Homocysteine and cognition: A systematic review of 111 studies

BACKGROUND: Elevated plasma homocysteine ??(Hcy) levels have been associated with cognitive dysfunction in a wide range of conditions. The aim of this review is to establish which cognitive domains and populations are the most affected. METHODS: We systematically review the literature and consider all articles that showed any relationship between plasma Hcy levels and scores achieved on cognitive performance tests in both, the general population and patients suffering from central nervous system disorders and other diseases. When effect sizes were available and combinable, several meta-analyses were performed. RESULTS: We found 111 pertinent articles. There were 24 cohort studies, 18 randomized trials, 21 case-control studies, and 48 cross-sectional studies. This review reveals a positive trend between cognitive decline and increased plasma Hcy concentrations in general population and in patients with cognitive impairments. Results from the meta-analyses also confirm this trend. Treatment with vitamin supplementation fails to show a reduction in cognitive decline. DISCUSSION: Further investigations are warranted to clarify this relationship. Earlier detection of the elevated Hcy levels may be an effective intervention to prevent cognitive impairment and dementia

Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatment

This study examines the association between insulin resistance, schizophrenia polygenic risk, and treatment outcomes in first-episode, antipsychotic-naive patients with schizophrenia.Funding/Support: This work was supported by grants from the Stanley Medical Research Institute (Dr Bahn)

Peripheral lymphocyte signaling pathway deficiencies predict treatment response in first-onset drug-naïve schizophrenia

Despite being a major cause of disability worldwide, the pathophysiology of schizophrenia and molecular basis of treatment response heterogeneity continue to be unresolved. Recent evidence suggests that multiple aspects of pathophysiology, including genetic risk factors, converge on key cell signaling pathways and that exploration of peripheral blood cells might represent a practical window into cell signaling alterations in the disease state. We employed multiplexed phospho-specific flow cytometry to examine cell signaling epitope expression in peripheral blood mononuclear cell (PBMC) subtypes in drug-naïve schizophrenia patients (n = 49) relative to controls (n = 61) and relate these changes to serum immune response proteins, schizophrenia polygenic risk scores and clinical effects of treatment, including drug response and side effects, over the longitudinal course of antipsychotic treatment. This revealed both previously characterized (Akt1) and novel cell signaling epitopes (IRF-7 (pS477/pS479), CrkL (pY207), Stat3 (pS727), Stat3 (pY705) and Stat5 (pY694)) across PBMC subtypes which were associated with schizophrenia at disease onset, and correlated with type I interferon-related serum molecules CD40 and CXCL11. Alterations in Akt1 and IRF-7 (pS477/pS479) were additionally associated with polygenic risk of schizophrenia. Finally, changes in Akt1, IRF-7 (pS477/pS479) and Stat3 (pS727) predicted development of metabolic and cardiovascular side effects following antipsychotic treatment, while IRF-7 (pS477/pS479) and Stat3 (pS727) predicted early improvements in general psychopathology scores measured using the Brief Psychiatric Rating Scale (BPRS). These findings suggest that peripheral blood cells can provide an accessible surrogate model for intracellular signaling alterations in schizophrenia and have the potential to stratify subgroups of patients with different clinical outcomes or a greater risk of developing metabolic and cardiovascular side effects following antipsychotic therapy

A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. CONCLUSION: DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorde

Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone

Background: Different effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. Method: From February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. A total of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n=55), risperidone (n=63), haloperidol (n=56), aripiprazole (n=78), ziprasidone (n=62), or quetiapine (n=62) and followed up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3 years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine=69.09, risperidone=71.43, aripiprazole=73.08%, ziprasidone=79.03%, haloperidol=89.28%, and quetiapine=95.53%) (x2=79.86; P=.000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank=92.240; P=.000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea. Conclusions: Olanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis

Validating prognostic surgical site infection indices from hospitals in Colombia

Objetivo Establecer la capacidad predictiva para infección del sitio quirúrgico (ISQ) de los índices de riesgo del National Nosocomial Infections Surveillance System (NNIS) y Study on the Efficacy of Nosocomial Infection Control (SENIC) en cinco hospitales y, evaluar la capacidad predictiva de otros factores de riesgo. Métodos Cohorte prospectiva de pacientes sometidos a cirugía entre julio de 2006 a febrero de 2007 en cinco hospitales de Colombia. Se definió ISQ según los criterios del CDC. Se evaluaron variables como: edad, género, coomorbilidad, tipo de cirugía, herida, especialidad, tiempo quirúrgico y desenlace. Se evaluó el desempeño operativo de los índices usando el área bajo la curva operador receptor; se construyó un modelo predictivo usando un modelo de regresión logística incondicional con las variables asociadas a infección en el análisis bivariado y/o aquellas conocidas por estudios previos. Resultados Fueron evaluados 7 022 procedimientos quirúrgicos con una tasa de ISQ de 2,9 %. El rendimiento de los índices de riesgo NNIS y SENIC fue muy similar para predecir ISQ (área bajo la curva de 0,682 IC95 % 0,641-0,710 y 0,668 IC95 % 0.641-0.722, respectivamente). Se construyó un modelo predictivo que incluía variables del NNIS y SENIC, además de edad, antecedente de diabetes, transfusiones y especialidad quirúrgica el cual mostró un desempeño de 0,746 (IC95 % 0,709-0,783), en ISQ superficial de 0,70 (IC95 % 0,659-0,741), en ISQ profunda de 0,712 (IC95 % 0,673-0,751) y en ISQ órgano espacio de 0,719 (IC95 % 0,683-0,755). Conclusiones Los modelos de predicción existentes para ISQ tienen una moderada capacidad discriminativa pero pueden ser mejorados con algunos factores locales.Objective Establishing the effectiveness of the National Nosocomial Infection Surveillance System (NNIS) and Study of the Efficacy of Nosocomial Infection Control’s (SENIC) prognostic surgical site infection (SSI) indices in Colombian hospitals and assessing the influence of other risk factors. Methods A prospective, multicentre cohort study was conducted in five Colombian hospitals. All patients undergoing surgery requiring hospitalisation or ambulatory surgeries having a greater risk of infection were enrolled. A case was defined as being those subjects who presented the CDC diagnostic criteria of incisional superficial, deep incisional or organ-space SSI. Age, gender, co-morbidities, type of surgery, procedures, medical specialty, type of wound, surgical time, antibiotic prophylaxis and patient outcome were used for developing a predictive model of SSI using logistical regression analysis. The indexes’ predictive ability was assessed by using the area under the receiver operating curve (ROC). Results 7,022 surgical procedures were evaluated and SSI rate was 2.9%. NNIS and SENIC risk index performance was similar to that for predicting SSI (0.68 cf 0.66 area under ROC, respectively). The new predictive model involved other factors such as age, diabetes mellitus, transfusions and surgical specialty showing 0.74 operating performance. Conclusions Existing SSI predictive models have a moderate ability for predicting SSI but this can be improved with some local factors

Understanding sex differences in long-term outcomes after a first episode of psychosis

While sex differences in schizophrenia have long been reported and discussed, long-term sex differences in outcomes among first episode of psychosis (FEP) patients in terms of the efficacy of Early Intervention Services (EIS) has been an under-explored area. A total of 209 FEP patients (95 females and 114 males) were reassessed after a time window ranging from 8 to 16 years after their first contact with an EIS program (PAFIP) that we will call the 10-year PAFIP cohort. Multiple clinical, cognitive, functioning, premorbid, and sociodemographic variables were explored at 1-year, 3-year and 10-year follow-ups. At first contact, females were older at illness onset, had higher premorbid adjustment and IQ, and were more frequently employed, living independently, and accompanied by a partner and/or children. Existence of a schizophrenia diagnosis, and cannabis and alcohol consumption were more probable among men. During the first 3 years, women showed a significantly better response to minimal antipsychotic dosages and higher rates of recovery than men (50% vs. 30.8%). Ten years later, more females continued living independently and had partners, while schizophrenia diagnoses and cannabis consumption continued to be more frequent among men. Females also presented a lower severity of negative symptoms; however, functionality and recovery differences did not show significant differences (46.7% vs. 34.4%). Between the 3- and 10-year follow-up sessions, an increase in dosage of antipsychotics was observed. These results suggest that the better outcomes seen among women during the first 3 years (while they were treated in an EIS) were in the presence of more favourable premorbid and baseline characteristics. After an average period of 10 years, with the only difference being in negative symptoms course, outcomes for women approximated those of men, drawing particular attention to the increase in dosage of antipsychotic medication once FEP patients were discharged from the EIS program towards community-based services. These findings help to pose the question of whether it is advisable to target sexes and lengthen EIS interventions

Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3?) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase C?1-calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions

Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

A significant proportion of the personal and economic burden of schizophrenia can be attributed to the late diagnosis or misdiagnosis of the disorder. A novel, objective diagnostic approaches could facilitate the early detection and treatment of schizophrenia and improve patient outcomes. In the present study, we aimed to identify robust schizophrenia-specific blood biomarkers, with the goal of developing an accurate diagnostic model. The levels of selected serum and peripheral blood mononuclear cell (PBMC) markers relevant to metabolic and immune function were measured in healthy controls (n?=?26) and recent-onset schizophrenia patients (n?=?36) using multiplexed immunoassays and flow cytometry. Analysis of covariance revealed significant upregulation of insulin receptor (IR) and fatty acid translocase (CD36) levels in T helper cells (F?=?10.75, P?=?0.002, Q?=?0.024 and F?=?21.58, P?=?2.8?×?10?5, Q?=?0.0004, respectively), as well as downregulation of glucose transporter 1 (GLUT1) expression in monocytes (F?=?21.46, P?=?2.9?×?10?5, Q?=?0.0004). The most robust predictors, monocyte GLUT1 and T helper cell CD36, were used to develop a diagnostic model, which showed a leave-one-out cross-validated area under the receiver operating characteristic curve (AUC) of 0.78 (95% CI: 0.66?0.92). The diagnostic model was validated in two independent datasets. The model was able to distinguish first-onset, drug-naïve schizophrenia patients (n?=?34) from healthy controls (n?=?39) with an AUC of 0.75 (95% CI: 0.64?0.86), and also differentiated schizophrenia patients (n?=?22) from patients with other neuropsychiatric conditions, including bipolar disorder, major depressive disorder and autism spectrum disorder (n?=?68), with an AUC of 0.83 (95% CI: 0.75?0.92). These findings indicate that PBMC-derived biomarkers have the potential to support an accurate and objective differential diagnosis of schizophrenia.ACKNOWLEDGEMENTS: We are grateful to the participants and their families for their cooperation in this study. We would like to thank blood donors and the clinical centres, for the provision of biological samples, in addition, to supporting staff at the affiliated institutions. We also thank IDIVAL biobank (Inés Santiuste and Jana Arozamena) and UMCU Biobank for clinical sample and data preparation, as well as the PAFIP members for the data collection. This work was supported by the Stanley Medical Research Institute (grant number: 12T-008) and the Dutch Research Council (NWO; grant number: 40–00812–98–12154) received by IES; by grants to SB from the Stanley Medical Research Institute (SMRI) and the Engineering and Physical Sciences Research Council UK (EPSRC); and by grants to BC-F: SAF2016–76046-R and SAF2013–46292-R (MINECO) and PI16/00156 (ISCIII and FEDER)

Proyecto multimedia con vídeos didácticos para la docencia de técnicas reconstructivas en cirugía oncológica de cabeza y cuello

En la actualidad, el empleo de tecnologías de la información y la comunicación permite la organización de contenidos educacionales, favoreciendo la retroalimentación entre docentes y alumnos y permitiendo su utilización acorde con las necesidades académicas del estudiante. Las actuales generaciones son reconocidas como nativos digitales, ya que incorporan la información multimedia, desde imágenes y videos, a su estrategia didáctica de aprendizaje reemplazando los textos tradicionales, y presentan una mayor predisposición a utilizar las tecnologías y los entornos digitales en actividades de experiencia educativa y de aprendizaje. Es por esto que los videos didácticos surgen como una herramienta eficaz para el proceso de enseñanza-aprendizaje activo a través de la entrega de información y la promoción de la participación de los estudiantes en su formación profesional. Las técnicas reconstructivas en cirugía oncológica de cabeza y cuello se utilizan de forma habitual por parte de los Servicios de Cirugía Maxilofacial, Otorrinolaringología, Cirugía Plástica, Cirugía General y Dermatología. Son técnicas que utilizan colgajos locales, regionales y microquirúrgicos para la reconstrucción de defectos óseos y de partes blandas en cabeza y cuello. La mayoría de los estudiantes realizan rotaciones cortas sólo en algunos de estos Servicios y no consiguen obtener una idea completa de la reconstrucción en cabeza y cuello. En las clases se describen las técnicas y características de los diferentes colgajos, pero los alumnos terminan su carrera universitaria sin ver ni tener una idea clara y precisa de estas técnicas. En este proyecto de innovación docente se propone la realización de vídeos didácticos de los diferentes colgajos utilizados en cirugía reconstructiva de cabeza y cuello por parte de los estudiantes y docentes de los diferentes Servicios implicados. El fin último de la realización de los videos didácticos es el fortalecimiento de aprendizajes previos, el refuerzo de contenidos y la evaluación de aprendizajes.Depto. de CirugíaFac. de MedicinaFALSEsubmitte