Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo

IMRT in oral cavity cancer

BACKGROUND: Except for early T1,2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is reported to be worse than for carcinoma in other sites of the head and neck (HNC). The aim of this work was to assess disease outcome in OCC following IMRT. Between January 2002 and January 2007, 346 HNC patients have been treated with curative intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich. Fifty eight of these (16%) were referred for postoperative (28) or definitive (30) radiation therapy of OCC. 40 of the 58 OCC patients (69%) presented with locally advanced T3/4 or recurred lesions. Doses between 60 and 70 Gy were applied, combined with simultaneous cisplatin based chemotherapy in 78%. Outcome analyses were performed using Kaplan Meier curves. In addition, comparisons were performed between this IMRT OCC cohort and historic in-house cohorts of 33 conventionally irradiated (3DCRT) and 30 surgery only patients treated over the last 10 years. RESULTS: OCC patients treated with postoperative IMRT showed the highest local control (LC) rate of all assessed treatment sequence subgroups (92% LC at 2 years). Historic postoperative 3DCRT patients and patients treated with surgery alone reached LC rates of ~70–80%. Definitively irradiated patients revealed poorest LC rates with ~30 and 40% following 3DCRT and IMRT, respectively. T1 stage resulted in an expectedly significantly higher LC rate (95%, n = 19, p < 0.05) than T2-4 and recurred stages (LC ~50–60%, n = 102). Analyses according to the diagnosis revealed significantly lower LC in OCC following definitive IMRT than that in pharyngeal tumors treated with definitive IMRT in the same time period (43% vs 82% at 2 years, p < 0.0001), while the LC rate of OCC following postoperative IMRT was as high as in pharyngeal tumors treated with postoperative IMRT (>90% at 2 years). CONCLUSION: Postoperative IMRT of OCC resulted in the highest local control rate of the assessed treatment subgroups. In conclusion, generous indication for IMRT following surgical treatment is recommended in OCC cases with unfavourable features like tight surgical margin, nodal involvement, primary tumor stage >T1N0, or already recurred disease, respectively. Loco-regional outcome of OCC following definitive IMRT remained unsatisfactory, comparable to that following definitive 3DCRT

Serine Protease PRSS23 Is Upregulated by Estrogen Receptor α and Associated with Proliferation of Breast Cancer Cells

Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor α (ERα), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ERα is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins

Erectile dysfunction, physical activity and metabolic syndrome: differences in markers of atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Erectile dysfunction (ED), impaired arterial elasticity, elevated resting heart rate as well as increased levels of oxidized LDL and fibrinogen associate with future cardiovascular events. Physical activity is crucial in the prevention of cardiovascular diseases (CVD), while metabolic syndrome (MetS) comprises an increased risk for CVD events. The aim of this study was to assess whether markers of subclinical atherosclerosis are associated with the presence of ED and MetS, and whether physical activity is protective of ED.</p> <p>Methods</p> <p>57 MetS (51.3 ± 8.0 years) and 48 physically active (PhA) (51.1 ± 8.1 years) subjects participated in the study. ED was assessed by the International Index of Erectile Function (IIEF) questionnaire, arterial elasticity by a radial artery tonometer (HDI/PulseWave™ CR-2000) and circulating oxLDL by a capture ELISA immunoassay. Fibrinogen and lipids were assessed by validated methods. The calculation of mean daily energy expenditure of physical exercise was based on a structured questionnaire.</p> <p>Results</p> <p>ED was more often present among MetS compared to PhA subjects, 63.2% and 27.1%, respectively (p < 0.001). Regular physical exercise at the level of > 400 kcal/day was protective of ED (OR 0.12, 95% CI 0.017-0.778, p = 0.027), whereas increased fibrinogen (OR 4.67, 95% CI 1.171-18.627, p = 0.029) and elevated resting heart rate (OR 1.07, 95% CI 1.003-1.138, p = 0.04) were independently associated with the presence of ED. In addition, large arterial elasticity (ml/mmHgx10) was lower among MetS compared to PhA subjects (16.6 ± 4.0 <it>vs</it>. 19.6 ± 4.2, p < 0.001), as well as among ED compared to non-ED subjects (16.7 ± 4.6 <it>vs</it>. 19.0 ± 3.9, p = 0.008). Fibrinogen and resting heart rate were highest and large arterial elasticity lowest among subjects with both MetS and ED.</p> <p>Conclusions</p> <p>Markers of subclinical atherosclerosis associated with the presence of ED and were most evident among subjects with both MetS and ED. Thus, especially MetS patients presenting with ED should be considered at high risk for CVD events. Physical activity, on its part, seems to be protective of ED.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01119404">NCT01119404</a></p

A written self-help intervention for depressed adults comparing behavioural activation combined with physical activity promotion with a self-help intervention based upon behavioural activation alone: study protocol for a parallel group pilot randomised controlled trial (BAcPAc)

notes: PMCID: PMC4061537types: Journal Article© 2014 Farrand et al.; licensee BioMed Central Ltd.Challenges remain to find ways to support patients with depression who have low levels of physical activity (PA) to overcome perceived barriers and enhance the perceived value of PA for preventing future relapse. There is an evidence-base for behavioural activation (BA) for depression, which focuses on supporting patients to restore activities that have been avoided, but practitioners have no specific training in promoting PA. We aimed to design and evaluate an integrated BA and PA (BAcPAc) practitioner-led, written, self-help intervention to enhance both physical and mental health.NPRI-

Integrating Communities of Practice in Technology Development Projects

Technology development projects usually benefit when knowledge and expertise are drawn from a variety of sources, including potential users. Orchestrating the involvement of people from disparate groups is a crucial task for project managers. It requires finding a balance between differentiation, when teams work in isolation, and integration, when groups come together to exchange knowledge. This article argues that a “community of practice” perspective can help project managers to achieve this balance, by drawing attention to the assumptions, interests, skills, and formal and tacit knowledge of the different groups involved. Successful integration can be achieved by ensuring that the developing technology is comprehensible to all the groups concerned, and making sure that it satisfies their various interests

MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature

Item does not contain fulltextPURPOSE: The clinical diagnosis and management of invasive lobular carcinoma (ILC) of the breast presents difficulties. Magnetic resonance imaging (MRI) has been proposed as the imaging modality of choice for the evaluation of ILC. Small studies addressing different aspects of MRI in ILC have been presented but no large series to date. To address the usefulness of MRI in the work-up of ILC, we performed a review of the currently published literature. MATERIALS AND METHODS: We performed a literature search using the query "lobular AND (MRI OR MR OR MRT OR magnetic)" in the Cochrane library, PubMed and scholar.google.com, to retrieve all articles that dealt with the use of MRI in patients with ILC. We addressed sensitivity, morphologic appearance, correlation with pathology, detection of additional lesions, and impact of MRI on surgery as different endpoints. Whenever possible we performed meta-analysis of the pooled data. RESULTS: Sensitivity is 93.3% and equal to overall sensitivity of MRI for malignancy in the breast. Morphologic appearance is highly heterogeneous and probably heavily influenced by interreader variability. Correlation with pathology ranges from 0.81 to 0.97; overestimation of lesion size occurs but is rare. In 32% of patients, additional ipsilateral lesions are detected and in 7% contralateral lesions are only detected by MRI. Consequently, MRI induces change in surgical management in 28.3% of cases. CONCLUSION: This analysis indicates MRI to be valuable in the work-up of ILC. It provides additional knowledge that cannot be obtained by conventional imaging modalities which can be helpful in patient treatment

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Optimizing Modern Family Size: Trade-offs between Fertility and the Economic Costs of Reproduction

Modern industrialized populations lack the strong positive correlations between wealth and reproductive success that characterize most traditional societies. While modernization has brought about substantial increases in personal wealth, fertility in many developed countries has plummeted to the lowest levels in recorded human history. These phenomena contradict evolutionary and economic models of the family that assume increasing wealth reduces resource competition between offspring, favoring high fertility norms. Here, we review the hypothesis that cultural modernization may in fact establish unusually intense reproductive trade-offs in wealthy relative to impoverished strata, favoring low fertility. We test this premise with British longitudinal data (the Avon Longitudinal Study of Parents and Children), exploring maternal self-perceptions of economic hardship in relation to increasing family size and actual socioeconomic status. Low-income and low-education-level mothers perceived the greatest economic costs associated with raising two versus one offspring. However, for all further increases to family size, reproduction appears most expensive for relatively wealthy and well-educated mothers. We discuss our results and review current literature on the long-term consequences of resource dilution in modern families

Promoting Functional Health in Midlife and Old Age: Long-Term Protective Effects of Control Beliefs, Social Support, and Physical Exercise

Previous studies have examined physical risk factors in relation to functional health, but less work has focused on the protective role of psychological and social factors. We examined the individual and joint protective contribution of control beliefs, social support and physical exercise to changes in functional health, beyond the influence of health status and physical risk factors in middle-aged and older adults. Given that functional health typically declines throughout adulthood, it is important to identify modifiable factors that can be implemented to maintain functioning, improve quality of life, and reduce disability.We conducted a national longitudinal study, Midlife in the United States (MIDUS), with assessments in 1995-1996 and 2004-2006, and 3,626 community-residing adults, aged 32 to 84, were included in the analyses. Functional health (Physical Functioning subscale of the SF-36) and protective factors were measured at both occasions. While controlling for socio-demographic, health status, and physical risk factors (large waist circumference, smoking, and alcohol or drug problems), a composite of the three protective variables (control beliefs, social support, and physical exercise) at Time 1 was significantly related to functional health change. The more of these factors at Time 1, the better the health maintenance over 10 years. Among middle-aged and older adults, declines in health were significantly reduced with an increased number of protective factors.Age-related declines in health were reduced among those with more protective factors up to a decade earlier in life. Modifiable psychological, social, and physical protective factors, individually and in the aggregate, are associated with maintenance of functional health, beyond the damaging effects of physical risk factors. The results are encouraging for the prospect of developing interventions to promote functional health and for reducing public health expenditures for physical disability in later life