The Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ) Binder Rasa3 Regulates Phosphoinositide 3-kinase (PI3K)-dependent Integrin α IIb β 3 Outside-in Signaling

The class I PI3K family of lipid kinases plays an important role in integrin αIIbβ3 function, thereby supporting thrombus growth and consolidation. Here, we identify Ras/Rap1GAP Rasa3 (GAP1IP4BP) as a major phosphatidylinositol 3,4,5-trisphosphate-binding protein in human platelets and a key regulator of integrin αIIbβ3 outside-in signaling. We demonstrate that cytosolic Rasa3 translocates to the plasma membrane in a PI3K-dependent manner upon activation of human platelets. Expression of wild-type Rasa3 in integrin αIIbβ3-expressing CHO cells blocked Rap1 activity and integrin αIIbβ3-mediated spreading on fibrinogen. In contrast, Rap1GAP-deficient (P489V) and Ras/Rap1GAP-deficient (R371Q) Rasa3 had no effect. We furthermore show that two Rasa3 mutants (H794L and G125V), which are expressed in different mouse models of thrombocytopenia, lack both Ras and Rap1GAP activity and do not affect integrin αIIbβ3-mediated spreading of CHO cells on fibrinogen. Platelets from thrombocytopenic mice expressing GAP-deficient Rasa3 (H794L) show increased spreading on fibrinogen, which in contrast to wild-type platelets is insensitive to PI3K inhibitors. Together, these results support an important role for Rasa3 in PI3K-dependent integrin αIIbβ3-mediated outside-in signaling and cell spreading

In-vessel inspection before head removal: TMI II: Phase I. (Conceptual development)

The objective of the task is to provide for an internal inspection of the reactor vessel and the fuel assemblies prior to reactor vessel head removal. Because the degree of damage to equipment and fuel in the TMI-II reactor is not precisely known, it is important that as much information as possible be obtained on present conditions inside the reactor. This information will serve to benchmark the various analyses already completed or underway and will also guide the development of programs to obtain more information on the TMI-II core damage. In addition, the early look will provide data for planning the reactor disassembly program

Urgent referral for suspected CNS cancer: which clinical features are associated with a positive predictive value of 3 % or more?

Background Urgent referral for suspected central nervous system (CNS) cancer is recommended, but little analysis of the referral criteria diagnostic performance has been conducted. New 2015 NICE guidance recommends direct brain imaging for patients with symptoms with positive predictive values (PPV) of 3 %, but further guidance is needed. Methods A 12-month retrospective evaluation of 393 patients referred under previous 2005 NICE 2-week rule criteria was conducted. Analysis was based on the three groups of symptoms forming the referral criteria, (1) CNS symptoms, (2) recent onset headaches, (3) rapidly progressive subacute focal deficit/cognitive/behavioural/personality change. Comparison was made with neuroimaging findings. Results Twelve (3.1 %) of 383 patients who attended clinic had CNS cancer suggesting the combination of clinical judgement and application of 2005 criteria matched the 2015 guideline’s PPV threshold. PPVs for the three groups of symptoms were (1) 4.1 % (95 % CIs 2.0 to 7.4 %), (2) 1.2 % (0.1 to 4.3 %) and (3) 3.7 % (0.1 to 19.0 %). Sensitivities were (1) 83.3 % (95 % CIs 51.6 to 97.9 %), (2) 16.7 % (2.1 to 48.4 %), and (3) 8.3 % (0.2 to 38.5 %); specificities were (1) 37.2 % (32.3 to 42.3 %), (2) 55.5 % (50.3 to 60.7 %) and (3) 93.0 % (89.9 to 95.4 %). Of 288 patients who underwent neuroimaging, 59 (20.5 %) had incidental findings, most commonly cerebrovascular disease. Conclusions The 2015 guidance is less prescriptive than previous criteria making clinical judgement more important. CNS symptoms had greatest sensitivity, while PPVs for CNS symptoms and rapidly progressive subacute deficit/cognitive/behavioural/personality change were closest to 3 %. Recent onset headaches had the lowest sensitivity and PPV

Effects of lifestyle education program for type 2 diabetes patients in clinics: study design of a cluster randomized trial

<p>Abstract</p> <p>Background</p> <p>The number of patients with type 2 diabetes is drastically increasing worldwide. It is a serious health problem in Japan as well. Lifestyle interventions can reduce progression from impaired glucose tolerance to type 2 diabetes, and glycemic control has been shown to improve postprandial plasma glucose levels. Moreover, several studies have suggested that continuous interventions (combined diet and exercise) can improve the plasma glucose level and reduce dosage of hypoglycemic agents.</p> <p>Although many interventional studies of lifestyle education for persons with diabetes in hospitals have been reported, only a few have been clinic-based studies employing an evidence-based lifestyle education program. This article describes the design of a cluster randomized controlled trial of the effectiveness of lifestyle education for patients with type 2 diabetes in clinics by registered dietitians.</p> <p>Methods/Design</p> <p>In Japan, general practitioners generally have their own medical clinics to provide medical care for outpatients in the community, including those with type 2 diabetes. With the collaboration of such general practitioners, the study patients were enrolled in the present study. Twenty general practitioners were randomly allocated to each provide patients for entry into either an intervention group (10) or a control group (10). In total, 200 participants will be included in the study. The intervention group will receive intensive education on lifestyle improvement related to type 2 diabetes by registered dietitians in clinics. Lifestyle education will be conducted several times during the study period. The control group will receive information on dietary intake and standard advice on glycemic control by registered dietitians. The primary endpoint is the change from the baseline value of HbA1c at 6 months. Data on health behavior and related issues will be gathered continuously over a 6-month period.</p> <p>Discussion</p> <p>This is the first study to evaluate lifestyle education in clinics by a cluster randomization trial in Japan. The proposed study will provide practical information about the usefulness of the intensive lifestyle improvement education program in primary care settings. The study was started in September 2007 and entry of subjects was completed in December 2010. Data on the effect evaluation will be available in 2011.</p> <p>Trial Registration</p> <p>UMIN000004049</p

A Conceptual Model of Natural and Anthropogenic Drivers and Their Influence on the Prince William Sound, Alaska, Ecosystem

Prince William Sound (PWS) is a semi-enclosed fjord estuary on the coast of Alaska adjoining the northern Gulf of Alaska (GOA). PWS is highly productive and diverse, with primary productivity strongly coupled to nutrient dynamics driven by variability in the climate and oceanography of the GOA and North Pacific Ocean. The pelagic and nearshore primary productivity supports a complex and diverse trophic structure, including large populations of forage and large fish that support many species of marine birds and mammals. High intra-annual, inter-annual, and interdecadal variability in climatic and oceanographic processes as drives high variability in the biological populations. A risk-based conceptual ecosystem model (CEM) is presented describing the natural processes, anthropogenic drivers, and resultant stressors that affect PWS, including stressors caused by the Great Alaska Earthquake of 1964 and the Exxon Valdez oil spill of 1989. A trophodynamic model incorporating PWS valued ecosystem components is integrated into the CEM. By representing the relative strengths of driver/stressors/effects, the CEM graphically demonstrates the fundamental dynamics of the PWS ecosystem, the natural forces that control the ecological condition of the Sound, and the relative contribution of natural processes and human activities to the health of the ecosystem. The CEM illustrates the dominance of natural processes in shaping the structure and functioning of the GOA and PWS ecosystems

Demographics of extra-articular calcaneal fractures: Including a review of the literature on treatment and outcome

Introduction: Extra-articular calcaneal fractures represent 25-40% of all calcaneal fractures and an even higher percentage of up to 60% is seen in children. A disproportionately small part of the literature on calcaneal fractures involves the extra-articular type. The aim of this study was to investigate the incidence of extra-articular calcaneal fractures in a Level 1 trauma centre, define the distribution of the various types of fractures and compare patient demographics between extra- and intra-articular calcaneal fractures. In addition the literature was reviewed for the most common types of extra-articular calcaneal fractures with regard to incidence, treatment and clinical outcome. Methods: The radiological records between 2003 and 2005 were reviewed for intra- and extra-articular calcaneal fractures. Patient gender-distribution and age were compared. A literature search was conducted for the treatment of extra-articular calcaneal fractures. Results: In this 3-year study period a total of 49 patients with 50 extra-articular calcaneal fractures and 91 patients with 101 intra-articular fractures were identified. The median age for the first group was 32.7 years, and for the second group 40.3 years; P = 0.04. Male predominance was significantly less pronounced for extra-articular (63%) compared with intra-articular fractures (79%; P = 0.04). Conclusion: One-third of all calcaneal fractures are extra-articular. Significant differences exist between the intra- and extra-articular groups, in terms of lower age and male-female ratio. The literature study shows inconsistencies in treatment options, but most extra-articular fractures are well manageable conservatively