Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies

Ecological correlates of elevational range shifts in tropical birds

Globally, birds have been shown to respond to climate change by shifting their elevational distributions. This phenomenon is especially prevalent in the tropics, where elevational gradients are often hotspots of diversity and endemism. Empirical evidence has suggested that elevational range shifts are far from uniform across species, varying greatly in the direction (upslope vs. downslope) and rate of change (speed of elevational shift). However, little is known about the drivers of these variable responses to climate change, limiting our ability to accurately project changes in the future. Here, we compile empirical estimates of elevational shift rates (m/yr) for 421 bird species from eight study sites across the tropics. On average, species shifted their mean elevations upslope by 1.63 ± 0.30 m/yr, their upper limits by 1.62 m ± 0.38 m/yr, and their lower limits by 2.81 ± 0.42 m/yr. Upslope shift rates increased in smaller-bodied, less territorial species, whereas larger species were more likely to shift downslope. When considering absolute shift rates, rates were fastest for species with high dispersal ability, low foraging strata, and wide elevational ranges. Our results indicate that elevational shift rates are associated with species’ traits, particularly body size, dispersal ability, and territoriality. However, these effects vary substantially across sites, suggesting that responses of tropical montane bird communities to climate change are complex and best predicted within the local or regional context

Deliquescence of NaCl–NaNO(3), KNO(3)–NaNO(3), and NaCl–KNO(3 )salt mixtures from 90 to 120°C

We conducted reversed deliquescence experiments in saturated NaCl–NaNO(3)–H(2)O, KNO(3)–NaNO(3)–H(2)O, and NaCl–KNO(3)–H(2)O systems from 90 to 120°C as a function of relative humidity and solution composition. NaCl, NaNO(3), and KNO(3 )represent members of dust salt assemblages that are likely to deliquesce and form concentrated brines on high-level radioactive waste package surfaces in a repository environment at Yucca Mountain, NV. Discrepancy between model prediction and experiment can be as high as 8% for relative humidity and 50% for dissolved ion concentration. The discrepancy is attributed primarily to the use of 25°C models for Cl–NO(3 )and K–NO(3 )ion interactions in the current Yucca Mountain Project high-temperature Pitzer model to describe the nonideal behavior of these highly concentrated solutions

Who bullies whom at a garden feeder? Interspecific agonistic interactions of small passerines during a cold winter

Interspecific agonistic interactions are important selective factors for maintaining ecological niches of different species, but their outcome is difficult to predict a priori. Here, we examined the direction and intensity of interspecific interactions in an assemblage of small passerines at a garden feeder, focussing on three finch species of various body sizes. We found that large and mediumsized birds usually initiated and won agonistic interactions with smaller species. Also, the frequency of fights increased with decreasing differences in body size between the participants. Finally, the probability of engaging in a fight increased with the number of birds at the feeder

Excited pions, rho- and omega-mesons and their decays in a chiral SU(2) x SU(2) Lagrangian

A chiral SU(2) x SU(2) Lagrangian containing, besides the usual meson fields, their first radial excitations is considered. The Lagrangian is derived by bosonization of the Nambu-Jona-Lasinio quark model with separable non-local interactions, with form factors corresponding to 3-dimensional ground and excited state wave functions. The spontaneous breaking of chiral symmetry is governed by the NJL gap equation. The first radial excitations of the pions, rho-and omega-mesons are described with the help of two form factors. The weak decay constant F_pi' is calculated. The values for the decay widths of the processes rho -> 2 pi, pi' -> rho pi, rho' -> 2 pi, rho' -> omega pi and omega' -> rho pi are obtained in agreement with the experimental data.Comment: 16 pages, Latex, epsfi

British industrial relations pluralism in the era of neoliberalism

This article provides a broad overview of the pluralist tradition in UK industrial relations scholarship, identifying its defining characteristics and mapping its evolution in recent decades. It deals in turn with the following: the appreciation of the relative interests of workers and employers that lies at the heart of the pluralist frame of reference, the research agenda that flows from this understanding, pluralist conceptions of context and agency within industrial relations, the standards that pluralists habitually use when assessing the employment relationship, the targets and modes of critique that pluralists direct against intellectual opponents, and the prescriptions that pluralists offer for industrial relations reform. Throughout the article there is a focus on change within the pluralist tradition and the manner in which it has adapted to the hegemony of neoliberalism in the realms of both ideas and policy

Losartan to slow the progression of mild-to-moderate Alzheimer's disease through angiotensin targeting: the RADAR RCT

BACKGROUND: Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. OBJECTIVE: This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo. DESIGN: A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months. SETTING: Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland. PARTICIPANTS: Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions. INTERVENTION: The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months. MAIN OUTCOMES AND MEASURES: Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability. RESULTS: A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (n = 105) or placebo (n = 106) arms. Of the 197 people (93%) who completed the study, 81% (n = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p = 0.19), and there was no evidence of benefit for any of the secondary outcome measures. LIMITATIONS: Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes. CONCLUSIONS: Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease. FUTURE WORK: Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 19. See the NIHR Journals Library website for further project information

The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast

The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. © 2013 Wysocka-Kapcinska et al

Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial

BACKGROUND: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease. METHODS: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed. FINDINGS: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group. INTERPRETATION: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods. FUNDING: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research)

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g