Pattern of access to cafeteria-style diet determines fat mass and degree of spatial memory impairments in rats.

Repeated 'cycling' between healthy and unhealthy eating is increasingly common but the effects of such cycling on cognitive function are unknown. Here we tested the effects of cycling between chow and a cafeteria diet (CAF) rich in saturated fat and refined carbohydrates on fat mass and place recognition memory in rats. Rats fed the chow diet (control group) were compared with groups fed CAF for either: 3 consecutive days per week followed by 4 days of chow, (3CAF:4CHOW group); 5 consecutive days per week followed by 2 days of chow (5CAF:2CHOW group); or 7 days per week (7CAF group). Total days of exposure to CAF were matched between the latter groups by staggering the introduction of CAF diet. After 16-18 days of CAF, spatial recognition memory was significantly worse in the 7CAF group relative to controls. After 23-25 days of CAF, both the 7CAF and 5CAF:2CHOW groups, but not the 3CAF:4CHOW group, were impaired relative to controls, mirroring changes in fat mass measured by EchoMRI. CAF feeding did not affect object recognition memory or total exploration time. These results indicate that even when matching total exposure, the pattern of access to unhealthy diets impairs spatial memory in a graded fashion

Male Rat Offspring Are More Impacted by Maternal Obesity Induced by Cafeteria Diet than Females-Additive Effect of Postweaning Diet.

Maternal obesity increases the risk of health complications in offspring, but whether these effects are exacerbated by offspring exposure to unhealthy diets warrants further investigation. Female Sprague-Dawley rats were fed either standard chow (n = 15) or 'cafeteria' (Caf, n = 21) diets across pre-pregnancy, gestation, and lactation. Male and female offspring were weaned onto chow or Caf diet (2-3/sex/litter), forming four groups; behavioural and metabolic parameters were assessed. At weaning, offspring from Caf dams were smaller and lighter, but had more retroperitoneal (RP) fat, with a larger effect in males. Maternal Caf diet significantly increased relative expression of ACACA and Fasn in male and female weanling liver, but not CPT-1, SREBP and PGC1; PPARα was increased in males from Caf dams. Maternal obesity enhanced the impact of postweaning Caf exposure on adult body weight, RP fat, liver mass, and plasma leptin in males but not females. Offspring from Caf dams appeared to exhibit reduced anxiety-like behaviour on the elevated plus maze. Hepatic CPT-1 expression was reduced only in adult males from Caf fed dams. Post weaning Caf diet consumption did not alter liver gene expression in the adult offspring. Maternal obesity exacerbated the obesogenic phenotype produced by postweaning Caf diet in male, but not female offspring. Thus, the impact of maternal obesity on adiposity and liver gene expression appeared more marked in males. Our data underline the sex-specific detrimental effects of maternal obesity on offspring

Neisseria meningitidis serogroup C sepsis and septic arthritis in an HIV-positive man

A patient with well-controlled HIV-1 infection presented with fever and rigors, a widespread maculopapular rash, and severe generalised arthralgia. Sepsis of unknown aetiology was diagnosed, and treatment with broad-spectrum antimicrobials commenced. Following initial clinical improvement, a right knee septic arthritis developed. Microscopy and culture of the joint aspirate were negative for organisms but 16S rDNA PCR identified Neisseria meningitidis DNA, subsequently verified as capsular genogroup C, thus confirming a diagnosis of disseminated meningococcal sepsis with secondary septic arthritis

Comparison of growth patterns in healthy dogs and dogs in abnormal body condition using growth standards

In dogs, optimal growth is critical for future health and wellbeing. Recently, a series of evidence-based growth standards, based on bodyweight, were developed for male and female dogs across 5 different size categories. The aim of the current study was to compare growth curves depicted by the standards with patterns of growth in dogs that were either healthy, had abnormal body condition, or had various diseases with the potential to affect growth. The data came from 2 research colonies in Europe (France and UK), and a large corporate network of primary care veterinary hospitals across the USA. Age and bodyweight data were used to model growth in healthy dogs, in dogs that became overweight or underweight by 3 years of age, and in dogs with diseases associated with altered growth. Centile line crossing during the growth phase was uncommon in healthy dogs, with 2 centile lines. In contrast, centile line crossing was more frequent in dogs with abnormal growth patterns or abnormal body condition. Dogs that developed obesity by 3 years grew faster than the growth standards predicted, and 68% crossed ≥2 centile lines in an upwards direction. Dogs with conditions associated with accelerated growth also grew faster than expected, and 54% crossed ≥2 centile lines. In contrast dogs that became underweight by 3 years gained weight slower than expected, and 49% crossed ≥2 centile lines in a downwards direction. These results suggest that the growth standards are useful for monitoring healthy growth in dogs. Prospective studies are now required to confirm these findings and to determine whether early intervention can prevent the development of diseases

Comparison of two interferon-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) in testing for latent tuberculosis infection among HIV-infected adults.

There is currently no 'gold standard' for diagnosis of latent tuberculosis infection (LTBI), and both the tuberculin skin test and interferon-gamma release assays (IGRAs) are used for diagnosis; the latter have a higher sensitivity than tuberculin skin tests for diagnosis of LTBI in HIV-infected individuals with lower CD4 counts. No evidence base exists for selection of IGRA methodology to identify LTBI among human immunodeficiency virus-infected patients in the UK. We prospectively evaluated two commercially available IGRA methods (QuantiFERON-TB Gold In Tube [QFG] and T-SPOT.TB) for testing LTBI among HIV-infected patients potentially nosocomially exposed to an HIV-infected patient with 'smear-positive' pulmonary tuberculosis. Among the exposed patients median CD4 count was 550 cells/µL; 105 (90%) of 117 were receiving antiretroviral therapy, of who 104 (99%) had an undetectable plasma HIV load. IGRAs were positive in 12 patients (10.3%); QFG positive in 11 (9.4%) and T-SPOT.TB positive in six (5.1%); both IGRAs were positive in five patients (4.3%). There was one indeterminate QFG and one borderline T-SPOT.TB result. Concordance between the two IGRAs was moderate (κ = 0.56, 95% confidence interval = 0.27-0.85). IGRAs were positive in only 4 (29%) of 14 patients with previous culture-proven tuberculosis. No patient developed tuberculosis during 20 months of follow-up

Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV

Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis.

BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB. METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection. RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1-negative individuals, and 0.85 in HIV-1-infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1. CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever. FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.This work was supported by a Medical Research Council Fellowship to JR (MR/L001756/1) and Wellcome Trust Fellowship to EG (107311/Z/15/Z), the Rosetrees Trust, the British Lung Foundation (TB05/11), and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Holocene vegetation dynamics of circum-Arctic permafrost peatlands

Vegetation shifts in circum-Arctic permafrost peatlands drive feedbacks with important consequences for peatland carbon budgets and the extent of permafrost thaw under changing climate. Recent shrub expansion across Arctic tundra environments has led to an increase in above-ground biomass, but the long-term spatiotemporal dynamics of shrub and tree growth in circum-Arctic peatlands remain unquantified. We investigate changes in peatland vegetation composition during the Holocene using previously-published plant macrofossil records from 76 sites across the circum-Arctic permafrost zone. In particular, we assess evidence for peatland shrubification at the continental scale. We identify increasing abundance of woody vegetation in circum-Arctic peatlands from ∼8000 years BP to present, coinciding with declining herbaceous vegetation and widespread Sphagnum expansion. Ecosystem shifts varied between regions and present-day permafrost zones, with late-Holocene shrubification most pronounced where permafrost coverage is presently discontinuous and sporadic. After ∼600 years BP, we find a proliferation of non-Sphagnum mosses in Fennoscandia and across the present-day continuous permafrost zone; and rapid expansion of Sphagnum in regions of discontinuous and isolated permafrost as expected following widespread fen-bog succession, which coincided with declining woody vegetation in eastern and western Canada. Since ∼200 years BP, both shrub expansion and decline were identified at different sites across the pan-Arctic, highlighting the complex ecological responses of circum-Arctic peatlands to post-industrial climate warming and permafrost degradation. Our results suggest that shrubification of circum-Arctic peatlands has primarily occurred alongside surface drying, resulting from Holocene climate shifts, autogenic peat accumulation, and permafrost aggradation. Future shrubification of circum-Arctic peatlands under 21st century climate change will likely be spatially heterogeneous, and be most prevalent where dry microforms persist

Modulation of gene-specific epigenetic states and transcription by non-coding RNAs

Emerging evidence points to a role for long non-coding RNAs in the modulation of epigenetic states and transcription in human cells. New insights, using various forms of small non-coding RNAs, suggest that a mechanism of action is operative in human cells, which utilizes non-coding RNAs to direct epigenetic marks to homology containing loci resulting ultimately in the epigenetic-based modulation of gene transcription. Importantly, insights into this mechanism of action have allowed for certain target sequences, which are either actively involved in RNA mediated epigenetic regulation or targets for non-coding RNA based epigenetic regulation, to be selected. As such, it is now feasible to utilize small antisense RNAs to either epigenetically silence a gene expression or remove epigenetic silencing of endogenous non-coding RNAs and essentially turn on a gene expression. Knowledge of this emerging RNA-based epigenetic regulatory network and our ability to cognitively control gene expression has deep implications in the development of an entirely new area of pharmacopeia

Synthesis of Sulfur-Substituted Bicyclo[1.1.1]pentanes by Iodo-Sulfenylation of [1.1.1]Propellane.

Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture