Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates

Because of a possible relationship between schizophrenia and celiac disease, a condition in some individuals who are sensitive to wheat gluten proteins in the diet, there has been interest in observations that peptides derived from wheat gluten proteins exhibit opioid-like activity in in vitro tests. To determine the origin of the peptides exhibiting opioid activity, wheat proteins were fractionated by size (gel filtration), by charge differences (ion exchange chromatography) and by differences in hydrophobicity (reversed-phase HPLC). These fractions were hydrolyzed by pepsin or pepsin and trypsin and the resulting peptides separated by gel filtration chromatography. The separated peptides were tested for opioid-like activity by competitive binding to opioid receptor sites in rat brain tissue in the presence of tritium-labeled dihydromorphine. The peptides showed considerable differences in activity; while some peptides exhibited no activity, 0.5 mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay. The most active peptides were derived from the gliadin fraction of the gluten complex.     

Tyrosine hydroxylase gene not linked to manic-depression in seven of eight pedigrees.

We ascertained 8 multigenerational pedigrees afflicted with multiple cases of bipolar and recurrent major depressive disorder. Alterations in dopaminergic and noradrenergic neurotransmission have been implicated in the pathogenesis of this disease, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of these two catecholamines. As TH mutations could underlie susceptibility to manic-depression, we carried out a linkage analysis between this disease in 8 families and two RFLP probes that map to the TH gene region on the short arm of chromosome 11. Evidence of linkage was not found in 7 of 8 kindreds.     

Specific regional differences of in vitro beta-endorphin metabolism in schizophrenics

Incubation of beta-endorphin (beta-E; 25 microM) with twice-washed brain membrane homogenates leads to the formation of several biologically active peptide fragments which have been shown to be present in the brain. Based on clinical studies, some of these endorphin fragments have been shown to be active in patients with neuropsychiatric disease states. We studied the regional specificity of beta-E metabolism in frontal cortex versus putamen from sex and age matched controls versus subjects with a diagnosis of schizophrenia. The present study demonstrates that cortical tissue has a lower rate of gamma-endorphin production from beta-E and a similar rate of des-tyrosine-gamma-endorphin production. Significant differences were noted in the production of other active fragments (beta-E (1-16, 2-16, 6-21)). These results support the hypothesis that there is a regional specificity of beta-E metabolism in the brain, and these differences may have important functional consequences to secreted peptides and important clinical consequences in schizophrenia.     

Endogenous opiates: 1980

Vast amounts of research have been done that have attempted to delineate the pharmacological and physiological effects of the endogenous opiate peptides. A great deal of knowledge has also been accumulated in a limited time span concerning the types and locations of the opiate receptors and peptides, as well as their functions. In 1980, reports were made concerning the effects of these peptides on analgesia, on tolerance and dependence, on activity, on learning and memory, on schizophrenia and other types of emotional disturbances, and on physiological responses such as eating and drinking, cardiovascular responses, and sexual function. Additional understanding was also gained concerning their interactions with neurotransmitters, other neuropeptides, and hormones. These and other studies published only in 1980 are reviewed in this paper, which is the third of an annual series.     

Human leukemia antigen-A~*0201-restricted epitopes of human endogenous retrovirus W family envelope(HERV-W env) induce strong cytotoxic T lymphocyte responses

Human endogenous retrovirus W family(HERV-W) envelope(env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity.However, there are no reports investigating whether human leukemia antigen(HLA)-A~*0201~+restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A~*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLAA~*0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A~*0201~+ donors with each of these peptides induced peptidespecific CD8~+ T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides(W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.     

Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese

Although dysfunction of catechol‐O‐methyltransferase (COMT)‐mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case–control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia‐Lifetime Version (SADS‐L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug‐naÏve or drug‐free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese.     

Arginine vasopressin in the cytoplasm and nuclear fraction of lymphocytes from healthy donors and patients with depression or schizophrenia

We investigated whether cytoplasmic or nuclear extracts of human peripheral blood lymphocytes contain AVP in samples from healthy controls and patients diagnosed as depressed or schizophrenic. Both the cytoplasmic and nuclear extracts contained AVP as determined by radioimmunoassay. AVP and other peptides were detected in the purified samples by matrix-assisted laser desorption/ionization time of flight mass spectrometry. It is the first time that AVP has been characterized in human lymphocytes of patients with depression or schizophrenia. This finding demonstrates the presence of another important component within the potential regulatory loop between immune and neuro-endocrine tissues.     

An Evaluation of Association between a Novel Hippocampal Biology Related SNP (rs7294919) and Schizophrenia

Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919’s association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.     

精神分裂症易感基因DKK4与中国人群大脑容量的相关性

精神分裂症是一种复杂的精神疾病,全世界约有1%的人患有这种疾病。以往的研究发现,精神分裂症患者的脑容量比正常人小,且一些精神分裂症易感基因的DNA序列多态性也同时与脑的结构异常有关,这与精神分裂症的神经发育假说是吻合的。最近研究发现,人的DKK4基因的SNP(rs2073665)与精神分裂症显著相关。为了研究DKK4精神分裂症易感SNP是否与脑发育相关,本文检测了961个正常人rs2073665的基因型并测量了他们的脑容量。相关性分析发现,rs2073665在加性模型下和显性模型下都与脑容量存在显著相关性,这为精神分裂症易感基因同时能影响脑容量提供了证据,同时也为精神分裂症的神经发育异常假说提供了佐证。     

Motor deficits in schizophrenia quantified by nonlinear analysis of postural sway

Motor dysfunction is a consistently reported but understudied aspect of schizophrenia. Postural sway area was examined in individuals with schizophrenia under four conditions with different amounts of visual and proprioceptive feedback: eyes open or closed and feet together or shoulder width apart. The nonlinear complexity of postural sway was assessed by detrended fluctuation analysis (DFA). The schizophrenia group (n = 27) exhibited greater sway area compared to controls (n = 37). Participants with schizophrenia showed increased sway area following the removal of visual input, while this pattern was absent in controls. Examination of DFA revealed decreased complexity of postural sway and abnormal changes in complexity upon removal of visual input in individuals with schizophrenia. Additionally, less complex postural sway was associated with increased symptom severity in participants with schizophrenia. Given the critical involvement of the cerebellum and related circuits in postural stability and sensorimotor integration, these results are consistent with growing evidence of motor, cerebellar, and sensory integration dysfunction in the disorder, and with theoretical models that implicate cerebellar deficits and more general disconnection of function in schizophrenia.     

Refining phenotype characterization in genetic linkage studies of schizophrenia

Abstract

A definitive replicable genetic linkage for a major locus underlying the susceptibility to schizophrenia has not been identified to date. Although there are several possible explanations for the failure to find linkage in schizophrenia, one major problem is that the range of phenotypic expressions of the genes for schizophrenia has not been clarified. A more refined understanding of the various phenotypic expressions of a gene related to schizophrenia would enhance the power of studies designed to detect a genetic linkage with a major chromosomal locus and would benefit other strategies for understanding the etiology of schizophrenia.

The genes for schizophrenia may be frequently expressed in relatives of schizophrenic patients, although with less severe symptoms than those of chronic schizophrenia. Two series of findings support this notion. Nonschizophrenic relatives of schizophrenic patients demonstrate an increased incidence of nonpsychotic schizophrenia‐like symptoms and traits, and they manifest deficit performances on several different laboratory tests of neurocognitive functioning. A more refined phenotypic expression of a schizophrenia‐related gene may thus be indicated by personality traits and subclinical neurocognitive deficits.

These personality traits and neurocognitive deficits are considered here as possible aids in the identification of affected cases in genetic linkage studies of schizophrenia. Terminology for different indicators of neurocognitive deficits is introduced, and the relative utility of personality traits and indicators of neurocognitive deficit for genetic linkage studies is discussed. As specific examples, schizophrenia‐related personality traits that are unrelated to affective symptoms and performance deficits on tasks of eye tracking and continuous attention are considered for strategies for broadening phenotype characterization without reducing the specificity of affected case identification.     

Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia

Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC‐derived susceptibility variants. Schizophrenia PRS at the P‐value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han‐Taiwanese samples, and the score itself had a P‐value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.     

Cigarette smoking in male patients with chronic schizophrenia in a Chinese population: prevalence and relationship to clinical phenotypes

The high prevalence of smoking in schizophrenia of European background may be related to smoking's reducing clinical symptoms and medication side effects. Because smoking prevalence and its associations with clinical phenotypes are less well characterized in Chinese than European patients with schizophrenia, we assessed these smoking behaviors using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND) in 776 Chinese male schizophrenia and 560 control subjects. Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). We found that the schizophrenia patients had a higher lifetime incidence of smoking (79% vs 63%), were more likely to be heavy smokers (61% vs 31%), and had lower smoking cessation rates (4% vs 9%) (all p<0.0001) than controls. Among the schizophrenia patients smoking prevalence increased with age, with the largest difference from controls in the age cohort of 55-75 years: 75% vs 46% (p<0.0001). Among the schizophrenia smokers 73% started to smoke before the onset of their illness by an average of 7.6 years. The patients with schizophrenia who were current smokers scored significantly lower on the PANSS negative symptom subscore (p<0.005), and on the SAES symptom scale (p<0.04; Bonferroni corrected p>0.05) than the non-smoking patients. These results suggest that Chinese males with schizophrenia smoke more frequently than the general population. Further, smokers with schizophrenia may display fewer negative symptoms and possibly less parkinsonism than non-smokers with schizophrenia.     

Social defeat and the culture of chronicity: or,why schizophrenia does so well over there and so badly here

The history of the way schizophrenia has been conceptualized in American psychiatry has led us to be hesitant to explore the role of social causation in schizophrenia. But there is now good evidence for social impact on the course, outcome, and even origin of schizophrenia, most notably in the better prognosis for schizophrenia in developing countries and in the higher rates of schizophrenia for dark-skinned immigrants to England and the Netherlands. This article proposes that “social defeat” may be one of the social factors that may impact illness experience and uses original ethnographic research to argue that social defeat is a common feature of the social context in which many people diagnosed with schizophrenia in America live today.     

Kinematic parameters of throwing performance in patients with schizophrenia using a markerless motion capture system

Abstract

Motor dysfunction is consistently reported but understudied in schizophrenia. It has been hypothesized that this abnormality may reflect a neuro-developmental disorder underlying this illness. The main goal of this study was to analyze movement patterns used by participants with schizophrenia and healthy controls during overarm throwing performance, using a markerless motion capture system. Thirteen schizophrenia patients and 16 healthy control patients performed the overarm throwing task in a markerless motion capture system. Participants were also examined for the presence of motor neurological soft signs (mNSS) using the Brief Motor Scale. Schizophrenia patients demonstrated a less developed movement pattern with low individualization of components compared to healthy controls. The schizophrenia group also displayed a higher incidence of mNSS. The presence of a less mature movement pattern can be an indicator of neuro-immaturity and a marker for atypical neurological development in schizophrenia. Our findings support the understanding of motor dysfunction as an intrinsic part of the disorder of schizophrenia.     

Diabetes and Cognitive Deficits in Chronic Schizophrenia: A Case-Control Study

Cognitive impairment occurs in both schizophrenia and diabetes. There is currently limited understanding whether schizophrenia with diabetes has more serious cognitive deficits than schizophrenia without diabetes or diabetes only. This study assessed cognitive performance in 190 healthy controls, 106 diabetes only, 127 schizophrenia without diabetes and 55 schizophrenia with diabetes. This study was conducted from January 2008 to December 2010. Compared to healthy controls, all patient groups had significantly decreased total and five index RBANS scores (all p<0.01–p<0.001), except for the visuospatial/constructional index. Schizophrenia with diabetes performed worse than schizophrenia without diabetes in immediate memory (p<0.01) and total RBANS scores (<0.05), and showed a trend for decreased attention (p = 0.052) and visuospatial/constructional capacity (p = 0.063). Schizophrenia with diabetes performed worse than diabetes only in immediate memory (p<0.001) and attention (p<0.05), and showed a trend for decreased total RBANS scores (p = 0.069). Regression analysis showed that the RBANS had modest correlations with schizophrenia’ PANSS scores, their duration of current antipsychotic treatment, and diagnosis of diabetes. Schizophrenia with co-morbid diabetes showed more cognitive impairment than schizophrenia without diabetes and diabetes only, especially in immediate memory and attention.     

A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia

Previous linkage analyses of families with multiple cases of schizophrenia by us and others have confirmed the involvement of the chromosome 11q22-24 region in the etiology of schizophrenia, with LOD scores of 3.4 and 3.1. We now report fine mapping of a susceptibility gene in the 11q22-24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls (for a total of 2,433 individuals: 1,354 with schizophrenia and 1,079 controls). Seven microsatellite or single-nucleotide polymorphism (SNP) markers localized within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia, by a global permutation test (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. Etiological base-pair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and to increase genetic susceptibility to schizophrenia.     

Auditory Mismatch Negativity and Repetition Suppression Deficits in Schizophrenia Explained by Irregular Computation of Prediction Error

BackgroundThe predictive coding model is rapidly gaining attention in schizophrenia research. It posits the neuronal computation of residual variance (‘prediction error’) between sensory information and top-down expectation through multiple hierarchical levels. Event-related potentials (ERP) reflect cortical processing stages that are increasingly interpreted in the light of the predictive coding hypothesis. Both mismatch negativity (MMN) and repetition suppression (RS) measures are considered a prediction error correlates based on error detection and error minimization, respectively.MethodsTwenty-five schizophrenia patients and 25 healthy controls completed auditory tasks designed to elicit MMN and RS responses that were investigated using repeated measures models and strong spatio-temporal a priori hypothesis based on previous research. Separate correlations were performed for controls and schizophrenia patients, using age and clinical variables as covariates.ResultsMMN and RS deficits were largely replicated in our sample of schizophrenia patients. Moreover, MMN and RS measures were strongly correlated in healthy controls, while no correlation was found in schizophrenia patients. Single-trial analyses indicated significantly lower signal-to-noise ratio during prediction error computation in schizophrenia.ConclusionsThis study provides evidence that auditory ERP components relevant for schizophrenia research can be reconciled in the light of the predictive coding framework. The lack of any correlation between the investigated measures in schizophrenia patients suggests a disruption of predictive coding mechanisms in general. More specifically, these results suggest that schizophrenia is associated with an irregular computation of residual variance between sensory input and top-down models, i.e. prediction error.