The long-term risk of recognized and unrecognized myocardial infarction for depression in older men.

BACKGROUND: The association between myocardial infarction (MI) and depression is well described. Yet, the underlying mechanisms are unclear and the contribution of psychological factors is uncertain. We aimed to determine the risk of recognized (RMI) and unrecognized (UMI) myocardial infections on depression, as both have a similar impact on cardiovascular health but differ in psychological epiphenomena. METHOD: Participants of the Rotterdam Study, 1823 men aged ⩾55 years, were followed for the occurrence of depression. RMI and UMI were ascertained using electrocardiography and medical history at baseline. We determined the strength of the association of RMI and UMI with mortality, and we studied the relationship of RMI and UMI with depressive symptoms and the occurrence of major depression. RESULTS: The risk of mortality was similar in men with RMI [adjusted hazard ratio (aHR) 1.71, 95% confidence interval (CI) 1.45-2.03] and UMI (aHR 1.58, 95% CI 1.27-1.97). Men with RMI had on average [unstandardized regression coefficient (B) 1.14, 95% CI 0.07-2.21] higher scores for depressive symptoms. By contrast, we found no clear association between UMI and depressive symptoms (B 0.55, 95% CI -0.51 to 1.62) in men. Analysis including occurrence of major depression as the outcome were consistent with the pattern of association. CONCLUSION: The discrepant association of RMI and UMI with mortality compared to depression suggests that the psychological burden of having experienced an MI contributes to the long-term risk of depression.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Cerebral small vessel disease is related to disturbed 24-h activity rhythms: a population-based study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is common in elderly persons. Patients with dementia or stroke frequently have cerebral small vessel disease and often experience disturbances in the sleep-wake rhythm. It is unknown whether cerebral small vessel disease is related to disturbances in sleep and 24-h activity rhythms. METHODS: This study was conducted in the Rotterdam Study. A total of 970 community-dwelling persons (mean age 59.2 years) underwent brain magnetic resonance imaging and actigraphy. Cerebral small vessel disease was defined as white matter lesions (total volume in millilitres) and the presence of cerebral microbleeds and lacunar infarcts. Twenty-four hour activity rhythms and sleep were measured with actigraphy by estimating the instability and fragmentation of the activity rhythm and total sleep time. Sleep quality was assessed with the Pittsburgh Sleep Quality Index. White matter lesions, instability, fragmentation and sleep quality were standardized for analyses. RESULTS: Higher white matter lesion volume (B = 0.09 per SD, 95% confidence interval 0.02; 0.15) and cerebral microbleeds (B = 0.19 per SD, 95% confidence interval 0.02; 0.37) were significantly related to more fragmented 24-h activity rhythms. None of the small vessel disease markers was related to total sleep time or sleep quality. CONCLUSIONS: White matter lesion volume and the presence of cerebral microbleeds are related to disturbed activity rhythms. This suggests that subclinical brain damage affects the 24-h activity rhythm.

DEcrease STress through RESilience training for Students (DESTRESS) Study: Protocol for a randomized controlled trial nested in a longitudinal observational cohort study.

INTRODUCTION: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress. METHODS AND ANALYSIS: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress. ETHICS AND REGISTRATION: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/.

Applications of neural networks in structure-activity relationships of a small number of molecules.

We investigated the applications of back propagation artificial neural networks (ANN) for a small dataset analysis in the field of structure-activity relationships. The derivatives of carboquinone were used as an example. It's been found that in this case the use of the same neural network results in unambiguous classification of new molecules. Predictions can be improved with statistical analysis of independent prognosis sets. We suggest that the sign criterion be used as a classification rule. We also compared neural networks with FALS and ALS in leave-one-out prediction. ANN applied to the same dataset has shown the same predictive ability as ALS but poorer than FALS.

HIV-1 reverse transcriptase inhibitor design using artificial neural networks.

Artificial neural networks were used to analyze and predict the human immunodeficiency virus type 1 reverse transcriptase inhibitors. The training and control sets included 44 molecules (most of them are well-known substances such as AZT, dde, etc.). The activities of the molecules were taken from literature. Topological indices were calculated and used as molecular parameters. The four most informative parameters were chosen and applied to predict activities of both new and control molecules. We used a network pruning algorithm and network ensembles to obtain the final classifier. Increasing of neural network generalization of the new data was observed, when using the aforementioned methods. The prognosis of new molecules revealed one molecule as possibly very active. It was confirmed by further biological tests.

The influence of pH alteration and pharmacological modulators of adenylate cyclase system on human serum albumin conformation.

The report describes the results of a study the effect of pH and binding of six physiologically active compounds (isoproterenol, yohimbine, theophylline, propranolol, clonidine and carbachol) on the molecular structure of human serum albumin (HSA) using dynamic light scattering. It was found that the albumin globule had the most compact configuration (Stokes diameter 59-62A) at physiological pH 7.4. The changes in pH both increased to 8.0 and decreased to 5.4, resulting in the growth of globule size to 72-81A. At acidic shift of pH an additional peak arose in the correlation spectra. This peak was caused by the light scattering on the structures with the Stokes diameters of 29-37A, which conformed to the sizes of the albumin subdomains. The additional peak was not displayed at basic shift of pH. The interaction with propranolol, clonidine and carbachol, which hinder adenylate cyclase (AdC) signaling system of a cell, initiated structural rearrangements similar to acidic transitions. Isoproterenol, yohimbine and theophylline, which activate AdC, caused the conformational changes of HSA similar to basic transitions.

Effects of haloperidol and chlorpromazine on smooth muscle contractility, platelet aggregation and neuronal calcium current.

Effects of chlorpromazine, haloperidol (neuroleptics and calmodulin antagonists), and verapamil on rat platelet aggregation induced by thrombin, on calcium current in snail neurones and on both tonic tension of high potassium contracture and phasic contraction of isolated guinea-pig ureter preparations were studied. Moreover, droperidol, sulpiride and prazosine effects were studied for models of phasic contractility and platelet aggregation. Sulpiride and prazosine were ineffective, verapamil was ineffective on platelet aggregation, while droperidol was the most potent inhibitor of platelet aggregation. These results, the similarity revealed in the blockage of neuronal calcium current by neuroleptics and verapamil, and the potent inhibitory action of haloperidol and chlorpromazine on contractility and aggregation suggest that both phenothiazine and butyrophenone neuroleptics possess some properties of calcium antagonists and may also have intracellular sites of action other than calmodulin.

Study of human serum albumin structure by dynamic light scattering: two types of reactions under different pH and interaction with physiologically active compounds.

The effect of pH and binding of ten physiologically active compounds (isoproterenol, yohimbine, propranolol, clonidine, phenylephrine, carbachol, tripeptide fMLP, diphenhydramine, chlorpromazine and atropine) on the molecular structure of human serum albumin (HSA) has been studied using the dynamic light scattering. It was found that albumin globule has the most compact configuration (Stokes diameter 59-62 A) at physiological pH 7.4. The changes in pH, both increase to 8.0 and decrease to 5.4, result in the growth of globule size to 72-81 A. At acidic shift of pH an additional peak arises in the correlation spectra caused by the light scattering on the structures with the Stokes diameters of 29-37 A. Those conform to the sizes of the albumin subdomains. The indicated peak is not displayed at basic shift of pH. The interaction with propranolol, clonidine, phenylephrine, carbachol and tripeptide fMLP which hinder adenylate cyclase (AdC) and activate Ca-polyphosphoinositide (Ca-PPI) signaling system of a cell initiates structural rearrangements similar to acidic transitions. Isoproterenol, yohimbine diphenhydramine, chlorpromazine and atropine, which activate AdC and hinder Ca-PPI, cause conformational changes of HSA similar to basic transitions.

[Application of neural networks using the volume learning algorithm for the study of structure-activity relationship in chemical compounds]. / Primenenie neironnykh setei, ispol'zuiushchikh algoritm prostranstvennogo obucheniia dlia issledovaniia sviazei struktura-aktivnost' khimicheskikh soedinenii.

A volume learning algorithm for artificial neural networks was developed to quantitatively describe the three-dimensional structure-activity relationships using as an example N-benzylpiperidine derivatives. The new algorithm combines two types of neural networks, the Kohonen and the feed-forward artificial neural networks, which are used to analyze the input grid data generated by the comparative molecular field approach. Selection of the most informative parameters using the algorithm helped to reveal the most important spatial properties of the molecules, which affect their biological activities. Cluster regions determined using the new algorithm adequately predicted the activity of molecules from a control data set.

[Evolutionary programming for finding "structure-activity" relationships in a series of 3-phenoxychromone and 3-phenoxy-4-hydroxycoumarin derivatives]. / Evoliutsionnoe programmirovanie dlia vyiavleniia zakonomernostei "struktura-aktivnost" v riadu proizvodnykh 3-fenoksikhromona i 3-fenoksi-4-gidroksikumarina.

Based on a set of compounds possessing hypolipidemic activity, it was demonstrated that evolutionary algorithms can be successfully used to compile an informative set of molecular parameters. The parameter sets selected using the method of potential functions allowed correct prediction of the activity of test molecules.

[The effect of the 5-lipoxygenase inhibitor quercetin on the functional and morphologic manifestations of myocardial lesions in ischemia and reperfusion of the heart]. / Vliianie blokatora 5-lipoksigenazy kvertsetina na funktsional'nye i morfologicheskie proiavleniia porazheniia miokarda pri ishemii i reperfuzii serdtsa.

In experimental canine myocardial infarction induced by an hour coronary artery occlusion, followed by 5-hour reperfusion, quercetin solution, 10 mg/kg, was demonstrated to improve left ventricular myocardial contractility, to reduce the incidence of rhythm and conduction disturbances, to promote the limitation of an ischemic lesion area, to produce a protective effect on the ultrastructure of coronary artery, contributing to the maintenance of vessel integrity, improvement of coronary blood flow, and prevention of intravascular thrombus formation.

[The principles of drug classification]. / Nekotorye printsipy klassifikatsii lekarstv.

The authors discuss a possibility of the design of the drug classification on the basis of their interaction with two systems of perception, conduction and realization of external signals by the cell. Review reciprocal interactions between the adenylate cyclase and polyphosphoinositide systems and the polytropic character of the action of biologically active substances within the limits of each system.

[Structural rearrangement in leukocyte membranes under the effect of quercetin and linoleic acid hydroxamate]. / [Strukturnye perestroiki v membranakh leikotsitov pri deistvii kvertsetina i gidroksamata linolevoi kisloty.

The character of structural rearrangements in leukocyte membranes affected by 5-lipoxygenase inhibitors: quercetin and linoleic acid hydroxamate, has been investigated. Quercetin has been shown to induce the translocation of tryptophanyls and tyrosyls from membrane protein inner regions to their surface. Linoleic acid hydroxamate produces the analogous transition of tyrosine residues only. Quercetin brings out disturbances of surface membrane proteins as was registered by ANS fluorescent parameters. It is likely able to arise from the increase of protein hydration. The linoleic acid hydroxamate elevates the quantity of ANS binding sites on the membrane surfaces without any change in their structural features. This effect is likely induced by the surface charge modification of the leukocyte membranes. The linoleic acid hydroxamate increases the level of protein descent into the lipid matrix and decreases the polarity and microviscosity of hydrophobic regions of the latter.

[Leukocyte mobility in modulation of activity of the cell signalling system]. / Izuchenie podvizhnosti leikotsitov v usloviiakh moduliatsii aktivnosti signal'nykh sistem kletki.

The mobility of the rat polymorphonuclear leukocytes (PMNL) has been studied. It was shown, that it is greatly determined by the balance of adenylate cyclase (AdC) and Ca-polyphosphoinositide (Ca-PPI) cell signalling systems. Various compounds whose action on the activity of the signalling systems was previously connected with the membrane receptors, proved to be capable to affect the activity of submembrane elements of these systems. It is concluded that multiple areas of bioregulators fixation within the limits of the signal cascades are available.

Ligand-receptor interactions. Multidimensional mathematical method of analysis.

The paper embraces information about the character of interaction between pharmacologically active ligands and 11 G-protein-dependent receptors of neurotransmitters. The data are analyzed by the methods of correlation and cluster analyses and of main components. An essential pharmacological affinity is revealed to exist between the receptors which regulate an inhibitory link of the adenylate cyclase system and receptors which activate Ca(2+)-mobilizing polyphosphoinositide system of secondary transmitters. Receptors which activate adenylate cyclase are rather different pharmacologically from two previous groups. Interrelation between the structure and physico-chemical properties of binding sites on receptors and efficiency of their interaction with ligand is discussed.

Mechanism of inhibiting effect of biologically active compounds on the active forms of oxygen reduction.

The impulse voltammetry methods with recording short-living radical-natured products of the reduction (in particular, hydroxyl radicals) are used to study the process of oxygen reduction steps. A possibility to study mechanisms of antioxidative action of biologically active compounds (BAC) through studying their influence on the separate steps of oxygen reduction (initial molecular oxygen, radical particles and peroxides) is shown. It provides a possibility for the purposeful search of BAC capable to affect certain steps of chain oxidation in biosystems.

Physico-chemical similarity of neurotransmitter receptor and transporter transmembrane domains.

Receptor and transporter of neurotransmitters similarity in ability of ligand-binding makes us consider them to possess the sites of similar structure and physico-chemical characteristics. However direct analysis of amino acid sequences alignment did not allow revealing such sites. For functionally similar proteins that differ in primary structure, the similarity extent is satisfactory estimated as based on physico-chemical properties of individual domain. We have analyzed transmembrane domains of a set of receptors and transporters of choline, norepinephrine, dopamine and serotonin. In our analysis in direction from extracellular border to intracellular one, amino acid sequences of transmembrane domains were divided into fragments each consisting of 4 amino acids. Every fragment was characterized by physico-chemical properties, such as hydrophilicity, hydrophobicity, polarity, etc. Hierarchical cluster analysis in space of the physico-chemical properties of these fragments was performed. As a result we have obtained both heterogeneous clusters, which contained receptor and transporter fragments, and homogeneous clusters which contained only receptor or transporter domains. An analysis of heterogeneous clusters has shown that the 4th, 5th and 6th transmembrane receptor domains and the 2d, 3d and 7th transmembrane transporter helices possess maximum similarity. The results obtained allow one to make a conclusion that these domains take part in formation of the ligand-binding centers.

[Effect of imipramine and ftoracizin on platelet aggregation and smooth muscle contraction of the ureter]. / Vliianie imipramina i ftoratsizina na agregatsiiu trombotsitov i sokratimost' gladkoi myshtsy mochetochnika.

The influence of the tricyclic antidepressants imipramine and ftoracizin on platelet aggregation and smooth muscle contractility was investigated in comparison with action of known smooth muscle relaxant and platelet aggregation inhibitor, papaverine. It has been shown that the tricyclic antidepressants possess potent spasmolytic activity but unlike papaverine have no effect on platelet aggregation. The biochemical mechanisms of the non-specific action of tricyclic antidepressants as well as some other structurally related-drugs are discussed.