Functional Analysis of a Novel Connexin30 Mutation in a Large Family with Hearing Loss, Pesplanus, Ichthyosis, Cutaneous Nodules, and Keratoderma.

Mutations in the gap-junction gene Cx30 (Connexin30, GJB6) are a known cause of hearing loss. Here, we report our findings on a large multigeneration family in which severe to profound sensorineural hearing impairment is associated with a variety of skin-related anomalies. Genome-wide analysis of the family showed that the locus maps to chromosome region 13ptel-q12.1 and that a novel mutation, p.N54K, in Cx30, cosegregates with the phenotype. Unlike wild-type Cx30, p.N54K Cx30 is predominantly localized in the cytoplasm and does not permit transfer of neurobiotin, suggesting improper cellular localization and abolishment of gap-junction activity.

Relative quantification of human ß-defensins by a proteomics approach based on selected reaction monitoring.

RATIONALE: A targeted proteomics method based on selected reaction monitoring (SRM) is a relevant approach for the analysis of multiple analytes in biological samples. Defensins are phylogenetically conserved small antimicrobial peptides contributing to innate host defense and exhibiting low immunogenicity, resistance to proteolysis and a broad range of antimicrobial activities. The goal of the present study was to develop and optimize SRM-based targeted proteomics methods for the detection of human ß-defensins 1-4 in various biological fluids. METHODS: An SRM-based targeted proteomics method was developed and validated for the detection of human ß-defensins 1-4. The supernatants of resting and IL-1ß-stimulated Caco2, HT-29 and SW-1116 colonic epithelial cells (CEC), cell lysates of CECs and tear samples of human healthy individuals were analyzed and the feasibility of the developed method was validated by ELISA and dot-blot analysis complemented by RT-qPCR. RESULTS: Our results demonstrate that the developed SRM method offers an alternative approach for the cost-effective and rapid analysis of human ß-defensins in samples with biological relevance. CONCLUSIONS: A semi-quantitative targeted mass spectrometry method was developed and validated for the relative quantification of ß-defensins 1-4 in cell culture supernatants and body fluid analyses.

The impact of ATRA on shaping human myeloid cell responses to epithelial cell-derived stimuli and on T-lymphocyte polarization.

Vitamin A plays an essential role in the maintenance of gut homeostasis but its interplay with chemokines has not been explored so far. Using an in vitro model system we studied the effects of human colonic epithelial cells (Caco2, HT-29, and HCT116) derived inflammatory stimuli on monocyte-derived dendritic cells and macrophages. Unstimulated Caco2 and HT-29 cells secreted CCL19, CCL21, and CCL22 chemokines, which could attract dendritic cells and macrophages and induced CCR7 receptor up-regulation by retinoic-acid resulting in dendritic cell migration. The chemokines Mk, CXCL16, and CXCL7 were secreted by all the 3 cell lines tested, and upon stimulation by IL-1ß or TNF-α this effect was inhibited by ATRA but had no impact on CXCL1, CXCL8, and CCL20 secretion in response to IL-1ß. In the presence of ATRA the supernatants of these cells induced CD103 expression on monocyte-derived dendritic cells and when conditioned by ATRA and cocultured with CD4(+) T-lymphocytes they reduced the proportion of Th17 T-cells. However, in the macrophage-T-cell cocultures the number of these effector T-cells was increased. Thus cytokine-activated colonic epithelial cells trigger the secretion of distinct combinations of chemokines depending on the proinflammatory stimulus and are controlled by retinoic acid, which also governs dendritic cell and macrophage responses.

Impact of substance use disorder on presentation and short-term course of schizophrenia.

The aim of the present study was to compare a cohort of schizophrenia patients with substance use disorder (SUD) with a similar cohort of schizophrenia patients without SUD with regard to sociodemographic variables, clinical variables, psychopathology, anxiety symptoms, depressive symptoms, treatment outcome, and side effect profile of drugs. A total of 143 consecutive inpatients with ICD-10 DCR diagnosis of schizophrenia were included after obtaining informed consent. Patients were evaluated by a semistructured data sheet and Maudsley Addiction Profile. They were then rated by Positive and Negative Symptoms Scale, Calgary Depression Scale, Hamilton Anxiety Rating Scale, and Brief Psychiatric Rating Scale at presentation, three weeks, and six weeks. At three weeks and six weeks, they were also evaluated by UKU Side Effect Rating Scale. Substance abuse was detected in 63.6% schizophrenia patients. Nicotine was the commonest substance followed by cannabis and alcohol. Substance users had longer untreated illness and more depressive symptoms at presentation and six-week follow-up. Dual diagnosis patients had difficulty in abstraction at three and six weeks but not at presentation. Schizophrenia patients with SUD had more depressive symptoms. SUD appeared to mask abstraction difficulties at presentation. Schizophrenia patients with SUD should be carefully assessed for presence of depression.

Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE.

Mutations in the autosomal genes TMPRSS3, TMC1, USHIC, CDH23 and TMIE are known to cause hereditary hearing loss. To study the contribution of these genes to autosomal recessive, non-syndromic hearing loss (ARNSHL) in India, we examined 374 families with the disorder to identify potential mutations. We found four mutations in TMPRSS3, eight in TMC1, ten in USHIC, eight in CDH23 and three in TMIE. Of the 33 potentially pathogenic variants identified in these genes, 23 were new and the remaining have been previously reported. Collectively, mutations in these five genes contribute to about one-tenth of ARNSHL among the families examined. New mutations detected in this study extend the allelic heterogeneity of the genes and provide several additional variants for structure-function correlation studies. These findings have implications for early DNA-based detection of deafness and genetic counseling of affected families in the Indian subcontinent.

Internal predictors of burnout in psychiatric nurses: An Indian study.

BACKGROUND: Research has not adequately focused on the issue of burnout in Psychiatric nurses, despite the fact that they suffer considerable stress in their work. Till date no study has been conducted on burnout among psychiatric nurses in India. Further, there is a particular lack of research in internal variables predicting burnout in them. AIMS: To determine whether there are any internal psychological factors relevant to burnout in psychiatric nurses in India. MATERIALS AND METHODS: We recruited 101 psychiatric nurses scoring less than two in General Health Questionnaire, version 12 (GHQ-12) from two psychiatric hospitals after obtaining informed consent. All subjects filled up a sociodemographic data sheet along with global adjustment scale, emotional maturity scale, PGI general well-being scale, locus of control scale, and Copenhagen burnout inventory (CBI). Correlations between burnout and sociodemographic/clinical variables were done by Pearson's r or Spearman's rho. Signi ficant variables were entered in a stepwise multiple linear regression analysis with total burnout score as dependent variable. RESULTS: Age, duration of total period of nursing, prior military training, locus of control, sense of general well-being, adjustment capabilities, and emotional maturity had significant relation with burnout. Of them, emotional maturity was the most significant protective factors against burnout along with adjustment capabilities, sense of physical well-being, and military training in decreasing significance. Together they explained 41% variation in total burnout score which is significant at <0.001 level. An internal locus of control was inversely correlated with burnout, but failed to predict it in regression analysis. CONCLUSION: Emotional maturity, adjustability, sense of general physical well-being as well as prior military training significantly predicted lower burnout. Of them, emotional maturity was the most important predictor. Internal locus of control was also correlated with lower burnout.

A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3.

Autosomal dominant nonsyndromic hearing loss (ADNSHL) accounts for about one-fifth of hereditary hearing loss in humans. In the present study, we have analyzed a three-generation family with 14 of its members manifesting ADNSHL, using a genome-wide linkage mapping approach. We found a novel locus DFNA59 between the D11S929 and D11S480 markers in the chromosome location 11p14.2-q12.3. The highest two-point lod score of 5.72 at recombination fraction = 0 was obtained for D11S4152, D11S4154, D11S1301, D11S905 and D11S1344. The critical genomic region comprising about 37 megabases of DNA is proposed to carry a gene for ADNSHL in the family. About 50 cochlear-expressed genes mapping to the region are strong candidates which we propose to examine to identify the gene responsible for the hearing impairment.

Neuroplasticity--a paradigm shift in neurosciences.

Neuroplasticity is the phenomenon in brain where different stimuli lead to increase or decrease in the number of brain cells and remodelling of synapses. Neuroplasticity research has now established beyond doubt that instead being a static cell mass, our brain is actually a dynamic system of neural network that has the capability of significant growth under favourable circumstances. This obviously opens up new possibilities in treatment of disorders where neural loss or synaptic decay is major factor in molecular aetiopathogeneis. Neuroplasticity research unravels the way stress acts. Similarly it gives new hypothesis regarding depression and epilepsy. Novel therapeutic approaches based on neuroplastic findings are also discussed.