Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

Small body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2–24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2–4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2–4 months, at 10–12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75162/1/j.1474-9728.2002.00006.x.pd

Observation of metastable Aβ amyloid protofibrils by atomic force microscopy

AbstractBackground: Brain amyloid plaque, a diagnostic feature of Alzheimer's disease (AD), contains an insoluble fibrillar core that is composed primarily of variants of the β-amyloid protein (Aβ). As Aβ amyloid fibrils may initiate neurodegeneration, the inhibition of fibril formation is a possible therapeutic strategy. Very little is known about the early steps of the process, however.Results: Atomic force microscopy was used to follow amyloid fibril formation in vitro by the Aβ variants Aβ1-40 and Aβ1-42. Both variants first form small ordered aggregates that grow slowly and then rapidly disappear, while prototypical amyloid fibrils of two discrete morphologies appear. Aβ1-42 aggregates much more rapidly than Aβ1-40, which is consistent with its connection to early-onset AD. We propose that the metastable intermediate species be called Aβ amyloid protofibrils.Conclusions: Aβ protofibrils are likely to be intermediates in the in vitro assembly of Aβ amyloid fibrils, but their in vivo role has yet to be determined. Numerous reports of a nonfibrillar form of Aβ aggregate in the brains of individuals who are predisposed to AD suggest the existence of a precursor form, possibly the protofibril. Thus, stabilization of Aβ protofibrils may be a useful therapeutic strategy

The Care Programme Approach and the end of indefinitely renewable Leave of Absence in Scotland

ObjectiveTo consider the relationship between the restriction of leave of absence (LOA) to 12 months, the introduction of community care orders (CCOs) and the implementation of the Care Programme Approach (CPA).DesignMultiple methods were employed: scrutiny of Mental Welfare Commission for Scotland (MWC) records; questionnaire to consultant psychiatrists and mental health officers (MHOs) regarding attitudes; survey of psychiatrists in respect of outcomes for named patients.SettingScotlandSubjectsTwo hundred and sixty six patients who were affected by the changes introduced by the Mental Health (Patients in the Community) Act 1995.ResultsInformation was available for 195 (73%) patients in relation to CPA. Of these 113 (58%) were included on CPA and for 63/113 (56%) (63/195 (32%)) CPA was considered to have enhanced patient care.Where CPA was considered useful it was because it was seen as bringing people together, enhancing the patient’s role in treatment and managing difficult situations. Negative comments regarding CPA were that it was unnecessary as the patient’s needs were straightforward, it duplicated current practices or it was too bureaucratic.ConclusionsDespite concerns expressed by professionals about the restriction to LOA and the guidance that patients should be on CPA, for only a minority of patients was CPA described as enhancing care. Questions are raised about the low use of CCOs and CPA by psychiatrists for patients who reached the new limits of LOA

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.</p> <p>Methods</p> <p>Cardiac sympathetic nervous integrity was investigated <it>in vivo </it>via biodistribution of the positron emission tomography radiotracer and NE analogue [¹¹C]<it>meta-</it>hydroxyephedrine ([¹¹C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.</p> <p>Results</p> <p>The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [¹¹C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.</p> <p>Conclusions</p> <p>Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.</p

Solid epoxy resin systems for automated composite manufacturing

© 2020 The Author(s) Thermosetting resins were formulated by mixing solid epoxy components, hardener and accelerator at elevated temperature. These mixtures were ground into uncured, solid resin powders and dispensed onto carbon fibres using a powder printer prior to vacuum curing. Using accelerators reduced curing time from 8 h to 16 min. Manufactured cross-ply carbon fibre laminates (0°/90°/0°) had comparable mechanical properties to composites manufactured using a liquid resin system. Tack behaviour of solid epoxy resin formulations was investigated and results compared to a conventional liquid resin system. Master curves of the storage and loss moduli of both solid and liquid resin formulations were generated by applying time-temperature superposition to shear moduli between 1 and 100 rad/s at multiple temperatures. This approach was used to determine optimum processing parameters to enable resin tack for automated fibre placement, demonstrating the importance of temperature control with respect to deposition rates

9th Annual Seminar on Legal Issues for Financial Institutions

Outline of speakers\u27 presentations from the 9th Annual Seminar on Legal Issues for Financial Institutions held by UK/CLE on March 10-11, 1989

Unique Footprint in the scl1.3 Locus Affects Adhesion and Biofilm Formation of the Invasive M3-Type Group A Streptococcus

The streptococcal collagen-like proteins 1 and 2 (Scl1 and Scl2) are major surface adhesins that are ubiquitous among group A Streptococcus (GAS). Invasive M3-type strains, however, have evolved two unique conserved features in the scl1 locus: (i) an IS1548 element insertion in the scl1 promoter region and (ii) a nonsense mutation within the scl1 coding sequence. The scl1 transcript is drastically reduced in M3-type GAS, contrasting with a high transcription level of scl1 allele in invasive M1-type GAS. This leads to a lack of Scl1 expression in M3 strains. In contrast, while scl2 transcription and Scl2 production are elevated in M3 strains, M1 GAS lack Scl2 surface expression. M3-type strains were shown to have reduced biofilm formation on inanimate surfaces coated with cellular fibronectin and laminin, and in human skin equivalents. Repair of the nonsense mutation and restoration of Scl1 expression on M3-GAS cells, restores biofilm formation on cellular fibronectin and laminin coatings. Inactivation of scl1 in biofilm-capable M28 and M41 strains results in larger skin lesions in a mouse model, indicating that lack of Scl1 adhesin promotes bacterial spread over localized infection. These studies suggest the uniquely evolved scl1 locus in the M3-type strains, which prevents surface expression of the major Scl1 adhesin, contributed to the emergence of the invasive M3-type strains. Furthermore these studies provide insight into the molecular mechanisms mediating colonization, biofilm formation, and pathogenesis of group A streptococci

Conducting robust ecological analyses with climate data

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require

Specialist Peri-Operative Allergy Clinic Services in the UK 2016: Results from the Royal College of Anaesthetists Sixth National Audit Project (NAP6)

BACKGROUND: Guidelines for investigation of perioperative drug allergy exist, but the quality of services is unknown. Specialist perioperative anaphylaxis services were surveyed through the Royal College of Anaesthetists 6(th) National Audit Project. OBJECTIVES: We compare self-declared UK practice in specialist perioperative allergy services with national recommendations. METHODS: A SurveyMonkey(™) questionnaire was distributed to providers of allergy services in the UK. Responses were assessed for adherence to the best practice recommendations of the British Society for Allergy and Clinical Immunology, the Association of Anaesthetists of Great Britain and Ireland and the National Institute for Health and Care Excellence (NICE) Guidance on Drug Allergy - CG183. RESULTS: Over 1200 patients were evaluated in 44 centres annually. Variation in workload, waiting times, access, staffing and diagnostic approach was noted. Paediatric centres had the longest routine waiting times (most wait >13 weeks) in contrast to adult centres (most wait <12 weeks). Service leads are allergists/immunologists (91%) or anaesthetists (7%). Potentially important differences were seen in: testing repertoire [10/44 (23%) lacked BSACI compliant NMBA panels and 17/44 (39%) lacked a NAP6-defined extended panel; many failed to screen all cases for chlorhexidine 19/44 (43%) or latex 21/44 (48%)], staffing [only 26/44 (59%) had specialist nurses and 18/44 (41%) an anaesthetist], and provision of information [18/44 (41%) gave immediate information in clinic, and 5/44 (11%) on support groups]. Most centres were able to provide diagnostic challenges to antibiotics [40/44 (91%]) and local anaesthetics [41/44 (93%)]. CONCLUSIONS AND CLINICAL RELEVANCE: Diagnostic testing is not harmonised, with marked variability in the NMBA panels used to identify safe alternatives. Chlorhexidine and latex are not part of routine testing in many centres. Poor access to services and patient information provision require attention. Harmonisation of diagnostic approach is desirable, particularly with regard to a minimum NMBA panel for identification of safe alternatives. This article is protected by copyright. All rights reserved

Coupled evolution of temperature and carbonate chemistry during the Paleocene–Eocene; new trace element records from the low latitude Indian Ocean

This is the final version. Available on open access from Elsevier via the DOI in this recordThe early Paleogene represents the most recent interval in Earth’s history characterized by global greenhouse warmth on multi-million year timescales, yet our understanding of long-term climate and carbon cycle evolution in the low latitudes, and in particular the Indian Ocean, remains very poorly constrained. Here we present the first long-term sub-eccentricity-resolution stable isotope (δ13 30 C and δ 18 O) and trace element (Mg/Ca and B/Ca) records spanning the late Paleocene–early Eocene (~58– 53 Ma) across a surface–deep hydrographic reconstruction of the northern Indian Ocean, resolving late Paleocene 405-kyr paced cyclicity and a portion of the PETM recovery. Our new records reveal a long-term warming of ~4–5°C at all depths in the water column, with absolute surface ocean temperatures and magnitudes of warming comparable to the low latitude Pacific. As a result of warming, we observe a long-term increase in δ 18 Osw of the mixed layer, implying an increase in net evaporation. We also observe a collapse in the temperature gradient between mixed layer- and thermocline-dwelling species from ~57–54 Ma, potentially due to either the development of a more homogeneous water column with a thicker mixed layer, or depth migration of the Morozovella in response to warming. Synchronous warming at both low and high latitudes, along with decreasing B/Ca ratios in planktic foraminifera indicating a decrease in ocean pH and/or increasing dissolved inorganic carbon, suggest that global climate was forced by rising atmospheric CO2 concentrations during this time.European Consortium for Ocean Research Drilling (ECORD)International Association of Sedimentologists (IAS)NSFNatural Environment Research Council (NERC