Saltmarsh plant responses to eutrophication

In saltmarsh plant communities, bottom-up pressure from nutrient enrichment is predicted to increase productivity, alter community structure, decrease biodiversity, and alter ecosystem functioning. Previous work supporting these predictions has been based largely on short-term, plot-level (e.g., 1-300 m(2)) studies, which may miss landscape-level phenomena that drive ecosystem-level responses. We implemented an ecosystem-scale, nine-year nutrient experiment to examine how saltmarsh plants respond to simulated conditions of coastal eutrophication. Our study differed from previous saltmarsh enrichment studies in that we applied realistic concentrations of nitrate (70-100 mu M NO3-), the most common form of coastal nutrient enrichment, via tidal water at the ecosystem scale (similar to 60,000 m(2) creeksheds). Our enrichments added a total of 1,700 kg N.creek(-1).yr(-1), which increased N loading 10-fold vs. reference creeks (low-marsh, 171 g N.m(-2).yr(-1); high-marsh, 19 g N.m(-2).yr(-1)). Nutrients increased the shoot mass and height of low marsh, tall Spartina alterniflora; however, declines in stem density resulted in no consistent increase in aboveground biomass. High-marsh plants S. patens and stunted S. alterniflora did not respond consistently to enrichment. Nutrient enrichment did not shift community structure, contrary to the prediction of nutrient-driven dominance of S. alterniflora and Distichlis spicata over S. patens. Our mild responses may differ from the results of previous studies for a number of reasons. First, the limited response of the high marsh may be explained by loading rates orders of magnitude lower than previous work. Low loading rates in the high marsh reflect infrequent inundation, arguing that inundation patterns must be considered when predicting responses to estuarine eutrophication. Additionally, we applied nitrate instead of the typically used ammonium, which is energetically favored over nitrate for plant uptake. Thus, the form of nitrogen enrichment used, not just N-load, may be important in predicting plant responses. Overall, our results suggest that when coastal eutrophication is dominated by nitrate and delivered via flooding tidal water, aboveground saltmarsh plant responses may be limited despite moderate-to-high water-column N concentrations. Furthermore, we argue that the methodological limitations of nutrient studies must be considered when using results to inform management decisions about wetlands

Visual dysfunction in Parkinson's disease

Patients with Parkinson's disease have a number of specific visual disturbances. These include changes in colour vision and contrast sensitivity and difficulties with complex visual tasks such as mental rotation and emotion recognition. We review changes in visual function at each stage of visual processing from retinal deficits, including contrast sensitivity and colour vision deficits to higher cortical processing impairments such as object and motion processing and neglect. We consider changes in visual function in patients with common Parkinson's disease-associated genetic mutations including GBA and LRRK2 We discuss the association between visual deficits and clinical features of Parkinson's disease such as rapid eye movement sleep behavioural disorder and the postural instability and gait disorder phenotype. We review the link between abnormal visual function and visual hallucinations, considering current models for mechanisms of visual hallucinations. Finally, we discuss the role of visuo-perceptual testing as a biomarker of disease and predictor of dementia in Parkinson's disease

Hearing and dementia: from ears to brain

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between ‘peripheral’ and ‘central’ hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer’s disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory ‘cognitive stress tests’ and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticit

Novel instructionless eye tracking tasks identify emotion recognition deficits in frontotemporal dementia

BACKGROUND: Current tasks measuring social cognition are usually 'pen and paper' tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD). METHODS: Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging. RESULTS: Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p < 0.05) for the simple emotion recognition task, and 15 (26)% for the control group compared with only 2 (18)% for the bvFTD group (p < 0.05) for the complex emotion recognition task. Worse performance in the bvFTD group correlated with atrophy in the right ventromedial prefrontal and orbitofrontal cortices, brain regions previously implicated in social cognition. CONCLUSIONS: In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks

Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.

We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis. Malignant cells in high-grade tumors displayed threefold to four fold higher expression of both receptor-interacting protein kinase (RIPK)1 and RIPK3 compared with non-tumor kidney tubular epithelium and low-grade tumors, but expression of both enzymes was induced in lower grade tumors in organ culture in response to TNFR1 stimulation. Furthermore, TNFR1 activation induced significant MLKL(Ser358) and Drp1(Ser616) phosphorylation, physical interactions in RCC between RIPK1-RIPK3 and RIPK3-phospho-MLKL(Ser358), and coincidence of phospho-MLKL(ser358) and phospho-Drp1(Ser616) at mitochondria in TUNEL-positive RCC. A caspase inhibitor only partially reduced the extent of cell death following TNFR1 engagement in RCC cells, whereas three inhibitors, each targeting a different step in the necroptotic pathway, were much more protective. Combined inhibition of caspases and necroptosis provided additive protection, implying that different subsets of cells respond differently to TNF-α, the majority dying by necroptosis. We conclude that most high-grade RCC cells express increased amounts of RIPK1 and RIPK3 and are poised to undergo necroptosis in response to TNFR1 signaling.National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre , Kidney Research UK and NIH grant R01-HL36003.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure: A Meta-Analysis of Randomized Controlled Trials

This is the final version. Available on open access from Elsevier via the DOI in this recordObjectives: This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL). Background: EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (VO2peak) or through submaximal tests, such as the 6-min walk test (6MWT). Methods: After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome. Results: Exercise-based CR is associated with positive effects on EC measured through VO2peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (VO2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for VO2peak and 80 m for 6MWT to predict a significant improvement in HRQOL. Conclusions: The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions.National Institute for Health Research (NIHR)University of Exete

Basal forebrain atrophy in frontotemporal dementia

Background: The basal forebrain is a subcortical structure that plays an important role in learning, attention, and memory. Despite the known subcortical involvement in frontotemporal dementia (FTD), there is little research into the role of the basal forebrain in this disease. We aimed to investigate differences in basal forebrain volumes between clinical, genetic, and pathological diagnoses of FTD. / Methods: 356 patients with FTD were recruited from the UCL Dementia Research Centre and matched on age and gender with 83 cognitively normal controls. All subjects had a T1-weighted MR scan suitable for analysis. Basal forebrain volumes were calculated using the Geodesic Information Flow (GIF) parcellation method and were compared between clinical (148 bvFTD, 82 svPPA, 103 nfvPPA, 14 PPA-NOS, 9 FTD-MND), genetic (24 MAPT, 15 GRN, 26 C9orf72) and pathological groups (28 tau, 3 FUS, 35 TDP-43) and controls. A subanalysis was also performed comparing pathological subgroups of tau (11 Pick's disease, 6 FTDP-17, 7 CBD, 4 PSP) and TDP-43 (12 type A, 2 type B, 21 type C). / Results: All clinical subtypes of FTD showed significantly smaller volumes than controls (p≤ 0.010, ANCOVA), with svPPA (10% volumetric difference) and bvFTD (9%) displaying the smallest volumes. Reduced basal forebrain volumes were also seen in MAPT mutations (18%, p<0.0005) and in individuals with pathologically confirmed FTDP-17 (17%), Pick's disease (12%), and TDP-43 type C (8%) (p<0.001). / Conclusion: Involvement of the basal forebrain is a common feature in FTD, although the extent of volume reduction differs between clinical, genetic, and pathological diagnoses. Tauopathies, particularly those with MAPT mutations, had the smallest volumes. However, atrophy was also seen in those with TDP-43 type C pathology (most of whom have svPPA clinically). This suggests that the basal forebrain is vulnerable to multiple types of FTD-associated protein inclusions

Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm

This is the final version of the article. Available on open access from BMJ Publishing Group via the DOI in this record.There is another record for this publication in ORE: http://hdl.handle.net/10871/32190INTRODUCTION: Individual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain, such as follows: (1) What is the additional contribution of IAD to prognostic risk estimation for cardiovascular and all-cause mortality? (2) What is the minimum cut-off value for IAD that defines elevated risk? (3) Is there a prognostic value of IAD and do different methods of IAD measurement impact on the prognostic value of IAD? We aim to address these questions by conducting an individual patient data (IPD) meta-analysis. METHODS AND ANALYSIS: This study will identify prospective cohort studies that measured blood pressure in both arms during recruitment, and invite authors to contribute IPD datasets to this collaboration. All patient data received will be combined into a single dataset. Using one-stage meta-analysis, we will undertake multivariable time-to-event regression modelling, with the aim of developing a new prognostic model for cardiovascular risk estimation that includes IAD. We will explore variations in risk contribution of IAD across predefined population subgroups (eg, hypertensives, diabetics), establish the lower limit of IAD that is associated with additional cardiovascular risk and assess the impact of different methods of IAD measurement on risk prediction. ETHICS AND DISSEMINATION: This study will not include any patient identifiable data. Included datasets will already have ethical approval and consent from their sponsors. Findings will be presented to international conferences and published in peer reviewed journals, and we have a comprehensive dissemination strategy in place with integrated patient and public involvement. PROSPERO REGISTRATION NUMBER: CRD42015031227.National Institute for Health Research (NIHR