Bevacizumab in the therapy for refractory metastatic colorectal cancer

Colorectal cancer is the second most common cause of cancer related deaths in the United States. Recent developments have led to prolonged survival with the use of sequential lines of chemotherapy agents. The addition of bevacizumab to active chemotherapy has further improved survival when used in the first and second lines of therapy for metastatic colorectal cancer. Evidence supporting the continued use of bevacizumab throughout lines of therapy is accumulating. Clinical trials are underway in which bevacizumab is continued beyond the first line of a chemotherapy and bevacizumab combination regimen. The mechanism by which colorectal cancer may become resistant to bevacizumab is poorly understood. Molecular and biochemical correlates which may identify bevacizumab resistance are an important component in the design of these clinical trials

Long-term high fat feeding of rats results in increased numbers of circulating microvesicles with pro-inflammatory effects on endothelial cells

Obesity and type 2 diabetes lead to dramatically increased risks of atherosclerosis and CHD. Multiple mechanisms converge to promote atherosclerosis by increasing endothelial oxidative stress and up-regulating expression of pro-inflammatory molecules. Microvesicles (MV) are small ( < 1 μm) circulating particles that transport proteins and genetic material, through which they are able to mediate cell–cell communication and influence gene expression. Since MV are increased in plasma of obese, insulin-resistant and diabetic individuals, who often exhibit chronic vascular inflammation, and long-term feeding of a high-fat diet (HFD) to rats is a well-described model of obesity and insulin resistance, we hypothesised that this may be a useful model to study the impact of MV on endothelial inflammation. The number and cellular origin of MV from HFD-fed obese rats were characterised by flow cytometry. Total MV were significantly increased after feeding HFD compared to feeding chow (P< 0·001), with significantly elevated numbers of MV derived from leucocyte, endothelial and platelet compartments (P< 0·01 for each cell type). MV were isolated from plasma and their ability to induce reactive oxygen species (ROS) formation and vascular cell adhesion molecule (VCAM)-1 expression was measured in primary rat cardiac endothelial cells in vitro. MV from HFD-fed rats induced significant ROS (P< 0·001) and VCAM-1 expression (P= 0·0275), indicative of a pro-inflammatory MV phenotype in this model of obesity. These findings confirm that this is a useful model to further study the mechanisms by which diet can influence MV release and subsequent effects on cardio-metabolic health

Fracture control methods for space vehicles. Volume 3: Space shuttle configurations

Engineering drawings are presented which represent the culmination of research efforts towards a space shuttle configuration with adequate fracture control properties

Management of dyslipidaemia in an HIV-positive cohort

Background: Dyslipidaemia, secondary to both HIV and the use of antiretroviral therapy (ART) is well recognised, with HIV replication and immune status also thought to contribute to the risk. Traditionally the HIV physician has looked after HIV with primary care physicians (GP) managing non-HIV-related medical issues. However with the ageing population and the effectiveness of ART the HIV physician is diversifying to focus management strategies on preventative measures also. Method: 127 subjects were recruited. All subjects were HIV-positive males without any traditional cardiovascular disease symptoms or history. Details of patients demographics, family history, statin therapy, and primary care physician contact were collected. Baseline parameters were recorded and fasting bloods taken. Results: 127 asymptomatic HIV-positive males were recruited. 74/127 (58.3%) met the EACS criteria for statin prescription. 33/74 (44.6%) were on a statin. There was no significant difference between the class of antiretroviral prescribed, (NNRTI v PI) and lipid abnormalities (p=0.628). Hypertension and increased waist:hip ratio significantly increased the chances of the patient being hyperlipidaemic. Patients were more likely to be prescribed a statin if they were older, had hypertension, an increased waist circumference, increased Framingham risk, increased brain natriuretic peptide (BNP), or were diagnosed HIV-positive for longer (p&#x3C;0.05). Pravastatin (21/33 [63.6%]), was most commonly prescribed statin. 24.2% received their statin prescription from their HIV physician, with 75.8% receiving their prescription from their GP. 5/21 (23.8%) on pravastatin met the target verses 7/7 (100%) on atorvastatin verses 2/2 (100%) on simvastatin versus 1/3 (33.3%) on rosuvastatin (p=0.02). Meeting lipid targets was less successful in the protease inhibitor group (1/9) 11.1% versus 11/21 (52.4%) in the NNRTI group (p=0.16). Conclusion: The majority met criteria for lipid management but less than half of those were prescribed it. Of those, most received treatment from their GP. Nearly half of those on statins did not meet lipid targets. HIV physicians were most likely to prescribe pravastatin and those on pravastatin were the least likely to achieve lipid targets when compared to the other statins. HIV physicians need to diversify their knowledge base and have clearly defined management strategies for the management of dyslipidaemia

Late gadolinium enhancement and subclinical cardiac dysfunction on cardiac MRI in asymptomatic HIV-positive men

Background: HIV is associated with an increased risk of cardiovascular disease (CVD) and related clinical events. While traditional risk factors play an important role in the pathology of cardiovascular disease, HIV infection and its sequelae of immune activation and inflammation may have significant effects on the myocardium before becoming clinically evident. Cardiac MRI (CMR) can be used to detect the pattern of these subclinical changes. This will lead to a better understanding of risk factors contributing to cardiovascular disease prior to it becoming clinically significant in HIV-positive patients. Methods: Prospective cohort study of 127 asymptomatic HIV-positive men on ART compared to 35 matched controls. Baseline demographics, HIV parameters, 12-lead ECG, routine biochemistry, and traditional cardiovascular risk factors were recorded. Images were acquired on a 3T Achieva Philips MRI scanner with 5 channel phase array cardiac coil and weight-based IV gadolinium was given at 0.15 mmol/kg dose with post-contrast inversion recovery imaging after 10 minutes. Results: 6/127 (4.7%) of asymptomatic HIV-positive men had late gadolinium enhancement (LGE) on MRI verses 1/35 (2.9%) in the control group. In 3/6 (50%) of cases this was in a classical infarction pattern with subendocardial involvement. 3/6 (50%) were consistent with prior myocarditis. There was no significant difference in mean LVEF (66.93% vs 65.18%), LVMI (60.05g/m2 vs 55.94g/m2) or posterolateral wall thickness (8.28 mm and 8.16 mm) between cases and controls respectively. There was significantly more diastolic dysfunction, E:A ratio &#60;&#x200A;1, found in the HIV-positive group, 18% vs 7% of controls (p&#x200A;=&#x200A;0.037). Framingham risk did not predict either of these outcomes. Conclusions: There is an increased incidence of LGE detected on CMR in this asymptomatic HIV-positive cohort. Two distinct pathological processes were identifed as causing these changes, myocardial infarction and myocarditis. These findings were independent of traditional cardiac risk factors, duration of HIV infection and ART therapy. Sub clinical cardiac dysfunction may be underreported in other cardiac evaluation studies. The true impact of other potential risk factors may also be underestimated, highlighting the need for the development of more complex prediction models

In the Interests of clients or commerce? Legal aid, supply, demand, and 'ethical indeterminacy' in criminal defence work

As a professional, a lawyer's first duty is to serve the client's best interests, before simple monetary gain. In criminal defence work, this duty has been questioned in the debate about the causes of growth in legal aid spending: is it driven by lawyers (suppliers) inducing unnecessary demand for their services or are they merely responding to increased demand? Research reported here found clear evidence of a change in the handling of cases in response to new payment structures, though in ways unexpected by the policy's proponents. The paper develops the concept of 'ethical indeterminacy' as a way of understanding how defence lawyers seek to reconcile the interests of commerce and clients. Ethical indeterminacy suggests that where different courses of action could each be said to benefit the client, the lawyer will tend to advise the client to decide in the lawyer's own interests. Ethical indeterminacy is mediated by a range of competing conceptions of 'quality' and 'need'. The paper goes on to question the very distinction between 'supply' and 'demand' in the provision of legal services

Biomass Burning Aerosols in the Amazon Basin, Characterised by Lidar, Optical Particle Counters, and Modelling

This is the final version. Available from EDP Sciences via the DOI in this record. This article has no abstract.Natural Environment Research Council (NERC)Met Offic

The PULSE@Parkes project: A new observing technique for long-term pulsar monitoring

The PULSE@Parkes project has been designed to monitor the rotation of radio pulsars over time spans of days to years. The observations are obtained using the Parkes 64-m and 12-m radio telescopes by Australian and international high school students. These students learn the basis of radio astronomy and undertake small projects with their observations. The data are fully calibrated and obtained with the state-of-the-art pulsar hardware available at Parkes. The final data sets are archived and are currently being used to carry out studies of 1) pulsar glitches, 2) timing noise, 3) pulse profile stability over long time scales and 4) the extreme nulling phenomenon. The data are also included in other projects such as gamma-ray observatory support and for the Parkes Pulsar Timing Array project. In this paper we describe the current status of the project and present the first scientific results from the Parkes 12-m radio telescope. We emphasise that this project offers a straightforward means to enthuse high school students and the general public about radio astronomy while obtaining scientifically valuable data sets.Comment: accepted for publication by PAS