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Background: Altered reward processing is increasingly recognised as a crucial mechanism underpinning apathy in many brain disorders. However despite its clinical relevance, little is known about the mechanisms of apathy following moderate-to-severe traumatic brain injury (TBI). In real-life situations, reward representations encompass both foreground (gains from current activity) and background (potential gains from the broader environment) elements. This latter variable provides a crucial set-point for switching behaviour in many naturalistic settings. We hypothesised apathy post-TBI would be associated with disrupted background reward sensitivity., Methods: We administered a computer-based foraging task to 45 people with moderate-to-severe TBI (20 with apathy, 39 males) and 37 matched controls. Participants decided when to leave locations (patches) where foreground reward rates depleted at differing rates, to pursue greater rewards from other patches in the environment, which had either a high or low background reward rate. Primary analysis was performed using linear mixed effects models, with patch leaving time the dependent variable., Results: Findings showed a significant interaction between apathy and background reward sensitivity, driven by apathetic TBI participants not altering patch-leaving decisions as environmental reward rate changed. In contrast, although TBI was associated with reduced sensitivity to changing foreground rewards, this did not vary as a function of apathy., Conclusions: These results provide the first evidence directly linking disrupted background reward processing to apathy in any brain disorder. They identify a novel mechanism for apathy following moderate-to-severe TBI, and point towards novel interventions to improve this debilitating complication of head injury., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Classical swine fever virus (CSFV) is an RNA virus that incurs severe economic costs to swine industries worldwide. This study was conducted to investigate the genetic diversity among CSFV strains circulating in Vietnam, with a focus on their genetic variants relative to four vaccine strains. Samples from clinical cases were collected from different provinces of Central and Southern Vietnam from 2017 to 2019. 21 CSFV-positive samples were selected for amplification and sequencing of the full-length E rns and E2 genes. Phylogenetic analyses of these two genes showed that most CSFV strains circulating in Central and Southern Vietnam from 2017 to 2019 belong to subgroup 2.1c, whereas the remaining strains cluster into subgroup 2.2. All CSFV field strains in this study were genetically distant from group 1 strains. Analysis of the E2 and E rns genes indicated that all CSFV field strains have low sequence identity with the vaccine strains (80-83.5% and 82.3-86% sequence identity for E2 and E rns , respectively). Likewise, amino acid-level sequence analysis showed 87.3-91.1% and 87.6-91.6% sequence identity for E2 and E rns , respectively. Together, our findings indicate that CSFV strains circulating in Vietnam belong to subtypes 2.2 and 2.1c, and we also provide novel insights into the epidemiology, molecular characteristics, genetic diversity, and evolution of these circulating CSFV strains., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Substantial research has found a robust relationship between stressful life events and increased negative health outcomes and a greater predisposition to various forms of substance use and gambling behavior; however, less is known about the individual factors that explain this relationship. The present study examines the moderating factors of gambling to cope and individual impulsivity factors (e.g., perseverance, premeditation, and negative urgency) on the relationship between stressful life events over the past year and gambling problems among a sample of college students. Participants included 653 total students (48.57% female; M = 26.31 years old; SD = 8.35 years) enrolled in universities across the United States who scored three or higher on the South Oaks Gambling Screen, an indicator of risk for problematic gambling. We found a positive relationship between stressful life events and gambling problems. Gambling to cope moderated the link between stressful life events and gambling problems such that for those higher in gambling to cope, stressful life events had little impact on gambling problems while those at lower to moderate levels of gambling to cope saw a positive relationship between stressful life events and gambling problems. Moreover, we found two significant three-way interactions between stressful life events, gambling to cope, and impulsivity factors of perseverance and premeditation in predicting problems. These findings suggest that prevention and/or treatment strategies should consider how gambling to cope and impulsivity factors in conjunction with an individual's report of stressful life events relate to problematic gambling and associated consequences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia., (Copyright © 2016. Published by Elsevier B.V.)

Tumor-initiating cells (TICs) often survive therapy and give rise to second-line tumors. We tested the plausibility of sphere cultures as models of TICs. Microarray data and microRNA data analysis confirmed the validity of spheres as models of TICs for breast and prostate cancer as well as mesothelioma cell lines. Microarray data analysis revealed the Trp pathway as the only pathway upregulated significantly in all types of studied TICs, with increased levels of indoleamine-2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme of Trp metabolism along the kynurenine pathway. All types of TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. IDO1 expression was regulated via both transcriptional and posttranscriptional mechanisms, depending on the cancer type. Serial transplantation of TICs in mice resulted in gradually increased IDO1. Mitocans, represented by α-tocopheryl succinate and mitochondrially targeted vitamin E succinate (MitoVES), suppressed IDO1 in TICs. MitoVES suppressed IDO1 in TICs with functional mitochondrial complex II, involving transcriptional and posttranscriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work indicates that IDO1 is increased in TICs and that mitocans suppress the protein., (© 2013 Elsevier Inc. All rights reserved.)

20-Hydroxyvitamin D(3) (20(OH)D(3)), the major product of CYP11A1 action on vitamin D(3), is biologically active and is produced in vivo. As well as potentially having important physiological actions, it is of interest as a therapeutic agent due to its lack of calcemic activity. In the current study we have examined the ability of CYP24A1, the enzyme that inactivates 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), to metabolize 20(OH)D(3). Rat CYP24A1 was expressed in Escherichia coli, purified by Ni-affinity chromatography and assayed with substrates incorporated into phospholipid vesicles which served as a model of the inner mitochondrial membrane. In this system CYP24A1 metabolized 1,25(OH)(2)D(3) with a catalytic efficiency 1.4-fold higher than that seen for 25-hydroxyvitamin D(3) (25(OH)D(3)). CYP24A1 hydroxylated 20(OH)D(3) to several dihydroxy-derivatives with the major two identified by NMR as 20,24-dihydroxyvitamin D(3) (20,24(OH)(2)D(3)) and 20,25-dihydroxyvitamin D(3) (20,25(OH)(2)D(3)). The catalytic efficiency of CYP24A1 for 20(OH)D(3) metabolism was more than 10-fold lower than for either 25(OH)D(3) or 1,25(OH)(2)D(3) and no secondary metabolites were produced. The two major products, 20,24(OH)(2)D(3) and 20,25(OH)(2)D(3), caused significantly greater inhibition of colony formation by SKMEL-188 melanoma cells than either 1,25(OH)(2)D(3) or the parent 20(OH)D(3), showing that CYP24A1 plays an activating, rather than an inactivating role on 20(OH)D(3)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Traumatic injury to the brain initiates an increase in astrocyte and microglial infiltration as part of an inflammatory response to injury. Increased astrogliosis around the injury impedes regeneration of axons through the injury, while activated microglia release inflammatory mediators. The persistent inflammatory response can lead to local progressive cell death. Modulating the astrocyte and microglial response to traumatic injury therefore has potential therapeutic benefit in brain repair. We examine the modulatory effect of a single bolus of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in combination on astrocytes and microglia to acute cerebral injury. A combination of VEGF and PDGF (20 pg) was injected into the striatum of adult male Sprague-Dawley rats. The effects of treatment were assessed by quantitative immunofluorescence microscopy analyzing astrocytes and microglia across the stab injury over time. Treatment delayed the onset of astrogliosis in the centre and edge of the stab injury up to day 5; however, increased astrogliosis at areas remote to the stab injury up to day 5 was observed. A persistent astrocytic response was observed in the centre and edge of the stab injury up to day 60. Treatment altered microglia cell morphology and numbers across the stab injury, with a decrease in ramified microglia, but an increase in activated and phagocytic microglia up to day 5 after stab injury. The increased microglial response from 10 until day 60 was comprised of the ramified morphology. Thus, VEGF and PDGF applied at the same time as a stab injury to the brain initially delayed the inflammatory response up to day 5 but evoked a persistent astrogliosis and microglial response up to 60 days., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

An HPLC method to determine simultaneously ketoconazole and formaldehyde in an anti-dandruff shampoo, originally developed on a long column, was transferred to two short columns with similar stationary phase properties, but with a length of at the most 30% of the initial one. Using the conventional column as reference, the fast HPLC methods on the short columns were validated. The validation characteristics consisted of selectivity, linearity range, precision (repeatability and time-different intermediate precision), bias and robustness. For the ketoconazole assay, linearity for peak area was found in the concentration range up to 0.20 mg/ml. For formaldehyde, two calibration ranges (0-10 x 10(-5) and 0-10 x 10(-4)%) were linear, both for peak area and height. The assays for both ketoconazole and formaldehyde in these ranges showed no bias and an acceptable precision, although the precision found with the short columns was slightly worse than with the long one. The robustness tests were performed applying a Plackett-Burman design. For the ketoconazole assay, 6 factors were examined in a 12 experiments design and for formaldehyde, 11 factors in 16 experiments. The methods were found to be robust. Despite the somewhat less good precision the transfer seems to be successful and the obtained assays on the short columns are applicable for fast routine analysis.

The aim of this study was to analyze whether the intention to quit smoking was associated with other lifestyle habits healthy for the heart, namely a low-fat diet and regular exercise, using variables suggested by the theory of planned behavior. Self-administered postal questionnaires were sent to 3,200 men 30 to 60 years of age residing in Laval, Quebec. With a response rate of 70.9%, 671 respondents (29.6%) were smokers. A significant proportion (43%) had all three risk behaviors--smoking, a high-fat diet, and sedentariness, and 42% had two--smoking and one of the other behaviors. The remaining had a single risk behavior, namely smoking. Regression analysis suggested that a healthy diet and exercise had no significant influence on the intention to quit smoking. However, men who had a stronger intention to quit smoking than others had a more favorable attitude toward the behavior, a stronger perception of approval in achieving it on the part of important referents, stronger perceived behavioral control, and were among those who smoked fewer cigarettes per day, but had made more attempts to quit. These results can assist in designing better heart-health intervention programs for this high-risk population.