Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease

The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer's disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of beta-amyloid (Abeta(1-42)), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of Abeta(1-42) (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal Abeta(1-42) implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to Abeta(1-42)-mediated neurodegeneration.     

Occupational therapy for patients with problems in personal activities of daily living after stroke: systematic review of randomised trials

Objective To determine whether occupational therapy focused specifically on personal activities of daily living improves recovery for patients after stroke.Design Systematic review and meta-analysis.Data sources The Cochrane stroke group trials register, the Cochrane central register of controlled trials, Medline, Embase, CINAHL, PsycLIT, AMED, Wilson Social Sciences Abstracts, Science Citation Index, Social Science Citation, Arts and Humanities Citation Index, Dissertations Abstracts register, Occupational Therapy Research Index, scanning reference lists, personal communication with authors, and hand searching.Review methods Trials were included if they evaluated the effect of occupational therapy focused on practice of personal activities of daily living or where performance in such activities was the target of the occupational therapy intervention in a stroke population. Original data were sought from trialists. Two reviewers independently reviewed each trial for methodological quality. Disagreements were resolved by consensus.Results Nine randomised controlled trials including 1258 participants met the inclusion criteria. Occupational therapy delivered to patients after stroke and targeted towards personal activities of daily living increased performance scores (standardised mean difference 0.18, 95% confidence interval 0.04 to 0.32, P=0.01) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio 0.67, 95% confidence interval 0.51 to 0.87, P=0.003). For every 100 people who received occupational therapy focused on personal activities of daily living, 11 (95% confidence interval 7 to 30) would be spared a poor outcome.Conclusions Occupational therapy focused on improving personal activities of daily living after stroke can improve performance and reduce the risk of deterioration in these abilities. Focused occupational therapy should be available to everyone who has had a stroke.     

Anadromous sea lampreys (Petromyzon marinus) are ecosystem engineers in a spawning tributary

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Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction

Introduction

Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.

Methods

Antigen-induced arthritis (AIA) was established in IL-10KO mice and wild-type controls. Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies, we explored the regulation of inflammasome components. These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays.

Results

In AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores. Here, focal bone erosions were associated with increased tartrate-resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1β. When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components. Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1. In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis.

Conclusions

These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0419-y) contains supplementary material, which is available to authorized users.     

Clinical,Immunological and Treatment-Related Factors Associated with Normalised CD4+/CD8+ T-Cell Ratio: Effect of Na?ve and Memory T-Cell Subsets

Background

Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

Methods

A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

Results

We recruited 190 subjects, age 42(36–48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6–10.2) years. Nadir and current CD4+ counts were 200(112–309) and 465(335–607) cells/mm³ respectively. Median CD4+/CD8+ ratio was 0.6(0.4–1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0–38.3)% were naïve, 36.8(29.0–40.0)% central memory and 27.4(20.0–38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2–25.5)% were naïve, 19.9(12.7–26.6)% central memory and 41.0(31.8–52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0–36.0)% versus 14.4(9.4–21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5–567) versus 765(603–1084) cells/mm³, p<0.001.

Conclusions

Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.     

Preventing falls in older adults: new interventions to promote more effective change-in-support balance reactions.

"Change-in-support" (CIS) balance-recovery reactions that involve rapid stepping or reaching movements play a critical role in preventing falls; however, age-related deficits in the neuro-musculoskeletal systems may impede ability to execute these reactions effectively. This review describes four new interventions aimed at reducing fall risk in older adults by promoting more effective CIS reactions: (1) balance training, (2) balance-enhancing footwear, (3) safer mobility aids, and (4) handrail cueing systems. The training program uses unpredictable support-surface perturbations to counter specific CIS control problems associated with aging and fall risk. Pilot testing has demonstrated that the program is well-tolerated by balance-impaired older adults, and a randomized controlled trial is now in progress. The balance-enhancing footwear insole improves control of stepping reactions by compensating for age-related loss of plantar cutaneous sensation. In a clinical trial, subjects wore the insole for 12 weeks with no serious problems and no habituation of the balance-enhancing benefits. The mobility-aid intervention involves changes to the design of pickup walkers so as to reduce impediments to lateral stepping. Finally, work is underway to investigate the effectiveness of handrail cueing in attracting attention to the rail and ensuring that the brain registers its location, thereby facilitating more rapid and accurate grasping.     

nGASP – the nematode genome annotation assessment project

Background  

While the C. elegans genome is extensively annotated, relatively little information is available for other Caenorhabditis species. The nematode genome annotation assessment project (nGASP) was launched to objectively assess the accuracy of protein-coding gene prediction software in C. elegans, and to apply this knowledge to the annotation of the genomes of four additional Caenorhabditis species and other nematodes. Seventeen groups worldwide participated in nGASP, and submitted 47 prediction sets across 10 Mb of the C. elegans genome. Predictions were compared to reference gene sets consisting of confirmed or manually curated gene models from WormBase.     

Community size structure varies with predator–prey size relationships and temperature across Australian reefs

Climate change and fisheries exploitation are dramatically changing the abundances, species composition, and size spectra of fish communities. We explore whether variation in ‘abundance size spectra’, a widely studied ecosystem feature, is influenced by a parameter theorized to govern the shape of size‐structured ecosystems—the relationship between the sizes of predators and their prey (predator–prey mass ratios, or PPMRs). PPMR estimates are lacking for avast number of fish species, including at the scale of trophic guilds. Using measurements of 8128 prey items in gut contents of 97 reef fish species, we established predator–prey mass ratios (PPMRs) for four major trophic guilds (piscivores, invertivores, planktivores, and herbivores) using linear mixed effects models. To assess the theoretical predictions that higher community‐level PPMRs leads to shallower size spectrum slopes, we compared observations of both ecosystem metrics for ~15,000 coastal reef sites distributed around Australia. PPMRs of individual fishes were remarkably high (median ~71,000), with significant variation between different trophic guilds (~890 for piscivores; ~83,000 for planktivores), and ~8700 for whole communities. Community‐level PPMRs were positively related to size spectrum slopes, broadly consistent with theory, however, this pattern was also influenced by the latitudinal temperature gradient. Tropical reefs showed a stronger relationship between community‐level PPMRs and community size spectrum slopes than temperate reefs. The extent that these patterns apply outside Australia and consequences for community structure and dynamics are key areas for future investigation.     

Numerical simulation of arterial dissection during balloon angioplasty of atherosclerotic coronary arteries

Balloon angioplasty is a standard clinical treatment for symptomatic coronary artery disease. In this procedure, controlled damage is applied intraluminally to the wall of a stenotic artery. Dissection of the coronary artery is a commonly observed clinical complication of angioplasty; however, not all dissections can be detected angioscopically. This work focuses on studying the dissection mechanisms triggered during the early stages of angioplasty in an atherosclerotic coronary artery, addressing the problem by means of a parametric study based on a simplified finite element model and cohesive interface modeling. Our results emphasize the presence of several damage mechanisms, at different locations, that are triggered near the very beginning of the process and evolve competitively, depending on both geometry and material properties of the atherosclerotic vessel. Small-scale damage was evidenced, which would not be detectable by angiography or intravascular ultrasound, but could potentially be sufficient to stimulate smooth muscle cell activation, promoting late-onset complications such as restenosis.