A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes.

Insulin-stimulated glucose uptake in fat and muscle is mediated by the major facilitative glucose transporter Glut4. Insulin controls the trafficking of Glut4 to the plasma membrane via regulation of a series of small G proteins, including RalA and Rab10. We demonstrate here that Rab10 is a bona fide target of the GTPase-activating protein AS160, which is inhibited after phosphorylation by the protein kinase Akt. Once activated, Rab10 can increase the GTP binding of RalA by recruiting the Ral guanyl nucleotide exchange factor, Rlf/Rgl2. Rab10 and RalA reside in the same pool of Glut4-storage vesicles in untreated cells, and, together with Rlf, they ensure maximal glucose transport. Overexpression of membrane-tethered Rlf compensates for the loss of Rab10 in Glut4 translocation, suggesting that Rab10 recruits Rlf to membrane compartments for RalA activation and that RalA is downstream of Rab10. Together these studies identify a new G protein cascade in the regulation of insulin-stimulated Glut4 trafficking and glucose uptake

Rigid endoscope-assisted tracheal intubation in a case of epiglottic cyst

Epiglottic cysts are of particular interest to both surgeons and anaesthetists because of the way in which they encroach on the airway. An epiglottic cyst in a 29-year-old woman was scheduled for endoscopic excision. It was located at the vallecula, and measured around 3 x 4 cm. As a fibre-optic bronchoscope was not available in our institution, endotracheal intubation was achieved with the help of a rigid endoscope and video-camera system.Keywords: epiglottic cyst, 300 nasal endoscope, nasotracheal intubatio

A Risk Assessment Methodology for Toxic Chemicals Evaporation from Circular Pools

This study presents a method for determining the mass transfer coefficient for the toxic chemicals evaporation from circular pools formed due to the failure of plant integrity or escape from valves. The approach used in this present research work is to develop a correlation by a robust optimization technique known as Genetic Algorithm from the experimental data. The developed correlation can be used to model the hydrocarbon evaporation from spills or releases at different wind speeds. From the mass transfer coefficient, the vapor concentration of the hydrocarbon spillage in the environment can be determined which can be used in quantitative risk analysis to predict the effect of toxic release

Ciliary body metastasis in a patient with non-small cell lung carcinoma — incidental detection with 18F-FDG PET/CT

Ciliary body metastasis in a case of lung cancer is very rare. Intraocular metastasis by any cancer most commonly involves choroid followed by iris and ciliary body. We present a case of a 71-year-old male with non-small cell lung cancer who was found to have an 18F-FDG avid right lung mass. Incidentally a focus of abnormal increased 18F-FDG uptake was noted in the region of ciliary body in the right eyeball. The findings were confirmed to be a metastatic lesion in ciliary body on Ultrasonography and MRI. Our case depicts this extremely rare occurrence corroborated by various modalities

Effectiveness of a web- and mobile phone-based intervention to promote physical activity and healthy eating in middle-Aged males: Randomized controlled trial of the manup study

Background: The high number of adult males engaging in low levels of physical activity and poor dietary practices, and the health risks posed by these behaviours, necessitate broad-reaching intervention strategies. IT-based (web and mobile phone) interventions can be accessed by large numbers of people, yet there are few reported IT-based interventions targeting males’ physical activity and dietary practices. Objective: This study examines the effectiveness of a 9-month IT-based intervention to improve the physical activity, dietary behaviours and health literacy in middle-aged males compared to a print-based intervention. Methods: Participants, recruited offline (e.g. newspaper ads), were randomized into either an IT-based or print-based intervention arm on a 2:1 basis in favour of the fully automated IT-based arm. Participants were adult males aged 35-54 years living in two regional cities in Queensland Australia who could access the internet, owned a mobile phone and were able to increase their activity level. The intervention, ManUp, was informed by social cognitive and self regulation theories and was specifically designed to target males. Educational materials were provided and self-monitoring of physical activity and nutrition behaviours was promoted. Intervention content was the same in both intervention arms, only the delivery mode differed, and content could be accessed throughout the 9-month study period. Participants’ physical activity, dietary behaviours, and health literacy were measured using online surveys at baseline, 3 months and 9 months. Results: A total of 301 participants completed baseline assessments, 205 in the ITbased arm and 96 in the print-based arm. A total of 124 participants completed all three assessments. There were no significant between group differences in physical 5 activity and dietary behaviours (p ≥0.05). Participants reported an increased number of minutes and sessions of physical activity at 3 months (b(exp)=1.45, 95% CI=1.09-1.95; b(exp)=1.61, 95% CI=1.17-2.22) and 9 months (b(exp)=1.55, 95% CI=1.14-2.10; b(exp)=1.51, 95% CI=1.15-2.00). Overall dietary behaviours improved at 3 months (b(exp)=1.07, 95% CI=1.03-1.11) and 9 months (b(exp)=1.10, 95% CI=1.05-1.13). The proportion of participants in both groups eating higher-fibre bread and low-fat milk increased at 3 months (b(exp) = 2.25, 95% CI = 1.29-3.92; b(exp)=1.65, 95% CI = 1.07-2.55). Participants in the IT-based arm were less likely to report that 30 minutes of physical activity per day improves health (b(exp)=0.48, 95% CI=0.26-0.90) and more likely to report that vigorous intensity physical activity 3 times per week is essential (b(exp)=1.70, 95% CI=1.02-2.82). The average number of logins to the IT-platform at 3 and 9 months was 6.99 (SE=0.86) and 9.22 (SE=1.47), respectively. The average number of self-monitoring entries at 3 and 9 months was 16.69 (SE=2.38) and 22.51 (SE=3.79), respectively. Conclusions: The ManUp intervention was effective in improving physical activity and dietary behaviours in middle aged males with no significant differences between IT- and print-based delivery modes

Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer is a disease that continues to plague females during their entire lifetime. IL-6 and CRP are found to be elevated in various inflammatory and malignant diseases and their levels are found to correlate with the extent of the disease. The primary objective of this study was to determine the preoperative serum levels of IL-6 and CRP in breast carcinoma, and to correlate them with the staging of the disease and the prognosis.</p> <p>Methods</p> <p>59 female patients admitted for breast cancer were identified for the study and were subjected to thorough evaluation. Serum levels of IL-6 were assessed via Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumour size, lymph node (LN) metastasis, and tumour staging. Relevant investigations were made to find out the presence of distant metastasis. Statistical analysis of the data was then processed.</p> <p>Results</p> <p>Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels correlated with LN metastasis (P < 0.001, P < 0.001) and TNM stage (P < 0.001, P < 0.001). Tumour invasion and the presence of distant metastasis is associated with higher IL-6 levels (P = 0.001, P = 0.009). When we established the cutoff value for IL-6 level (20.55 pg/dl) by ROC curve, we noted a significant difference in overall survival (OS; P = 0.008). However, CRP evidenced no significance with regard to patient's OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.579, P < 0.01)</p> <p>Conclusion</p> <p>Serum levels of IL-6 correlates well with the extent of tumor invasion, LN metastasis, distant metastasis and TNM staging thus enveloping all aspects of breast cancer.</p

Natural Variation in the Thermotolerance of Neural Function and Behavior due to a cGMP-Dependent Protein Kinase

Although it is acknowledged that genetic variation contributes to individual differences in thermotolerance, the specific genes and pathways involved and how they are modulated by the environment remain poorly understood. We link natural variation in the thermotolerance of neural function and behavior in Drosophila melanogaster to the foraging gene (for, which encodes a cGMP-dependent protein kinase (PKG)) as well as to its downstream target, protein phosphatase 2A (PP2A). Genetic and pharmacological manipulations revealed that reduced PKG (or PP2A) activity caused increased thermotolerance of synaptic transmission at the larval neuromuscular junction. Like synaptic transmission, feeding movements were preserved at higher temperatures in larvae with lower PKG levels. In a comparative assay, pharmacological manipulations altering thermotolerance in a central circuit of Locusta migratoria demonstrated conservation of this neuroprotective pathway. In this circuit, either the inhibition of PKG or PP2A induced robust thermotolerance of neural function. We suggest that PKG and therefore the polymorphism associated with the allelic variation in for may provide populations with natural variation in heat stress tolerance. for's function in behavior is conserved across most organisms, including ants, bees, nematodes, and mammals. PKG's role in thermotolerance may also apply to these and other species. Natural variation in thermotolerance arising from genes involved in the PKG pathway could impact the evolution of thermotolerance in natural populations

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from ‘Myeloma XI’, a multicentre, open-label, randomised, phase III trial

Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The ‘Myeloma XI’ trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1–21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1–7 and 15–21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96–1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76–1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance

Msb2 Shedding Protects Candida albicans against Antimicrobial Peptides

Msb2 is a sensor protein in the plasma membrane of fungi. In the human fungal pathogen C. albicans Msb2 signals via the Cek1 MAP kinase pathway to maintain cell wall integrity and allow filamentous growth. Msb2 doubly epitope-tagged in its large extracellular and small cytoplasmic domain was efficiently cleaved during liquid and surface growth and the extracellular domain was almost quantitatively released into the growth medium. Msb2 cleavage was independent of proteases Sap9, Sap10 and Kex2. Secreted Msb2 was highly O-glycosylated by protein mannosyltransferases including Pmt1 resulting in an apparent molecular mass of >400 kDa. Deletion analyses revealed that the transmembrane region is required for Msb2 function, while the large N-terminal and the small cytoplasmic region function to downregulate Msb2 signaling or, respectively, allow its induction by tunicamycin. Purified extracellular Msb2 domain protected fungal and bacterial cells effectively from antimicrobial peptides (AMPs) histatin-5 and LL-37. AMP inactivation was not due to degradation but depended on the quantity and length of the Msb2 glycofragment. C. albicans msb2 mutants were supersensitive to LL-37 but not histatin-5, suggesting that secreted rather than cell-associated Msb2 determines AMP protection. Thus, in addition to its sensor function Msb2 has a second activity because shedding of its glycofragment generates AMP quorum resistance