Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress

Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1−/−) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls. In this study, we show that primary dermal fibroblasts and primary myoblasts derived from Irs1−/− mice are no more resistant to a range of oxidant and nonoxidant chemical stressors than cells derived from WT mice

Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice

The mechanistic target of rapamycin (mTOR) signalling pathway plays a highly conserved role in aging; mice lacking ribosomal protein S6 kinase 1 (S6K1-/-) have extended lifespan and healthspan relative to wild type (WT) controls. Exactly how reduced mTOR signalling induces such effects is unclear, although preservation of stem cell function may be important. We show, using gene expression analyses, that there was a reduction in expression of cell cycle genes in young (12 week) and aged (80 week) S6K1-/- BM-derived c-Kit+ cells when compared to age-matched WT mice, suggesting that these cells are more quiescent in S6K1-/- mice. In addition, we investigated hematopoietic stem cell (HSC) frequency and function in young and aged S6K1-/- and WT mice. Young, but not aged, S6K1-/- mice had more LSK (lineage-, c-Kit+, Sca-1+) cells (% of bone marrow (BM)), including the most primitive long-term repopulating HSC (LT-HSC) relative to WT controls. Donor-derived engraftment of LT-HSCs in recipient mice was unaffected by genotype in young mice, but was enhanced in transplants using LT-HSCs derived from aged S6K1-/- mice. Our results are the first to provide evidence that age-associated HSC functional decline is ameliorated in a long-lived mTOR mutant mouse

Is diagnostic tonsillectomy indicated in all children with asymmetrically enlarged tonsil?

Objectives. The aims of the study were: (i) to determine the necessity for diagnostic tonsillectomy in children with asymmetrically enlarged tonsils; (ii) to determine the accuracy of clinical assessment of tonsillar asymmetry; and (iii) to determine how to manage children with clinical tonsillar asymmetry in a developing-world practice. Methods. A prospective study was carried out at Red Cross War Memorial Children’s Hospital in Cape Town, over an 8-month period. All children undergoing tonsillectomy or adenotonsillectomy had a clinical assessment of tonsil symmetry done, and all tonsil and adenoid specimens were examined histologically. The maximum diameter and volume of the resected tonsils were measured. A comparison was done of true tonsil asymmetry in patients with asymmetrical tonsils and a subgroup of matched controls with symmetrical tonsils. Results. A total of 344 tonsils were analysed (172 patients). The 13 patients (7.6%) diagnosed as having clinically asymmetrically enlarged tonsils had no significant pathological diagnosis. In the patients with symmetrical tonsils there were abnormal pathological findings (tuberculosis of the adenoids and T-cell lymphoma of the tonsils and adenoids). In the clinically asymmetrical tonsil group, true tonsillar asymmetry was 3 mm (maximum diameter), and 2.2 cm3 (volume), compared with 1.9 mm and 1.5 cm3 in the symmetrical tonsil group. When patients with clinical tonsillar asymmetry and symmetry were compared, the difference in maximum diameter (p = 0.62) and volume (p = 0.73) was not significantly different. Conclusions. Clinical tonsillar asymmetry is usually apparent rather than real. The incidence of significant pathology in children with asymptomatic, asymmetrical tonsils is low. Diagnostic tonsillectomy is indicated in children with asymmetrically enlarged tonsils associated with constitutional symptoms, cervical lymphadenopathy, rapid tonsil enlargement or significant tonsillar asymmetry

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

Nasopharyngeal carriage of pneumococcus in children in England up to ten years after PCV13 introduction: persistence of serotypes 3 and 19A and emergence of 7C.

BACKGROUND: Monitoring changes in pharyngeal carriage of pneumococcus in children following 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the UK in 2010 informs understanding of patterns of invasive pneumococcal disease (IPD) incidence. METHODS: Nasopharyngeal swabs from healthy children vaccinated with PCV13 according to schedule (2, 4, 12 months) were cultured and serotyped. Results for children aged 13-48 months were compared between 2014/15 and 2017/19, and with children aged 6-12 months (2017/20). Blood was obtained from a subset of children for pneumococcal serotype-specific IgG. RESULTS: Total pneumococcal carriage at 13-48 months was 47.9% (473/988) in 2014/15 and 51.8% (412/795) in 2017/19 (p = 0.10); at age 6-12 months this value was 44.6% (274/615). In 2017/19, 2.9% (95% CI 1.8-4.3%) of children aged 13-48 months carried PCV13 serotypes (mainly 3 (1.5%) and 19A (0.8%)) and over 20% carried the additional PCV20 serotypes. Similar proportions of children had IgG ≥0.35 IU/mL for each serotype in 2014/15 and 2017/19.Serotype 7C carriage increased significantly (p < 0.01) between 2014/15 and 2017/19. Carriage of PCV20 serotypes 8 and 12F, both major causes of IPD, was rare. DISCUSSION: Introduction of PCV20, if licensed for children, could significantly change the composition of pneumococcal serotypes carried in the pharynx of UK children

Optical Atomic Clock Comparison through Turbulent Air

We use frequency comb-based optical two-way time-frequency transfer (O-TWTFT) to measure the optical frequency ratio of state-of-the-art ytterbium and strontium optical atomic clocks separated by a 1.5 km open-air link. Our free-space measurement is compared to a simultaneous measurement acquired via a noise-cancelled fiber link. Despite non-stationary, ps-level time-of-flight variations in the free-space link, ratio measurements obtained from the two links, averaged over 30.5 hours across six days, agree to $6\times10^{-19}$, showing that O-TWTFT can support free-space atomic clock comparisons below the $10^{-18}$ level

Accurate and Rapid Estimation of Phosphene Thresholds (REPT)

To calibrate the intensity of transcranial magnetic stimulation (TMS) at the occipital pole, the phosphene threshold is used as a measure of cortical excitability. The phosphene threshold (PT) refers to the intensity of magnetic stimulation that induces illusory flashes of light (phosphenes) on a proportion of trials. The existing PT estimation procedures lack the accuracy and mathematical rigour of modern threshold estimation methods. We present an improved and automatic procedure for estimating the PT which is based on the well-established Ψ Bayesian adaptive staircase approach. To validate the new procedure, we compared it with another commonly used procedure for estimating the PT. We found that our procedure is more accurate, reliable, and rapid when compared with an existing PT measurement procedure. The new procedure is implemented in Matlab and works automatically with the Magstim Rapid2 stimulator using a convenient graphical user interface. The Matlab program is freely available for download