Polygenic analysis suggests the involvement of calcium signaling in executive function in schizophrenia patients

European Archives of Psychiatry and Clinical Neuroscience - Cognitive deficits are increasingly recognized as a core dimension rather than a consequence of schizophrenia (SCZ). The previous...     

Evidence that the COMTVal158Met polymorphism moderates subclinical psychotic and affective symptoms in unaffected first-degree relatives of patients with schizophrenia.

OBJECTIVES: Psychotic patients with COMT(Val158Met) Met alleles were recently found to display more intense psychotic and affective responses to daily life stressors. We aimed to test the hypothesis that the Met allele is implicated in the development of affective and psychotic symptomatology in subjects genetically at risk for schizophrenia, by testing if unaffected first-degree relatives of patients with schizophrenia who share a Met allele have greater concordance of symptomatology than relatives not sharing a Met allele. METHODS: Unaffected relatives (n=38) were arranged in as many genetically related pairs as possible (n=26), and Met-sharing between Index Unaffected Subject (IUS) and Related Unaffected Subject (RUS) was assessed. Symptomatology was assessed with the Brief Psychiatric Rating Scale (BPRS) total score. RESULTS: Multilevel regression revealed an interaction between RUS BPRS score and Met-sharing in the model of IUS BPRS score (interaction chi(2)=3.78, p=0.05). Stratified analyses revealed that IUS-RUS total BPRS scores were significantly associated in the case of Met-sharing (B=0.57, 95% CI: 0.22-0.93, p=0.002), but were not when there was no Met-sharing. CONCLUSION: These findings support the hypothesis that the Met allele may be involved in the causation of psychopathology, at least in populations with a genetic predisposition to psychosis.     

Associations between COMTVal158Met polymorphism and cognition: direct or indirect effects?

BACKGROUND: Previous work suggests that reaction time variability (RTV) in attentional tasks, as a measure of cognitive stability, is associated with degree of Val loading in COMT Val(158)Met genotype, and that this association may be relevant for the aetiology of schizophrenia. This study examined (i) to what degree RTV pertaining to tasks of varying cognitive complexity would be associated with increased risk for schizophrenia and (ii) to what degree this would be mediated by Val loading. METHODS: COMT genotyping was investigated in a sample of 23 patients with schizophrenia, 33 first-degree relatives, and 21 controls. All participants performed the Flanker continuous performance test. RESULTS: Schizophrenia liability was associated with number of correct trials of the Flanker test, but not with RTV, and this association was not mediated by COMT Val(158)Met genotype. Similarly, Met loading was associated with number of correct trials and with RTV, but this was not mediated by schizophrenia liability. CONCLUSIONS: Associations between COMT Val(158)Met genotype and RTV do not appear to reflect transmission of schizophrenia liability in families. Differential associations with Val and Met alleles across studies suggest indirect effects through gene-gene interactions or the influence of a functional polymorphism near COMT Val(158)Met.     

Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia

Genotype–phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype–phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS ‘top-10'' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Göttingen Research Association for Schizophrenia) Data Collection. We found that the ‘top-10'' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups.     

Association study between novel promoter variants at the 5-HT2C receptor gene and human patients with bipolar affective disorder

Two recently described adjacent DNA polymorphisms [(GT)12-18 and (CT)4-5] in the 5'-regulatory region of 5-HT2C receptor gene were analysed in a sample of 88 bipolar patients and 162 controls, all of Spanish origin. Statistical analyses revealed no overall allele or genotype associations with the disease. A haplotype analyses between the (GT)12-18/(CT)4-5 motif and a Cys23Ser variant of the 5-HT2C gene (which had previously been genotyped in the same sample) showed similar distributions between cases and controls. Only a slight increase of s-Ser23 haplotype was found in the subgroup of bipolar women with family history of psychiatric illness (OR=1.24 [95%CI: 1.12-1.38]).     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.     

Low-doses aspirin doesn't increase surgical bleedind nor transfusion rate in total knee arthroplasty

ObjectivesSurgical bleeding. transfusion rate and cardiovascular complications were analized in patients undergoing chronic treatment with low-doses aspirin and scheduled to unilateral primary knee arthroplasty.Patients and methodsWe retrospectively studied 117 patients between 2005 and 2006 scheduled for elective knee replacement that received antiplatelet therapy with aspirin (100 mg/day). Aspirin medication was maintained or discontinued preoperatively according to medical criteria. We analyzed the biological, clinical and anesthetic data, blood-saving techniques used, surgical bleeding, allogeneic blood transfusion rate, cardiocirculatory complications (myocardial, cerebral or peripheral ischemia), hospital stay and mortality. This population was compared with 190 patients (control group) who underwent the same operation at the same time interval but did not receive aspirin therapy.ResultsThe aspirin-treated group was significantly older, with higher weight and poorer health state (higher incidence of ischemic heart disease, cerebral ischemia and diabetes). The hidden and external surgical bleeding and transfusion rate were similar if the aspirin were interrupted or not, preoperatively. Bleeding and transfusion rates were independent of time of interruption of the aspirin. Hospital mortality was zero in the 2 groups. A acute myocardial infarction and a transient stroke happened in two patients wich aspirin treatment was discontinued.ConclusionsPreoperative treatment with low doses of aspirin does not increase surgical bleeding and transfusion rate in total knee arthroplasty. Preoperative discontinuation can cause severe cardiocirculatory complications.     

Acute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection

Introduction

Little information exists about the impact of acute kidney injury (AKI) in critically ill patients with the pandemic 2009 influenza A (H1N1) virus infection.

Methods

We conducted a prospective, observational, multicenter study in 148 Spanish intensive care units (ICUs). Patients with chronic renal failure were excluded. AKI was defined according to Acute Kidney Injury Network (AKIN) criteria.

Results

A total of 661 patients were analyzed. One hundred eighteen (17.7%) patients developed AKI; of these, 37 (31.4%) of the patients with AKI were classified as AKI I, 15 (12.7%) were classified as AKI II and 66 (55.9%) were classified as AKI III, among the latter of whom 50 (75.7%) required continuous renal replacement therapy. Patients with AKI had a higher Acute Physiology and Chronic Health Evaluation II score (19.2 ± 8.3 versus 12.6 ± 5.9; P < 0.001), a higher Sequential Organ Failure Assessment score (8.7 ± 4.2 versus 4.8 ± 2.9; P < 0.001), more need for mechanical ventilation (MV) (87.3% versus 56.2%; P < 0.01, odds ratio (OR) 5.3, 95% confidence interval (CI) 3.0 to 9.4), a greater incidence of shock (75.4% versus 38.3%; P < 0.01, OR 4.9, 95% CI, 3.1 to 7.7), a greater incidence of multiorgan dysfunction syndrome (92.4% versus 54.7%; P < 0.01, OR 10.0, 95% CI, 4.9 to 20.21) and a greater incidence of coinfection (23.7% versus 14.4%; P < 0.01, OR 1.8, 95% CI, 1.1 to 3.0). In survivors, patients with AKI remained on MV longer and ICU and hospital length of stay were longer than in patients without AKI. The overall mortality was 18.8% and was significantly higher for AKI patients (44.1% versus 13.3%; P < 0.01, OR 5.1, 95% CI, 3.3 to 7.9). Logistic regression analysis was performed with AKIN criteria, and it demonstrated that among patients with AKI, only AKI III was independently associated with higher ICU mortality (P < 0.001, OR 4.81, 95% CI 2.17 to 10.62).

Conclusions

In our cohort of patients with H1N1 virus infection, only those cases in the AKI III category were independently associated with mortality.