Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent

Lithium Isotopes A Tracer of Past and Present Silicate Weathering

Lithium isotopes are a relatively novel tracer of present and past silicate weathering processes

Lithium Isotopes: A Tracer of Past and Present Silicate Weathering

Lithium isotopes are a relatively novel tracer of present and past silicate weathering processes. Given that silicate weathering is the primary long-term method by which CO2 is removed from the atmosphere, Li isotope research is going through an exciting phase. We show the weathering processes that fractionate dissolved and sedimentary Li isotope ratios, focusing on weathering intensity and clay formation. We then discuss the carbonate and silicate archive potential of past seawater δ7Li. These archives have been used to examine Li isotope changes across both short and long timescales. The former can demonstrate the rates at which the climate is stabilised from perturbations via weathering, a fundamental piece of the puzzle of the long-term carbon cycle

Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD) : study protocol for a randomised controlled trial

Background: Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol (R), a herbal, polyphenol-rich extract. Methods: This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol r to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHDRating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. Discussion: This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH

Causes of death in people with liver cirrhosis in England compared with the general population: a population-based cohort study.

OBJECTIVES: There is a need for unbiased estimates of cause-specific mortality by etiology in patients with liver cirrhosis. The aim of this study is to use nationwide linked electronic routine healthcare data from primary and secondary care alongside the national death registry data to report such estimates. METHODS: We identified from the linked Clinical Practice Research Datalink (CPRD) and English Hospital Episode Statistics adults with an incident diagnosis of liver cirrhosis linked to the Office for National Statistics between 1998 and 2009. Age-matched controls from the CPRD general population were selected. We calculated the cumulative incidence (adjusting for competing risks) and excess risk of death by 5 years from diagnosis for different causes of death, stratified by etiology and stage of disease. RESULTS: Five thousand one hundred and eighteen patients with cirrhosis were matched to 152,903 controls. Among compensated patients, the 5-year excess risk of liver-related death was higher than that of any other cause of death for all patients, except those of unspecified etiology. For example, those of alcohol etiology had 30.8% excess risk of liver-related death (95% confidence interval (CI): 27.9%, 33.1%) compared with 9.9% excess risk of non-liver-related death. However, patients of unspecified etiology had a higher excess risk of non-liver-related compared with liver-related death (10.7% vs. 6.7%). This was due to a high excess risk of non-liver neoplasm death (7.7%, 95% CI: 5.9%, 9.5%). All decompensated patients had a higher excess of liver-related mortality than any other cause. CONCLUSIONS: In order to reduce associated mortality among people with liver cirrhosis, patients' care pathways need to be tailored depending on the etiology and stage of the disease

‘It’s too late’. Is it really? Considerations for amblyopia treatment in older children

In recent years, media coverage has demonstrated instances in which families of children aged 7 and older, newly diagnosed with strabismic and/or anisometropic amblyopia through community eyecare services, were told it was ‘too late’ for their child to effectively respond to conventional amblyopia treatment (occlusion or atropine penalisation). Formal guidance pertaining to binocular vision anomalies from eyecare professional bodies does not specifically make reference to a child’s age, beyond stating the importance of early diagnosis and treatment of strabismus/amblyopia. However, there have been many changes in the way we view the recovery period for amblyopia, and it is well demonstrated both within literature and clinical practice that conventional treatment can improve amblyopic eye visual acuity in children beyond the age of 7 years. The occurrence of these media described cases within the community eyecare sphere would suggest it is worthwhile revisiting the literature on the subject of amblyopia treatment in older children (aged 7+ years), to address misconceptions and place in the spotlight current considerations facing clinicians when treating newly diagnosed amblyopia within this age group. This perspective review provides an evidence-based update covering the various considerations associated with treatment of amblyopia in older children, along with recent amblyopia treatment advances that could have an impact on treatment prospects for this patient group. Considerations include the risks, benefits and efficacy of treating newly diagnosed amblyopia in older children, monitoring density of suppression to mitigate intractable diplopia risk, and recent findings regarding binocular treatments for amblyopia

Transcriptome Analysis of Targeted Mouse Mutations Reveals the Topography of Local Changes in Gene Expression.

The unintended consequences of gene targeting in mouse models have not been thoroughly studied and a more systematic analysis is needed to understand the frequency and characteristics of off-target effects. Using RNA-seq, we evaluated targeted and neighboring gene expression in tissues from 44 homozygous mutants compared with C57BL/6N control mice. Two allele types were evaluated: 15 targeted trap mutations (TRAP); and 29 deletion alleles (DEL), usually a deletion between the translational start and the 3' UTR. Both targeting strategies insert a bacterial beta-galactosidase reporter (LacZ) and a neomycin resistance selection cassette. Evaluating transcription of genes in +/- 500 kb of flanking DNA around the targeted gene, we found up-regulated genes more frequently around DEL compared with TRAP alleles, however the frequency of alleles with local down-regulated genes flanking DEL and TRAP targets was similar. Down-regulated genes around both DEL and TRAP targets were found at a higher frequency than expected from a genome-wide survey. However, only around DEL targets were up-regulated genes found with a significantly higher frequency compared with genome-wide sampling. Transcriptome analysis confirms targeting in 97% of DEL alleles, but in only 47% of TRAP alleles probably due to non-functional splice variants, and some splicing around the gene trap. Local effects on gene expression are likely due to a number of factors including compensatory regulation, loss or disruption of intragenic regulatory elements, the exogenous promoter in the neo selection cassette, removal of insulating DNA in the DEL mutants, and local silencing due to disruption of normal chromatin organization or presence of exogenous DNA. An understanding of local position effects is important for understanding and interpreting any phenotype attributed to targeted gene mutations, or to spontaneous indels

Specifying who delivers behaviour change interventions: development of an Intervention Source Ontology [version 1; peer review: awaiting peer review]

BACKGROUND: Identifying how behaviour change interventions are delivered, including by whom, is key to understanding intervention effectiveness. However, information about who delivers interventions is reported inconsistently in intervention evaluations, limiting communication and knowledge accumulation. This paper reports a method for consistent reporting: The Intervention Source Ontology. This forms one part of the Behaviour Change Intervention Ontology, which aims to cover all aspects of behaviour change interventions. METHODS: The Intervention Source Ontology was developed following methods for ontology development and maintenance used in the Human Behaviour-Change Project, with seven key steps: 1) define the scope of the ontology, 2) identify key entities and develop their preliminary definitions by reviewing existing classification systems (top-down) and reviewing 100 behaviour change intervention reports (bottom-up), 3) refine the ontology by piloting the preliminary ontology on 100 reports, 4) stakeholder review by 34 behavioural science and public health experts, 5) inter-rater reliability testing of annotating intervention reports using the ontology, 6) specify ontological relationships between entities and 7) disseminate and maintain the Intervention Source Ontology. RESULTS: The Intervention Source Ontology consists of 140 entities. Key areas of the ontology include Occupational Role of Source, Relatedness between Person Source and the Target Population, Sociodemographic attributes and Expertise. Inter-rater reliability was found to be 0.60 for those familiar with the ontology and 0.59 for those unfamiliar with it, levels of agreement considered ‘acceptable’. CONCLUSIONS: Information about who delivers behaviour change interventions can be reliably specified using the Intervention Source Ontology. For human-delivered interventions, the ontology can be used to classify source characteristics in existing behaviour change reports and enable clearer specification of intervention sources in reporting

Graphs Identified by Logics with Counting

We classify graphs and, more generally, finite relational structures that are identified by C2, that is, two-variable first-order logic with counting. Using this classification, we show that it can be decided in almost linear time whether a structure is identified by C2. Our classification implies that for every graph identified by this logic, all vertex-colored versions of it are also identified. A similar statement is true for finite relational structures. We provide constructions that solve the inversion problem for finite structures in linear time. This problem has previously been shown to be polynomial time solvable by Martin Otto. For graphs, we conclude that every C2-equivalence class contains a graph whose orbits are exactly the classes of the C2-partition of its vertex set and which has a single automorphism witnessing this fact. For general k, we show that such statements are not true by providing examples of graphs of size linear in k which are identified by C3 but for which the orbit partition is strictly finer than the Ck-partition. We also provide identified graphs which have vertex-colored versions that are not identified by Ck.Comment: 33 pages, 8 Figure

Unravelling the controls on the molybdenum isotope ratios of river waters

The molybdenum (Mo) isotope ratios (δ98/95Mo) of river waters control the δ98/95Mo values of seawater and impact on the use of Mo isotope ratios as a proxy of past redox conditions. The δ98/95Mo values of river waters vary by more than 2 ‰, yet the relative roles of lithology versus fractionation during weathering remain contested. Here, we combine measurements from river waters (δ98/95Modiss), river bed materials (δ98/95MoBM) and soils from locations with contrasting lithology. The δ98/95Mo values of river bed materials (δ98/95MoBM), set by rock type, vary by ~1 ‰ between rivers in New Zealand, the Mackenzie Basin, and Iceland. However, the difference between dissolved and solid phase Mo isotopes (Δ98/95Modiss-BM) varies from +0.3 ‰ to +1.0 ‰. We estimate Mo removal from solution using the mobile trace element rhenium and find that it correlates with Δ98/95Modiss-BM across the sample set. The adsorption of Mo to Fe-Mn-(oxyhydr) oxides can explain the observed fractionation. Together, the amount of Mo released through dissolution and taken up by (oxyhydr)oxide formation on land may cause changes in the δ98/95Mo values of rivers, driving long term changes in the Mo isotope ratios of seawater