An investigation into the effect of salt (sodium chloride) on immunity in patients with kidney disease

The salt (sodium chloride; NaCl) content of a western diet far exceeds the amount that we consumed through most of our evolutionary history. It is accepted that excess sodium intake causes hypertension and cardiovascular disease, but it has been recently shown that sodium also affects immunity, and high salt diets worsen animal models of autoimmune disease. Sodium has been shown to activate multiple immune cells, including Th17 cells, which provide protection from bacterial and fungal infection but which are also implicated in autoimmune disease. The mechanism by which sodium polarises Th17 cells, whether salt depletion has clinical consequences, and if altering sodium balance affects the development of inflammatory kidney diseases are unknown. In this project, I investigate the effect of salt on IL-17 responses and how this is relevant in patients with kidney disease. I demonstrate that NaCl promotes IL-17 responses in both CD4+ (Th17) and CD8+ (Tc17) cells. This effect is mediated by sodium altering calcium flux during T cell activation and may be abrogated by inhibition of the sodium-potassium-chloride (NKCC) transporter and the epithelial sodium channel (ENaC) on immune cells. Patients with inherited salt losing tubulopathies (SLTs) have clinical features of immunodeficiency with increased infections and allergic disease. This is associated with a reduced ratio of circulating Th17:Th2 cells, and Th17 polarisation in SLT patients is impaired compared with controls. I show that SLT patients have reduced sodium stores and that the typical extracellular ionic environment in SLT is inhibitory to Th17 polarisation. Salt supplementation in vitro rescues IL-17 responses in SLT patients. Lastly, I demonstrate that Th17 cells are salt responsive in patients with inflammatory kidney disease despite in vivo immunosuppression. A high salt diet did not alter the development of an animal model of glomerulonephritis, but a low salt diet was a feasible therapeutic intervention in kidney transplant recipients

A general construction of strictly Neumaier graphs and related switching

In this paper we propose a construction of Neumaier graphs with nexus 1, which generalises two known constructions. We then discuss small strictly Neumaier graphs obtained from the general construction and give a geometric description for some of them. Finally, we apply a variation of the Godsil-McKay switching to the general construction

Very-low-density lipoprotein: complex particles in cardiac energy metabolism.

The heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids. Nonesterified fatty acids (NEFA) were thought to be a favoured carbon source, but their quantitative contribution is limited because of their relative histotoxicity. Circulating triacylglycerols (TAGs) in the form of chylomicrons (CMs) and very-low-density lipoprotein (VLDL) are an alternative source of fatty acids and are now believed to be important in cardiac metabolism. However, few studies on cardiac utilisation of VLDL have been performed and the role of VLDL in cardiac energy metabolism remains unclear. Hearts utilise VLDL to generate ATP, but the oxidation rate of VLDL-TAG is relatively low under physiological conditions; however, in certain pathological states switching of energy substrates occurs and VLDL may become a major energy source for hearts. We review research regarding myocardial utilisation of VLDL and suggest possible roles of VLDL in cardiac energy metabolism: metabolic regulator and extracardiac energy storage for hearts.Peer Reviewe

Very-Low-Density Lipoprotein: Complex Particles in Cardiac Energy Metabolism

The heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids. Nonesterified fatty acids (NEFA) were thought to be a favoured carbon source, but their quantitative contribution is limited because of their relative histotoxicity. Circulating triacylglycerols (TAGs) in the form of chylomicrons (CMs) and very-low-density lipoprotein (VLDL) are an alternative source of fatty acids and are now believed to be important in cardiac metabolism. However, few studies on cardiac utilisation of VLDL have been performed and the role of VLDL in cardiac energy metabolism remains unclear. Hearts utilise VLDL to generate ATP, but the oxidation rate of VLDL-TAG is relatively low under physiological conditions; however, in certain pathological states switching of energy substrates occurs and VLDL may become a major energy source for hearts. We review research regarding myocardial utilisation of VLDL and suggest possible roles of VLDL in cardiac energy metabolism: metabolic regulator and extracardiac energy storage for hearts

Help or hinder: Bayesian models of social goal inference

Everyday social interactions are heavily influenced by our snap judgments about others’ goals. Even young infants can infer the goals of intentional agents from observing how they interact with objects and other agents in their environment: e.g., that one agent is ‘helping’ or ‘hindering’ another’s attempt to get up a hill or open a box. We propose a model for how people can infer these social goals from actions, based on inverse planning in multiagent Markov decision problems (MDPs). The model infers the goal most likely to be driving an agent’s behavior by assuming the agent acts approximately rationally given environmental constraints and its model of other agents present. We also present behavioral evidence in support of this model over a simpler, perceptual cue-based alternative.United States. Army Research Office (ARO MURI grant W911NF-08-1-0242)United States. Air Force Office of Scientific Research (MURI grant FA9550-07-1-0075)National Science Foundation (U.S.) (Graduate Research Fellowship)James S. McDonnell Foundation (Collaborative Interdisciplinary Grant on Causal Reasoning

Laboratory-based surveillance of Campylobacter and Salmonella infection and the importance of denominator data

Laboratory data are the cornerstone in surveillance of infectious disease. We investigated whether changes in reported incidence of Campylobacter and Salmonella infection might be explained by changes in stool sampling rates. Data were extracted from a national database on 585 843 patient stool samples tested by microbiology laboratories in Wales between 1998 and 2008. Salmonella incidence fell from 43 to 19 episodes/100 000 population but Campylobacter incidence after declining from 111/100 000 in 1998 to 84/100 000 in 2003 rose to 119/100 000 in 2008. The proportion of the population sampled rose from 2·0% in 1998 to 2·8% in 2008, mostly due to increases in samples from hospital patients and older adults. The proportion of positive samples declined for both Salmonella and Campylobacter from 3·1% to 1·1% and from 8·9% to 7·5%, respectively. The decline in Salmonella incidence is so substantial that it is not masked even by increased stool sampling, but the recent rise in Campylobacter incidence may be a surveillance artefact largely due to the increase in stool sampling in older people

Simple Process-Led Algorithms for Simulating Habitats (SPLASH v.1.0): Robust Indices of Radiation, Evapotranspiration and Plant-Available Moisture

Bioclimatic indices for use in studies of ecosystem function, species distribution, and vegetation dynamics under changing climate scenarios depend on estimates of surface fluxes and other quantities, such as radiation, evapotranspi- ration and soil moisture, for which direct observations are sparse. These quantities can be derived indirectly from me- teorological variables, such as near-surface air temperature, precipitation and cloudiness. Here we present a consolidated set of simple process-led algorithms for simulating habitats (SPLASH) allowing robust approximations of key quantities at ecologically relevant timescales. We specify equations, derivations, simplifications, and assumptions for the estima- tion of daily and monthly quantities of top-of-the-atmosphere solar radiation, net surface radiation, photosynthetic photon flux density, evapotranspiration (potential, equilibrium, and actual), condensation, soil moisture, and runoff, based on analysis of their relationship to fundamental climatic drivers. The climatic drivers include a minimum of three meteoro- logical inputs: precipitation, air temperature, and fraction of bright sunshine hours. Indices, such as the moisture index, the climatic water deficit, and the Priestley–Taylor coeffi- cient, are also defined. The SPLASH code is transcribed in C++, FORTRAN, Python, and R. A total of 1 year of results are presented at the local and global scales to exemplify the spatiotemporal patterns of daily and monthly model outputs along with comparisons to other model results

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation.

AIMS: The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress. METHODS AND RESULTS: Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels. CONCLUSIONS: Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway