of sexual and reproductive health and rights (SRHR) interventions. The expanding evidence base suggests that the inclusion of pleasure can improve SRHR outcomes and increase safer sex practices. However, there is a lack of research into how to include pleasure in applied SRHR work, particularly outside of key groups. This study aims to present the experiences of a cohort of pleasure implementers and develop a series of implementation best practices. Data were gathered from a structured survey filled out by pleasure implementers (n = 8) twice between September 2021 and October 2022 at 6-month intervals. Focus group discussions (FGDs) were carried out remotely with pleasure implementers, those that funded their pleasure work (n = 2) or provided technical support (n = 2) in January 2023. Pleasure implementers, based in Central, East and Southern Africa and India, reported tangible outcomes of their pleasure-based work in various contexts and across diverse groups. Themes that emerged from analysis of the FGDs and survey responses included pleasure as a portal to positive outcomes, barriers to a pleasure approach, and mechanisms by which pleasure allows for open and non-judgmental discussion about sex and pleasure. A series of best practices emerged from pleasure implementer experiences. This study concludes that a pleasure-based approach can be introduced to a wide range of groups and communities, even those assumed too conservative to accept a pleasure approach. The best practices developed offer a range of practically driven recommendations, that others can lean on when integrating a pleasure approach into their work.

A Late-Detected Paraganglioma in a Young Patient with Resistant Hypertension and Severe Aortic Regurgitation-A Case Report and Review of the Literature.

BACKGROUND: Paraganglioma is a rare neuroendocrine tumor derived from chromaffin cells. The overproduction of catecholamines accounts for the presenting symptoms and cardiovascular complications. The clinical presentation frequently overlaps with the associated cardiac diseases, delaying the diagnosis. Multimodality imaging and a multidisciplinary team are essential for the correct diagnosis and adequate clinical management. CASE SUMMARY: A 37-year-old woman with a personal medical history of long-standing arterial hypertension and radiofrequency ablation for atrioventricular nodal reentry tachycardia presented with progressive exertional dyspnea and elevated blood pressure values, despite a comprehensive pharmacological treatment with six antihypertensive drugs. The echocardiography showed a bicuspid aortic valve and severe aortic regurgitation. The computed tomography angiography revealed a retroperitoneal space-occupying solid lesion, with imaging characteristics suggestive of a paraganglioma. The multidisciplinary team concluded that tumor resection should be completed first, followed by an aortic valve replacement if necessary. The postoperative histopathology examination confirmed the diagnosis of paraganglioma. After the successful resection of the tumor, the patient was asymptomatic, and the intervention for aortic valve replacement was delayed. DISCUSSION: This was a rare case of a late-detected paraganglioma in a young patient with resistant hypertension overlapping the clinical presentation and management of severe aortic regurgitation. A multimodality imaging approach including transthoracic and transesophageal echocardiography, computed tomography, and magnetic resonance imaging had an emerging role in establishing the diagnosis and in guiding patient management and follow-up. The resection of paraganglioma was essential for the optimal timing of surgical correction for severe aortic regurgitation. We further reviewed various cardiovascular complications induced by pheochromocytomas and paragangliomas.

Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder.

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

[Art therapy and "art brut"]. / Muvészetterapia és art brut.

The authors in this article explor the most important steps of the development of the research on the psychopathology of expression. They introduce the development of Art Brut and it's place in art history. They deal with the characteristics of art therapy.

The role of echocardiography in the diagnosis and management of a giant unruptured sinus of Valsalva aneurysm.

Sinus of Valsalva Aneurysm (SVA) is an aortic root anomaly, consisting of a lack of continuity between the aortic media and the aortic annulus, caused by a structural deficiency of muscular and elastic tissue. We present the case of a 49-year-oldman with atypical chest pain. Echocardiographic imaging described a giant unruptured aneurysm of the right sinus of Valsalva which was confirmed by cardiac computed tomography and coronary angiography. The obstruction of the right coronary artery without intravascular thrombosis and the compression of the right ventricular outflow tract with dynamic obstruction gradient represent the particularities of our case.

Pannus-related prosthetic valve dysfunction. Case report.

Pannus-related prosthetic valve dysfunction, a complication of mechanical prosthetic valve replacement, is rare, with a slowly progressive evolution, but it can be acute, severe, requiring surgical reintervention. We present the case of a patient with a mechanical single disc aortic prosthesis, with moderate prosthesis-patient mismatch, minor pannus found on previous ultrasound examinations, who presented to our service with angina pain with a duration of 1 hour, subsequently interpreted as non-ST segment elevation myocardial infarction (NSTEMI) syndrome. Coronarography showed normal epicardial coronary arteries, an ample movement of the prosthetic disc, without evidence of coronary thromboembolism, and Gated Single-Photon Emission Computerized Tomography (SPECT) with Technetium (Tc)-99m detected no perfusion defects. Transthoracic echocardiography (TTE) evidenced a dysfunctional prosthesis due to a subvalvular mass; transesophageal echocardiography (TOE) showed the interference of this mass, with a pannus appearance, with the closure of the prosthetic disc. Under conditions of repeated angina episodes, under anticoagulant treatment, surgery was performed, with the intraoperative confirmation of pannus and its removal. Postoperative evolution was favorable. This case reflects the diagnostic and therapeutic management problems of pannus-related prosthetic valve dysfunction.

Papillary fibroelastoma of the pulmonary valve: a case report.

Papillary fibroelastoma is a rare, benign cardiac tumor typically found on the heart valves, which is usually discovered incidentally on echocardiography. The clinical presentation of cardiac papillary fibroelastoma varies from no symptoms to severe embolic sequelae. We report the case of a 55-year-old female patient, with a suspicion of pulmonary embolism one year before, presently admitted to the hospital for mild respiratory symptoms; the trans-esophageal echocardiography (TEE) revealed a 10/10 mm tumoral mass attached on the pulmonary valve, confirmed also by the contrast-enhanced magnetic resonance imaging (MRI). Considering the embolization risk, we decided surgical removal, with favorable outcome. The pathologic exam of the removed tumor established the diagnosis of papillary fibroelastoma. The clinical and imaging assessment one month after surgery were within normal limits. The surgical removal of the papillary fibroelastoma of the pulmonary valve is mandatory for the elimination of embolization risk. The intervention is relatively secure, with low rates of morbidity and mortality.

Evaluation of laboratory methods routinely used to detect the effect of aspirin against new reference methods.

BACKGROUND: Aspirin, a commonly used antiplatelet agent, blocks platelet thromboxane A2 (TXA2) formation from arachidonic acid (AA) by acetylating platelet cyclooxygenase-1 (COX-1). Laboratory methods currently used to detect this antiplatelet effect of aspirin provide variable results. We have reported three methods that assess platelet COX-1 acetylation (inactivation) by aspirin and its direct consequences. The first and second assays use monoclonal anti-human-COX-1 antibodies that only detect acetylated (inactivated) COX-1 and active (non-acetylated) COX-1, respectively. The third method measures platelet production of TXB2 (the stable metabolite of TXA2) in vitro in response to AA. We compared the results of these three reference methods with other routinely used methods for assessing the functional consequences aspirin treatment. METHODS: 108 healthy volunteers were treated with low-dose aspirin for 7 days. On day 7 following aspirin treatment COX-1 in the platelets was fully acetylated whereas only non-acetylated COX-1 was present in the day 0 platelets. Further, TXB2 production by day 7 platelets was completely blocked. The following tests were performed on the samples obtained from study participants before and after seven days of aspirin treatment: PFA-100 closure time with collagen/epinephrine cartridge, VerifyNow (VN) Aspirin Assay, platelet aggregation and ATP secretion using AA, ADP, epinephrine and collagen as agonists. RESULTS: Comparing the pre-treatment and day 7 values, methods that use AA as platelet agonist (AA-induced platelet aggregation/secretion and VN Aspirin Assay) showed high discriminative power. In contrast, results of the other tests showed considerable overlap between day 7 and day 0 values. CONCLUSIONS: Only assays that clearly distinguish between acetylated and non-acetylated platelet COX-1 are useful for establishing the antiplatelet effect of aspirin. The other tests are not suitable for this purpose.

New direct and indirect methods for the detection of cyclooxygenase 1 acetylation by aspirin; the lack of aspirin resistance among healthy individuals.

BACKGROUND: Aspirin is widely used in the prevention of acute atherothrombotic complications. It acetylates Ser529 residue in cyclooxygenase-1 (COX-1) and prevents thromboxane A2 (TXA2) formation from arachidonic acid (AA) in platelets. Laboratory methods used for the detection of aspirin effect provide inconsistent results. METHODS: Two new methods were developed for the direct and indirect detection of COX-1 acetylation by aspirin in 108 healthy volunteers treated daily with 100mg enteric-coated aspirin for 7days. Monoclonal antibodies were raised against acetylated and non-acetylated nonapeptides corresponding to the amino acid sequence of human COX-1 525-533 residues. Using Western blotting technique the antibodies clearly distinguished between acetylated and non-acetylated COX-1 in platelet lysate. The second method measures AA-induced TXB2 production of platelets in diluted platelet rich plasma. RESULTS: No acetylated COX-1 was detected in platelets before aspirin treatment. At the same time antibodies raised against non-acetylated peptide gave intense reaction with COX-1 on the Western blot. In contrast, after 7days of aspirin treatment, with a single exception, only acetylated COX-1 could be detected in the platelet lysate. The non-responding volunteer showed full response to aspirin after controlled drug intake. In parallel experiments aspirin treatment for 7days practically completely inhibited AA-induced TXB2 production by platelets. CONCLUSIONS: Chemical ("true") aspirin resistance, if it exists, must be a rarity among healthy individuals. The new methods could be used for detecting the acetylation of COX-1 by aspirin in patients on preventive aspirin therapy and for evaluating methods routinely used for such purpose.