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In vivo proton ((1)H) Magnetic Resonance spectroscopy ((1)H MRS) has shown abnormalities in young first-episode patients with schizophrenia. It is unclear whether these abnormalities reflect trait related vs. state related alterations in schizophrenia. We compared young first-degree relatives of schizophrenia patients and healthy controls using (1)H MRS. We hypothesized alterations in the (1)H MRS metabolites N-acetyl aspartate (NAA) and glutamate in corticostriatal and thalamic brain regions. We obtained multi-voxel, short-TE (1)H MRS measurements at 1.5 Tesla in 40 consenting adolescent offspring at risk for schizophrenia (HR), and 48 age matched healthy controls (HC). Absolute levels of NAA, phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol and glutamate plus glutamine (Glu+Gln) were obtained from the seven different anatomical brain areas (nominal voxel size of 4.5cm(3) each) and corrected for tissue voxel composition. HR subjects showed NAA (p=.0049), PCr+Cr (p=0.028) and GPC+PC (p=0.0086) reductions in the caudate compared with HC subjects. Male HR subjects had significant Glu+Gln reductions compared to male HC subjects (p=.0022). HR subjects had increased NAA in prefrontal white matter. NAA levels in the prefrontal white matter and Glu+Gln levels in the inferior parietal/occipital region were both increased in HR without psychopathology compared with HC subjects. Lower NAA, PCr+Cr and GPC+PC levels may reflect an overall reduction in cellular processes in the caudate of HC subjects, perhaps related to decreases in cell density, or synaptic overpruning. Further studies are needed to examine the pathophysiologic significance of these observations, and their potential predictive value for schizophrenia related psychopathology that may emerge in these at risk relatives during adolescence and early adulthood. [ABSTRACT FROM AUTHOR]

Non-invasive brain imaging has played a critical role in establishing our understanding of the neural properties that contribute to the emergence of psychiatric disorders. However, characterizing core neurobiological mechanisms of psychiatric symptomatology requires greater structural, functional, and neurochemical specificity than is typically obtainable with standard field strength MRI acquisitions (e.g., 3T). Ultra-high field (UHF) imaging at 7 Tesla (7T) provides the opportunity to identify neurobiological systems that confer risk, determine etiology, and characterize disease progression and treatment outcomes of major mental illnesses. Increases in scanner availability, regulatory approval, and sequence availability have made the application of UHF to clinical cohorts more feasible than ever before, yet the application of UHF approaches to the study of mental health remains nascent. In this technical review, we describe core neuroimaging methodologies which benefit from UHF acquisition, including high resolution structural and functional imaging, single ( 1 H) and multi-nuclear (e.g., 31 P) MR spectroscopy, and quantitative MR techniques for assessing brain tissue iron and myelin. We discuss advantages provided by 7T MRI, including higher signal- and contrast-to-noise ratio, enhanced spatial resolution, increased test-retest reliability, and molecular and neurochemical specificity, and how these have begun to uncover mechanisms of psychiatric disorders. Finally, we consider current limitations of UHF in its application to clinical cohorts, and point to ongoing work that aims to overcome technical hurdles through the continued development of UHF hardware, software, and protocols., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Adolescent-onset schizophrenia (AOS) is rare, under-studied, and associated with more severe cognitive impairments and poorer outcomes than adult-onset schizophrenia. Neuroimaging has shown altered regional activations (first-order effects) and functional connectivity (second-order effects) in AOS compared to controls. The pairwise maximum entropy model (MEM) integrates first- and second-order factors into a single quantity called energy, which is inversely related to probability of occurrence of brain activity patterns. We take a combinatorial approach to study multiple brain-wide MEMs of task-associated components; hundreds of independent MEMs for various sub-systems are fit to 7 Tesla functional MRI scans. Acquisitions were collected from 23 AOS individuals and 53 healthy controls while performing the Penn Conditional Exclusion Test (PCET) for executive function, which is known to be impaired in AOS. Accuracy of PCET performance was significantly reduced among AOS compared to controls. A majority of the models showed significant negative correlation between PCET scores and the total energy attained over the fMRI. Across all instantiations, the AOS group was associated with significantly more frequent occurrence of states of higher energy, assessed with a mixed effects model. An example MEM instance was investigated further using energy landscapes, which visualize high and low energy states on a low-dimensional plane, and trajectory analysis, which quantify the evolution of brain states throughout this landscape. Both supported patient-control differences in the energy profiles. Severity of psychopathology was correlated positively with energy. The MEM's integrated representation of energy in task-associated systems can help characterize pathophysiology of AOS, cognitive impairments, and psychopathology., Competing Interests: Conflicts of Interest All authors declare no conflicts of interest associated with this work.

The fascinating electronic applications attracted researchers to explore the field of nonlinear optical (NLO) materials. The slow evaporation of solvent technique (SEST) was employed to grow the 2-cyanopyridinium perchlorate (2-CPPC) NLO single crystals. The cell parameters of the grown 2-CPPC crystal are confirmed by the single crystal X-ray diffraction (SCXRD) study. The powder X-ray diffraction studies confirm the crystallinity of 2-CPPC crystals, and the peaks were indexed. The computation for the geometry optimization, HOMO-LUMO energy gap, global reactivity parameters, natural bond orbital (NBO) analysis, polarizability, and hyperpolarizability of the 2-CPPC molecule was done using B3LYP (6-311G basis set) functional of DFT method. The experimental FTIR and UV-Vis results of the 2-CPPC compound were compared with the simulated results. The second harmonic generation (SHG) study for the 2-CPPC crystal was employed using Kurtz-Perry powder technique. Single beam Z-scan technique using He-Ne laser is used to study the third-order NLO properties., (© 2024. The Author(s).)

Aims: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh., Methods: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership., Results: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes., Conclusions: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments., (© 2024 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

This article considers the problem of classifying individuals in a dataset of diverse psychosis spectrum conditions, including persons with subsyndromal psychotic-like experiences (PLEs) and healthy controls. This task is more challenging than the traditional problem of distinguishing patients with a diagnosed disorder from controls using brain network features, since the neurobiological differences between PLE individuals and healthy persons are less pronounced. Further, examining a transdiagnostic sample compared to controls is concordant with contemporary approaches to understanding the full spectrum of neurobiology of psychoses. We consider both support vector machines (SVMs) and graph convolutional networks (GCNs) for classification, with a variety of edge selection methods for processing the inputs. We also employ the MultiVERSE algorithm to generate network embeddings of the functional and structural networks for each subject, which are used as inputs for the SVMs. The best models among SVMs and GCNs yielded accuracies >63%. Investigation of network connectivity between persons with PLE and controls identified a region within the right inferior parietal cortex, called the PGi, as a central region for communication among modules (network hub). Class activation mapping revealed that the PLE group had salient regions in the dorsolateral prefrontal, orbital and polar frontal cortices, and the lateral temporal cortex, whereas the controls did not. Our study demonstrates the potential usefulness of deep learning methods to distinguish persons with subclinical psychosis and diagnosable disorders from controls. In the long term, this could help improve accuracy and reliability of clinical diagnoses, provide neurobiological bases for making diagnoses, and initiate early intervention strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Existing neuroimaging studies of psychotic and mood disorders have reported brain activation differences (first-order properties) and altered pairwise correlation-based functional connectivity (second-order properties). However, both approaches have certain limitations that can be overcome by integrating them in a pairwise maximum entropy model (MEM) that better represents a comprehensive picture of fMRI signal patterns and provides a system-wide summary measure called energy. This study examines the applicability of individual-level MEM for psychiatry and identifies image-derived model coefficients related to model parameters., Method: MEMs are fit to resting state fMRI data from each individual with schizophrenia/schizoaffective disorder, bipolar disorder, and major depression (n=132) and demographically matched healthy controls (n=132) from the UK Biobank to different subsets of the default mode network (DMN) regions., Results: The model satisfactorily explained observed brain energy state occurrence probabilities across all participants, and model parameters were significantly correlated with image-derived coefficients for all groups. Within clinical groups, averaged energy level distributions were higher in schizophrenia/schizoaffective disorder but lower in bipolar disorder compared to controls for both bilateral and unilateral DMN. Major depression energy distributions were higher compared to controls only in the right hemisphere DMN., Conclusions: Diagnostically distinct energy states suggest that probability distributions of temporal changes in synchronously active nodes may underlie each diagnostic entity. Subject-specific MEMs allow for factoring in the individual variations compared to traditional group-level inferences, offering an improved measure of biologically meaningful correlates of brain activity that may have potential clinical utility., Competing Interests: Conflicts of Interest: All authors declare no conflicts of interest associated with this work.

The threat of antimicrobial resistance to antibiotics requires a continual effort to develop alternative treatments. Arylglycines (or phenylglycines) are one of the signature amino acids found in many natural peptide antibiotics, but their propensity for epimerization in solid-phase peptide synthesis (SPPS) has prevented their use in long peptide sequences. We have now identified an optimized protocol that allows the synthesis of challenging non-ribosomal peptides including precursors of the glycopeptide antibiotics and an analogue of feglymycin (1 analogue, 20%). We have exploited this protocol to synthesize analogues of the peptide antibiotic ramoplanin using native chemical ligation/desulfurization (1 analogue, 6.5%) and head-to-tail macrocyclization in excellent yield (6 analogues, 3-9%), with these compounds extensively characterized by NMR (U-shaped structure) and antimicrobial activity assays (two clinical isolates). This method significantly reduces synthesis time (6-9 days) when compared with total syntheses (2-3 months) and enables drug discovery programs to include arylglycines in structure-activity relationship studies and drug development., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: Structural and functional brain connectomes represent macroscale data collected through techniques such as magnetic resonance imaging (MRI). Connectomes may contain noise that contributes to false-positive edges, thereby obscuring structure-function relationships and data interpretation. Thresholding procedures can be applied to reduce network density by removing low-signal edges, but there is limited consensus on appropriate selection of thresholds. This article compares existing thresholding methods and introduces a novel alternative "objective function" thresholding method. Methods: The performance of thresholding approaches, based on percolation and objective functions, is assessed by (1) computing the normalized mutual information (NMI) of community structure between a known network and a simulated, perturbed networks to which various forms of thresholding have been applied, and by (2) comparing the density and the clustering coefficient (CC) between the baseline and thresholded networks. An application to empirical data is provided. Results: Our proposed objective function-based threshold exhibits the best performance in terms of resulting in high similarity between the underlying networks and their perturbed, thresholded counterparts, as quantified by NMI and CC analysis on the simulated functional networks. Discussion: Existing network thresholding methods yield widely different results when graph metrics are subsequently computed. Thresholding based on the objective function maintains a set of edges such that the resulting network shares the community structure and clustering features present in the original network. This outcome provides a proof of principle that objective function thresholding could offer a useful approach to reducing the network density of functional connectivity data.

Altered gene expressions may mechanistically link genetic factors with brain morphometric alterations. Existing gene expression studies have examined selected morphometric features using low-resolution atlases in medicated schizophrenia. We examined the relationship of gene expression with cortical thickness (CT), surface area (SA), and gray matter volume (GMV) of first-episode antipsychotic-naïve psychosis patients (FEAP = 85) and 81 controls, hypothesizing that gene expressions often associated with psychosis will differentially associate with different morphometric features. We explored such associations among schizophrenia and non-schizophrenia subgroups within FEAP group compared to controls. We mapped 360 Human Connectome Project atlas-based parcellations on brain MRI on to the publicly available brain gene expression data from the Allen Brain Institute collection. Significantly correlated genes were investigated using ingenuity pathway analysis to elucidate molecular pathways. CT but not SA or GMV correlated with expression of 1137 out of 15 633 genes examined controlling for age, sex, and average CT. Among these ≈19%, ≈39%, and 8% of genes were unique to FEAP, schizophrenia, and non-schizophrenia, respectively. Variants of 10 among these 1137 correlated genes previously showed genome-wide-association with schizophrenia. Molecular pathways associated with CT were axonal guidance and sphingosine pathways (common to FEAP and controls), selected inflammation pathways (unique to FEAP), synaptic modulation (unique to schizophrenia), and telomere extension (common to NSZ and healthy controls). We demonstrate that different sets of genes and molecular pathways may preferentially influence CT in different diagnostic groups. Genes with altered expressions correlating with CT and associated pathways may be targets for pathophysiological investigations and novel treatment designs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Hippocampal abnormalities are associated with psychosis-risk states. Given the complexity of hippocampal anatomy, we conducted a multipronged examination of morphometry of regions connected with hippocampus, and structural covariance network (SCN) and diffusion-weighted circuitry among 27 familial high-risk (FHR) individuals who were past the highest risk for conversion to psychoses and 41 healthy controls using ultrahigh-field high-resolution 7 Tesla (7T) structural and diffusion MRI data. We obtained fractional anisotropy and diffusion streams of white matter connections and examined correspondence of diffusion streams with SCN edges. Nearly 89 % of the FHR group had an axis-I disorder including 5 with schizophrenia. Therefore, we compared the entire FHR group regardless of the diagnosis (All_FHR = 27) and FHR-without-schizophrenia (n = 22) with 41 controls in this integrative multimodal analysis. We found striking volume loss in bilateral hippocampus, particularly the head, bilateral thalamus, caudate, and prefrontal regions. All_FHR and FHR-without-SZ SCNs showed significantly lower assortativity and transitivity but higher diameter compared to controls, but FHR-without-SZ SCN differed on every graph metric compared to All_FHR suggesting disarrayed network with no hippocampal hubs. Fractional anisotropy and diffusion streams were lower in FHR suggesting white matter network impairment. White matter edges showed significantly higher correspondence with SCN edges in FHR compared to controls. These differences correlated with psychopathology and cognitive measures. Our data suggest that hippocampus may be a "neural hub" contributing to psychosis risk. Higher correspondence of white matter tracts with SCN edges suggest that shared volume loss may be more coordinated among regions within the hippocampal white matter circuitry., Competing Interests: Declaration of competing interest None of the authors have conflict interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In 2018, ovarian carcinoma ranked as the eighth most common cancer diagnosed and the leading cause of cancer death in women. High-grade serous carcinoma is the most common histological type seen among malignant cases. A diverse group of neoplasms is seen in the ovary with variable clinical, morphological, and histological features, so assessing the nature of ovarian neoplasms further assists in the treatment of the disease., Aim: This study was conducted to assess the different histopathological variants of ovarian neoplasms according to the latest 2020 World Health Organization (WHO) classification of ovarian tumors. Further analysis of the frequency, age, clinical features in patients, and distribution of various ovarian tumors is assessed., Materials and Methods: A retrospective study was conducted in the Department of Pathology at Patna Medical College and Hospital (PMCH), Patna. The data of the patients from the past three years, from February 2020 to February 2023, were retrieved and assessed. Gross and microscopic findings, including clinical details of patients with ovarian masses, were analyzed from the previous records., Result: A total of 110 cases of ovarian neoplasms on histopathology were analyzed. The age range was 11-70 years. The types of specimens received were those of total abdominal hysterectomy, salphingoopherectomy, and unilateral or bilateral ovarian cystectomy. The most common presentation was an abdominal mass, followed by pain in the abdomen. The majority of the tumors were benign (69%), malignancy was observed in 24.5% of cases, and borderline tumors were seen in 5.4% of cases. Epithelial tumors were the commonest tumors, accounting for 70%, followed by germ cell tumors (21%). Serous cystadenoma was the commonest benign tumor, followed by mature teratoma and serous cystadenocarcinoma. High-grade serous cystadenocarcinoma was the commonest malignant ovarian tumor (9%), followed by low-grade serous cystadenocarcinoma (4.5%) and metastatic carcinoma of the ovary. Krukenberg tumor was seen in two cases, and a very rare case of sclerosing stromal tumor was seen in one of the cases., Conclusion: Ovarian neoplasms usually present with a variety of clinicomorphological and histological features. The most common neoplasm observed in the ovary is surface epithelial tumors, which are benign lesions that commonly affect reproductive age groups. Newer advancements like immunohistochemistry (IHC) and genetic studies have made the diagnosis easier and more precise. However, in institutes with limited resources, a histopathological study is still the gold standard in the diagnosis and prognostic evaluation of these tumors., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Mehra et al.)

The family of apicomplexan specific proteins contains caspases-like proteins called "metacaspases". These enzymes are present in the malaria parasite but absent in human; therefore, these can be explored as potential drug targets. We deleted the MCA-2 gene from Plasmodium berghei genome using a gene knockout strategy to decipher its precise function. This study has identified that MCA-2 plays an important role in parasite transmission since it is critical for the formation of gametocytes and for maintaining an appropriate number of infectious sporozoites required for sporogony. It is noticeable that a significant reduction in gametocyte, oocysts, ookinete and sporozoites load along with a delay in hepatocytes invasion were observed in the MCA-2 knockout parasite. Furthermore, a study found the two MCA-2 inhibitory molecules known as C-532 and C-533, which remarkably inhibited the MCA-2 activity, abolished the in vitro parasite growth, and also impaired the transmission cycle of P. falciparum and P. berghei in An. stephensi . Our findings indicate that the deletion of MCA-2 hampers the Plasmodium development during erythrocytic and exo-erythrocytic stages, and its inhibition by C-532 and C-533 critically affects the malaria transmission biology.

Cognition shares substantial genetic overlap with schizophrenia, yet it remains unclear whether such genetic effects become significant during developmental periods of elevated risk for schizophrenia, such as the peak age of onset. We introduce an investigative framework integrating epidemiological, developmental, and genetic approaches to determine whether genetic effects shared between schizophrenia and cognition are significant across periods of differing risk for schizophrenia onset, and whether these effects are shared with depression. 771 European-American participants, including 636 (ages 15-84 years) from families with at least two first-degree relatives with schizophrenia and 135 unrelated controls, were divided into three age-risk groups based on ages relative to epidemiological age of onset patterns for schizophrenia: Pre-Peak (before peak age-of-onset: 15 to 22 years), Post-Peak (after peak age-of-onset: 23-42 years), and Plateau (during plateau of age-of-onset: over 42 years). For general cognition and 11 specific cognitive traits, we estimated genetic correlations with schizophrenia and with depression within each age-risk group. Genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant before peak age of onset, yet were high and significant after peak age of onset and during the plateau of onset. These age-dependent genetic effects were largely consistent across specific cognitive traits and not transdiagnostically shared with depression. Schizophrenia genetic effects appear to influence cognitive traits in an age-dependent manner, supporting late developmental and perhaps neurodegenerative models that hypothesize increased expression of schizophrenia risk genes during and after the peak age of risk. Our findings underscore the utility of cognitive traits for tracking schizophrenia genetic effects across the lifespan., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438)., Methods: We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections., Results: Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts., Conclusions: Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Metacaspases are novel cysteine proteases found in apicomplexan whose function is poorly understood. Our earlier studies on Plasmodium falciparum metacaspase-2 (PfMCA-2) revealed that the caspase inhibitor, Z-FA-FMK efficiently inhibited PfMCA-2 activity and, expression, and significantly blocked in vitro progression of the parasite developmental cycle via apoptosis-like parasite death. Building on these findings, we synthesized a set of novel inhibitors based on structural modification of Z-FA-FMK with the amides of piperic acid and investigated their effect on PfMCA-2. One of these analogs, SS-5, specifically inhibited the activity and expression of PfMCA-2. The activities of some other known malarial proteases (falcipains, plasmepsins and vivapain), and human cathepsins-B, D and L, and caspase-3 and -7 were not inhibited by SS-5. SS-5 blocked the development of P. falciparum in vitro (IC50 1 µM) and caused prominent morphological distortions. Incubation with SS-5 led to persistent parasite oxidative stress accompanied by depolarization of mitochondrial potential and accumulation of intracellular Ca2+. SS-5 also inhibited the development of P. berghei in a murine model. Our results suggest that the inhibition of PfMCA-2 results in oxidative stress, leading to apoptosis-like parasite death. Thus, SS-5 offers a starting point for the optimization of new antimalarials, and PfMCA-2 could be a novel target for antimalarial drug discovery., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Existing data on altered membrane phospholipid metabolism in schizophrenia are diverse. We conducted a meta-analysis of studies of phosphorus magnetic resonance spectroscopy, a noninvasive imaging approach that can assess molecular biochemistry of cortex by measuring phosphomonoester (PME) and phosphodiester (PDE) levels, which can provide evidence of altered biochemical processes involved in neuropil membrane expansion and contraction in schizophrenia., Methods: We analyzed PME and PDE data in the frontal and temporal lobes in subjects with schizophrenia from 24 peer-reviewed publications using the MAVIS package in R by building random- and fixed-effects models. Heterogeneity of effect sizes, effects of publication bias, and file drawer analysis were also assessed., Results: Subjects with schizophrenia showed lower PME levels in the frontal regions (p = .008) and elevated PDE levels in the temporal regions (p < .001) with significant heterogeneity. We noted significant publication bias and file drawer effect for frontal PME and PDE and temporal PDE levels, but not for temporal PME levels. Fail-safe analysis estimated that a high number of negative studies were required to provide nonsignificant results., Conclusions: Despite methodological differences, these phosphorus magnetic resonance spectroscopy studies demonstrate regionally specific imbalance in membrane phospholipid metabolism related to neuropil in subjects with schizophrenia compared with control subjects reflecting neuropil contraction. Specifically, decreased PME levels in the frontal regions and elevated PDE levels in the temporal regions provide evidence of decreased synthesis and increased degradation of neuropil membrane, respectively. Notwithstanding significant heterogeneity and publication bias, a large number of negative studies are required to render the results of this meta-analysis nonsignificant. These findings warrant further postmortem and animal studies., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: After infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and Alzheimer's disease (AD) pathology. HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid beta-protein (Aβ) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aβ and phosphorylated tau accumulation in cell-culture models. Cognitive impairment is greater in patients with HSV seropositive, and antiviral drugs show robust efficacy against peripheral HSV infection. Recent studies of electronic health records databases demonstrate that HSV infections increase dementia risk, and that antiviral medication treatment reduces this risk. The generic antiviral drug valacyclovir was superior to placebo in improving memory in a schizophrenia pilot trial but has not been tested in AD., Methods and Analysis: In patients with mild AD who test positive for HSV1 or HSV2 serum antibodies, valacyclovir, repurposed as an anti-AD drug, will be compared with placebo (lactose pills) in 130 patients (65 valacyclovir and 65 placebo) in a randomised, double-blind, 78-week phase II proof-of-concept trial. Patients on valacyclovir, dose-titrated from 2 g to a targeted oral dose of 4 g daily, compared with placebo, are hypothesised to show smaller cognitive and functional decline, and, using 18 F-Florbetapir positron emission tomography (PET) and 18 F-MK-6240 PET imaging, to show less amyloid and tau accumulation, respectively. In the lumbar puncture subsample, cerebrospinal fluid acyclovir will be assayed to assess central nervous system valacyclovir penetration., Ethics and Dissemination: The trial is being overseen by the New York State Psychiatric Institute Institutional Review Board (protocol 7537), the National Institute on Ageing, and the Data Safety Monitoring Board. Written informed consent is obtained for all subjects. Results will be disseminated via publication, clinicaltrials.gov, media and conferences., Trial Registration Number: ClinicalTrials.gov identifier (NCT03282916) Pre-results., Competing Interests: Competing interests: AM, QR, KMP, DAD, WCK, EA, HA, JP, MK have no competing interests. DPD is a consultant to Acadia, Eisai, Genentech, Avanir, Neuronix, Grifols and BXcel Therapeutics and has grant support from the National Institute of Aging. EDH is a consultant to Biogen and Ionis. TW is a consultant to Alzemend Neuro, Inc. and Grifols and has grant support from the National Institute of Health and the National Institute on Aging. KLB has grant support from Lilly, Amylx and Biohaven. AAG is contracted with Merck. GHP has grant support from the National Institute on Aging. YS is a consultant to Eli Lilly, Axovant, Takeda, and AbbVie, has donated to Piramal Imaging Limited, has grant support from California Walnut Commission, and has a license for the Dependence Scale., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Schizophrenia is a chronic psychotic disorder with a lifetime prevalence of about 1%. Onset is typically in adolescence or early adulthood; characteristic symptoms include positive symptoms, negative symptoms, and impairments in cognition. Neuroimaging studies have shown substantive evidence of brain structural, functional, and neurochemical alterations that are more pronounced in the association cortex and subcortical regions. These abnormalities are not sufficiently specific to be of diagnostic value, but there may be a role for imaging techniques to provide predictions of outcome. Incorporating multimodal imaging datasets using machine learning approaches may offer better diagnostic and predictive value in schizophrenia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the relationship between gabapentin use and dose with substance use disorders (SUDs) prior to inpatient mental health treatment., Methods: A cross-sectional study was performed in current gabapentin users admitted to inpatient psychiatry services from December 2015 through January 2017 in a large urban teaching hospital. The primary analysis examined rates and doses of gabapentin use in relation to SUD. A multinomial logistic regression was performed to assess a predictive model for SUD in gabapentin users. The secondary analysis examined trends of off-label gabapentin use., Results: Of 1,483 admissions to inpatient psychiatry services, 345 subjects (23.1%) were prescribed gabapentin as an outpatient prior to admission. Current SUD was identified in 88.1% of the sample, with 65.2% identified as polysubstance positive. Mean daily doses of gabapentin were higher in subjects with positive SUD than in those with no history of SUD. Gabapentin doses ≥ 1,800 mg/d were associated with opiate misuse (P < .001), need for detoxification (P = .004), and positive hepatitis C status (P = .001). Multinomial linear regression revealed that use of gabapentin doses ≥ 1,800 mg/d was predictive of opiate misuse and positive hepatitis C status, with 68.7% positive predictive value., Conclusion: High-dose gabapentin use can be predictive of opiate misuse disorder. Requests for high-dose gabapentin from patients may signal potential opioid misuse., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

A recent report suggested Complement 4 (C4A) gene copy numbers (GCN) as risk factors for schizophrenia. Rodent model showed association of C4 with synaptic pruning suggesting its pathophysiological significance (Sekar, A. et al. (2016)). We, therefore, predicted that C4A GCN would be positively correlated with neuropil contraction in the human brain among schizophrenia patients showing more prominent correlations in ventral regions among young adults and dorsal regions among adolescents since neuromaturation progresses dorsoventrally. Whole-brain, multi-voxel, in vivo phosphorus magnetic resonance spectroscopy ( 31 P MRS) assessed neuropil changes by estimating levels of membrane phospholipid (MPL) precursors and catabolites. Increased MPL catabolites and/or decreased MPL precursors indexed neuropil contraction. Digital droplet PCR-based assay was used to estimate C4A and C4B GCN. We evaluated two independent cohorts (young adult-onset early-course schizophrenia (YASZ = 15) and adolescent-onset schizophrenia (AOSZ = 12) patients), and controls matched for each group, n = 22 and 15, respectively. Separate forward stepwise linear regression models with Akaike information Criterion were built for MPL catabolites and precursors. YASZ cohort: Consistent with the rodent model (Sekar, A. et al. 2016)), C4A GCN positively correlated with neuropil contraction (increased pruning/decreased formation) in the inferior frontal cortex and inferior parietal lobule. AOSZ cohort: C4A GCN positively correlated with neuropil contraction in the dorsolateral prefrontal cortex and thalamus. Exploratory analysis of C4B GCN showed positive correlation with neuropil contraction in the cerebellum and superior temporal gyrus among YASZ while AOSZ showed neuropil contraction in the prefrontal and subcortical structures. Thus, C4A and C4B GCN are associated with neuropil contraction in regions often associated with schizophrenia, and may be neuromaturationally dependent.

Background: Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with lifelong latent infection in neurons. HSV-1 infected individuals have greater cognitive dysfunction than uninfected individuals, particularly persons with schizophrenia - even without encephalitis. We investigated whether HSV-1 related cognitive dysfunction is progressive or remediable., Methods: In a prospective naturalistic follow up sample (PNFU), temporal changes in cognitive functions were analyzed in relation to baseline HSV-1 infection in persons with/without schizophrenia (N=226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5G twice daily for 16weeks) or placebo (PLA) added to standard antipsychotic treatment, using a stratified randomization design, following placebo run-in (N=67). In both samples, HSV-1 infection (seropositivity) was estimated using serum IgG antibodies. Clinical evaluations were blinded to HSV-1 or treatment status. Standardized Z scores for accuracy on eight cognitive domains were analyzed for temporal trajectories using generalized linear models (PNFU) and VAL/PLA differences compared with intent to treat analyses (RCT)., Results: PNFU: At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p=0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p=0.03). RCT: EMOD improved in VAL-treated patients (p=0.048, Cohen's d=0.43)., Conclusions: A proportion of age related decline in EMOD is attributable to HSV-1 infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Impaired connectivity is proposed to underlie pathophysiology of schizophrenia. Existing studies on functional connectivity show inconsistent results. We examined functional connectivity in a clinically homogenous sample of 34 early course schizophrenia patients compared with/to 19 healthy controls using resting state functional magnetic resonance imaging (rsfMRI). Mean duration of illness for schizophrenia patients was 4 ± 1.78 years. Following a comprehensive clinical assessment, rsfMRI data were acquired using a 3.0 T magnetic resonance imaging scanner, and analyzed using FSL version 5.01 software (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl). Compared to healthy controls, schizophrenia patients had significantly decreased functional connectivity in the left fronto-parietal network, lateral and medial visual network, motor network, default mode network and auditory network. Our data suggests significant functional hypoconnectivity in selected brain networks in early schizophrenia patients compared to controls. It is likely that the observed functional hypoconnectivity may be associated with features of schizophrenia other than those examined in this study. It is possible that hypoconnectivity is necessary but not sufficient to the clinical manifestation of schizophrenia. The examination of functional connectivity as a biomarker should be extended to a wider array of disease phenotypes to better understand its significance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

A theoretical model of time-dependent peristaltic viscous fluid flow through a curved channel in the presence of an applied magnetic field is investigated. The results for stream function, pressure distribution and mechanical efficiency are obtained under the assumptions of long wavelength and low Reynolds number approximation. Pressure fluctuations due to an integral and a non-integral number of waves along the channel length are discussed under influence of channel curvature and magnetic parameter. Two inherent characteristics of peristaltic flow regimes (trapping and reflux) are discussed numerically. The mechanical efficiency of curved magnetohydrodynamic peristaltic pumping is also examined. The magnitude of pressure increases with an increasing channel curvature and magnetic parameter. Reflex phenomenon is analyzed in the Lagrangian frame of reference. It is observed that reflex in the curved channel is higher than in the straight channel. The trapped fluid in a curved channel is studied in the Eulerian frame of reference and it contains two asymmetric boluses. The size of the lower bolus grows and the upper bolus decreases with increasing effect of magnetic strength. Pumping efficiency of the peristaltic pump is low for curved channel flow than for straight channel flow. Also, the pumping efficiency is comparatively low at the high effect of the magnetic parameter., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The burden of sub-patent malaria is difficult to recognize in low endemic areas due to limitation of diagnostic tools, and techniques. Polymerase chain reaction (PCR), a molecular based technique, is one of the key methods for detection of low parasite density infections. The study objective was to assess the additional burden of asymptomatic and sub-patent malaria infection among tribal populations inhabiting three endemic villages in Keshkal sub-district, Chhattisgarh, India. A cross-sectional survey was conducted in March-June 2016, during the low transmission season, to measure and compare prevalence of malaria infection using three diagnostics: rapid diagnostic test, microscopy and nested-PCR., Results: Out of 437 individuals enrolled in the study, 103 (23.6%) were malaria positive by PCR and/or microscopy of whom 89.3% were Plasmodium falciparum cases, 77.7% were afebrile and 35.9% had sub-patent infections., Conclusions: A substantial number of asymptomatic and sub-patent malaria infections were identified in the survey. Hence, strategies for identifying and reducing the hidden burden of asymptomatic and sub-patent infections should focus on forest rural tribal areas using more sensitive molecular diagnostic methods to curtail malaria transmission.

Background & Objectives: Increase in prevalence and intensity of insecticide-resistance in vectors of vector-borne diseases is a major threat to sustainable disease control; and, for their effective management, studies on resistance mechanisms are important to come out with suitable strategies. Esterases are major class of detoxification enzymes in mosquitoes, which confers protection against insecticides in causing resistance. This study was aimed at biochemical characterization of esterases responsible for malathion resistance in Anopheles stephensi mosquitoes, along with its validation through biochemical techniques and native-PAGE assays., Methods: Laboratory maintained susceptible and resistant An. stephensi mosquitoes were used for assessing the activity and effect of α - and β -esterases on malathion. Bioassay, synergist bioassay, biochemical assay and native- PAGE were employed to characterize the role of esterases in conferring malathion-resistance., Results: Notably significant (p < 0.0001) enhancement in α - and β -esterases activity was observed with 2-fold increase in resistant An. StephensiGOA compared to susceptible An. StephensiBB. native-PAGE depicted two major bands 'a' (Rf = 0.80) and 'b' (Rf = 0.72) in susceptible An. stephensiBB , while one intense band 'b' (Rf = 0.72) was visible in resistant An. stephensiGOA. Inhibition assay revealed complete inhibition of α - and β -esterases activity in presence of 1 mM malathion in susceptible strain compared to observed partial inhibition in resistant strain on native-PAGE., Interpretation & Conclusion: This study provides a better understanding on the role of esterase enzyme (carboxylesterase) in conferring malathion-resistance in An. stephensi mosquitoes, as evident from the native-PAGE assay results. The study results could be used in characterizing the resistance mechanisms in vectors and for suggesting alternative chemical insecticide based resistance management strategies for effective vector-borne disease control.

Somatization in dermatology patients is a challenge to diagnose and manage. Somatization presents as medically unexplained dermatologic symptoms, which are commonly encountered in dermatology and psychiatry practices. These cutaneous symptoms are often intriguing and do not fit into any particular known dermatologic condition. Sometimes, they may evoke negative feelings in the practicing dermatologist. The dermatologic somatic symptoms might be one way of communicating psychologic distress in a culturally acceptable method. These somatic symptoms may be masking another psychiatric disorder such as depression. They could also be an adaptive response to a difficult psychosocial situation and means of coping in a culturally meaningful way; therefore, the underlying conflicts need to be understood and managed in the sociocultural context of the symptoms. This chapter discusses the various unexplained physical symptoms in dermatology patients and the need for comprehensive evaluation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Schizophrenia is characterized by impaired -social and non social cognition both of which lead to functional deficits. These deficits may benefit from cognitive remediation, but the neural underpinnings of such improvements have not been clearly delineated., Methods: We conducted a functional magnetic resonance (fMRI) study in early course schizophrenia patients randomly assigned to cognitive enhancement therapy (CET) or enriched supportive therapy (EST) and treated for two years. Imaging data over three time points including fMRI blood oxygen level dependent (BOLD) data were acquired during performance of a cognitive control paradigm, the Preparing to Overcome Prepotency (POP) task, and functional connectivity data, were analyzed., Results: During the two years of treatment, CET patients showed a continual increase in BOLD activity in the right dorsolateral prefrontal cortex (DLPFC), whereas EST patients tended to show no change in prefrontal brain function throughout treatment. Increases in right DLPFC activity were modestly associated with improved neurocognition (β = .14, p = .041), but not social cognition. Functional connectivity analyses showed reduced connectivity between the DLPFC and the anterior cingulate cortex (ACC) in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement., Conclusions: These findings suggest that CET leads to enhanced neural activity in brain regions mediating cognitive control and increased efficiency in prefrontal circuits; such changes may be related to the observed therapeutic effects of CET on neurocognitive function., (Copyright © 2017. Published by Elsevier Inc.)

Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations ( p  < 1 e-8 ) for schizophrenia or rheumatoid arthritis, evaluating patterns of linkage disequilibrium and apparent pleiotropic risk profiles. Single nucleotide polymorphisms that conferred risk for both schizophrenia and rheumatoid arthritis were localized solely to the extended HLA region. Among single nucleotide polymorphisms that conferred differential risk for schizophrenia and rheumatoid arthritis, the majority were localized to HLA-B , TNXB , NOTCH4 , HLA-C , HCP5 , MICB , PSORS1C1 , and C6orf10 ; published functional data indicate that HLA-B and HLA-C have the most plausible pathogenic roles in both disorders. Interactomes of these eight genes were constructed from protein-protein interaction information using publicly available databases and novel computational predictions. The genes harboring apparently pleiotropic single nucleotide polymorphisms are closely connected to rheumatoid arthritis and schizophrenia associated genes through common interacting partners. A separate and independent analysis of the interactomes of rheumatoid arthritis and schizophrenia genes showed a significant overlap between the two interactomes and that they share several common pathways, motivating functional studies suggesting a relationship in the pathogenesis of schizophrenia/rheumatoid arthritis.

Fruit wastes constituting up to half of total fruit weight represent a large pool of untapped resources for isolation of starch with diverse applications. In this work, the possibility of isolating starch from tropical fruit wastes and its extended application as a natural coagulant was elucidated. Amongst the 12 various parts of fruit wastes selected, only jackfruit seeds contained more than 50% of total starch content. Using alkaline extraction procedures, starch has been successfully isolated from local jackfruit seeds with a yield of approximately 18%. Bell-shaped starch granules were observed under SEM with a granule size ranging from 1.1 to 41.6 μm. Detailed starch characteristics were performed to provide a comparison between the isolated seed starch and also conventional starches. Among them, chemical properties such as the content of starch, amylose, amylopectin and the corresponding molecular weights are some of the key characteristics which governed their performance as natural coagulants. The potential use of isolated seed starch as an aid was then demonstrated in both suspensions of kaolin (model synthetic system) and Chlorella sp. microalga (real-time application) with plausible outcomes. At optimized starch dosage of 60 mg/L, the overall turbidity removal in kaolin was enhanced by at least 25% at a fixed alum dosage of 2.1 mg/L. Positive turbidity and COD removals were also observed in the treatment of Chlorella suspensions. Starches which served as bridging agents aided in the linkage of neighbouring microflocs and subsequently, forming macroflocs through a secondary coagulation mechanism: adsorption and bridging.

Introduction: Neuropathological studies suggest neuropil reduction in schizophrenia. Altered synaptic pruning is proposed to underlie neuropil reduction. Underlying factors and clinical correlates of synaptic pruning are poorly understood. Using phosphorus magnetic resonance spectroscopy ( 31 P MRS), it is feasible to assess membrane phospholipid (MPL) metabolites in the brain that specifically and sensitively reflect neuropil expansion (elevated MPL precursors) or contraction (elevated MPL catabolites)., Methods: We examined MPL metabolites and their cognitive, clinical and immunologic correlates among 28 early-course schizophrenia individuals (illness duration 1.99±1.33 years; antipsychotic-naïve=18) and 21 controls. We acquired whole-brain multi-voxel 31 P MRS data from 12 unique brain regions. Interleukin-6 and C-reactive protein (CRP) were assayed in the serum. Generalized linear mixed models examined case-control differences in MPL metabolites in these regions correcting for multiple testing. Partial correlations accounting for multiple tests examined the relationship of Interleukin-6 and CRP levels with MPL metabolite levels., Results: MPL catabolite levels were increased in the thalamus in schizophrenia compared to controls. Interleukin-6 and CRP levels did not show case-control differences. Interleukin-6 levels positively correlated with MPL catabolite levels in the thalamus after correcting for multiple tests. The left thalamus MPL catabolite levels correlated negatively with sustained attention (corrected p=0.039)., Discussion: Elevated MPL catabolites in the thalamus suggest increased neuropil contraction that may be related to excessive synaptic pruning. The thalamic neuropil contraction is associated with Interleukin-6 levels suggesting central pathogenic mechanisms for the inflammatory mediators. Correlation of increased thalamic MPL catabolite levels with cognitive impairments suggests clinical correlates of neuropil contraction., Competing Interests: Conflict of Interest All authors report no biomedical financial interests or potential conflicts of interest.

Genetic factors may underlie beneficial and adverse responses to antipsychotic treatment. These relationships may be easier to identify among patients early in the course of disease who have limited exposure to antipsychotic drugs. We examined 86 first episode patients (schizophrenia, psychotic bipolar disorder and major depressive disorder with psychotic features) who had minimal to no prior antipsychotic exposure in a 6-week pharmacogenomic study of antipsychotic treatment response. Response was measured by change in Brief Psychiatric Rating Scale total score. Risperidone monotherapy was the primary antipsychotic treatment. Pharmacogenomic association studies were completed to (1) examine candidate single-nucleotide polymorphisms (SNPs) in genes known to be involved with glutamate signaling, and (2) conduct an exploratory genome-wide association study of symptom response to identify potential novel associations for future investigation. Two SNPs in GRM7 (rs2069062 and rs2014195) were significantly associated with antipsychotic response in candidate gene analysis, as were two SNPs in the human glutamate receptor delta 2 (GRID2) gene (rs9307122 and rs1875705) in genome-wide association analysis. Further examination of these findings with those from a separate risperidone-treated study sample demonstrated that top SNPs in both studies were overrepresented in glutamate genes and that there were similarities in neurodevelopmental gene categories associated with drug response from both study samples. These associations indicate a role for gene variants related to glutamate signaling and antipsychotic response with more broad association patterns indicating the potential importance of genes involved in neuronal development.

Objective: Despite its long history as a psychiatric diagnosis, little is known about the sociodemographic and clinical profile of persistent delusional disorder (PDD) or its subtypes, treatment response, and outcomes, particularly in India. We examined the clinical characteristics and course of PDD in patients presenting to a tertiary neuropsychiatry center in India., Method: A retrospective chart review of patients diagnosed with PDD (ICD-10) between January 2000 and May 2014 was conducted. Sociodemographic and clinical data including age at onset, total duration of the illness, clinical symptoms and treatment, hospitalizations, occupational functioning, and follow-up were extracted from the files. The study was approved by the institute ethics committee., Results: The sample (N = 455) consisted of 236 men and 219 women. The mean age at onset was 32.36 ± 10.47 years. The most common delusion was infidelity (n = 203, 44.6%) followed by persecution (n = 149, 32.7%). Hallucinations were present in 78 (17.1%), depressive symptoms in 187 (41.1%), and comorbid substance dependence in 61 (13.4%) subjects; 141 subjects (31.0%) had a family history of mental illness. Follow-up data were available for 308 subjects, of whom 285 (92.5%) reported good compliance with medication. Of the subjects, 163 (52.9%) showed a good response to treatment. The diagnosis of PDD remained unchanged in 274 of 308 subjects (88.9%)., Conclusion: In our center, PDD appears to be uncommon and has a near-equal gender representation. Infidelity was the most common delusion, which is in contrast to the reported literature. The diagnosis of PDD appears to be stable with good response to atypical antipsychotics if compliance can be ensured.

Objective: Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm., Method: The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT)., Results: [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power., Conclusions: This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Background: Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients., Methods: Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls., Results: HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10(-4); 2-back, P = 1.39 × 10(-5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons., Conclusions: The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Rationale: Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated., Objectives: The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment., Methods: Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions., Results: Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment., Conclusions: These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.