New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Air ambulance services in the Arctic 1999-2009 : a Norwegian study.

Air ambulance services in the Arctic have to deal with remote locations, long distances, rough weather conditions and seasonable darkness. Despite these challenges, the people living in the area expect a high quality of specialist health care. The objective of this study was to analyse the air ambulance operations performed in the Norwegian Arctic and study variations in diagnoses and flight patterns around the year. A retrospective analysis. All air ambulance operations performed during the time 1999 – 2009 period were analysed. The subjects were patients transported and flights performed. The primary outcome measures were patients’ diagnoses and task patterns around the year. A total of 345 patients were transported and 321 flights performed. Coronary heart and vascular disease, bone fractures and infections were the most common diagnoses. Most patients (85%) had NACA score 3 or 4. Half of all fractures occurred in April and August. Most patients were males (66%), and one fourth was not Norwegian. The median flying time (one way) was 3 h 33 m. Ten percent of the flights were delayed, and only 14% were performed between midnight and 8.00 AM. The period April to August was the busiest one (58% of operations). Norway has run a safe air ambulance service in the Arctic for the last 11 years. In the future more shipping and polar adventure operations may influence the need for air ambulances, especially during summer and autumn

Delayed β-cell response and glucose intolerance in young women with Turner syndrome

<p>Abstract</p> <p>Background</p> <p>To investigate glucose homeostasis in detail in Turner syndrome (TS), where impaired glucose tolerance (IGT) and type 2 diabetes are frequent.</p> <p>Methods</p> <p>Cross sectional study of women with Turner syndrome (TS)(n = 13) and age and body mass index matched controls (C) (n = 13), evaluated by glucose tolerance (oral and intravenous glucose tolerance test (OGTT and IVGTT)), insulin sensitivity (hyperinsulinemic, euglycemic clamp), beta-cell function (hyperglycaemic clamp, arginine and GLP-1 stimulation) and insulin pulsatility.</p> <p>Results</p> <p>Fasting glucose and insulin levels were similar. Higher glucose responses was seen in TS during OGTT and IVGTT, persisting after correction for body weight or muscle mass, while insulin responses were similar in TS and C, despite the higher glucose level in TS, leading to an insufficient increase in insulin response during dynamic testing. Insulin sensitivity was comparable in the two groups (TS vs. control: 8.6 ± 1.8 vs. 8.9 ± 1.8 mg/kg*30 min; p = 0.6), and the insulin responses to dynamic β-cell function tests were similar. Insulin secretion patterns examined by deconvolution analysis, approximate entropy, spectral analysis and autocorrelation analysis were similar. In addition we found low IGF-I, higher levels of cortisol and norepinephrine and an increased waist-hip ratio in TS.</p> <p>Conclusions</p> <p>Young normal weight TS women show significant glucose intolerance in spite of normal insulin secretion during hyperglycaemic clamping and normal insulin sensitivity. We recommend regularly testing for diabetes in TS.</p> <p>Trial Registration</p> <p>Registered with <url>http://clinicaltrials.com</url>, ID nr: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00419107">NCT00419107</a></p

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l−1, 1=C-reactive protein >10 mg l−1, and 2=C-reactive protein >10 mg l−1 and albumin<35 g l−1) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54–9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29–11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11–4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99–3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05–4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82–3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01–2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response

Cisplatin neurotoxicity in the treatment of metastatic germ cell tumour: time course and prognosis

In order to ascertain the incidence and prognosis of cisplatin-induced neurotoxicity in testis cancer patients undergoing combination chemotherapy, 29 patients with metastatic disease were studied prospectively. Assessments included enquiry into neurological symptoms, measurement of sural nerve sensory action potential and conduction velocity, and vibration threshold in the left big toe. At the end of chemotherapy (3 to 4 cycles) only 3 out of 26 (11%) patients had paraesthesiae, but 3 months later the proportion rose to 65%. Resolution occurred in the majority over the ensuing 12 months so that only 17% had persistent symptoms. None of the 11 patients treated with 3 cycles of chemotherapy had persisting symptoms. Vibration thresholds showed a significant deterioration during chemotherapy (P = 0.032), further deterioration in the 3 months following chemotherapy (P = 0.009) and significant improvement between 3 and 12 months after chemotherapy (P = 0.038). Sural nerve sensory action potentials and conduction velocities were unhelpful.© 2001 Cancer Research Campaignhttp://www.bjcancer.co

MicroRNA-Integrated and Network-Embedded Gene Selection with Diffusion Distance

Gene network information has been used to improve gene selection in microarray-based studies by selecting marker genes based both on their expression and the coordinate expression of genes within their gene network under a given condition. Here we propose a new network-embedded gene selection model. In this model, we first address the limitations of microarray data. Microarray data, although widely used for gene selection, measures only mRNA abundance, which does not always reflect the ultimate gene phenotype, since it does not account for post-transcriptional effects. To overcome this important (critical in certain cases) but ignored-in-almost-all-existing-studies limitation, we design a new strategy to integrate together microarray data with the information of microRNA, the major post-transcriptional regulatory factor. We also handle the challenges led by gene collaboration mechanism. To incorporate the biological facts that genes without direct interactions may work closely due to signal transduction and that two genes may be functionally connected through multi paths, we adopt the concept of diffusion distance. This concept permits us to simulate biological signal propagation and therefore to estimate the collaboration probability for all gene pairs, directly or indirectly-connected, according to multi paths connecting them. We demonstrate, using type 2 diabetes (DM2) as an example, that the proposed strategies can enhance the identification of functional gene partners, which is the key issue in a network-embedded gene selection model. More importantly, we show that our gene selection model outperforms related ones. Genes selected by our model 1) have improved classification capability; 2) agree with biological evidence of DM2-association; and 3) are involved in many well-known DM2-associated pathways

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors

Socioeconomic questionnaire and clinical assessment in the HELENA Cross-sectional Study: methodology

Rationale: Environmental factors such as dietary habits, breastfeeding, socioeconomic conditions and educational factors are strong influences on nutritional and puberty status, physical activity, food choices and their interactions. Several diseases of adulthood seem to be linked to, or to originate from, lifestyle in childhood and adolescence. Objective: The aims of this study are to describe birth parameters and socioeconomic factors and to assess clinical status in adolescents aged 13-16 years from 10 European countries participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Cross-Sectional Study (CSS). Methodology: A self-report questionnaire on the socioeconomic status, a parental questionnaire concerning neonatal period and also a case report form (CRF), in which clinical items during clinical examination (such as medical history, treatments, anthropometry, Tanner staging, blood pressure, heart rate) were assessed. To develop these documents, first a list of items was established, a search of existing documents was performed and the advice of local and international experts was taken. All documents (questionnaires and an operations manual) were discussed in plenary HELENA meetings; a final version of these documents was fixed, and the process of translation and back translation was performed. Results: The questionnaires and CRF were tested for validation in all 10 participant cities; 208 adolescents were enrolled during the pilot study. All items that caused problems or questions in one or more participating centers or were completed by < 85% of the adolescents were reviewed before the beginning of the HELENA-CSS. Conclusion: These final questionnaires and CRF will contribute to better understanding of the inequalities in nutrition, behavior and health in the European adolescent population. The experience and process should be useful for other multicenter studies