Validation of social cognition and interaction training's (SCIT) videos and photographs in Indian setting.

Background: Social cognition deficit is one of the marked characteristics of schizophrenia. Accumulated evidence suggests that social cognition and interaction training (SCIT) is associated with improved performance in social cognition and social skills in patients diagnosed with psychotic disorders. The cultural influence on social cognition is quite considerable. So, studies in the area of social cognition domains need to adapt and use culturally appropriate tools and measures to see the effectiveness. This study aimed to validate the materials used in SCIT training in Indian setting. Materials and Methods: The original script of video clips was translated into Hindi and was reshot, and the images were remade. A panel of experts rated the videos and images on a 5-point Likert scale. Furthermore, the content validity and internal consistency of the materials were calculated. Results: The content validity ratio (CVR) critical value was 0.357, and all the videos and images received more than the CVR critical value. The intraclass correlation coefficient for videos was 0.974, for SCIT photographs was 0.971, for "spotting character" was 0.975, and for "emotion shaping" was 0.965, indicating good internal consistency. Discussion: The majority of the experts in the panel found the videos and images adequate and appropriate for the Indian setting. In addition, the videos and photographs both yielded good internal consistency.

Resting state and activated brain glutamate-glutamine, brain lactate, cognition, and psychopathology among males with schizophrenia: A 3 Tesla proton magnetic resonance spectroscopic (1H-MRS) study.

Background: Research on glutamate (Glu) in schizophrenia has so far been inconclusive. Based on preclinical studies on Glu lactate interaction, researchers have now focused on brain lactate level as a sign of major pathology, including cognitive dysfunctions in the brain. Our study aimed to examine changes at resting and activated states in brain lactate and Glu-glutamine (Glx) at the anterior cingulate cortex (ACC) in schizophrenia. Methods: A hospital-based prospective study was conducted with twenty-two male cases of schizophrenia and matched healthy controls (HCs). Positive and Negative Syndrome Scale (PANSS), Montreal Cognitive Assessment (MoCA), and Stroop tasks were administered among patients. Brain lactate and Glx at ACC were measured at resting state and during the Stroop test with proton magnetic resonance spectroscopy (1H-MRS) both at baseline and at remission and once among HC. Result: Though MoCA scores improved significantly (P < 0.001) at remission from baseline among cases, repeated-measures analysis of variance (RM-ANOVA) did not find a significant time effect for Glx (P = 0.82) and lactate (P = 0.30) among cases from baseline to remission. Glx and lactate changed differently from baseline to remission. Conclusion: Our study did not find significant differences in Glx and lactate between schizophrenia patients and HC. No significant time effect on Glx and lactate was observed from baseline to remission among schizophrenia cases. Different changes observed in Glx and lactate from baseline to remission require replication in future studies with larger sample size, longer follow-up period, and multivoxel MR assessment.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Role of High-Sensitivity C-Reactive Protein as a Biomarker and Endophenotype in Mania.

Objective: To assess the role of high-sensitivity C-reactive protein (hs-CRP) as a biomarker, trait marker, and endophenotype in mania.Methods: Forty patients with mania, 40 of their first-degree relatives, and 30 healthy controls were recruited via a purposive sampling method from May 2020 to February 2021. hs-CRP levels were measured in all groups at baseline. The patient group was evaluated with the Young Mania Rating Scale, and hs-CRP levels were assessed in all participants at baseline, 2 weeks, and 6 weeks. Data were analyzed with SPSS version 25.Results: hs-CRP levels were significantly higher in patients than in controls and first-degree relatives (P = .001). However, hs-CRP levels were not higher in first-degree relatives compared to healthy controls. There was a significant reduction in total YMRS and domain scores and hs-CRP levels in patients at weeks 2 and 6 compared to baseline (P = .02).Conclusions: The blood hs-CRP level is a biomarker in mania, which may be a newer approach to detect disease progression and perhaps guide novel therapies. hs-CRP as an endophenotype requires further evaluation in future studies.

Kaempferol attenuates viability of ex-vivo cultured post-NACT breast tumor explants through downregulation of p53 induced stemness, inflammation and apoptosis evasion pathways.

Early onset of chemotherapy evasion is a therapeutic challenge. Chemotherapy-induced upregulation of stem cell markers imparts invasiveness and metastatic property to the resident tumor. The efficacy of Kaempferol in attenuating epithelial to mesenchymal transition has earlier been established in the breast cancer cell. In our study population, progression-free survival was observed to be statistically more significant in post-NACT low-grade tumors than the high-grade tumors. Further, in post-NACT TNBCs, high-grade tumors showed a preponderance of strong nuclear p53 expression and very low expression of Caspase 3, indicating that, altered p53 expression predisposes these tumors to apoptosis escape and up-regulation of stemness markers. Herein, we report the robust efficacy of Kaempferol on ex-vivo grown breast tumors, derived from post-NACT TNBC patients, through downregulation of nuclear p53, CD44, ALDH1, NANOG, MDR1, Ki67, BCL2 and upregulation of Caspase 3. Such tumors also showed concurrent deregulated RNA and protein expression of CD44, NANOG, ALDH1 and MDR1 with upregulation of Caspase 3 and cleaved Caspase 3, upon Kaempferol treatment. Validation of efficacy of the treatment dosage of Kaempferol through immunophenotyping on MDA-MB-231, suggested that Kaempferol at its IC-50 dosage was effective against CD44 and CD326 positive breast cancer through deregulating their expression. Protein-protein interaction network through STRING pathway analysis and co-expression study of candidate proteins showed the highest degree of co-expression of p53 and KI-67, CD44, NF- kappaB, ALDH1, NANOG, MDR1, and BCL2. Thus, potentially targetable oncogenic protein markers, that are susceptible to downregulation by Kaempferol, provides insight into biomarker-driven therapeutic approaches with it.

HIWI2 induces G2/M cell cycle arrest and apoptosis in human fibrosarcoma via the ROS/DNA damage/p53 axis.

AIMS: Piwi-like RNA-mediated gene silencing 4 (PIWIL4) or HIWI2, are seen deregulated in human cancers and possibly play critical roles in tumorigenesis. It is unknown what role HIWI2 plays in the regulation of fibrosarcoma, an early metastatic lethal type of soft tissue sarcoma (STS). The present study aimed to investigate the role of HIWI2 in the tumorigenesis of fibrosarcoma. MAIN METHODS: The expression of HIWI2 in HT1080 fibrosarcoma cells was determined by qRT-PCR and western blotting. The MTT assay, colony formation assay, cell cycle, and PE-AnnexinV/7AAD apoptosis assay using flow cytometry, DNA laddering assay, comet assay, and γH2AX accumulation assay were performed to study the effect of HIWI2 overexpression in HT1080 cells. Further, the effect of silencing of HIWI2 was determined by cell viability assay, transwell migration, and invasion assay. KEY FINDINGS: HIWI2 is under-expressed in STS cell lines and tissues, which is associated with poor disease-free survival, disease-specific survival, and progression-free survival of the patients. Overexpression of HIWI2 in HT1080 cells causes DNA damage by increasing intracellular ROS by inhibiting the expression of antioxidant genes (SOD1, SOD2, GPX1, GPX4, and CAT). Furthermore, an increase in H2AX phosphorylation was observed, which activates p53 that promotes p21 expression and caspase-3 activation, leading to G2/M phase cell cycle arrest and apoptosis. HIWI2 silencing, on the contrary, promotes cell growth, migration, and invasion by activating MMP2 and MMP9. SIGNIFICANCE: These results are the first to show that HIWI2 acts as a tumor suppressor in fibrosarcoma by modulating the ROS/DNA damage/p53 pathway.

Clinical efficacy and neurobiological correlates of electroconvulsive therapy in patients with clozapine-resistant/intolerant schizophrenia: study protocol of multi-site parallel arm double-blind randomized sham-controlled study.

Background: A substantial proportion of patients with treatment resistant schizophrenia do not respond well or partially to clozapine, with a subset that does not tolerate an adequate trial of clozapine. Electroconvulsive therapy (ECT) is regarded as one of the augmenting options, but there is a lack of high-quality evidence for this practice. This protocol describes a double-blind randomised sham-controlled modified-ECT trial to evaluate its efficacy in patients with clozapine resistant/intolerant schizophrenia. The study also involves multimodal investigations to identify the response predictors and the mechanistic basis of modified ECT in this population. Methods: One hundred consenting schizophrenia patients with resistance/intolerance to clozapine referred by clinicians for ECT would be randomly assigned to receive true ECT or sham ECT at three study centers. Sham ECT would mimic all the procedures of modified ECT including anaesthesia and muscle relaxation, except the electrical stimulation. After a blinded course, non-responders to sham ECT would be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging [MRI], electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphism) would be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial would evaluate the improvement in positive symptoms (scale for assessment of positive symptoms) of schizophrenia as the primary outcome measure with prediction of this change by resting-state functional-MRI based brain-connectivity as the second primary objective. Registration: Clinical Trial Registry of India (Reg no: CTRI/2021/05/033775) on 24 th May 2021.

Ribonucleotide reductase subunit M2 is a potential prognostic marker and therapeutic target for soft tissue sarcoma.

Soft tissue sarcomas (STSs) are highly aggressive malignant tumors that exhibit poor therapeutic outcomes. Hence, we aimed to track down a potential gene that can be used as a prognostic marker and therapeutic target for this malignancy. We integrated omics analysis of clinical data and in vitro studies and identified Ribonucleotide reductase subunit M2 (RRM2) as a potential oncogene associated with STS prognosis. We found RRM2 is highly expressed in STS cell lines and tissues. STS patients with increased RRM2 levels showed worse overall survival, disease-free survival, progression-free survival, and disease-specific survival. Further, overexpression of RRM2 in HT1080 cells induces proliferation, migration, invasion, and colony formation, whereas its silencing arrest the cell cycle at G0/G1 phase and induces apoptosis. Taken together, we established RRM2 to be positively associated with oncogenesis and prognosis of STS and therefore could be a promising prognostic marker and therapeutic target.

miR-197-5p increases Doxorubicin-mediated anticancer cytotoxicity of HT1080 fibrosarcoma cells by decreasing drug efflux.

Doxorubicin (Dox) is one of the most used drugs in the treatment of Soft tissue sarcoma. However, acquired resistance linked with poor survival and numerous side effects are the major challenges. Meanwhile, miRNAs are reported to influence the chemotherapeutic responses. However, there is hardly any evidence on the involvement of tumor-suppressive miR-197 reported in our previous study in augmenting the sensitivity of fibrosarcoma cells to Dox. Therefore, in this study, we intend to decipher if miR-197-5p combined with Dox could increase the anticancer cytotoxicity. For this, we evaluated the antitumorigenic effects of Dox and miR-197-5p individually and in combination by performing a series of molecular assays. We noticed that the sub-lethal concentration of miR-197-5p markedly enhanced the sensitivity of HT1080 fibrosarcoma cells to Dox by promoting apoptosis and G2/M cell cycle arrest. We also observed miR-197-5p sensitizes HT1080 cells to Dox by increasing drug influx, possibly due to suppression of MDR genes (ABCC1, MVP). Moreover, we found that KIAA0101, a target of miR-197-5p is inhibited by Dox, which is further repressed when treated in combination with miRNA. We also observed a marked upregulation of p53, known to be negatively correlated with KIAA0101 in Dox and miR-197-5p combination treatment compared to Dox alone. Taken together, our study revealed that Dox chemotherapy in combination with miR-197-5p could overcome the problem of drug efflux and enhance its antitumor effects on fibrosarcoma.

Efficacy of continuous theta burst stimulation - repetitive trancranial magnetic stimulation on the orbito frontal cortex as an adjunct to naltrexone in patients of opioid use disorder and its correlation with serum BDNF levels: a sham-controlled study.

Background: Opoid use disorder (OUD) is a global illness and reduction in craving by repeatative Transcranial Magnetic Stimulation (RTMS) is one of its management approaches. Orbito-frontal Cortex is implicated in the several behavioral aspects of substance use including craving. Brain derived neurotrophic factor (BDNF) has a critical role in addictive properties of drugs of use. Previous studies have shown significant improvement in craving with RTMS and demonstrated alterations of serum BDNF levels in various substance dependent individual associated with craving. Aim: To examine the efficacy of continuous Theta Burst Stimulation RTMS (CTBS-RTMS) over the right OFC as an adjunct to Naltrexone in patients of OUD and its correlation with serum BDNF levels. Methods: Forty patients with OUD were recruited with purposive sampling. At the end of detoxification CTBS -RTMS was applied by dividing them into two equal groups as active and sham group using alternate allocation. Obsessive compulsive drug use scale (OCDUS) was applied and serum BDNF level was measured overtime till the end of CTBS-RTMS session. Data was analyzed by SPSS version 25. Results: Both groups had shown significant reduction in craving (OCDUS score) and serum BDNF from the baseline to 14th session of the RTMS. But there was no significant difference when compared between the two groups. Significant correlation was observed between serum BDNF levels overtime with different clinical variables in active group. Conclusion: The study adds to the literature in building an understanding of how rTMS could be used in reducing cravings for opioids.

piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair.

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3'UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.

Resting state quantitative electroencephalogram gamma power spectra in patients with first episode psychosis: An observational study.

INTRODUCTION: Electrophysiological abnormalities, especially in the gamma frequency range, have been well documented in schizophrenia. This study was aimed to investigate the gamma spectral power of the brain in patients with first episode psychosis, using high-resolution electroencephalography. METHODOLOGY: Twenty-nine neuroleptic naïve/free male patients with non-affective psychosis as per ICD 10 DCR clinical criteria were compared with thirty age, sex, education and handedness matched healthy individuals as controls. All participants underwent 192-channel resting electroencephalography (EEG) recording. Gamma spectral power was calculated for low (31-50 Hz) and high-gamma (51-70 and 71-100 Hz) bands and compared between two groups using MANOVA and supplementary one-way ANOVA. Pearson correlation and linear regression analyses were conducted between spectral power parameters and various clinical variables. RESULTS: The gamma spectral power in 31-50 Hz and 51-70 Hz frequency bands was found to be significantly higher in patients in most brain regions. Duration of illness predicted the gamma spectral power in both right and left frontal regions of the brain in the frequency range 31-50 Hz and 71-100 Hz, as well as in the right temporal region in 71-100 Hz range, where it was negatively correlated. CONCLUSION: Patients with first episode psychosis have increased gamma spectral power, which might be indirectly related to the duration of illness.

Expressed Emotions and Coping among Relapsed Persons with Alcohol Dependence Syndrome: A Comparative Study.

BACKGROUND: Alcohol dependence is a global public health issue; it is a chronic and relapsing illness. Relapse is multifaceted by both neurobiological and psychosocial processes. AIM: To examine the expressed emotions and coping among persons with alcohol dependence. METHODS: The study was descriptive and hospital-based. A purposive sampling technique was used. This study was conducted at the Centre for Addiction Psychiatry, CIP, Ranchi. The total sample size was 50. Twenty-five persons with alcohol dependence who relapsed within six months following treatment formed a study group. Another 25 persons with alcohol dependence who were abstinent for a minimum period of six months after treatment formed a comparative group. Ways of coping questionnaire and the level of expressed emotions scale were used, and informed consent was taken from the participants. Chi-square and independent sample 't' test, Pearson's correlation was used to analyse the data. RESULTS: Mean age of relapsed patients was 35.3 years (S.D±7.6), and abstinent patients were 35.4 yrs (S.D±6.8), years of education of relapsed patients score was 12 yrs ±2.63 and 11.6 yrs ±3.26 in abstinent patients. A majority (60% )of relapsed patients were from rural background, 92% in the abstinent group were employed. 60% of abstinent patients had a family history of alcohol dependence. Abstinent patients had scored significantly high in all the domains of ways of coping. Relapse patients had higher scores in perceived lack of emotional support, perceived irritability, perceived intrusiveness, and perceived criticism compared to abstinent patients. CONCLUSION: The study provided further evidence that coping and perceived expressed emotions significantly influenced relapse among persons with alcohol dependence.

Serum Lipids among Drug Naïve or Drug-Free Patients with Obsessive Compulsive Disorder and their Association with Impulsivity: A Comparative Study.

BACKGROUND: The derangement of serum lipids is well documented in psychiatric disorders like schizophrenia, mania, and depression but not in obsessive compulsive disorder (OCD), where it has been inadequately examined. Also, serum lipid abnormalities are increasingly found in "impulsivity," an important sub-construct of OCD. Our study aimed to examine serum lipid profile among patients with OCD and its association with clinical profile and impulsivity among them. METHODS: Forty drug naïve or drug-free (four weeks for oral and eight weeks for any depot psychotropics) patients with OCD according to International Classification of Disease -10th version (ICD-10): Diagnostic Criteria for Research (DCR) by the World Health Organization (WHO), from outpatient and inpatient departments of a tertiary care psychiatric hospital were recruited. Measures like Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamliton Rating Scale for Depression (HAM-D), Barratt's Impulsivity Scale (BIS-11), and Hamilton Rating Scale for Anxiety (HAM-A) were administered. Forty age and sex-matched healthy controls (HC) were recruited after screening with General Health Questionnaire 12 (GHQ-12). Serum lipids were assessed in both the groups. RESULTS: Serum high density lipoproteins (HDL) (P < 0.001; partial η2 = 0.176) and apolipoprotein B (P < 0.001; partial η2 = 0.531) were significantly higher in OCD group than age- and sex-matched HC. A trend toward lower serum HDL (P = 0.06; partial η2 = 0.060) was observed among patients of OCD with high impulsivity. Serum HDL was negatively correlated with BIS attention (rs =-0.32; p = 0.03), BIS motor (rs = 0.40; P = 0.01), BIS non-planning (rs = - 0.36; P = 0.02), and BIS total (rs = - 0.36; P = 0.01) scores. Serum triglycerides (TG) (rs = 0.34; P = 0.03) and apolipoprotein B (rs = -0.32; P = 0.04) were negatively correlated with Y-BOCS compulsion score. Serum TG (rs = -0.45, P < 0.01) and serum very low density lipoprotein (VLDL) was negatively (rs = -0.39; P = 0.01) correlated with Y-BOCS total scores. Serum VLDL was positively (rs = 0.34; P = 0.03) correlated with BIS motor scores. CONCLUSIONS: Serum lipid fractions are deranged among patients with OCD. Different lipid fractions have different associations with clinical profiles of OCD. Impulsivity among patients with OCD may have a specific association with serum lipids. A small sample size, use of self-report measure without adaptation for impulsivity, a lack of metabolic profile assessment among participants, and a lack of assessment of impulsivity among HC were the limitations of our tudy.