The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential into a muscle fiber action potential (MFAP). Efficient information transfer requires both cholinergic signaling, responsible for the generation of endplate potentials (EPPs), and excitation, the activation of postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here we probed the function of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'). Synapses formed normally in ΔIg3-MuSK animals, but the postsynaptic apparatus was fragmented from the first weeks of life. Anatomical denervation was not observed at any age examined. Moreover, spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable to WT. However, trains of nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as revealed by increased jitter and blocking in single fiber electromyography. Further, nerve-evoked compound muscle action potentials (CMAPs), as well as twitch and tetanic muscle torque force production, were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK synapses but not at the extrajunctional sarcolemma, indicating that the observed excitability defects are the result of impaired localization of this voltage-gated ion channel at the NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 receptor necessary for establishing and maintaining cholinergic signaling, and as a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked muscle excitability and force production. The MuSK-BMP pathway thus emerges as a target for modulating excitability and functional innervation, which are defective in conditions such as congenital myasthenic syndromes and aging.

Can fruit and vegetable aggregation systems better balance improved producer livelihoods with more equitable distribution?

The need for food systems to generate sustainable and equitable benefits for all is a global imperative. However, whilst ample evidence exists linking smallholder farmer coordination and aggregation (i.e. the collective transport and marketing of produce on behalf of multiple farmers) to improved market participation and farmer incomes, the extent to which interventions that aim to improve farmer market engagement may co-develop equitable consumer benefits remains uncertain. This challenge is pertinent to the horticultural systems of South Asia, where the increasing purchasing power of urban consumers, lengthening urban catchments, underdeveloped rural infrastructures and inadequate local demands combine to undermine the delivery of fresh fruits and vegetables to smaller, often rural or semi-rural markets serving nutritionally insecure populations. To this end, we investigate the potential for aggregation to be developed to increase fruit and vegetable delivery to these neglected smaller markets, whilst simultaneously improving farmer returns. Using an innovative system dynamics modelling approach based on an aggregation scheme in Bihar, India, we identify potential trade-offs between outcomes relating to farmers and consumers in smaller local markets. We find that changes to aggregation alone (i.e. scaling-up participation; subsidising small market transportation; mandating quotas for smaller markets) are unable to achieve significant improvements in smaller market delivery without risking reduced farmer participation in aggregation. Contrastingly, combining aggregation with the introduction of market-based cold storage and measures that boost demand improves fruit and vegetable availability significantly in smaller markets, whilst avoiding farmer-facing trade-offs. Critically, our study emphasises the benefits that may be attained from combining multiple nutrition-sensitive market interventions, and stresses the need for policies that narrow the fruit and vegetable cold storage deficits that exist away from more lucrative markets in developing countries. The future pathways and policy options discovered work towards making win-win futures for farmers and disadvantaged consumers a reality.

Current and future trade in livestock products.

Rising per capita consumption, economic growth, and urbanisation, particularly in developing countries, have been driving an increased global demand for food. These changing socio-economic trends, which have greatly influenced changes in dietary patterns globally and, more specifically, have increased consumption of livestock products in developing countries, are expected to endure and to place new pressures on livestock-sector infrastructure and the delivery of veterinary services. This paper summarises current trade in meat and presents plausible projections for the future. It highlights the impact of animal disease on trade and considers the effect of ongoing disease outbreaks, particularly the outbreaks of African swine fever and COVID-19, on current and future trade dynamics. The authors analysed published statistics on the demand for, and international trade in, livestock products at national and regional levels and made projections of the same up to 2050, generated from an integrated model of the global agricultural and food system. The resulting analyses identified patterns of trade consistent with growing populations, increasing incomes and changing diets in developing countries. The analyses also pointed to slow expansion of livestock production, and the impacts of countries' disease status on livestock trade. For most of the livestock products analysed, economic model projections indicate increased consolidation of production and exports among a few countries. Marked increases in the trade in livestock products suggest a changing role for Veterinary Services in facilitating trade and extension in the years to come.

La demande mondiale en denrées alimentaires connaît une hausse continue sous l'effet conjugué de la progression de la consommation par habitant, de la croissance économique et de l'urbanisation, en particulier dans les pays en développement. Ces tendances socio-économiques ont modifié les structures des régimes alimentaires dans le monde, plus spécifiquement dans les pays en développement où la consommation de denrées alimentaires d'origine animale s'est accrue, et elles vont très certainement perdurer et exercer de nouvelles pressions sur les infrastructures du secteur de l'élevage comme sur les prestations de services vétérinaires. Les auteurs font une synthèse de l'état actuel des échanges internationaux de viande et présentent quelques projections plausibles concernant l'avenir. Ils soulignent l'impact des maladies animales sur les échanges et examinent les répercussions que les foyers actuels de maladies peuvent avoir sur les dynamiques actuelles et futures des échanges, en citant la peste porcine africaine et l'épidémie de COVID-19 à titre d'illustrations. Les auteurs analysent ensuite les statistiques publiées relatives à la demande en produits issus de l'élevage et aux échanges internationaux de ces produits à l'échelle nationale et régionale, et présentent leurs propres projections de ces tendances jusqu'en 2050, élaborées à partir d'un modèle intégré du système agricole et alimentaire mondial. Les analyses qui en résultent font apparaître que les structures des échanges évolueront parallèlement à la croissance démographique, à l'augmentation des revenus et aux modifications des régimes alimentaires dans les pays en développement. Les analyses relèvent également une croissance lente de l'élevage, ainsi que les conséquences du statut sanitaire des pays sur les échanges commerciaux. Pour la plupart des produits issus de l'élevage pris en compte dans cette analyse, les projections du modèle économique prévoient une concentration accrue de la production et des exportations, dans un nombre limité de pays. Une augmentation marquée des échanges de produits issus de l'élevage devra s'accompagner d'une évolution du rôle des Services vétérinaires afin de faciliter les échanges et de soutenir leur extension dans les années à venir.

El aumento del consumo per cápita, el crecimiento económico y los procesos de urbanización, especialmente en los países en desarrollo, han venido induciendo una mayor demanda mundial de alimentos. Estas tendencias socioeconómicas han influido sobremanera en la evolución de los regímenes alimentarios en todo el mundo y, más concretamente, han llevado a un mayor consumo de productos ganaderos en los países en desarrollo. Según apuntan las previsiones, esta evolución se prolongará en el tiempo y ejercerá nuevas presiones sobre la infraestructura del sector pecuario y la prestación de servicios veterinarios. Los autores resumen la situación actual del comercio de productos cárnicos y presentan proyecciones plausibles de lo que puede deparar el futuro. Tras destacar el peso que tienen las enfermedades animales en el comercio, examinan los efectos de brotes infecciosos hoy en curso, en particular de peste porcina africana y COVID-19, sobre la dinámica actual y futura del comercio. Los autores analizaron las estadísticas publicadas sobre la demanda y el comercio internacional de productos procedentes de la ganadería, por países y regiones, tras lo cual hicieron proyecciones del curso de estas tendencias hasta 2050, generadas a partir de un modelo integrado del sistema agrícola y alimentario mundial. Los análisis resultantes depararon una configuración del comercio coherente con poblaciones cada vez más numerosas, un creciente nivel de ingresos y cambios en el régimen alimentario en los países en desarrollo. Los análisis también apuntaban a una lenta expansión de la producción pecuaria y ponían de relieve la influencia de la situación sanitaria de los países en el comercio de ganado. Para la mayoría de los productos ganaderos analizados, las proyecciones de los modelos económicos apuntaban a una mayor concentración en unos pocos países de la actividad de producción y exportación. La marcada intensificación del comercio de productos ganaderos lleva a pensar en una evolución del papel de los Servicios Veterinarios para facilitar el comercio y su extensión en los próximos años.

Quantitative value chain approaches for animal health and food safety.

Economic impact assessments are increasingly important in the context of animal health and food safety, although much of the existing literature does not address the broader systems context in which disease transmission takes place. In this paper, we discuss the role of system dynamics modeling in addressing the value chain impacts associated with animal health and food safety issues. System dynamics methods hold promise as a means of capturing the complex feedbacks that exist between the biology, economics, and behavioral aspects of food safety and animal health systems. We provide a proof-of-concept of this approach in the context of food safety and animal health in the smallholder pig sector of Viet Nam. Results highlight the important tradeoffs that exist between policy objectives and the costs required to achieve them.

Animal production, animal health and food safety: Gaps and challenges in the chilean industry.

This paper summarizes the gaps and challenges related to animal production, health, and food safety as discussed by a panel at the 1st International Symposium of Food Safety (ISFS) in Santiago, Chile, in December 2016. Participating representatives of academia, industry, and government and statements from the audience confirmed that food safety is essential for increasing food security. First, panelists identified the need for a science-based regulatory framework to implement effective regulations. Second, they highlighted the importance of a risk analysis framework to quantify the risk of the potential for antimicrobial resistance associated with the use of antimicrobials, and the need of studies to evaluate foodborne prevention/control strategies. Third, the challenges of filling the gaps between industry and academia were addressed, including examples of successful collaboration, opportunities, and weakness identified by industry. Finally, challenges in animal food production included issues related to changing consumer preferences, animal welfare, the use of antimicrobials, and sustainable animal production. The symposium provided a regional platform to share experiences from the implementation of methods and approaches for food safety. The roundtable successfully explored the future science and technology challenges that are of strategic importance for Chile and the region in animal health and food safety.

The economic impact of a new animal disease: same effects in developed and developing countries?

Animal disease outbreaks generate a range of economic and non-economic impacts. While a significant number of research studies have estimated the effects of various diseases in a variety of contexts, examining the differential impacts and implications associated with the introduction of a novel disease into a developing country, as opposed to a developed one, is a rich area for further research. In this paper, the authors highlight some of the key dimensions and implications associated with the impacts of new diseases, how they differ in different contexts, and their implications for public policy.

La survenue de foyers de maladies animales entraîne des effets divers, de nature économique et non économique. Si l'estimation de l'impact de nombreuses maladies dans différents contextes a fait l'objet de très nombreuses études, l'évaluation différentielle de l'impact de l'introduction d'une maladie nouvelle dans un pays en développement et de ses conséquences, par opposition à ce qu'ils seraient dans un pays développé, constitue un domaine de recherche au riche potentiel largement inexploré. Les auteurs mettent en avant les dimensions et conséquences majeures de l'impact des maladies nouvelles et en soulignent les spécificités selon les contextes ainsi que leurs conséquences en termes de politiques publiques.

Los brotes de enfermedades animales traen consigo una serie de consecuencias de orden económico y no económico. Si bien ha habido numerosas investigaciones destinadas a evaluar los efectos de varias enfermedades en distintos contextos, el estudio del impacto y las repercusiones diferenciales que se siguen de la introducción de una nueva enfermedad en un país en desarrollo, por oposición a un país desarrollado, constituye un prometedor ámbito de investigación para el futuro. Los autores destacan algunas de las principales dimensiones y repercusiones ligadas a las consecuencias de nuevas enfermedades y examinan cómo difieren en función del contexto y cómo repercuten en las políticas públicas.

The epidemiological and economic effects from systematic depopulation of Norwegian marine salmon farms infected with pancreas disease virus.

Pancreas disease (PD) is a viral disease associated with significant economic losses in Scottish, Irish, and Norwegian marine salmon aquaculture. In this paper, we investigate how disease-triggered harvest strategies (systematic depopulation of infected marine salmon farms) towards PD can affect disease dynamics and salmon producer profits in an endemic area in the southwestern part of Norway. Four different types of disease-triggered harvest strategies were evaluated over a four-year period (2011-2014), each scenario with different disease-screening procedures, timing for initiating the harvest interventions on infected cohorts, and levels of farmer compliance to the strategy. Our approach applies a spatio-temporal stochastic model for simulating the spread of PD in the separate scenarios. Results from these simulations were then used in cost-benefit analyses to estimate the net benefits of different harvest strategies over time. We find that the most aggressive strategy, in which infected farms are harvested without delay, was most efficient in terms of reducing infection pressure in the area and providing economic benefits for the studied group of salmon producers. On the other hand, lower farm compliance leads to higher infection pressure and less economic benefits. Model results further highlight trade-offs in strategies between those that primarily benefit individual producers and those that have collective benefits, suggesting a need for institutional mechanisms that address these potential tensions.

The economic benefits of disease triggered early harvest: A case study of pancreas disease in farmed Atlantic salmon from Norway.

Pancreas disease (PD) is an important viral disease in Norwegian, Scottish and Irish aquaculture causing biological losses in terms of reduced growth, mortality, increased feed conversion ratio, and carcass downgrading. We developed a bio-economic model to investigate the economic benefits of a disease triggered early harvesting strategy to control PD losses. In this strategy, the salmon farm adopts a PCR (Polymerase Chain Reaction) diagnostic screening program to monitor the virus levels in stocks. Virus levels are used to forecast a clinical outbreak of pancreas disease, which then initiates a prescheduled harvest of the stock to avoid disease losses. The model is based on data inputs from national statistics, literature, company data, and an expert panel, and use stochastic simulations to account for the variation and/or uncertainty associated with disease effects and selected production expenditures. With the model, we compared the impacts of a salmon farm undergoing prescheduled harvest versus the salmon farm going through a PD outbreak. We also estimated the direct costs of a PD outbreak as the sum of biological losses, treatment costs, prevention costs, and other additional costs, less the costs of insurance pay-outs. Simulation results suggests that the economic benefit from a prescheduled harvest is positive once the average salmon weight at the farm has reached 3.2kg or more for an average Norwegian salmon farm stocked with 1,000,000smolts and using average salmon sales prices for 2013. The direct costs from a PD outbreak occurring nine months (average salmon weight 1.91kg) after sea transfer and using 2013 sales prices was on average estimated at NOK 55.4 million (5%, 50% and 90% percentile: 38.0, 55.8 and 72.4) (NOK=€0.128 in 2013). Sensitivity analyses revealed that the losses from a PD outbreak are sensitive to feed- and salmon sales prices, and that high 2013 sales prices contributed to substantial losses associated with a PD outbreak.

Controlling emerging infectious diseases in salmon aquaculture.

In this paper, the authors review the impacts of diseases facing salmon aquaculture, drawing lessons from terrestrial animal diseases. They discuss the implementation of current control strategies, taking into account transmission patterns (vertical versus horizontal), disease reservoirs, and interactions with wild fish. In addition, the decision-making context of aquatic disease control and the institutional organisation of control strategies are considered, with particular emphasis on the roles and responsibilities of regulatory authorities and the private sector. Case studies on the emergence and control of infectious salmon anaemia worldwide and pancreas disease in Norway are used to examine some of the controversies that may influence decision making and provide lessons for the future.

In vitro molecular magnetic resonance imaging detection and measurement of apoptosis using superparamagnetic iron oxide + antibody as ligands for nucleosomes.

Recent research in cell biology as well as oncology research has focused on apoptosis or programmed cell death as a means of quantifying the induced effects of treatment. A hallmark of late-stage apoptosis is nuclear fragmentation in which DNA is degraded to release nucleosomes with their associated histones. In this work, a method was developed for detecting and measuring nucleosome concentration in vitro with magnetic resonance imaging (MRI). The indirect procedure used a commercially available secondary antibody-superparamagnetic iron oxide (SPIO) particle complex as a contrast agent that bound to primary antibodies against nucleosomal histones H4, H2A and H2B. Using a multiple-echo spin-echo sequence on a 1.5 T clinical MRI scanner, significant T2 relaxation enhancement as a function of in vitro nucleosomal concentration was measured. In addition, clustering or aggregation of the contrast agent was demonstrated with its associated enhancement in T2 effects. The T2 clustering enhancement showed a complex dependence on relative concentrations of nucleosomes, primary antibody and secondary antibody + SPIO. The technique supports the feasibility of using MRI measurements of nucleosome concentration in blood as a diagnostic, prognostic and predictive tool in the management of cancer.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Treatment interruption after pregnancy: effects on disease progression and laboratory findings.

OBJECTIVE: To assess clinical progression and inflammatory markers among women stopping or continuing antiretroviral therapy (ART) after pregnancy. METHODS: ART-naïve women with CD4+ lymphocyte counts >350 cells/uL initiating ART during pregnancy had clinical events and laboratory markers compared over one year postpartum between those stopping (n = 59) or continuing (n = 147) ART. RESULTS: Slopes in CD4 count and HIV RNA did not differ between groups overall and in subsets of ZDV or combination therapy. The hazard ratio (HR) of a new class B event was 2.09 (95% CI 0.79-5.58) among women stopping ART, 1.24 (0.31-4.95) in those stopping ZDV, and 2.93 (0.64-13.36) among those stopping combination therapy. Women stopping ART had increased immune activation. No significant differences were seen in C-reactive protein, lipids, leptin, or interleukin-6. CONCLUSIONS: While changes in CD4 and HIV RNA levels over one year were similar between women stopping or continuing ART postpartum, higher immune activation among women stopping therapy requires further study.

Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease.

BACKGROUND: At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. METHODS: Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH-), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. RESULTS: At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH- and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH- and FHp (p < 0.05). CONCLUSIONS: A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD.

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD.

Very little data exist to evaluate the value of longitudinal CSF biological markers for Alzheimer's disease (AD). Most studies indicate that tau and amyloid beta markers do not reflect disease progression. We now report on a longitudinal, three-time point, CSF Isoprostane (IsoP) and quantitative MRI study that examined 11 normal elderly (NL) volunteers and 6 Mild Cognitive Impairment (MCI) patients. After 4 years, all 6 MCI patients declined to AD and 2 of the NL subjects declined to MCI. At baseline and longitudinally, the MCI patients showed reduced delayed memory, increased IsoP levels, and reduced medial temporal lobe gray matter concentrations as compared to NL. A group comprised of all decliners to AD or to MCI (n = 8) was distinguished at baseline from the stable NL controls (n = 9) by IsoP with 100% accuracy.Moreover, both at baseline and longitudinally, the IsoP measures significantly improved the diagnostic and predictive outcomes of conventional memory testing and quantitative MRI measurements. These data indicate that IsoP is potentially useful for both the early detection of AD-related pathology and for monitoring the course of AD.

Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease.

It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Poverty impacts of foot-and-mouth disease and the poverty reduction implications of its control.

Foot-and-mouth disease (FMD) remains one of the most important livestock diseases of the world, given its highly infectious nature, its broad economic impacts on animal wellbeing and productivity, and its implications for successful access to domestic and export markets for livestock and products. The impacts of the disease vary markedly between developed and developing countries, and also within many developing countries. These differences in impact shape some markedly heterogeneous incentives for FMD control and eradication, which become of particular importance when setting priorities for poverty reduction in developing countries. Some consider that the benefits from FMD control accrue only to the better off in such societies and, as such, may not be a priority for investments targeted at poverty reduction. But is that view justified? Others see the control of FMD as a major development opportunity in a globalised environment. In this paper, Brian Perry and Karl Rich summarise the differential impacts of FMD and its control, and link these findings with the growing understanding of how the control of this globally important disease may contribute to the processes of pro-poor growth in certain countries of the developing world.

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy.

Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N'-bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

Relevance of postmortem radiology to the diagnosis of fatal cerebral gas embolism from compressed air diving.

AIMS: To test the hypothesis that artefact caused by postmortem off-gassing is at least partly responsible for the presence of gas within the vascular system and tissues of the cadaver following death associated with compressed air diving. METHODS: Controlled experiment sacrificing sheep after a period of simulated diving in a hyperbaric chamber and carrying out sequential postmortem computed tomography (CT) on the cadavers. RESULTS: All the subject sheep developed significant quantities of gas in the vascular system within 24 hours, as demonstrated by CT and necropsy, while the control animals did not. CONCLUSIONS: The presence of gas in the vascular system of human cadavers following diving associated fatalities is to be expected, and is not necessarily connected with gas embolism following pulmonary barotrauma, as has previously been claimed.

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment.

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.

A review of economic tools for the assessment of animal disease outbreaks.

This paper demonstrates how currently underutilised economic modelling techniques can enrich the analysis of animal disease problems. Increasingly, analyses of animal health programmes are expected to address a range of economic and social questions. These expectations can be addressed by better integration of epidemiological modelling with economic techniques whose application to animal health has not been thoroughly discussed in past reviews. This paper describes a range of economic models that can be applied in animal health research and provides guidance for determining the appropriate method given the issues at hand. The complexity of some of these approaches underlines the importance of multidisciplinary research and education.