Recent advances in understanding schizophrenia

Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia. This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work). Despite the effort of many experts in the field, however, schizophrenia remains a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan. Comprehensive treatment entails a multi-modal approach, including psychopharmacology, psychosocial interventions, and assistance with housing and financial sustenance. Research to date suggests a network of genetic, neural, behavioral, and environmental factors to be responsible for its development and course. This article aims to summarize and explain recent advancements in research on schizophrenia, to suggest how these recent discoveries may lead to a better understanding and possible further development of effective therapies, and to highlight the paradigm shifts that have taken place in our understanding of the diagnosis, etiopathology, and treatment

Inflammation subtypes in psychosis and their relationships with genetic risk for psychiatric and cardiometabolic disorders

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n = 86 psychosis, n = 36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p = 0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR = 2.037, p = 0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness

Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders

Background: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. Methods: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. Results: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p \u3c 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). Conclusions: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders

Cardiac H11 kinase/Hsp22 stimulates oxidative phosphorylation and modulates mitochondrial reactive oxygen species production: Involvement of a nitric oxide-dependent mechanism.

International audienceH11 kinase/Hsp22 (Hsp22), a small heat shock protein upregulated by ischemia/reperfusion, provides cardioprotection equal to ischemic preconditioning (IPC) through a nitric oxide (NO)-dependent mechanism. A main target of NO-mediated preconditioning is the mitochondria, where NO reduces O(2) consumption and reactive oxygen species (ROS) production during ischemia. Therefore, we tested the hypothesis that Hsp22 overexpression modulates mitochondrial function through an NO-sensitive mechanism. In cardiac mitochondria isolated from transgenic (TG) mice with cardiac-specific overexpression of Hsp22, mitochondrial basal, ADP-dependent, and uncoupled O(2) consumption was increased in the presence of either glucidic or lipidic substrates. This was associated with a decrease in the maximal capabilities of complexes I and III to generate superoxide anion in combination with an inhibition of superoxide anion production by the reverse electron flow. NO synthase expression and NO production were increased in mitochondria from TG mice. Hsp22-induced increase in O(2) consumption was abolished either by pretreatment of TG mice with the NO synthase inhibitor l-N(G)-nitroarginine methyl ester (l-NAME) or in isolated mitochondria by the NO scavenger phenyltetramethylimidazoline-1-oxyl-3-oxide. l-NAME pretreatment also restored the reverse electron flow. After anoxia, mitochondria from TG mice showed a reduction in both oxidative phosphorylation and H(2)O(2) production, an effect partially reversed by l-NAME. Taken together, these results demonstrate that Hsp22 overexpression increases the capacity of mitochondria to produce NO, which stimulates oxidative phosphorylation in normoxia and decreases oxidative phosphorylation and reactive oxygen species production after anoxia. Such characteristics replicate those conferred by IPC, thereby placing Hsp22 as a potential tool for prophylactic protection of mitochondrial function during ischemia

Deep retinal layer microvasculature alterations in schizophrenia

A subset of individuals with schizophrenia (SZ) are thought to have a microvascular component to their illness with studies demonstrating alterations in retinal superficial, deep, and choroidal microvasculature networks. However, the direction and location of these alterations have differed across studies. In a recent study, we reported that individuals with SZ demonstrated lower superficial layer perfusion density than a healthy control (HC) group. The current study investigated characteristics of the deep vascular layer in SZ. We included 28 individuals with a diagnosis of SZ or schizoaffective disorder, and 37 HCs. Optical coherence tomography angiography (OCTA) data was collected to measure deep retinal layer perfusion density, skeletonized vessel density, vessel diameter index, and fractal dimension. We conducted between-group comparisons to examine differences in these OCTA variables between SZ and HC groups. A trend analysis was conducted to determine if differences reflected a linear trend according to age and illness length, and Spearman correlations were conducted to determine associations between deep and superficial layer density. Individuals with SZ demonstrated significantly lower bilateral perfusion density and vessel diameter index, as well as lower left eye skeletonized vessel density and fractal dimension. There was a significant linear trend in the data indicating that individuals with chronic SZ demonstrated the lowest OCTA values, followed by individuals within two years of their first episode of psychosis who did not differ from older controls, followed by younger controls, who demonstrated the highest values in at least one eye. Lower density values in the deep retinal layer were also significantly associated with lower density values in the superficial layer. Overall, results suggest that microvascular alterations are present in multiple retinal layers in SZ and that they may be useful visual system biomarkers of neurovascular changes in the disorder

Cálculo 2-CE85-201701

Este es un curso de formación general dirigido a los estudiantes de tercer ciclo para las carreras de ingeniería Industrial Civil Sistema de Información e ingeniería de Redes y Comunicación; de carácter teórico-práctico y se dicta en la modalidad blended; con él se busca desarrollar las siguientes competencias:Razonamiento cuantitativo: Proporciona la capacidad para operar interpretar representar y utilizar datos alfanuméricos para sacar conclusiones y construir argumentos basados en contenidos de la matemática. ABET Outcome (A1): Se busca aplicar conocimientos del cálculo matemático en la solución de los problemas relacionados a la Ingeniería

Cálculo 2-CE85-201702

Este es un curso de formación general dirigido a los estudiantes de tercer ciclo para las carreras de ingeniería Industrial Civil Sistema de Información e ingeniería de Redes y Comunicación; de carácter teórico-práctico y se dicta en la modalidad blended; con él se busca desarrollar las siguientes competencias:Razonamiento cuantitativo: Proporciona la capacidad para operar interpretar representar y utilizar datos alfanuméricos para sacar conclusiones y construir argumentos basados en contenidos de la matemática. ABET Outcome (A1): Se busca aplicar conocimientos del cálculo matemático en la solución de los problemas relacionados a la Ingeniería

Electroretinographic dysfunction, insulin resistance, and childhood trauma in early-course psychosis: A case-control exploratory study

Background: Electroretinographic dysfunction is observed in psychosis, with a-wave and b-wave amplitudes potentially serving as biomarkers. Insulin resistance (IR) and childhood trauma (CT) have also been associated with psychosis-spectrum disorders, particularly schizophrenia. Electroretinographic dysfunction in early-course psychosis (EP) lacks exploration. This case-control exploratory study aimed to understand electroretinographic dysfunction in EP and its relationship with IR and CT. Methods: The study involved healthy controls (n=13) and EP individuals (n=14) and included photopic and scotopic flash-electroretinography (fERG), blood collection for IR assessment, and the Childhood Trauma Questionnaire (CTQ). Data were analyzed using SPSS v.29.0. Case-control differences across fERG conditions were explored using repeated-measures ANCOVA (3 flash conditions X 2 groups) adjusted for gender and age. Sub-analyses included Fisher’s, Mann-Whitney, partial correlations, and logistic and linear regressions. Results: Compared to controls, EP participants showed (1) lower photopic a-wave and b-wave amplitudes, specifically in the left eye and under the P1 condition, (2) greater odds for IR, and (3) higher CTQ scores. IR was associated with a higher CTQ score and a lower P2b amplitude. A higher CTQ score was associated with lower P2b amplitude in the left eye when adjusting for its interacting effect with IR. Conclusion: These findings suggest lower photopic a-wave and b-wave amplitudes, IR, and CT are explanatory markers in EP. CT may dysregulate the hypothalamic-pituitary-adrenal axis, increasing the risk of experiencing later-life psychosis. IR might be a biomarker in psychosis, contributing to electroretinographic dysfunction and neurodegeneration of cone post-synaptic cells. Further investigations are needed

Effect of N-terminus mutant Hsp22 on mitochondrial respiration in intact neonatal rat cardiac myocytes.

<p>Mitochondrial respiration measured by Clark electrode in intact myocytes transfected with Ad-WT-Hsp22 or Ad-N20-Hsp22 compared to β-Gal. Mitochondrial respiration is presented on the left Y axis as OCR after addition of oligomycin and OCR after addition of FCCP, and, on the right Y axis, as the ratio of both rates (FCCP/oligomycin). *, P<0.05 versus β-Gal; #, P<0.05 vs Ad-WT-Hsp22. n = 5 per group.</p