Exhausted CD4⁺ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4⁺ T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4⁺ T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4⁺ T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4+ T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4⁺ T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4⁺ T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4⁺ T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4⁺ T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4⁺ T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4⁺ T cells during malaria infection and other chronic conditions

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

The first legal mortgagor: a consumer without adequate protection?

This article contends that the UK government’s attempt to create a well-functioning consumer credit market will be undermined if it fails to reform the private law framework relating to the first legal mortgage. Such agreements are governed by two distinct regulatory regimes that are founded upon very different conceptions of the mortgagor. The first, the regulation of financial services overseen by the Financial Conduct Authority, derives from public law and is founded upon a conception of the mortgagor as “consumer”. The other is land law, private law regulation implemented by the judiciary and underpinned by a conception of the mortgagor as “landowner”. Evidence suggests that the operation of these two regimes prevents mortgagors from receiving fair and consistent treatment. The current reform of financial services regulation therefore will change only one part of this governance regime and will leave mortgagors heavily reliant upon a regulator that still has to prove itself. What this article argues is that reform of the rules of private law must also be undertaken with the aim of initiating a paradigm shift in the conception of the mortgagor from “landowner” to “consumer”. Cultural shifts of this kind take time but the hope is that this conceptual transformation will occur in time to deter the predicted rise in mortgage possessions

Evolution of the Thrombolytic Treatment Window for Acute Ischemic Stroke

Ischemic stroke is a major cause of morbidity and mortality for which the only approved treatment in the acute setting is intravenous thrombolysis. The efficacy and safety of recombinant tissue plasminogen activator (rt-PA) have been firmly established within 3 h of symptom onset; however, few patients are eligible for treatment in this time window. Expanding the time for treatment has been challenging, but new evidence has demonstrated a modest statistical improvement in selected patients when rt-PA is administered within 4.5 h. This important finding hopefully will enable more patients to receive treatment and simultaneously provides an opportunity to reaffirm that the benefits of rt-PA diminish with time

Novel image–novel location object recognition task sensitive to age-related cognitive decline in nondemented elderly

Traditional tests used in the clinic to identify dementia, such as the mini-mental state examination (MMSE), are useful to identify severe cognitive impairments but might be less sensitive to detect more subtle age-related cognitive changes. Previously, the novel image–novel location (NINL) object recognition test was shown to be sensitive to detect effects of apolipoprotein E4, a risk factor for developing age-related cognitive decline and Alzheimer’s disease, in nondemented elderly. In the present longitudinal study, performance on the MMSE and the NINL tests were compared over a 4-year period. Individual NINL scores over this period were highly correlated. In addition, while MMSE scores did not change over the 4-year period, NINL scores did. In a final testing session of a subset of the participants, NINL scores correlated with logical memory and word recall lists, cognitive tasks used to detect dementia in the clinic, as well as clinical dementia rating scales. These results support that the NINL might be a valuable tool to assess age-related cognitive decline

Cigarette smoking, health status, socio-economic status and access to health care in diabetes mellitus: a cross-sectional survey

BACKGROUND: In diabetes mellitus, cigarette smoking is associated with increased risk of cardiovascular mortality and microvascular complications. We evaluated cigarette smoking in people with diabetes mellitus in a socio-economically deprived area. METHODS: We carried out a cross-sectional survey of people registered with diabetes mellitus at 29 general practices in inner London. Responses were analysed for 1,899 (64%) respondents out of 2,983 eligible. RESULTS: There were 1,899 respondents of whom 968 (51%) had never smoked, 296 (16%) were current smokers and 582 (31%) were ex-smokers. Smoking was more frequent in white Europeans (men 22%, women 20%), than in African Caribbeans (men 15%, women 10%) or Africans (men 8%, women 2%). Smoking prevalence decreased with age. Smokers were more likely to be living in rented accommodation (odds ratio, OR 2.02, 95% confidence interval 1.48 to 2.74). After adjusting for confounding, current smokers had lower SF-36 scores than subjects who had never smoked (mean difference in physical functioning score -5.6, 95% confidence interval -10.0 to -1.2; general health -6.1, -9.7 to -2.5). Current smokers were less likely to have attended a hospital diabetic clinic in the last year (OR 0.59, 0.44 to 0.79), and their hypertension was less likely to be treated (OR 0.47, 0.30 to 0.74). CONCLUSIONS: Compared with non-smokers, smokers had lower socio-economic status and worse health status, but were less likely to be referred to hospital or treated for their hypertension. People with diabetes who smoke can be regarded as a vulnerable group who need more intensive support and treatment

Modeling Routes of Chronic Wasting Disease Transmission: Environmental Prion Persistence Promotes Deer Population Decline and Extinction

Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R0, may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress

Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development. Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions. Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing

Genome-Wide Linkage Analysis of Global Gene Expression in Loin Muscle Tissue Identifies Candidate Genes in Pigs

BACKGROUND: Nearly 6,000 QTL have been reported for 588 different traits in pigs, more than in any other livestock species. However, this effort has translated into only a few confirmed causative variants. A powerful strategy for revealing candidate genes involves expression QTL (eQTL) mapping, where the mRNA abundance of a set of transcripts is used as the response variable for a QTL scan. METHODOLOGY/PRINCIPAL FINDINGS: We utilized a whole genome expression microarray and an F(2) pig resource population to conduct a global eQTL analysis in loin muscle tissue, and compared results to previously inferred phenotypic QTL (pQTL) from the same experimental cross. We found 62 unique eQTL (FDR <10%) and identified 3 gene networks enriched with genes subject to genetic control involved in lipid metabolism, DNA replication, and cell cycle regulation. We observed strong evidence of local regulation (40 out of 59 eQTL with known genomic position) and compared these eQTL to pQTL to help identify potential candidate genes. Among the interesting associations, we found aldo-keto reductase 7A2 (AKR7A2) and thioredoxin domain containing 12 (TXNDC12) eQTL that are part of a network associated with lipid metabolism and in turn overlap with pQTL regions for marbling, % intramuscular fat (% fat) and loin muscle area on Sus scrofa (SSC) chromosome 6. Additionally, we report 13 genomic regions with overlapping eQTL and pQTL involving 14 local eQTL. CONCLUSIONS/SIGNIFICANCE: Results of this analysis provide novel candidate genes for important complex pig phenotypes