Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx

Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S35 and 3H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress. © 2013 Singh et al.published_or_final_versio

Patient perspectives of managing fatigue in ankylosing spondylitis, and views on potential interventions: a qualitative study

<p>Background: Fatigue is a major component of living with ankylosing spondylitis (AS), though it has been largely over-looked, and currently there are no specific agreed management strategies.</p> <p>Methods: This qualitative exploratory study involved participants who are members of an existing population-based ankylosing spondylitis (PAS) cohort. Participants residing in South West Wales were invited to participate in a focus group to discuss; (1) effects of fatigue, (2) self-management strategies and (3) potential future interventions. The focus groups were audio-recorded and the transcripts were analysed using thematic analysis.</p> <p>Results: Participants consisted of 3 males/4 females (group 1) and 4 males/3 females (group 2), aged between 35 and 73 years (mean age 53 years). Three main themes were identified: (1) The effects of fatigue were multi-dimensional with participants expressing feelings of being ‘drained’ (physical), ‘upset’ (emotional) and experiencing ‘low-mood’ (psychological); (2) The most commonly reported self-management strategy for fatigue was a balanced combination of activity (exercise) and rest. Medication was reluctantly taken due to side-effects and worries over dependency; (3) Participants expressed a preference for psychological therapies rather than pharmacological for managing fatigue. Information on Mindfulness-Based Stress Reduction (MBSR) was received with interest, with recommendations for delivery in a group format with the option of distance-based delivery for people who were not able to attend a group course.</p> <p>Conclusions: Patients frequently try and manage their fatigue without any formal guidance or support. Our research indicates there is a need for future research to focus on psychological interventions to address the multi-faceted aspects of fatigue in AS.</p&gt

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

Farmers’ perceptions of climate change : identifying types

Ambitious targets to reduce greenhouse gas (GHG) emissions from agriculture have been set by both national governments and their respective livestock sectors. We hypothesize that farmer self-identity influences their assessment of climate change and their willingness to im- plement measures which address the issue. Perceptions of climate change were determined from 286 beef/sheep farmers and evaluated using principal component analysis (PCA). The analysis elicits two components which evaluate identity (productivism and environmental responsibility), and two components which evaluate behavioral capacity to adopt mitigation and adaptation measures (awareness and risk perception). Subsequent Cluster Analyses reveal four farmer types based on the PCA scores. ‘The Productivist’ and ‘The Countryside Steward’ portray low levels of awareness of climate change, but differ in their motivation to adopt pro-environmental behavior. Conversely, both ‘The Environmentalist’ and ‘The Dejected’ score higher in their awareness of the issue. In addition, ‘The Dejected’ holds a high sense of perceived risk; however, their awareness is not conflated with an explicit understanding of agricultural GHG sources. With the exception of ‘The Environmentalist’, there is an evident disconnect between perceptions of agricultural emission sources and their contribution towards GHG emissions amongst all types. If such linkages are not con- ceptualized, it is unlikely that behavioral capacities will be realized. Effective communication channels which encour- age action should target farmers based on the groupings depicted. Therefore, understanding farmer types through the constructs used in this study can facilitate effective and tai- lored policy development and implementation

Experimental Assessment of the Water Quality Influence on the Phosphorus Uptake of an Invasive Aquatic Plant: Biological Responses throughout Its Phenological Stage

International audienceUnderstanding how an invasive plant can colonize a large range of environments is still a great challenge in freshwater ecology. For the first time, we assessed the relative importance of four factors on the phosphorus uptake and growth of an invasive macrophyte Elodea nuttallii (Planch.) St. John. This study provided data on its phenotypic plasticity, which is frequently suggested as an important mechanism but remains poorly investigated. The phosphorus uptake of two Elodea nuttallii subpopulations was experimentally studied under contrasting environmental conditions. Plants were sampled in the Rhine floodplain and in the Northern Vosges mountains, and then maintained in aquaria in hard (Rhine) or soft (Vosges) water. Under these conditions, we tested the influence of two trophic states (eutrophic state, 100 mu g.l(-1) P-PO43- and hypertrophic state, 300 mu g.l(-1) P-PO43-) on the P metabolism of plant subpopulations collected at three seasons (winter, spring and summer). Elodea nuttallii was able to absorb high levels of phosphorus through its shoots and enhance its phosphorus uptake, continually, after an increase of the resource availability (hypertrophic > eutrophic). The lowest efficiency in nutrient use was observed in winter, whereas the highest was recorded in spring, what revealed thus a storage strategy which can be beneficial to new shoots. This experiment provided evidence that generally, the water trophic state is the main factor governing P uptake, and the mineral status (softwater > hardwater) of the stream water is the second main factor. The phenological stage appeared to be a confounding factor to P level in water. Nonetheless, phenology played a role in P turnover in the plant. Finally, phenotypic plasticity allows both subpopulations to adapt to a changing environment

Predictive habitat suitability models to aid conservation of elasmobranch diversity in the central Mediterranean Sea

Commercial fisheries have dramatically impacted elasmobranch populations worldwide. With high capture and bycatch rates, the abundance of many species is rapidly declining and around a quarter of the world’s sharks and rays are threatened with extinction. At a regional scale this negative trend has also been evidenced in the central Mediterranean Sea, where bottom-trawl fisheries have affected the biomass of certain rays (e.g. Raja clavata) and sharks (e.g. Mustelus spp.). Detailed knowledge of elasmobranch habitat requirements is essential for biodiversity conservation and fisheries management, but this is often hampered by a poor understanding of their spatial ecology. Habitat suitability models were used to investigate the habitat preference of nine elasmobranch species and their overall diversity (number of species) in relation to five environmental predictors (i.e. depth, sea surface temperature, surface salinity, slope and rugosity) in the central Mediterranean Sea. Results showed that depth, seafloor morphology and sea surface temperature were the main drivers for elasmobranch habitat suitability. Predictive distribution maps revealed different species-specific patterns of suitable habitat while high assemblage diversity was predicted in deeper offshore waters (400–800 m depth). This study helps to identify priority conservation areas and diversity hot-spots for rare and endangered elasmobranchs in the Mediterranean Sea

Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most

The effect of weight loss on lameness in obese dogs with osteoarthritis

This paper describes the effect of weight loss on lameness in obese dogs with osteoarthritis (OA). Fourteen obese client-owned dogs with clinical and radiographic signs of OA participated in an open prospective clinical trial. After a screening visit and a visit for collection of baseline data, the dogs were fed a restricted-calorie diet over a study period of 16 weeks that incorporated six follow-up visits. At each visit, body weight and pelvic circumference were measured and severity of lameness was assessed using a numeric rating scale (NRS), a visual analogue scale (VAS) and kinetic gait analysis. This is the first study to assess both subjectively and objectively, the effect of weight loss alone on lameness in obese dogs with OA. The results indicate that body weight reduction causes a significant decrease in lameness from a weight loss of 6.10% onwards. Kinetic gait analysis supported the results from a body weight reduction of 8.85% onwards. These results confirm that weight loss should be presented as an important treatment modality to owners of obese dogs with OA and that noticeable improvement may be seen after modest weight loss in the region of 6.10 – 8.85% body weight

The Hot (Invisible?) Hand: Can Time Sequence Patterns of Success/Failure in Sports Be Modeled as Repeated Random Independent Trials?

The long lasting debate initiated by Gilovich, Vallone and Tversky in is revisited: does a “hot hand” phenomenon exist in sports? Hereby we come back to one of the cases analyzed by the original study, but with a much larger data set: all free throws taken during five regular seasons () of the National Basketball Association (NBA). Evidence supporting the existence of the “hot hand” phenomenon is provided. However, while statistical traces of this phenomenon are observed in the data, an open question still remains: are these non random patterns a result of “success breeds success” and “failure breeds failure” mechanisms or simply “better” and “worse” periods? Although free throws data is not adequate to answer this question in a definite way, we speculate based on it, that the latter is the dominant cause behind the appearance of the “hot hand” phenomenon in the data