MPTP Neurotoxicity and Testosterone Induce Dendritic Remodeling of Striatal Medium Spiny Neurons in the C57Bl/6 Mouse

Nigrostriatal damage is increased in males relative to females. While estrogen is neuroprotective in females, less is known about potential protective effects of testosterone in males. We determined if castration enhances neuronal injury to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Castrates or sham-castrated mice were sacrificed 1 week following injection of MPTP (4 × 20 mg/kg) or saline (n = 11-12/group). The right striatum was immunostained for tyrosine hydroxylase (TH). The left hemisphere was stained by Golgi Cox to quantify neuronal morphology in medium spiny neurons (MSNs) of the dorsolateral striatum. MPTP reduced TH, but there was no effect of castration and no interaction. For MSN dendritic morphology, MPTP decreased the highest branch order and increased spine density on 2nd-order dendrites. Castrated males had shorter 5th-order dendrites. However, there was no interaction between gonadal status and MPTP. Thus, castration and MPTP exert nonoverlapping effects on MSN morphology with castration acting on distal dendrites and MPTP acting proximally

Sexual Differentiation of the Surge Mode of Gonadotropin Secretion: Prenatal Androgens Abolish the Gonadotropin‐Releasing Hormone Surge in the Sheep

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106142/1/j.1365-2826.1996.tb00698.x.pd

Entrainment of the Melatonin Rhythms in Early Postnatal Lambs and Their Mothers

Although the developing sheep can produce an appropriately timed melatonin rhythm as early as 1 week after birth, it is not known whether the lamb is able to adjust its melatonin rhythm to a change in daylength. The ability of the young lamb to entrain its pattern of melatonin secretion to a new photoperiod was determined in the present study. Eight female lambs and their mothers were raised in long days (LD 16:8) beginning 2 weeks post partum. At 7 weeks of age, the time of lights-off was advanced 8 hr, the short-day photoperiod then being LD 8:16; the time of lights-on remained unchanged. Concentrations of melatonin were measured in blood samples collected hourly on days - 1, 0, 2, 4, 6, and 13 relative to the light change. On day 0, all mothers and daughters had advanced the onset of melatonin secretion by at least 1 hr, and by day 13, 12 of 16 had completely entrained to the new photoperiod. The rate of entrainment among individuals varied; the mean rate for lambs and mothers did not differ. This study provides evidence that the melatonin-rhythm-generating system matures shortly after birth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68290/2/10.1177_074873048900400405.pd

An observational study of patient characteristics associated with the mode of admission to acute stroke services in North East, England

Objective Effective provision of urgent stroke care relies upon admission to hospital by emergency ambulance and may involve pre-hospital redirection. The proportion and characteristics of patients who do not arrive by emergency ambulance and their impact on service efficiency is unclear. To assist in the planning of regional stroke services we examined the volume, characteristics and prognosis of patients according to the mode of presentation to local services. Study design and setting A prospective regional database of consecutive acute stroke admissions was conducted in North East, England between 01/09/10-30/09/11. Case ascertainment and transport mode were checked against hospital coding and ambulance dispatch databases. Results Twelve acute stroke units contributed data for a mean of 10.7 months. 2792/3131 (89%) patients received a diagnosis of stroke within 24 hours of admission: 2002 arrivals by emergency ambulance; 538 by private transport or non-emergency ambulance; 252 unknown mode. Emergency ambulance patients were older (76 vs 69 years), more likely to be from institutional care (10% vs 1%) and experiencing total anterior circulation symptoms (27% vs 6%). Thrombolysis treatment was commoner following emergency admission (11% vs 4%). However patients attending without emergency ambulance had lower inpatient mortality (2% vs 18%), a lower rate of institutionalisation (1% vs 6%) and less need for daily carers (7% vs 16%). 149/155 (96%) of highly dependent patients were admitted by emergency ambulance, but none received thrombolysis. Conclusion Presentations of new stroke without emergency ambulance involvement were not unusual but were associated with a better outcome due to younger age, milder neurological impairment and lower levels of pre-stroke dependency. Most patients with a high level of pre-stroke dependency arrived by emergency ambulance but did not receive thrombolysis. It is important to be aware of easily identifiable demographic groups that differ in their potential to gain from different service configurations

Risk assessment for hospital admission in patients with COPD; a multi-centre UK prospective observational study.

In chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD requiring hospital admission is associated with mortality and healthcare costs. The ERICA study assessed multiple clinical measures in people with COPD, including the short physical performance battery (SPPB), a simple test of physical function with 3 components (gait speed, balance and sit-to-stand). We tested the hypothesis that SPPB score would relate to risk of hospital admissions and length of hospital stay. Data were analysed from 714 of the total 729 participants (434 men and 280 women) with COPD. Data from this prospective observational longitudinal study were obtained from 4 secondary and 1 tertiary centres from England, Scotland, and Wales. The main outcome measures were to estimate the risk of hospitalisation with acute exacerbation of COPD (AECOPD and length of hospital stay derived from hospital episode statistics (HES). In total, 291 of 714 individuals experienced 762 hospitalised AECOPD during five-year follow up. Poorer performance of SPPB was associated with both higher rate (IRR 1.08 per 1 point decrease, 95% CI 1.01 to 1.14) and increased length of stay (IRR 1.18 per 1 point decrease, 95% CI 1.10 to 1.27) for hospitalised AECOPD. For the individual sit-to-stand component of the SPPB, the association was even stronger (IRR 1.14, 95% CI 1.02 to 1.26 for rate and IRR 1.32, 95% CI 1.16 to 1.49 for length of stay for hospitalised AECOPD). The SPPB, and in particular the sit-to-stand component can both evaluate the risk of H-AECOPD and length of hospital stay in COPD. The SPPB can aid in clinical decision making and when prioritising healthcare resources

Gene-obesogenic environment interactions in the UK Biobank study

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). METHODS: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a 'Westernized' diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. RESULTS: We found gene-environment interactions with TDI (Pinteraction = 3 × 10(-10)), self-reported TV watching (Pinteraction = 7 × 10(-5)) and self-reported physical activity (Pinteraction = 5 × 10(-6)). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. CONCLUSIONS: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. Of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible.J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). A.R.W., H.Y. and T.M.F. are supported by the European Research Council grant: 323195:SZ-245 50371- GLUCOSEGENES-FP7-IDEAS-ERC. R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. R.M.A is supported by the Wellcome Trust Institutional Strategic Support Award (WT105618MA). Z.K. is funded by Swiss National Science Foundation (31003A-143914). The funders had no influence on study design, data collection and analysis, decision to publish or preparation of the manuscript. The data reported in this paper are available via application directly to the UK Biobank

Implementation of U.K. Earth system models for CMIP6

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere-land-ocean-sea ice model HadGEM3-GC3.1 and the Earth system model UKESM1 which adds a carbon-nitrogen cycle and atmospheric chemistry to HadGEM3-GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions.We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3-GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation.We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Cosmological constraints combining H(z), CMB shift and SNIa observational data

Recently H(z) data obtained from differential ages of galaxies have been proposed as a new geometrical probe of dark energy. In this paper we use those data, combined with other background tests (CMB shift and SNIa data), to constrain a set of general relativistic dark energy models together with some other models motivated by extra dimensions. Our analysis rests mostly on Bayesian statistics, and we conclude that LCDM is at least substantially favoured, and that braneworld models are less favoured than general relativistic ones.Comment: 17 pages, 11 figures; improved discussion, new figures, updated to match published versio

British Torture in the 'War on Terror'

Despite longstanding allegations of UK involvement in prisoner abuse during counterterrorism operations as part of the US-led ‘war on terror’, a consistent narrative emanating from British government officials is that Britain neither uses, condones nor facilitates torture or other cruel, inhuman, degrading treatment and punishment. We argue that such denials are untenable. We have established beyond reasonable doubt that Britain has been deeply involved in post-9/11 prisoner abuse, and we can now provide the most detailed account to date of the depth of this involvement. We argue that it is possible to identify a peculiarly British approach to torture in the ‘war on terror’, which is particularly well-suited to sustaining a narrative of denial. To explain the nature of UK involvement, we argue that it can be best understood within the context of how law and sovereign power have come to operate during the ‘war on terror’. We turn here to the work of Judith Butler, and explore the role of Britain as a ‘petty sovereign’, operating under the state of exception established by the US Executive. UK authorities have not themselves suspended the rule of law so overtly, and indeed have repeatedly insisted on their commitment to it. They have nevertheless been able to construct a rhetorical, legal and policy ‘scaffold’ that has enabled them to demonstrate at least procedural adherence to human rights norms, while at the same time allowing UK officials to acquiesce in the arbitrary exercise of sovereignty over individuals who are denied any access to appropriate representation or redress in compliance with the rule of law