Diagnosis and treatment of anti-insulin antibody-mediated labile glycaemia in insulin-treated diabetes.

AIMS: Anti-insulin antibodies in insulin-treated diabetes can derange glycaemia, but are under-recognised. Detection of significant antibodies is complicated by antigenically distinct insulin analogues. We evaluated a pragmatic biochemical approach to identifying actionable antibodies, and assessed its utility in therapeutic decision making. METHODS: Forty people with insulin-treated diabetes and combinations of insulin resistance, nocturnal/matutinal hypoglycaemia, and unexplained ketoacidosis were studied using broad-specificity insulin immunoassays, polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC) with or without ex vivo insulin preincubation. RESULTS: Twenty-seven people had insulin immunoreactivity (IIR) below 3000 pmol/L that fell less than 50% after PEG precipitation. Insulin binding by antibodies in this group was low and judged insignificant. In 8 people IIR was above 3000 pmol/L and fell by more than 50% after PEG precipitation. GFC demonstrated substantial high molecular weight (HMW) IIR in 7 of these 8. In this group antibodies were judged likely significant. In 2 people immunosuppression was introduced, with a good clinical result in one but only a biochemical response in another. In 6 people adjustment of insulin delivery was subsequently informed by knowledge of underlying antibody. In a final group of 5 participants IIR was below 3000 pmol/L but fell by more than 50% after PEG precipitation. In 4 of these GFC demonstrated low levels of HMW IIR and antibody significance was judged indeterminate. CONCLUSIONS: Anti-insulin antibodies should be considered in insulin-treated diabetes with unexplained glycaemic lability. Combining immunoassays with PEG precipitation can stratify their significance. Antibody depletion may be beneficial, but conservative measures often suffice.

A novel experimental chamber for the characterization of free-falling particles in volcanic plumes.

Volcanic plumes pose a hazard to health and society and a particular risk for aviation. Hazard mitigation relies on forecasting plume dispersion within the atmosphere over time. The accuracy of forecasts depends on our understanding of particle dispersion and sedimentation processes, as well as on the accuracy of model input parameters, such as the initial particle size distribution and concentrations of volcanic particles (i.e., volcanic ash) in the atmosphere. However, our understating of these processes and the accurate quantification of input parameters remain the main sources of uncertainty in plume dispersion modeling. It is usually impractical to sample volcanic plumes directly, but particle sedimentation can be constrained in the laboratory. Here, we describe the design of a new experimental apparatus for investigating the dynamics of free-falling volcanic particles. The apparatus can produce a sustained column of falling particles with variable particle concentrations appropriate to a volcanic plume. Controllable experimental parameters include particle size distributions, types, and release rates. A laser-illuminated macrophotography system allows imaging of in-flight particles and their interactions. The mass of landing particles is logged to inform deposition rates. Quantitative measurements include particle morphology characterization, settling velocities, flow rates, and estimation of concentrations. Simultaneous observations of particle interaction processes and settling dynamics through direct control over a wide range of parameters will improve our parameterization of volcanic plume dynamics. Although the apparatus has been specifically designed for volcanological investigations, it can also be used to explore the characteristics of free-falling particle columns occurring in both environmental and industrial settings.

Intermittent exposure of cultured endothelial cells to physiologically relevant fructose concentrations has a profound impact on nitric oxide production and bioenergetics.

Hyperglycaemia is known to induce endothelial dysfunction and changes in metabolic function, which could be implicated in diabetes-induced cardiovascular disease. To date, however, little is known about the impact of physiologically relevant concentrations of fructose on endothelial cells. A novel in vitro model was devised to establish the impact of substitution of a small proportion of glucose with an equal concentration (0.1 mM or 1 mM) of fructose on EA.hy926 endothelial cells during periodic carbohydrate "meals" superimposed on a normoglycaemic (5.5 mM) background. Parallel experiments were conducted using meals consisting of normoglycaemic glucose, intermediate glucose (12.5 mM) or profound hyperglycaemia (25 mM), each delivered for 2 h, with and without substituted fructose over 50 h. Outcome measures included nitrite as a surrogate marker of the mediator of healthy endothelial function, nitric oxide (NO), and a range of bioenergetic parameters using a metabolic analyser. Despite its relatively low proportion of carbohydrate load, intermittent fructose induced a substantial reduction (approximately 90%) in NO generation in cells treated with either concentration of fructose. Cell markers of oxidative stress were not altered by this treatment regimen. However, the cells experienced a marked increase in metabolic activity induced by fructose, irrespective of the glucose concentration delivered simultaneously in the "meals". Indeed, glucose alone failed to induce any metabolic impact in this model. Key metabolic findings were a 2-fold increase in basal oxygen consumption rate and a similar change in extracellular acidification rate-a marker of glycolysis. Non-metabolic oxygen consumption also increased substantially in cells exposed to fructose. There was no difference between results with 0.1 mM fructose and those with 1 mM fructose. Low, physiologically relevant concentrations of fructose, delivered in a pattern that mimics mealtime consumption, had a profound impact on endothelial function and bioenergetics in an in vitro cell model. The results suggest that endothelial cells are exquisitely sensitive to circulating fructose; the potential ensuing dysfunction could have major implications for development of atherosclerotic disease associated with high fructose consumption.

Testing a generalized leaf mass estimation method for diverse tree species and climates of the continental United States.

Estimating tree leaf biomass can be challenging in applications where predictions for multiple tree species is required. This is especially evident where there is limited or no data available for some of the species of interest. Here we use an extensive national database of observations (61 species, 3628 trees) and formulate models of varying complexity, ranging from a simple model with diameter at breast height (DBH) as the only predictor to more complex models with up to 8 predictors (DBH, leaf longevity, live crown ratio, wood specific gravity, shade tolerance, mean annual temperature, and mean annual precipitation), to estimate tree leaf biomass for any species across the continental United States. The most complex with all eight predictors was the best and explained 74%-86% of the variation in leaf mass. Consideration was given to the difficulty of measuring all of these predictor variables for model application, but many are easily obtained or already widely collected. Because most of the model variables are independent of species and key species-level variables are available from published values, our results show that leaf biomass can be estimated for new species not included in the data used to fit the model. The latter assertion was evaluated using a novel "leave-one-species-out" cross-validation approach, which showed that our chosen model performs similarly for species used to calibrate the model, as well as those not used to develop it. The models exhibited a strong bias toward overestimation for a relatively small subset of the trees. Despite these limitations, the models presented here can provide leaf biomass estimates for multiple species over large spatial scales and can be applied to new species or species with limited leaf biomass data available.

Technology-enabled remote management of diabetes foot disease and potential for reduction in associated health costs: a pilot study.

Diabetes-related foot disease, particularly when associated with amputation, affects quality of life and has a significant impact on health care costs. A pilot study using enhanced technology to facilitate remote access and video conferencing from rural locations to the diabetes MDT through a new service pathway confirmed high levels of patient satisfaction with 89% of foot ulcers improved or stable and only two minor amputations. A health economic analysis suggested potential for significant cost savings if this was scaled up regionally. Further evaluation of an integrated pathway, impact on lower limb amputation rates and full health economic assessment is recommended.

Fractal dimension of tree crowns explains species functional-trait responses to urban environments at different scales.

The evolution of form and function of trees of diverse species has taken place over hundreds of millions of years, while urban environments are relatively new on an evolutionary time scale, representing a novel set of environmental constraints for trees to respond to. It is important to understand how trees of different species, planted in these anthropogenically-structured urban ecosystems, are responding to them. Many theories have been advanced to understand tree form and function, including several that suggest the fractal-like geometry of trees is a direct reflection of inherent and plastic morphological and physiological traits that govern tree growth and survival. In this research, we analyzed the "fractal dimension" of thousands of tree crowns of many different tree species, growing in different urban environments across the United States, to learn more about the nature of trees and their responses to urban environments at different scales. Our results provide new insights regarding how tree crown fractal dimension relates to balances between hydraulic- and light-capture-related functions (e.g., drought and shade tolerance). Our findings indicate that trees exhibit reduced crown fractal dimension primarily to reduce water loss in hotter cities. More specifically, the intrinsic drought tolerance of the studied species arises from lower surface to volume ratios at both whole-crown and leaf scales, preadapting them to drought stress in urban ecosystems. Needle-leaved species showed a clear trade-off between optimizing the fractal dimension of their crowns for drought vs. shade tolerance. Broad-leaved species showed a fractal crown architecture that responded principally to inherent drought tolerance. Adjusting for the temperature of cities and intrinsic species effects, the fractal dimension of tree crowns was lower in more heavily urbanized areas (with greater paved area or buildings) and due to crowns conflicting with utility wires. With expectations for more urbanization and generally hotter future climates, worldwide, our results add new insights into the physiological ecology of trees in urban environments, which may help humans to provide more hospitable habitats for trees in urbanized areas and to make better decisions about tree selection in urban forest management.

Over half of western United States' most abundant tree species in decline.

Changing forest disturbance regimes and climate are driving accelerated tree mortality across temperate forests. However, it remains unknown if elevated mortality has induced decline of tree populations and the ecological, economic, and social benefits they provide. Here, we develop a standardized forest demographic index and use it to quantify trends in tree population dynamics over the last two decades in the western United States. The rate and pattern of change we observe across species and tree size-distributions is alarming and often undesirable. We observe significant population decline in a majority of species examined, show decline was particularly severe, albeit size-dependent, among subalpine tree species, and provide evidence of widespread shifts in the size-structure of montane forests. Our findings offer a stark warning of changing forest composition and structure across the western US, and suggest that sustained anthropogenic and natural stress will likely result in broad-scale transformation of temperate forests globally.

The impact of glucose exposure on bioenergetics and function in a cultured endothelial cell model and the implications for cardiovascular health in diabetes.

Cardiovascular disease is the primary driver of morbidity and mortality associated with diabetes. Hyperglycaemia is implicated in driving endothelial dysfunction that might underpin the link between diabetes and cardiovascular disease. This study was designed to determine the impact of chronic preconditioning of cells to hyperglycaemia and transient switching of cultured endothelial cells between hyper- and normo-glycaemic conditions on bioenergetic and functional parameters. Immortalised EA.hy926 endothelial cells were cultured through multiple passages under normoglycaemic (5.5 mM) or hyperglycaemic (25 mM) conditions. Cells were subsequently subjected (48 h) to continued normo- or hyperglycaemic exposure, or were switched to the alternative glycaemic condition, or to an intermediate glucose concentration (12.5 mM) and metabolic activity, together with key markers of function were measured. Cells habituated to hyperglycaemia were energetically quiescent. Functional activity, characterised by the measurement of nitric oxide, endothelin-1, tissue plasminogen activator and plasminogen activator inhibitor-1, was depressed by exposure to high glucose, with the reduction in nitric oxide production being the most notable. Function was more responsive to acute changes in extracellular glucose than were bioenergetic changes. We conclude that glucose is a key determinant of endothelial function. The study highlights the importance of chronic glucose exposure on cell phenotype and emphasises the need to pay close attention to glucose preconditioning in interpreting results under culture conditions.

Trans-species predictors of tree leaf mass.

Tree leaf mass is a small, highly variable, but critical, component of forest ecosystems. Estimating leaf mass on standing trees with models is challenging because leaf mass varies both within and between tree species and at different locations and points in time. Typically, models for estimating tree leaf mass are species specific, empirical models that predict intraspecific variation from stem diameter at breast height (dbh). Such models are highly limited in their application because there are many other factors beyond tree girth and species that cause leaf mass to vary and because such models provide no way to predict leaf mass for species for which data are not available. We conducted destructive sampling of 17 different species in Michigan, covering multiple life history traits and sizes, to investigate the potential for using a single, "trans-species" model for predicting leaf mass for all the trees in our study. Our results show the most important predictors of tree leaf mass are dbh, five-year basal area increment, crown class, and competition index, none of which are species specific. Species-specific variation could be captured by leaf longevity and shade tolerance. Wood specific gravity was a statistically significant, but marginally important predictor. Together, these variables describing tree size, life-history traits, and competitive environment allowed us to develop a generalized leaf mass model applicable to a diverse set of species, without having to develop species-specific equations.

Reducing Amputations in People with Diabetes (RAPID): Evaluation of a New Care Pathway.

People with diabetes are at increased risk of foot ulcers, which, if left untreated, can lead to infection, gangrene, and subsequent amputation. Management by a multidisciplinary diabetes foot team has been shown to reduce amputation rates; however, accessing specialist treatment is made particularly difficult when living in remote and rural locations, such as many individuals cared for within NHS Highland. The RAPID project was made up of two phases: firstly, to evaluate the technical feasibility of a new integrated care pathway using innovative technology, and secondly, to establish process enhancement of the pathway to justify a larger-scale study. Omni-HubTM enabled a face-to-face consultation by the community podiatrist to be enhanced by virtual consultation with members of the multidisciplinary foot team, including specialist diabetes podiatrists and a diabetes consultant. The technical feasibility study provided recommended changes focused around adaptations to the equipment used and the best means to gain successful connectivity. The process enhancement study demonstrated positive outcomes in the process with positive effects both in the service received by patients and experiences of healthcare professionals involved. The RAPID project provides evidence and justification for a larger-scale empirical study to test an embedded pathway and technology solution, which will inform policy change and a paradigm shift in the management of foot ulceration in the community.

Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03.

INTRODUCTION: TROG 09.03 prospectively studied the utility of Fluorine-18 Fluorodeoxyglucose (18-FDG) PET in the management of Merkel cell carcinoma of skin. METHODS: Following consent and registration, a pre-treatment FDG-PET/CT was performed. Sites of avid disease were confirmed by cytology where practicable. Following surgery, patients with AJCCv7 Stages IIA-IIIB disease were treated with chemo-radiotherapy and reassessed with a post-treatment PET. RESULTS: Fifty-eight subjects (45 males and 13 females, median age 68 years) were enrolled between 2011 and 2015, 43 patients of whom went on to receive chemo-radiotherapy. An occult primary was present in 22 (37.9%), T1 in 22 (37.9%) and T2 disease in 14 (24.1%). Nodal disease was present in 69% of cases. Fifty per cent of subjects had gross residual disease at the primary site and/or nodal site at the time of registration. 18-FDG PET/CT had a sensitivity of 94.74% (95% CI 82-99.3%) and a specificity of 88.24% (95% CI 63.56-98.54). The positive predictive value was 94.74% (83.01-98.51) and the negative predictive value was 88.24% (95% CI 65.81-96.69). The pre-treatment PET influenced a treatment decision in 27.6% of cases. Upstaging occurred in 15 (25.9%), with no down staging. Other diseases were identified in 4 (6.9%) patients. Univariate analysis failed to demonstrate that pre-treatment SUV levels or a negative post-treatment PET had any impact on overall survival. PET staged patients had 89% 3-year in-field loco-regional control and 76% 3-year overall survival. CONCLUSION: Staging 18-FDG-PET significantly influenced treatment decisions in approximately one-third of cases of MCC and should be considered in the routine pre-treatment work-up. Post-treatment PET was not found to be prognostic. Funding through the Medicare Benefits Schedule needs to be considered for high risk MCC.

Explaining variation in adult Anopheles indoor resting abundance: the relative effects of larval habitat proximity and insecticide-treated bed net use.

BACKGROUND: Spatial determinants of malaria risk within communities are associated with heterogeneity of exposure to vector mosquitoes. The abundance of adult malaria vectors inside people's houses, where most transmission takes place, should be associated with several factors: proximity of houses to larval habitats, structural characteristics of houses, indoor use of vector control tools containing insecticides, and human behavioural and environmental factors in and near houses. While most previous studies have assessed the association of larval habitat proximity in landscapes with relatively low densities of larval habitats, in this study these relationships were analysed in a region of rural, lowland western Kenya with high larval habitat density. METHODS: 525 houses were sampled for indoor-resting mosquitoes across an 8 by 8 km study area using the pyrethrum spray catch method. A predictive model of larval habitat location in this landscape, previously verified, provided derivations of indices of larval habitat proximity to houses. Using geostatistical regression models, the association of larval habitat proximity, long-lasting insecticidal nets (LLIN) use, house structural characteristics (wall type, roof type), and peridomestic variables (cooking in the house, cattle near the house, number of people sleeping in the house) with mosquito abundance in houses was quantified. RESULTS: Vector abundance was low (mean, 1.1 adult Anopheles per house). Proximity of larval habitats was a strong predictor of Anopheles abundance. Houses without an LLIN had more female Anopheles gambiae s.s., Anopheles arabiensis and Anopheles funestus than houses where some people used an LLIN (rate ratios, 95% CI 0.87, 0.85-0.89; 0.84, 0.82-0.86; 0.38, 0.37-0.40) and houses where everyone used an LLIN (RR, 95% CI 0.49, 0.48-0.50; 0.39, 0.39-0.40; 0.60, 0.58-0.61). Cooking in the house also reduced Anopheles abundance across all species. The number of people sleeping in the house, presence of cattle near the house, and house structure modulated Anopheles abundance, but the effect varied with Anopheles species and sex. CONCLUSIONS: Variation in the abundance of indoor-resting Anopheles in rural houses of western Kenya varies with clearly identifiable factors. Results suggest that LLIN use continues to function in reducing vector abundance, and that larval source management in this region could lead to further reductions in malaria risk by reducing the amount of an obligatory resource for mosquitoes near people's homes.

Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct.

BACKGROUND AND AIMS: The effects of glucocorticoids on fuel metabolism are complex. Acute glucocorticoid excess promotes lipolysis but chronic glucocorticoid excess causes visceral fat accumulation. We hypothesized that interactions between cortisol and insulin and adrenaline account for these conflicting results. We tested the effect of cortisol on lipolysis and glucose production with and without insulin and adrenaline in humans both in vivo and in vitro. MATERIALS AND METHODS: A total of 20 healthy men were randomized to low and high insulin groups (both n = 10). Subjects attended on 3 occasions and received low (c. 150 nM), medium (c. 400 nM) or high (c. 1400 nM) cortisol infusion in a randomized crossover design. Deuterated glucose and glycerol were infused intravenously along with a pancreatic clamp (somatostatin with replacement of glucagon, insulin and growth hormone) and adrenaline. Subcutaneous adipose tissue was obtained for analysis. In parallel, the effect of cortisol on lipolysis was tested in paired primary cultures of human subcutaneous and visceral adipocytes. RESULTS: In vivo, high cortisol increased lipolysis only in the presence of high insulin and/or adrenaline but did not alter glucose kinetics. High cortisol increased adipose mRNA levels of ATGL, HSL and CGI-58 and suppressed G0S2. In vitro, high cortisol increased lipolysis in the presence of insulin in subcutaneous, but not visceral, adipocytes. CONCLUSIONS: The acute lipolytic effects of cortisol require supraphysiological concentrations, are dependent on insulin and adrenaline and are observed only in subcutaneous adipose tissue. The resistance of visceral adipose tissue to cortisol's lipolytic effects may contribute to the central fat accumulation observed with chronic glucocorticoid excess.

Cyberinfrastructure for Open Science at the Montreal Neurological Institute.

Data sharing is becoming more of a requirement as technologies mature and as global research and communications diversify. As a result, researchers are looking for practical solutions, not only to enhance scientific collaborations, but also to acquire larger amounts of data, and to access specialized datasets. In many cases, the realities of data acquisition present a significant burden, therefore gaining access to public datasets allows for more robust analyses and broadly enriched data exploration. To answer this demand, the Montreal Neurological Institute has announced its commitment to Open Science, harnessing the power of making both clinical and research data available to the world (Owens, 2016a,b). As such, the LORIS and CBRAIN (Das et al., 2016) platforms have been tasked with the technical challenges specific to the institutional-level implementation of open data sharing, including: Comprehensive linking of multimodal data (phenotypic, clinical, neuroimaging, biobanking, and genomics, etc.)Secure database encryption, specifically designed for institutional and multi-project data sharing, ensuring subject confidentiality (using multi-tiered identifiers).Querying capabilities with multiple levels of single study and institutional permissions, allowing public data sharing for all consented and de-identified subject data.Configurable pipelines and flags to facilitate acquisition and analysis, as well as access to High Performance Computing clusters for rapid data processing and sharing of software tools.Robust Workflows and Quality Control mechanisms ensuring transparency and consistency in best practices.Long term storage (and web access) of data, reducing loss of institutional data assets.Enhanced web-based visualization of imaging, genomic, and phenotypic data, allowing for real-time viewing and manipulation of data from anywhere in the world.Numerous modules for data filtering, summary statistics, and personalized and configurable dashboards. Implementing the vision of Open Science at the Montreal Neurological Institute will be a concerted undertaking that seeks to facilitate data sharing for the global research community. Our goal is to utilize the years of experience in multi-site collaborative research infrastructure to implement the technical requirements to achieve this level of public data sharing in a practical yet robust manner, in support of accelerating scientific discovery.

Use of fluoride-containing water for the irrigation of soil-plant systems.

Many groundwaters used for irrigation contain elevated concentrations of F, but much remains unknown regarding how this F behaves within soils and plants. The present study investigated the adsorption and desorption of F from several soils in short- to medium-term irrigation systems and related foliar F concentrations in three forage plant species to the maximum tolerable level (MTL) in the diets of grazing animals (being 1.8 µmol/g for young cattle, for example). Although adsorption isotherms could be successfully used to predict the behavior (adsorption and desorption) of F within the soil, this was not related to the subsequent accumulation of F in plant foliage. In addition, the extent to which F accumulated in the foliage depended on the plant species. Regardless, F generally did not accumulate in plant foliage to levels exceeding the MTL when used at rates equivalent to irrigation for 25 years. In addition to uptake by roots, F may accumulate in foliar tissues directly due to retention from overhead irrigation. The data presented here regarding the behavior of F in soils and plants will assist in the rigorous regulation of F-containing irrigation water to ensure maximum plant growth while simultaneously minimizing potential harm.

A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers.

BACKGROUND: The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work-up. METHODS: This was a single-institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work-up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. RESULTS: Fifty-six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6-26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2-12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV < 5). CONCLUSIONS: PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery.

Asymptomatic and mild primary hyperparathyroidism.

Primary hyperparathyroidism is common, with epidemiological studies suggesting it may effect up to 1% of the population, and up to 3% of post-menopausal females. Many cases are diagnosed incidentally on routine blood sampling, with the majority of patients being seemingly asymptomatic at diagnosis, and often having mild hypercalcaemia of <2.85mmol/L. Individuals with this so-called mild or asymptomatic primary hyperparathyroidism may however have undiagnosed complications, along with subtle neuropsychological symptoms, and possibly increased cardiovascular risk. Revised international guidelines suggest a more proactive approach to screening for vertebral fractures and renal stones, although the thresholds for recommending definitive surgical management with parathyroidectomy remain similar. The natural history of mild primary hyperparathyroidism will be reviewed, with particular reference to the Parathyroid Epidemiology and Audit Research Study (PEARS), which has used population level data from Tayside, Scotland (UK), along with recent data describing an association with cardiovascular disease. Results of intervention studies, including randomised controlled trials, will also be discussed.

Blood-brain barrier dysfunction following traumatic brain injury: correlation of K(trans) (DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B.

OBJECTIVE: Damage to the blood-brain barrier (BBB) is an important secondary mechanism that occurs following traumatic brain injury (TBI) and may provide a potential therapeutic target to improve patient outcome. For such a progress to be realised, an accurate assessment of BBB compromise needs to be established. METHODS: Fourteen patients with TBI were prospectively recruited. Post-traumatic BBB dysfunction was assessed using dynamic contrast-enhanced MRI (DCE-MRI), single-photon emission computerised tomography (SPECT) and serum S100B levels. RESULTS: A statistically significant correlation between standardised uptake value ratio (SUVR) calculated from 99mTc-DTPA SPECT and K(trans) (a volume transfer constant) from DCE-MRI was found for those eight patients who had concurrent scans. The positive correlation persisted when the data were corrected for patient age, number of days following trauma and both parameters combined. We found no statistically significant correlation between either of the imaging modalities and concurrent serum S100B levels. DISCUSSION: The correlation of SPECT with DCE-MRI suggests that either scan may be used to assess post-traumatic BBB damage. We could not support serum S100B to be an accurate measure of BBB damage when sampled a number of days following injury but the small number of patients, the heterogeneity in TBI patients and the delay following injury makes any firm conclusions regarding S100B and BBB difficult.

5α-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents.

5α-Reductase type 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5αR1 allele (5αR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5α-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5αR1-KO mice demonstrated greater mean weight gain (21.6 ± 1.4 vs 16.2 ± 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 ± 103 vs. 313 ± 66 ng ⋅ mL(-1) ⋅ min), and hepatic steatosis (liver triglycerides 136.1 ± 17.0 vs. 89.3 ± 12.1 µmol ⋅ g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid ß-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5α-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 µmol ⋅ g(-1)) in obese male Zucker rats, both intact and castrated. 5αR1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with nonselective 5α-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease.

Modeling larval malaria vector habitat locations using landscape features and cumulative precipitation measures.

BACKGROUND: Predictive models of malaria vector larval habitat locations may provide a basis for understanding the spatial determinants of malaria transmission. METHODS: We used four landscape variables (topographic wetness index [TWI], soil type, land use-land cover, and distance to stream) and accumulated precipitation to model larval habitat locations in a region of western Kenya through two methods: logistic regression and random forest. Additionally, we used two separate data sets to account for variation in habitat locations across space and over time. RESULTS: Larval habitats were more likely to be present in locations with a lower slope to contributing area ratio (i.e. TWI), closer to streams, with agricultural land use relative to nonagricultural land use, and in friable clay/sandy clay loam soil and firm, silty clay/clay soil relative to friable clay soil. The probability of larval habitat presence increased with increasing accumulated precipitation. The random forest models were more accurate than the logistic regression models, especially when accumulated precipitation was included to account for seasonal differences in precipitation. The most accurate models for the two data sets had area under the curve (AUC) values of 0.864 and 0.871, respectively. TWI, distance to the nearest stream, and precipitation had the greatest mean decrease in Gini impurity criteria in these models. CONCLUSIONS: This study demonstrates the usefulness of random forest models for larval malaria vector habitat modeling. TWI and distance to the nearest stream were the two most important landscape variables in these models. Including accumulated precipitation in our models improved the accuracy of larval habitat location predictions by accounting for seasonal variation in the precipitation. Finally, the sampling strategy employed here for model parameterization could serve as a framework for creating predictive larval habitat models to assist in larval control efforts.