Discovery and synthesis of 2-amino-1-methyl-1H-imidazol-4(5H)-ones as GPCR ligands; an approach to develop breast cancer drugs via GPCR associated PAR1 and PI3Kinase inhibition mechanism.

Efforts were taken to synthesis and characterize 2-amino-1-methyl-1H-imidazole-4(5H)-one derivatives (4a-u) through a four-step reaction. The achieved compounds in remarkable yield have characterized through standard analytical techniques such as FTIR, LC-MS, NMR, HRMS, and elemental analysis. Present study mainly aimed to evaluate 4a-u as G protein-coupled receptors (GPCR). In the mechanism, stimulation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a general reaction activated by a series of membrane-bound receptors such as GPCR. Protease-activated receptor-1 (PAR1) is a subfamily of related GPCR, which triggered by the division of fragment of its extracellular domain. Therefore, molecular docking is done to ensure the inhibition of PAR1 and PI3Kinase. PI3Kinase is a chief enzyme in the development of breast cancer via the Akt/mTOR pathway. Thus, in vitro PI3Kinase inhibition and anti-breast cancer studies has also done to screen medicinally important compounds among (4a-u). Based on the best binding affinity, in vitro relative % activity and IC50 values, compounds 4a, 4g, 4i, 4n, and 4u were screened for further preclinical studies in animal model evaluations.

Twelve-month prevalence and treatment gap for common mental disorders: Findings from a large-scale epidemiological survey in India.

BACKGROUND: Common mental disorders, such as mood, anxiety, and substance use disorders, are significant contributors to disability globally, including India. Available research is, however, limited by methodological issues and heterogeneities. AIM: The present paper focuses on the 12-month prevalence and 12-month treatment for anxiety, mood, and substance use disorders in India. MATERIALS AND METHODS: As part of the World Health Organization World Mental Health (WMH) Survey Initiative, in India, the study was conducted at eleven sites. However, the current study focuses on the household sample of 24,371 adults (≥18 years) of eight districts of different states, covering rural and urban areas. Respondents were interviewed face-to-face using the WMH Composite International Diagnostic Interview after translation and country-specific adaptations. Diagnoses were generated as per the International Classification of Diseases, 10th edition, Diagnostic Criteria for Research. RESULTS: Nearly 49.3% of the sample included males. The 12-month prevalence of common mental disorders was 5.52% - anxiety disorders (3.41%), mood disorders (1.44%), and substance use disorders (1.18%). Females had a relatively higher prevalence of anxiety and mood disorders, and lower prevalence of substance use disorders than males. The 12-month treatment for people with common mental disorders was 5.09% (range 1.66%-11.55% for individual disorders). The survey revealed a huge treatment gap of 95%, with only 5 out of 100 individuals with common mental disorders receiving any treatment over the past year. CONCLUSION: The survey provides valuable data to understand the mental health needs and treatment gaps in the Indian population. Despite the 12-month prevalence study being restricted to selected mental disorders, these estimates are likely to be conservative due to under-reporting or inadequate detection due to cultural factors.

Phaeovibrio sulfidiphilus gen. nov., sp. nov., phototrophic alphaproteobacteria isolated from brackish water.

Two strains (JA480(T) and JA481) of phototrophic alphaproteobacteria were isolated from sediment samples collected from brackish water near Nagapattinam, India. They were Gram-negative, vibrioid cells containing bacteriochlorophyll a and rhodopin as major photosynthetic pigments. Most cells of both strains were non-flagellated; 1 % of cells showed two monopolar flagella. Cells showed positive phototaxis. Both strains showed chimeric intracellular photosynthetic membranes, where both lamellar stacks and vesicles were present together in a single cell. The major fatty acids were C(18 : 1)ω7c and C(16 : 0) in both strains. The genomic G+C content was 67.2-68.8 mol% and the two strains were closely related (mean DNA-DNA hybridization >85 %). 16S rRNA gene sequence comparisons indicated that the isolates represent members of the Rhodospirillaceae within the class Alphaproteobacteria. According to the sequence comparison data, strain JA480(T) is positioned distinctly outside the group formed by the phototrophic genera Rhodospirillum, Rhodocista, Phaeospirillum, Rhodovibrio, Rhodospira and Roseospira, with only 80-92 % 16S rRNA gene sequence similarity. Distinct morphological, physiological and genotypic differences from previously described taxa support the classification of this isolate as a representative of a novel species in a new genus, for which the name Phaeovibrio sulfidiphilus gen. nov., sp. nov. is proposed. The type strain of Phaeovibrio sulfidiphilus is JA480(T) ( = KCTC 5825(T)  = NBRC 106163(T)  = DSM 23193(T)).

Propranolol-responsive akathisia following acute encephalitis.

OBJECTIVE: The objective of this case report is to highlight the possibility of akathisia in any patient who has recently recovered from encephalitis and now presents with motor restlessness. METHODS: We describe a 15-year-old boy presenting with the onset of abnormal and excessive motor restlessness following successful resolution of encephalitis. After thorough investigations and repeated psychiatric examinaton patient was diagnosed as suffering from postencephalitic akathisia. RESULTS: Thioridazine proved of no help. Patient achieved near complete recovery after treatment with propanolol within 2 weeks. CONCLUSION: Clinician should keep in mind that akathisia can have various etiologies and encephalitis may be the one of them. Propanolol is quite effective in patients with postencephalitic akathisia.

Gender differences in medically serious suicide attempts: a study from south India.

Studying gender differences in suicidal behaviour is important in developing specific need-based service provisions. We aimed to identify gender-specific characteristics associated with attempted suicide in a general hospital sample in south India. Two hundred and three patients admitted to medical wards following suicide attempts were assessed using a detailed clinical interview, measures of suicide intent (Suicide Intent Scale), lethality (Risk Rescue Rating), depression (Montgomery-Asberg Depression Rating Scale) and recent stress (Presumptive Stressful Life Events Scale). The majority of men attempting suicide were single. Men were more likely to use organophosphate poisons in their attempt to kill themselves and had higher rates of mental illness than women. As compared with men, women were more likely to come from rural areas, had a lower educational status, and had lower rates of employment outside the home. In women, the most common method of suicide attempt was by using plant poisons. Suicide attempt by self-immolation was significantly higher among women. Men had higher suicidal intent than women, although lethality, depression and stress were comparable between the genders. Rural women were more disadvantaged in education; however, in urban areas, men had higher psychiatric morbidity. Our results emphasise the need for a gender-specific approach among people who have attempted suicide.

Characteristics of high intent suicide attempters admitted to a general hospital.

BACKGROUND: Suicide intent is a strong predictor of repetition of attempts and subsequent suicide. This study aimed to compare socio-demographics, clinical factors and method of attempt in high and low intent suicide attempters. METHOD: All patients admitted following attempted suicide to a teaching hospital were interviewed. Socio-demographic information, details of the attempt and psychiatric diagnosis were recorded. Scales for assessing suicide intent, lethality, recent life-events and depression were administered. Comparison between high intent and low intent groups were done to identify the characteristics of patients who had high suicidal intent. RESULTS: The sample comprised 203 patients, 84 of whom were classified as high intent attempters using the Suicide Intent Scale. The high intent group were significantly more likely to be male (p = 0.01), of single marital status (p = 0.04), have a psychiatric diagnosis, especially depression (p = 0.001) and use self immolation to attempt suicide (p = 0.001). Patients with high intent had significantly higher lethality (p = 0.001) and recent stressful life-event scores (p = 0.001). CONCLUSIONS: High intent suicide attempts are associated with distinct socio-demographic profiles and psychiatric morbidity. Routine assessment of intent may help to identify individuals with high risk, who can be offered targeted interventions.

Dhat (semen loss) syndrome: a functional somatic syndrome of the Indian subcontinent?

OBJECTIVE: To study the illness characteristics of Dhat syndrome, which has been widely regarded as a culture-bound syndrome. METHODS: The sample was selected from a general hospital and included 29 patients with Dhat syndrome and 32 medical controls. Somatization Screening Index (SSI), Illness Behaviour Questionnaire (SIBQ), Somatosensory Amplification Scale (SAS), Whitley Index (WI) and Chalder Fatigue Scale were administered to both groups. RESULTS: Patients with Dhat syndrome scored significantly higher on all the measures except the SAS. DISCUSSION: The results indicate that patients with Dhat syndrome have significantly different illness beliefs and behaviours compared to controls and have similarities with other functional somatic syndromes (FSSs).

Effectiveness of clozapine in treatment-resistant schizophrenia.

BACKGROUND: Clozapine has been shown to be superior to chlorpromazine in improving the positive and negative symptoms of schizophrenia. However, technical experience with clozapine in Indian patients has not been documented. AIM: To assess the improvement in psychopathology of treatment-resistant schizophrenia with clozapine therapy and to study the relationship between sociodemographic and various psychopathology variables among patients with treatment-resistant schizophrenia. METHODS: Twenty-two patients with treatment-resistant schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, Calgary Depression Scale, Global Assessment of Functioning (GAF) Scale and Abnormal Involuntary Movement Scale (AIMS). These scales were used to determine the level of psychopathology, depression, overall functioning and severity of abnormal involuntary movements in the patients. The patients were admitted to the hospital for a short time to initiate clozapine therapy. At discharge, patients were stabilized on 300-400 mg/day of clozapine. The patients were re-evaluated after 20 months. RESULTS: The study group showed better global functioning after clozapine therapy. The therapy was well-tolerated though moderate side-effects were seen. Suicidal thoughts declined with clozapine therapy. There was a significant reduction in the negative symptom and general psychopathology scores of PANSS. CONCLUSION: Clozapine has therapeutic efficacy in some but not all treatment-resistant patients with schizophrenia.

The combination of pamidronate and calcitriol reverses particle- and TNF-alpha-induced altered functions of bone-marrow-derived stromal cells with osteoblastic phenotype.

Periprosthetic bone loss after total joint arthroplasty is a major clinical problem resulting in aseptic loosening of the implant. Among many cell types, osteoblasts play a crucial role in the development of peri-implant osteolysis. In this study, we tested the effects of calcitriol (1alpha,25-dihydroxy-vitamin-D3) and the bisphosphonate pamidronate on titanium-particle- and TNF-alpha-induced release of interleukin-6 and suppression of osteoblast-specific gene expressions in bone-marrow-derived stromal cells with an osteoblastic phenotype. We monitored the expression of procollagen alpha1[1], osteocalcin, osteonectin and alkaline phosphatase mRNAs by Northern blots and real-time reverse transcription and polymerase chain reaction analyses. The release of various cytokines was also analysed by ELISA. We found that calcitriol or pamidronate could only partially recover the altered functions of osteoblasts when added alone. Only a combination of these compounds restored all the tested functions of osteoblasts. The local delivery of these drugs may have therapeutic potential to prevent or to treat periprosthetic osteolysis and aseptic loosening of implants.

Abnormal sexual behavior in an adult male with obsessive compulsive disorder.

A male patient with homosexual obsession in obsessive compulsive disorder shows a better outcome following a combination of pharmacotherapy and psychotherapy. This case report emphasizes the importance of combination therapy in obsessive compulsive disorder with abnormal sexual impulses and behavior.

Psychiatric and personality disorders in survivors following their first suicide attempt.

The aim of the study was to determine the prevalence of psychiatric and personality disorders in survivors following their first suicide attempt. Three hundred and fortyone survivors who received treatment from the various medical wards of a general hospital participated in the study. ICDIO psychiatric disorders were diagnosed in 47.2% of the cases. The most common diagnosis was depressive episode (31 %). Only 7 % qualified for a diagnosis of personality disorder. A significant proportion of patients (52..8%) did not suffer from any identifiable ICD- 10 psychiatric disorder.

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes.

BACKGROUND: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. AIM: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. DESIGN: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. METHODS: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records. RESULTS: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]. CONCLUSIONS: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.

Acute polymorphic psychotic disorder: diagnostic stability over 3 years.

OBJECTIVE: Acute polymorphic psychotic disorder without symptoms of schizophrenia (APPD) in ICD-10 is unique in many characteristics. This study aimed at investigating the diagnostic stability of APPD over 3 years. METHOD: Forty-five patients with first episode APPD were followed up and assessed at regular intervals over a period of 3 years. RESULTS: Thirty-two patients were females. Average age of the sample was 26.9 years. Thirty-three cases retained their index diagnosis of APPD, while 12 cases required diagnostic revision: 10 to bipolar affective disorder and the rest to unspecified non-organic psychosis. Shorter duration of illness (<1 month) and abrupt onset (<48 h) predicted a stable diagnosis of APPD. CONCLUSION: APPD is a relatively stable diagnosis and argues for a distinct diagnostic entity.

Insight, psychopathology & schizophrenia.

25 inpatients with schizophrenia were examined to explore the relationship between insight and psychopathology and illness severity over a four-week period. The average degree of insight improved irrespective of the type of recovery. There was no consistent relationship between the changes in insight and changes in psychopathology. The severity of mental illness and awareness of mental disorder showed a semi-independent pattern of association. It is concluded that insight operates to some extent independent of psychopathology and severity of illness.

Coping startegies of the relatives of schizophrenic patients.

Families caring for a member with a chronic severe mental illness like schizophrenia have to cope with a lot of burden and distress. The coping styles used by these families and their relationship to burden has not been studied in Indian families. This study aims to identify the coping styles adopted by the relatives of schizophrenic patients. 44 patients with schizophrenia and 44 relatives from an outpatient psychiatric clinic were assessed. Resignation, an emotion-focussed coping strategy, was found to be more commonly employed by the relatives, than other strategies. Majority of the relatives failed to maintain social contacts. Levels of burden and negative symptoms correlated significantly with the resignation strategy. Analysis of the coping strategies of the relatives is essential before clinical interventions with families are planned to improve the coping skills of the carers.

Three-dimensional structure of the sodium salt of iota-carrageenan.

The three-dimensional structure of the sodium salt of iota-carrageenan has been determined by using X-ray diffraction data collected from its polycrystalline and oriented fibers. The molecule forms a half-staggered, parallel, threefold, right-handed double helix that is stabilized by interchain hydrogen bonds from 2- and 6-hydroxyl groups in the galactosyl units. Three helices are organized in a trigonal unit cell, of dimensions a=24.02 and c=12.93 A, with a lateral separation of 13.9 A for each pair. Both 2- and 4-sulfate groups are essential in helix-helix interactions that are mediated only by sodium ions and water molecules.

Antibody-induced shedding of CD44 from adherent cells is linked to the assembly of the cytoskeleton.

CD44 is a widely expressed integral membrane glycoprotein that serves as a specific adhesion receptor for the extracellular matrix glycosaminoglycan hyaluronan. CD44 participates in a variety of physiological and pathological processes through its role in cell adhesion. Under appropriate conditions, the ectodomain of CD44 is proteolytically removed from the cell surface. In this study we show that excessive CD44 shedding can be induced in mouse fibroblasts and monocytes upon exposure of these cells to a CD44-specific Ab immobilized on plastic, whereas treatment with phorbol ester induces significantly enhanced CD44 release from the monocytes only. CD44 shedding proceeds normally in fibroblasts and monocytes deficient in TNF-alpha converting enzyme (TACE), a sheddase involved in the processing of several substrates. Conversely, activation of the CD44 protease has no effect on the release of TNF-alpha from TACE-expressing cells, although the same metalloprotease inhibitor effectively blocks both TACE and the CD44 sheddase. Concomitant with anti-CD44 Ab- or phorbol ester-induced CD44 shedding, dramatic changes are observed in cell morphology and the structure of the actin cytoskeleton. Disruption of actin assembly with cytochalasin reduces CD44 shedding, but not the release of TNF-alpha. Moreover, pharmacological activation of Rho family GTPases Rac1 and Cdc42, which regulate actin filament assembly into distinct cytoskeletal structures, has a profound effect on CD44 release. We conclude that the CD44 sheddase and TACE are distinct enzymes, and that Ab- and phorbol ester-enhanced cleavage of CD44 is controlled in a cell type-dependent fashion by Rho GTPases through the cytoskeleton.