Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs

Starting the conversation: land issues and critical conservation studies in post-colonial Africa

This thematic issue brings together the scholarly fields of critical conservation studies and African land issues, a relationship largely unexplored to date. The alienation of land for conservation purposes, introduced to Africa under colonial rule and still taking place today, has fundamental impacts on the politics of land and land use, and is contested in contemporary nation-states - including those that are attempting to implement land restitution and reform. The contributors explore these issues in a range of African contexts. Three key themes are identified: the problematic constructions of ‘community’ by outside agencies; spatial exclusion and the silencing of local voices; and the neoliberalisation of conservation spaces. In contributing to new perspectives on these themes, this thematic issue shows how discourses and practices of conservation, increasingly shaped by neoliberalism, currently impact on land ownership, access and use. It further highlights some important historical continuities. These trends can be observed in transfrontier conservation areas, on state-owned land used for conservation and ‘green’ initiatives, but also on private land where conservation is increasingly turned to commercial purposes.International Bibliography of Social Science

Small RNA combination therapy for lung cancer

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)National Institutes of Health (U.S.) (Grant 2-PO1-CA42063)National Institutes of Health (U.S.) (Grant RO1-EB000244)National Institutes of Health (U.S.) (Grant RO1-CA115527)National Institutes of Health (U.S.) (Grant RO1-CA132091)National Cancer Institute (U.S.) (1K99CA169512)American Association for Cancer Research (Fellowship)Leukemia & Lymphoma Society of America (Fellowship)National Science Foundation (U.S.). Graduate Research Fellowship ProgramMassachusetts Institute of Technology. Presidential FellowshipUnited States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship

Modifier loci condition autoimmunity provoked by Aire deficiency

Loss of function mutations in the autoimmune regulator (Aire) gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients and mutant mice lead to autoimmune manifestations that segregate as a monogenic trait, but with wide variation in the spectrum of organs targeted. To investigate the cause of this variability, the Aire knockout mutation was backcrossed to mice of diverse genetic backgrounds. The background loci strongly influenced the pattern of organs that were targeted (stomach, eye, pancreas, liver, ovary, thyroid, and salivary gland) and the severity of the targeting (particularly strong on the nonobese diabetic background, but very mild on the C57BL/6 background). Autoantibodies mimicked the disease pattern, with oligoclonal reactivity to a few antigens that varied between Aire-deficient strains. Congenic analysis and a whole genome scan showed that autoimmunity to each organ had a distinctive pattern of genetic control and identified several regions that controlled the pattern of targeting, including the major histocompatibility complex and regions of Chr1 and Chr3 previously identified in controlling type 1 diabetes

Recent emergence and worldwide spread of the red tomato spider mite, [i]Tetranychus evansi[/i]: genetic variation and multiple cryptic invasions

Publication Inra prise en compte dans l'analyse bibliométrique des publications scientifiques mondiales sur les Fruits, les Légumes et la Pomme de terre. Période 2000-2012. http://prodinra.inra.fr/record/256699Plant biosecurity is increasingly challenged by emerging crop pests. The spider mite Tetranychus evansi has recently emerged as a new threat to solanaceous crops in Africa and the Mediterranean basin, with invasions characterized by a high reproductive output and an ability to withstand a wide range of temperatures. Mitochondrial (868 bp of COI) and nuclear (1,137 bp of ITS) loci were analyzed in T. evansi samples spanning the current geographical distribution to study the earliest stages of the invasive process. The two sets of markers separate the samples into two main clades that are only present together in South America and Southern Europe. The highest COI diversity was found in South America, consistent with the hypothesis of a South American origin of T. evansi. Among the invaded areas, the Mediterranean region displayed a high level of genetic diversity similar to that present in South America, that is likely the result of multiple colonization events. The invasions of Africa and Asia by T. evansi are characterized by a low genetic variation associated with distinct introductions. Genetic data demonstrate two different patterns of invasions: (1) populations in the Mediterranean basin that are a result of multiple cryptic introductions and (2) emerging invasions of Africa and Asia, each likely the result of propagules from one or limited sources. The recent invasions of T. evansi illustrate not only the importance of human activities in the spread of agricultural pests, but also the limits of international quarantine procedures, particularly for cryptic invasion

Mechanical performance of statically loaded flat face epoxy bonded concrete joints

One of the main challenges in the offshore renewable energy industry is the reduction in the levelised cost of energy of wind, wave and tidal devices. The use of concrete as the primary construction material in such devices presents a low unit cost, high marine durability alternative to steel, however, to maximise material efficiency factors such as mix constituent design, structural detailing and manufacturing processes have to take into account the specific conditions of the marine environment. Pre-cast segmental construction can be considered as one of the fastest and cheapest construction options. However the challenges regarding performance of epoxy bonded concrete in marine environment should be taken into account. This paper presents the results of an experimental programme on the performance of shear and tensile capacity of flat face concrete joints, focussing on the effect of substrate surface preparation, joint thickness, properties of epoxy resins, exposure to seawater and presence of joint defects on the ultimate failure load. The ultrasonic pulse velocity (UPV) method for detection of defects in the adhesive layer was examined and digital image correlation is used to observe the surface strain flow through the joint. The results indicate that the epoxy joints behave monolithically and remain undamaged under different types of static loading. The joints do not significantly interrupt the flow of strain but can locally affect the distribution of strain (and thus stiffness and stresses) in a structure. An increase in the density of the epoxy (and the filler content) leads to the increase in the joint strength and thicker joints are less affected by small defects in the bonding layer. The majority of tested specimens failed by cracking of concrete rather than by debonding of the joint, whilst compressive stresses acting on the joint can help to augment its shear strength. Sandblasting of bonded surfaces can improve performance of joints, whereas UPV testing may be used for quality control of epoxy-bonded joints

The effect of gender, age, and geographical location on the incidence and prevalence of renal replacement therapy in Wales

BACKGROUND: This study used a cross sectional survey to examine the effect of gender, age, and geographical location on the population prevalence of renal replacement therapy (RRT) provision in Wales. METHODS: Physicians in renal centres in Wales and in adjacent areas of England were asked to undertake a census of patients on renal replacement therapy on 30 June 2004 using an agreed protocol. Data were collated and analysed in anonymous form. RESULTS: 2434 patients were on RRT in Wales at the census date. Median age of patients on RRT was 56 years, peritoneal dialysis 58 years, haemodialysis 66 years and transplantation 50 years. The three treatment modalities had significantly different age-specific peak prevalence rates and distributions. RRT age-specific prevalence rates peaked at around 70 years (1790 pmp), transplantation at around 60 years (924 pmp), haemodialysis at around 80 years (1080 pmp) and peritoneal dialysis did not have a clear peak prevalence rate. Age-specific incidence of RRT peaked at a rate of 488 pmp at 79 years, as did incidence rates for haemodialysis, which peaked at the same age. Age had less effect on the initiation of peritoneal dialysis, which had a broad plateau between the early fifties and late seventies. Kidney transplantation rates were highest in the early fifties but were markedly absent in old age. CONCLUSION: Differences in the provision of RRT are evident, particularly in the very elderly, where the gender difference for haemodialysis is particularly marked. The study illustrates that grouping patients over 75 years into a single age-band may mask significant diversity within this age group. Significant numbers of very elderly patients who are currently not receiving RRT may wish to receive RRT as the elderly population increases, and as technology improves survival and quality of life on RRT. The study suggests that if technologies that are more effective were developed, and which had a lower impact on quality of life, there might be up to a 17% increase in demand for RRT in those aged over 75 years; around 90% of this increased demand would be for haemodialysis

CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells

Here we show that CK2 inhibition by CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells, implicating an alternative strategy to target NOTCH1 signaling in refractory/relapsed T-ALL