TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related G protein-coupled receptor (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8-22, respectively. However, the signaling pathways and transduction channels activated downstream of these pruritogens are largely unknown. We found that TRPA1 is the downstream target of both MrgprA3 and MrgprC11 in cultured sensory neurons and heterologous cells. TRPA1 is required for Mrgpr-mediated signaling, as sensory neurons from TRPA1-deficient mice exhibited markedly diminished responses to chloroquine and BAM8-22. Similarly, TRPA1-deficient mice displayed little to no scratching in response to these pruritogens. Our findings indicate that TRPA1 is an essential component of the signaling pathways that promote histamine-independent itch.     

Metabolomics reveals elevated macromolecular degradation in periodontal disease

Periodontitis is a chronic inflammatory disease characterized by tissue destruction. In the diseased oral environment, saliva has primarily been considered to act as a protectant by lubricating the tissue, mineralizing the bones, neutralizing the pH, and combating microbes. To understand the metabolic role that saliva plays in the diseased state, we performed untargeted metabolomic profiling of saliva from healthy and periodontitic individuals. Several classes of biochemicals, including dipeptide, amino acid, carbohydrate, lipids, and nucleotide metabolites, were altered, consistent with increased macromolecular degradation of proteins, triacylglycerol, glycerolphospholipids, polysaccharides, and polynucleotides in the individuals with periodontal disease. These changes partially reflected the enhanced host-bacterial interactions in the diseased state as supported by increased levels of bacterially modified amino acids and creatine metabolite. More importantly, the increased lipase, protease, and glycosidase activities associated with periodontitis generated a more favorable energy environment for oral bacteria, potentially exacerbating the disease state.     

Evaluation of Structurally Diverse Benzoazepines Clubbed with Coumarins as Mycobacterium tuberculosis Agents

Tuberculosis caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. In continuation with our anti‐tuberculosis research programme, in this work, we have prepared molecularly diverse coumarins clubbed with benzothiazepines as well as its aza‐analogues‐benzodiazepines by molecular hybridization. The resulting compounds were screened for their M. tuberculosis activity against H₃₇Rv strains using microplate alamar blue assay. Among the designed diversity, the compounds 5k, 5n and 5o were found significantly active in primary anti‐tuberculosis assay at minimum inhibitory concentration <6.25 μm . Moreover, the IC₅₀ values of 5k and 5o in level‐2 screening were observed as >10 μg/mL and 3.63 μg/mL, respectively. Design and synthesis of more focused library and its three‐dimensional quantitative structure activity relationship analysis are underway.     

Examination of the Utility of Psychotherapy for Patients with Treatment Resistant Depression: A Systematic Review

OBJECTIVE  

To examine the utility of psychotherapy in managing treatment resistant depression.     

One plug may not be enough: a novel technique for the occlusion of high-flow vascular connections: combined AGA vascular plug II and coil occlusion of a sequester artery in a patient with Scimitar Syndrome

A 5-year-old male presented at birth with tachypnea and abnormal chest x-ray. He was diagnosed with Scimitar Syndrome in the neonatal period by ultrasound, which revealed partial anomalous pulmonary venous return (PAPVR) of the right pulmonary vein to the inferior vena cava, as well as dextroversion of the heart, hypoplastic right pulmonary artery, and right lung hypoplasia. Due to the large shunt volume, the patient exhibited signs of congestive heart failure with dilatation of the left atrium and left ventricle. The patient underwent cardiac catheterization, which confirmed the presence of PAPVR as well as a large aorto-pulmonary collateral connecting the sequester to the descending aorta. Due to the high flow within the sequester artery a combined "sandwich" technique was used with two AGA vascular plugs (II) and MWCE Tornado coils. Complete closure of the collateral was achieved.     

Arsenite Tolerance is Related to Proportional Thiolic Metabolite Synthesis in Rice (Oryza sativa L.)

Thiol metabolism is the primary detoxification strategy by which rice plants tolerate arsenic (As) stress. In light of this, it is important to understand the importance of harmonised thiol metabolism with As accumulation and tolerance in rice plant. For this aim, tolerant (T) and sensitive (S) genotypes were screened from 303 rice (Oryza sativa) genotypes on exposure to 10 and 25 μM arsenite (As^III) in hydroponic culture. On further As accumulation estimation, contrasting (13-fold difference) T (IC-340072) and S (IC-115730) genotypes were selected. This difference was further evaluated using biochemical and molecular approaches to understand involvement of thiolic metabolism vis-a-vis As accumulation in these two genotypes. Various phytochelatin (PC) species (PC₂, PC₃ and PC₄) were detected in both the genotypes with a dominance of PC₃. However, PC concentrations were greater in the S genotype, and it was noticed that the total PC (PC₂ + PC₃ + PC₄)–to–As^III molar ratio (PC-SH:As^III) was greater in T (2.35 and 1.36 in shoots and roots, respectively) than in the S genotype (0.90 and 0.15 in shoots and roots, respectively). Expression analysis of several metal(loid) stress–related genes showed significant upregulation of glutaredoxin, sulphate transporter, and ascorbate peroxidase in the S genotype. Furthermore, enzyme activity of phytochelatin synthase and cysteine synthase was greater on As accumulation in the S compared with the T genotype. It was concluded that the T genotype synthesizes adequate thiols to detoxify metalloid load, whereas the S genotype synthesizes greater but inadequate levels of thiols to tolerate an exceedingly greater load of metalloids, as evidenced by thiol-to-metalloid molar ratios, and therefore shows a phytotoxicity response.     

The effectiveness of inter‐professional working for older people living in the community: a systematic review

Health and social care policy in the UK advocates inter‐professional working (IPW) to support older people with complex and multiple needs. Whilst there is a growing understanding of what supports IPW, there is a lack of evidence linking IPW to explicit outcomes for older people living in the community. This review aimed to identify the models of IPW that provide the strongest evidence base for practice with community dwelling older people. We searched electronic databases from 1 January 1990–31 March 2008. In December 2010 we updated the findings from relevant systematic reviews identified since 2008. We selected papers describing interventions that involved IPW for community dwelling older people and randomised controlled trials (RCT) reporting user‐relevant outcomes. Included studies were classified by IPW models (Case Management, Collaboration and Integrated Team) and assessed for risk of bias. We conducted a narrative synthesis of the evidence according to the type of care (interventions delivering acute, chronic, palliative and preventive care) identified within each model of IPW. We retrieved 3211 records and included 37 RCTs which were mapped onto the IPW models: Overall, there is weak evidence of effectiveness and cost‐effectiveness for IPW, although well‐integrated and shared care models improved processes of care and have the potential to reduce hospital or nursing/care home use. Study quality varied considerably and high quality evaluations as well as observational studies are needed to identify the key components of effective IPW in relation to user‐defined outcomes. Differences in local contexts raise questions about the applicability of the findings and their implications for practice. We need more information on the outcomes of the process of IPW and evaluations of the effectiveness of different configurations of health and social care professionals for the care of community dwelling older people.