Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension

Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O2) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast

Effects of Transitioning From Conventional Methods to Liquid Based Methods on Unsatisfactory Pap Tests: Results from a Multicenter U.S. Study (poster)

Background: Pap testing has transitioned from conventional preparations (CP) to liquid based preparations (LBP) due to perceived superiority of LBPs. Many studies conclude LBPs reduce unsatisfactory (UNSAT) tests however some believe the evidence to substantiate this claim is weak. We studied the effect of the transition from CPs to LBPs on the proportion of UNSAT Pap tests (PT) in four health care systems in the United States participating in the NIH-funded SEARCH project. Methods: Our study cohort consisted of 548,174 women with 1,443,725 total PTs, ages 21-65 years, between 2000 and 2010. We used segmented regression analysis to estimate the effect of adopting LBPs on the proportion of UNSAT PTs after adjusting for age. Results: Three sites implementing SurePath LBP experienced significant reductions in UNSAT PTs (Site 1 estimated effect: -2.46% [95% CI: -1.47%, -3.45%], Site 2: -1.78% [95% CI: -1.54%, -2.02%], Site 3: -8.25% [95% CI: -7.33%, -9.17%]. The fourth site implementing ThinPrep LBP did not experience a reduction in UNSAT studies. The relative risk of an UNSAT PT in women \u3e 50 increased after the transition to LBPs (SurePath: RR 2.1 [95% CI: 1.9, 2.2] and ThinPrep: RR 1.7 [95% CI: 1.5, 2.0]). Conclusions: The observed changes in the proportion of UNSAT PTs varied across the participating sites and it was dependent on the type of LBP technology, age of women and the rates prior to the implementation of this technology

A multi-perspective evaluation of specialist mental health clinical pharmacist prescribers practising withing general practices in NHS Highland.

Mental health issues are a common feature of primary care consultations and around a third of GP consultations have a mental health element. The Scottish Government’s 10 year Mental Health Strategy has ambitions to transform services so every GP practice has multi-disciplinary teams (MDTs) who can support and treat patients with mental health issues while ensuring good communication with community mental health teams (CMHT) and secondary care services. Despite these strategic plans, there is currently a lack of specialist mental health clinical pharmacist prescriber input to the care of patients with mental health issues within general practice in NHS Highland. A 12 month pilot, funded by the Scottish Government’s Primary Care Transformation Fund, has been conducted during which two specialist mental health clinical pharmacist prescribers consulted with patients with depression and anxiety by appointment at one of two GP Practices in NHS Highland

A Family of Water Immiscible, Dipolar Aprotic, Diamide Solvents from Succinic Acid

Three dipolar aprotic solvents were designed to possess high dipolarity and low toxicity: N , N , N ', N '-tetrabutylsuccindiamide (TBSA), N , N '-diethyl- N , N '-dibutylsuccindiamide (EBSA), N , N '-dimethyl- N , N '-dibutylsuccindiamide (MBSA). They were synthesized catalytically using a K60 silica catalyst in a solventless system. Their water-immiscibility stands out as an unusual and useful property for dipolar aprotic solvents. They were tested in a model Heck reaction, metal-organic framework syntheses, and a selection of polymer solubility experiments where their performances were found to be comparable to traditional solvents. Furthermore, MBSA was found to be suitable for the production of an industrially-relevant membrane from polyethersulphone. An integrated approach involving in silico analysis based on available experimental information, prediction model outcomes and read across data, as well as a panel of in vitro reporter gene assays covering a broad range of toxicological endpoints was used to assess toxicity. These in silico and in vitro tests suggested no alarming indications of toxicity in the new solvents

Improving Together: A National Framework for Quality and GP Clusters in Scotland

Improving together will complement the development of the Scottish national GP contract that sets out the role of GPs and their important contribution as clinical leaders and expert medical generalists working in a community setting. This framework will be reviewed by the Scottish Government and the Scottish General Practitioners Committee of the BMA on a periodic basis, attentive to feedback from those involved in delivering its intent. As such, it is a framework that will develop to its full potential over time, as elements of the transformation of primary care in Scotland create the capacity to do so

Association Between Time Spent Interpreting, Level of Confidence, and Accuracy of Screening Mammography

To examine the effect of time spent viewing images and level of confidence on a screening mammography test set on interpretive performance

Resource use, governance and case load of rapid response teams in Australia and New Zealand in 2014

Background: Rapid response teams (RRTs) are a mandatory element of Australian national health care policy. However, the uptake, resourcing, case load and funding of RRTs in Australian and New Zealand hospitals remain unknown.Aim: To assess the clinical activity, funding, staffing and governance of RRTs in Australian and New Zealand hospitals.Methods: Survey of Australian and New Zealand hospitals as part of a biannual audit of intensive care resources and capacity.Results: Of 207 hospitals surveyed, 165 (79.7%) participated, including 22 (13.3%) from New Zealand. RRTs were present in 138/143 (95.5%) Australian and 11/22 (50%) New Zealand hospitals equipped with intensive care units (P < 0.001). Additional funding was provided in 43/146 hospitals (29.4%) but was more likely in tertiary ICUs (P < 0.001) and in New Zealand (P = 0.012). ICU staff participated in 147/148 RRTs (99.3%), which involved medical staff only (10.2%), nursing staff only (6.8%), and both medical and nursing staff (76.2%). Isolated ICU nursing involvement was more common in smaller ICUs (P = 0.005), in rural/regional and metropolitan hospitals (P = 0.04), and in New Zealand (P = 0.006). Dedicated ICU outreach registrars and consultants were present in 19/146 hospitals (13.0%) and 14/145 hospitals (9.7%), respectively. The ICU provided oversight for 122/147 RRTs (83%). In the 2013–14 financial year, there were more than 104 000 RRT calls.Conclusion: In cases where data were known, ICU staff provided staff for most RRTs, and oversight for more than 80% of RRTs. However, additional funding for ICU RRT staff and dedicated doctors was relatively uncommon

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation