883 research outputs found

    Genetic and Biochemical Evidence That Haploinsufficiency of the Nf1 Tumor Suppressor Gene Modulates Melanocyte and Mast Cell Fates in Vivo

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    Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's “two hit” model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1−/− murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W41 mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras–mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W41) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types

    Biopolitics meets Terrapolitics: Political Ontologies and Governance in Settler-Colonial Australia

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    Crises persist in Australian Indigenous affairs because current policy approaches do not address the intersection of Indigenous and European political worlds. This paper responds to this challenge by providing a heuristic device for delineating Settler and Indigenous Australian political ontologies and considering their interaction. It first evokes Settler and Aboriginal ontologies as respectively biopolitical (focused through life) and terrapolitical (focused through land). These ideal types help to identify important differences that inform current governance challenges. The paper discusses the entwinement of these traditions as a story of biopolitical dominance wherein Aboriginal people are governed as an “included-exclusion” within the Australian political community. Despite the overall pattern of dominance, this same entwinement offers possibilities for exchange between biopolitics and terrapolitics, and hence for breaking the recurrent crises of Indigenous affairs

    Treatment of anorexia and weight loss with megestrol acetate in patients with cystic fibrosis

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    Four patients with severe cystic fibrosis lung disease, anorexia and weight loss, received Megestrol Acetate (MA), as an appetite stimulant. The initial dose was 400–800 mg daily and was continued for 6–15 months. Appetite was improved, with significant weight gain in all patients and an increase in their weight for age percentile from <5% at the start of the study to approximately the 25 th percentile after 6 months of use and improvement in quality of life. One patient discontinued MA after 6 months, and subsequently appetite and weight were depressed. Pediatr Pulmonol. 1999; 28:380–382. © 1999 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35316/1/11_ftp.pd

    Negotiating care in the context of Finnish and Italian elder care policies

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    Negotiation is an integral part of all elder care, which by definition involves a relation between at least two people. In this article we analyse negotiations concerning elder care in the context of Finnish and Italian elder care policies. At the macro level negotiations on elder care are shaped by elder care policies and at the micro level by individual skills and resources. Our focus is on the negotiations on eligibility that take place when elders attempt to access care. The data consist of qualitative interviews with Finnish and Italian elders in need of care. The analysis of individual experiences of care negotiations reflects the implementation of elder care policies. The results indicate that the most negotiated eligibility criteria when seeking access to elder care are need, money and social relations. These criteria are negotiated when seeking eligibility to different sources of care: informal care, grey market, market-based, non-profit and public services. In Italy, negotiation is particularly crucial when accessing grey market care. Cash as the main Italian elder care policy tool tends to enhance the role of and need for negotiation. In Finland, a greater part of elder care is provided by the public sector and therefore the process of negotiation is more standardized than in Italy

    Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality - A meta-analysis

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    CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS
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