Heritable anisotropy associated with cognitive impairments among patients with schizophrenia and their non-psychotic relatives in multiplex families.

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.

The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.

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.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution.

Newly isolated serotypes of AAV readily cross the endothelial barrier to provide efficient transgene delivery throughout the body. However, tissue-specific expression is preferred in most experimental studies and gene therapy protocols. Previous efforts to restrict gene expression to the myocardium often relied on direct injection into heart muscle or intracoronary perfusion. Here, we report an AAV vector system employing the cardiac troponin T (cTnT) promoter. Using luciferase and enhanced green fluorescence protein (eGFP), the efficiency and specificity of cardiac reporter gene expression using AAV serotype capsids: AAV-1, 2, 6, 8 or 9 were tested after systemic administration to 1-week-old mice. Luciferase assays showed that the cTnT promoter worked in combination with each of the AAV serotype capsids to provide cardiomyocyte-specific gene expression, but AAV-9 followed closely by AAV-8 was the most efficient. AAV9-mediated gene expression from the cTnT promoter was 640-fold greater in the heart compared with the next highest tissue (liver). eGFP fluorescence indicated a transduction efficiency of 96% using AAV-9 at a dose of only 3.15 × 10(10) viral particles per mouse. Moreover, the intensity of cardiomyocyte eGFP fluorescence measured on a cell-by-cell basis revealed that AAV-mediated gene expression in the heart can be modeled as a Poisson distribution, requiring an average of nearly two vector genomes per cell to attain an 85% transduction efficiency.

Evaluation of coloring efficacy of lac dye in comminuted meat product.

Effect of incorporation of graded levels (4, 6, 8, 10, 25 ppm) of lac dye on coloring efficacy and possible use of this natural color in processed meat products was studied. Inclusion of lac dye at different concentrations did not affect the pH significantly whereas a linear increase in the Lovibond red color unit of chicken nuggets was noted with raising the level of lac dye from 4 to 10 ppm. The sensory rating for color was highest at addition level of 25 ppm of lac dye and it was comparable to color score of the product containing 200 ppm sodium nitrite. Lac dye inclusion in nuggets at all concentrations studied had better antimicrobial properties as compared to 200 ppm sodium nitrite. It was concluded that lac dye from 10 to 25 ppm could be incorporated in comminuted meat products as a natural colorant with antimicrobial action.

Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial.

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 (Aß) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aß 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 18F-Florbetapir positron emission tomography (PET) and 18F-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.

Time-dependent peristaltic analysis in a curved conduit: Application to chyme movement through intestine.

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.

Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes.

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.

Malignant Melanoma of Nasal Cavity- A Case Report.

Malignant Melanoma of nasal cavity is an extremely rare tumour and is more aggressive than its cutaneous counterpart. Primary malignant melanoma of nasal cavity arise from melanocytes located in the mucous membrane. Only 0.5% of malignant melanoma arises in nasal cavity. We report a case of malignant melanoma of the nasal cavity in a 51-year-old male who presented with swelling of nose, nasal block and epistaxis. By brush cytology and CT scan imaging, the pre operative diagnosis of malignant melanoma was made which was later confirmed by histopathology examination along with immunohistochemistry by using S100 and HMB 45. Malignant melanoma of nose is rare tumour, with aggressive behavior and poor prognosis. Rarity of this lesion warrants its mention and emphasizes the importance of considering malignant melanoma among the differential diagnosis of tumours of nose and paranasal sinuses.

Molecular events in the membrane transport of methotrexate in human CCRF-CEM leukemia cell lines.

A variant line (CEM-7A) "overproducing" the reduced folate/MTX carrier system was isolated from human CCRF-CEM leukemia cells grown under selective conditions in medium containing 0.25 nM 5-formyl-THF as the sole folate source. This line exhibits a 95-fold increased Vmax for [3H]-MTX influx as compared to parental cells. The values for [3H]-MTX influx Km, efflux t1/2 and structural specificity for other (anti)folate compounds were unchanged. The amount of carrier protein, estimated by NHS-[3H]-MTX affinity labeling, was approximately 30-fold higher in CEM-7A cells than in parental cells. Influx of [3H]-MTX in CEM-7A cells was found to be down-regulated 6-7-fold after preincubation of cells with adenosine, 5-formyl-THF or 5-methyl-THF, but could be prevented exclusively by inhibitors of dihydrofolate reductase. The underlying mechanism(s) of these effects have not as yet been elucidated. A radioiodinated photoaffinity analog of MTX was used to prove the molecular events in carrier-mediated MTX uptake in parental CCRF-CEM cells, CEM-7A cells, and a line exhibiting a MTX-transport defect (CEM-MTX). Specific labeling of an 80-85 kDa membrane protein was observed in parental cells, but not in CEM/MTX cells. Uptake of photoprobe and levels of the 80-85 kDa membrane protein were significantly increased in CEM-7A cells. Due to extensive glycosylation the MW of the carrier protein in human cells seems to be substantially higher than that of its counterpart in murine L1210 leukemia cells (46-48 kDa). Pulse-labeling experiments at 37 degrees C demonstrated that in CEM-7A cells photoprobe uptake proceeds via a specific pathway. The 80-85 kDa membrane protein is involved in the initial binding and translocation of photoprobe, after which a 38 kDa cytosolic protein is responsible for further intracellular distribution. At this time, the combination of photoaffinity labeling techniques and the availability of variant cell lines overexpressing the reduced folate/MTX carrier protein has provided new insights into the MTX transport process in human leukemia cell lines. In the near future this approach should also allow a further elucidation of the regulatory aspects of carrier function.

Prevalence of alcohol dependence in a town in Nepal as assessed by the CAGE questionnaire.

BACKGROUND: In spite of a perception that alcohol use is rampant in Nepal, there has been no survey to assess the extent of alcohol dependence in the country. AIMS: (i) To assess prevalence of alcohol dependence in the community of Dharan and (ii) to correlate this with various socio-demographic characteristics. DESIGN: The CAGE questionnaire was administered to all adult individuals in houses selected randomly in the township of Dharan. FINDINGS: Among 2344 adults assessed, the prevalence of alcohol dependence was found to be 25.8%. The prevalence of alcohol dependence increased with age to peak in the age group 45-54 years and was more than twice as common in men as in women. Also, alcohol dependence was more common among those with lower level of education, widowers and divorcees and those belonging to the Matwali community. The extent of dependence was influenced by socio-cultural sanctions. CONCLUSIONS: The prevalence of alcohol dependence is too high for comfort in Dharan, a town in eastern Nepal. There is an urgent need to formulate a policy for substance abuse in the country taking into account the findings of this study.

Evaluation of colour quality of complexometric indicators in the titration of Nickel(II) with EDTA by tristimulus colorimetry.

Trichromatic colorimetry was applied to the specification of colour changes of metallochromic indicators viz., murexide, pyrocatechol violet, bromopyrogallol red, pyrogallol red and chromazurol S in the complexometric titration of Nickel(II) with ethylene-diaminetetraacetic acid (EDTA), in order to assess the quality of colour change at the equivalence point with the help of CIE L*a*b* 1976 system and the values of SCD (Specific Colour Discrimination) parameter. A screened indicator, a mixture of murexide and methylene blue in the ratio 10:1 (m/m), is proposed as an ideal indicator in this titration as evidenced by the plots of a* vs. b* and from the numerical values of standard deviation for a large number of visual titrations.

Specification of colour changes of metallochromic indicators in the titration of bismuth with EDTA.

The quality of the colour changes at the end-point in the complexometric titration of bismuth(III) with EDTA, using the indicators Hemotoxylin, PAN [1-(2-Pyridylazo)-Naphthol-2], PAR [4-(2-Pyridylazo)-Resorcinol], Xylenol Orange and Thoran is studied by means of the CIE 1931 trichromatic system, using specific colour discrimination (SCD) and colour difference (DeltaE*). The indicators are arranged in order of colour change quality. Of the indicators studied, Hemotoxylin is recommended as the most suitable for this titration.

Basic aspects and applications of tristimulus colorimetry.

A detailed account of the specification of colour using the 1931 Commission International de L'Eclairage tristimulus coordinates and subsequent colour spaces for the measurement of small differences in colour is provided along with a review of the application of quantitative parameters for the evaluation of colour changes of acid-base and complexometric indicators. The development of screened indicators to improve the quality of colour changes at the equivalence point is discussed. Various computer programs proposed to calculate the different parameters by different algorithms are reviewed.

Spectrophotometric determination of bio-active compounds with chloramine-T and gallocyanine.

A simple, sensitive and selective method for the spectrophotometric determination of drugs, viz., sulphamethoxazole, tetracycline HCl, amidopyrine, nifurtimox and isoniazid and biologically important amino acids, cysteine, aspartic acid and arginine based on their reactivity with chloramine-T (CAT) is proposed. The method involves the addition of excess CAT of a known concentration in the presence of 0.25 M HCl and the determination of the unreacted CAT by measurement of the decrease in the absorbance of the dye, gallocyanine (lambda(max): 540 nm), the most suitable of several dyes that were tested. This method was applied to the determination of drug contents in pharmaceutical formulations and to the measurement of the aspartic acid content of some protein hydrolysates. The method is useful for the determination of the target compounds in microgram quantities from 0.4-5.6 microg mL(-1) with the exceptions of arginine (1.0-8.0 microg mL(-1)) and nifurtimox (0.8-5.6 microg mL(-1)). Standard deviations were typically 0.5 mg per dose (RSD 0.5-1.2%). No interferences were observed from common excipients in formulations, and detailed interference studies of other amino acids in the determination of cysteine, aspartic acid and arginine are reported. The validity of the method was tested against spectrophotometric and titrimetric reference methods. Recoveries were 99.8-102.1%.

Safety of acute normovolemic haemodilution with hydroxyethyl starch during intracranial surgery.

The effect of acute normovolemic haemodilution on haemodynamics, serum osmolality and coagulation parameters was studied in 20 patients undergoing intracranial surgical procedures. After induction of anaesthesia, 740+/-153 ml of blood was collected and the same was replaced with an equal volume of 6% hexaethyl starch. Heart rate (HR), blood pressure (BP), central venous pressure (CVP) and end tidal carbon dioxide tension (Et CO2) were monitored for 45 min. Haemoglobin concentration (Hb), haematocrit (Hct), serum osmolality (Osm), bleeding time (BT), prothrombin time (PT) and platelet count were determined before and 45 min after haemodilution. Hb and Hct were significantly lower following haemodilution (13.1+/-1.8 and 10.3+/-1.7 g/dL for Hb and 38.0+/-4.6%. and 30.1+/-4.5% for Hct). There was no significant change in the HR, BP and Et CO2 throughout the study period. CVP increased marginally from 35 to 45 min but was within normal limits. There was no significant change in serum osmolality, bleeding time and prothrombin time following haemodilution. Platelet count decreased following haemodilution but the values were within normal limits. The brain relaxation, as assessed by a semiquantitative scale, was satisfactory in all cases. None of the patients developed intraoperative brain swelling. In conclusion, acute normovolemic haemodilution with hexaethyl starch is tolerated well haemodynamically. It does not cause changes in serum osmolality which can increase brain oedema. It has no adverse effect on intraoperative haemostasis. It is a safe technique to decrease homologous blood transfusion during intracranial surgery.

Evaluation of thyroid hormones in chronic renal failure.

When chronic renal failure becomes advanced, the serum levels of most hormones are altered because of several interplaying mechanisms. This study was carried out to evaluate the level of total thyroxine (T4), triiodothyronine (T3) and thyrotropin (TSH) in 96 clinically euthyriod patient with chronic renal failure and 25 healthy individual as control. The patients were grouped into two groups, 62 patient on conservative management and 34 patients on chronic haemodialysis. The patient of both groups showed significant decrease in total T3 and T4 level as compared to normal control. Serum TSH level were similar in both groups as well as in control and were with in normal limit except 3 patients on conservative management which showed TSH level above normal chronic haemodialysis did not have positive effect in alteration of serum T3, T4 and TSH level.

Retroperitonial, teratoma as fetus in fetu--a case report.

We report a rare case of Retroperitonial teratoma containing Axial Skeleton long bone. Jaw, pelvis & scapula in a 27 yrs old male. Aberration in monozygotic twinning may rarely present as Fetus in Fetu. Rarer is presentation in Adult.

Fasciolopsis buski (giant intestinal fluke)--a case report.

A girl, aged 20 years presented with diarrhoea, vomiting, pain abdomen and loss of weight, the routine Stool examination revealed Fasciolopsis buski (giant intestinal fluke) in large numbers. Despite treatment with Praziquantel, she died after three days.

Candidate genes and their interactions with other genetic/environmental risk factors in the etiology of schizophrenia.

Identification of causative factors for common, chronic disorders is a major focus of current human health science research. These disorders are likely to be caused by multiple etiological agents. Available evidence also suggests that interactions between the risk factors may explain some of their pathogenic effects. While progress in genomics and allied biological research has brought forth powerful analytic techniques, the predicted complexity poses daunting analytic challenges. The search for pathogenesis of schizophrenia shares most of these challenges. We have reviewed the analytic and logistic problems associated with the search for pathogenesis. Evidence for pathogenic interactions is presented for selected diseases and for schizophrenia. We end by suggesting 'recursive analyses' as a potential design to address these challenges. This scheme involves initial focused searches for interactions motivated by available evidence, typically involving identified individual risk factors, such as candidate gene variants. Putative interactions are tested rigorously for replication and for biological plausibility. Support for the interactions from statistical and functional analyses motivates a progressively larger array of interactants that are evaluated recursively. The risk explained by the interactions is assessed concurrently and further elaborate searches may be guided by the results of such analyses. By way of example, we summarize our ongoing analyses of dopaminergic polymorphisms, as well as infectious etiological factors in schizophrenia genesis.