Role of astrocytes in epilepsy Coulter, Douglas A; Steinhäuser, Christian
Cold Spring Harbor perspectives in medicine,
03/2015, Letnik:
5, Številka:
3
Journal Article
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Astrocytes express ion channels, transmitter receptors, and transporters and, thus, are endowed with the machinery to sense and respond to neuronal activity. Recent studies have implicated that ...astrocytes play important roles in physiology, but these cells also emerge as crucial actors in epilepsy. Astrocytes are abundantly coupled through gap junctions allowing them to redistribute elevated K(+) and transmitter concentrations from sites of enhanced neuronal activity. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial K(+) and water channels. In addition, malfunction of glutamate transporters and the astrocytic glutamate-converting enzyme, glutamine synthetase, has been observed in epileptic tissue. These findings suggest that dysfunctional astrocytes are crucial players in epilepsy and should be considered as promising targets for new therapeutic strategies.
ObjectiveSedentary behaviour (SB) has distinct deleterious health outcomes, yet there is no consensus on best practice for measurement. This study aimed to identify the optimal self-report tool for ...population surveillance of SB, using a systematic framework.DesignA framework, TAxonomy of Self-reported Sedentary behaviour Tools (TASST), consisting of four domains (type of assessment, recall period, temporal unit and assessment period), was developed based on a systematic inventory of existing tools. The inventory was achieved through a systematic review of studies reporting SB and tracing back to the original description. A systematic review of the accuracy and sensitivity to change of these tools was then mapped against TASST domains.Data sourcesSystematic searches were conducted via EBSCO, reference lists and expert opinion.Eligibility criteria for selecting studiesThe inventory included tools measuring SB in adults that could be self-completed at one sitting, and excluded tools measuring SB in specific populations or contexts. The systematic review included studies reporting on the accuracy against an objective measure of SB and/or sensitivity to change of a tool in the inventory.ResultsThe systematic review initially identified 32 distinct tools (141 questions), which were used to develop the TASST framework. Twenty-two studies evaluated accuracy and/or sensitivity to change representing only eight taxa. Assessing SB as a sum of behaviours and using a previous day recall were the most promising features of existing tools. Accuracy was poor for all existing tools, with underestimation and overestimation of SB. There was a lack of evidence about sensitivity to change.ConclusionsDespite the limited evidence, mapping existing SB tools onto the TASST framework has enabled informed recommendations to be made about the most promising features for a surveillance tool, identified aspects on which future research and development of SB surveillance tools should focus.Trial registration numberInternational prospective register of systematic reviews (PROPSPERO)/CRD42014009851.
Abstract
The ejecta velocities of Type Ia supernovae (SNe Ia), as measured by the Si
ii
λ
6355 line, have been shown to correlate with other supernova properties, including color and standardized ...luminosity. We investigate these results using the Foundation Supernova Survey, with a spectroscopic data release presented here, and photometry analyzed with the SALT2 light-curve fitter. We find that the Foundation data do not show significant evidence for an offset in color between SNe Ia with high and normal photospheric velocities, with Δ
c
= 0.004 ± 0.015. Our SALT2 analysis does show evidence for redder high-velocity SNe Ia in other samples, including objects from the Carnegie Supernova Project, with a combined sample yielding Δ
c
= 0.018 ± 0.008. When split on velocity, the Foundation SNe Ia also do not show a significant difference in Hubble diagram residual, Δ
HR
= 0.015 ± 0.049 mag. Intriguingly, we find that SN Ia ejecta velocity information may be gleaned from photometry, particularly in redder optical bands. For high-redshift SNe Ia, these rest-frame red wavelengths will be observed by the Nancy Grace Roman Space Telescope. Our results are in line with previous work that suggests SN Ia host-galaxy stellar mass is correlated with ejecta velocity: high-velocity SNe Ia are found nearly exclusively in high-stellar-mass hosts. However, host-galaxy properties alone do not explain velocity-dependent differences in supernova colors and luminosities across samples. Measuring and understanding the connection between intrinsic explosion properties and supernova environments, across cosmic time, will be important for precision cosmology with SNe Ia.
Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of the commonest neurosurgical procedures worldwide. Infection of the implanted shunt affects up to 15% of these patients, resulting ...in prolonged hospital treatment, multiple surgeries, and reduced cognition and quality of life. Our aim was to determine the clinical and cost-effectiveness of antibiotic (rifampicin and clindamycin) or silver shunts compared with standard shunts at reducing infection.
In this parallel, multicentre, single-blind, randomised controlled trial, we included patients with hydrocephalus of any aetiology undergoing insertion of their first ventriculoperitoneal shunt irrespective of age at 21 regional adult and paediatric neurosurgery centres in the UK and Ireland. Patients were randomly assigned (1:1:1 in random permuted blocks of three or six) to receive standard shunts (standard shunt group), antibiotic-impregnated (0·15% clindamycin and 0·054% rifampicin; antibiotic shunt group), or silver-impregnated shunts (silver shunt group) through a randomisation sequence generated by an independent statistician. All patients and investigators who recorded and analysed the data were masked for group assignment, which was only disclosed to the neurosurgical staff at the time of operation. Participants receiving a shunt without evidence of infection at the time of insertion were followed up for at least 6 months and a maximum of 2 years. The primary outcome was time to shunt failure due the infection and was analysed with Fine and Gray survival regression models for competing risk by intention to treat. This trial is registered with ISRCTN 49474281.
Between June 26, 2013, and Oct 9, 2017, we assessed 3505 patients, of whom 1605 aged up to 91 years were randomly assigned to receive either a standard shunt (n=536), an antibiotic-impregnated shunt (n=538), or a silver shunt (n=531). 1594 had a shunt inserted without evidence of infection at the time of insertion (533 in the standard shunt group, 535 in the antibiotic shunt group, and 526 in the silver shunt group) and were followed up for a median of 22 months (IQR 10–24; 53 withdrew from follow-up). 32 (6%) of 533 evaluable patients in the standard shunt group had a shunt revision for infection, compared with 12 (2%) of 535 evaluable patients in the antibiotic shunt group (cause-specific hazard ratio csHR 0·38, 97·5% CI 0·18–0·80, p=0·0038) and 31 (6%) of 526 patients in the silver shunt group (0·99, 0·56–1·74, p=0·96). 135 (25%) patients in the standard shunt group, 136 (25%) in the antibiotic shunt group, and 140 (27%) in the silver shunt group had adverse events, which were not life-threatening and were mostly related to valve or catheter function.
The BASICS trial provides evidence to support the adoption of antibiotic shunts in UK patients who are having their first ventriculoperitoneal shunt insertion. This practice will benefit patients of all ages by reducing the risk and harm of shunt infection.
UK National Institute for Health Research Health Technology Assessment programme.
Abstract The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may ...undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro Monnerie and Le Roux, (2007) Exp Neurol 205:367–382, (2008) Exp Neurol 213:145–153. An N-methyl- d -aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation and inhibition that is often observed after injury.
Adherence is a primary determinant of the effectiveness of any intervention. Exercise is considered essential in the management of spondyloarthritis (SpA); however, the overall adherence to exercise ...programmes and factors affecting adherence are unknown. The aim of this systematic review was to examine measures of, and factors influencing adherence to, prescribed exercise programmes in people with SpA. A search was performed in August 2018 using five data bases; the Cochrane library, CINAHL, EMBASE, MEDLINE, and Web of Science Collections. Inclusion criteria were: studies with adults (> 18 years) with SpA, with a prescribed exercise intervention or educational programme with the aim of increasing exercise participation. Article quality was independently assessed by two assessors. Extracted descriptive data included: populations, interventions, measures of adherence and factors affecting adherence. Percentage adherence rates to prescribed exercises were calculated if not reported. Nine studies were included with a total of 658 participants, 95% of participants had a diagnosis of ankylosing spondylitis. Interventions and measurement of adherence varied, making comparisons difficult. Rates of adherence ranged from 51.4 to 95%. Single studies identified; adherence improved following educational programmes, and higher disease severity and longer diagnostic delays were associated with higher adherence. Conflicting evidence was found as to whether supervision of exercise improved adherence. Three consecutive studies demonstrated adherence reduced over time. Adherence to prescribed exercise in SpA was poorly reported and predominately for people with AS. The levels of adherence and factors affecting prescribed exercise in SpA remain unclear. Future research should measure adherence across a longer time period and investigate possible factors which may influence adherence.
Sedentary behaviour is a public health concern that requires surveillance and epidemiological research. For such large scale studies, self-report tools are a pragmatic measurement solution. A large ...number of self-report tools are currently in use, but few have been validated against an objective measure of sedentary time and there is no comparative information between tools to guide choice or to enable comparison between studies. The aim of this study was to provide a systematic comparison, generalisable to all tools, of the validity of self-report measures of sedentary time against a gold standard sedentary time objective monitor.
Cross sectional data from three cohorts (N = 700) were used in this validation study. Eighteen self-report measures of sedentary time, based on the TAxonomy of Self-report SB Tools (TASST) framework, were compared against an objective measure of postural sitting (activPAL) to provide information, generalizable to all existing tools, on agreement and precision using Bland-Altman statistics, on criterion validity using Pearson correlation, and on data loss.
All self-report measures showed poor accuracy compared with the objective measure of sedentary time, with very wide limits of agreement and poor precision (random error > 2.5 h). Most tools under-reported total sedentary time and demonstrated low correlations with objective data. The type of assessment used by the tool, whether direct, proxy, or a composite measure, influenced the measurement characteristics. Proxy measures (TV time) and single item direct measures using a visual analogue scale to assess the proportion of the day spent sitting, showed the best combination of precision and data loss. The recall period (e.g. previous week) had little influence on measurement characteristics.
Self-report measures of sedentary time result in large bias, poor precision and low correlation with an objective measure of sedentary time. Choice of tool depends on the research context, design and question. Choice can be guided by this systematic comparative validation and, in the case of population surveillance, it recommends to use a visual analog scale and a 7 day recall period. Comparison between studies and improving population estimates of average sedentary time, is possible with the comparative correction factors provided.
Activation of AMPA receptors assembled with the GluA1 subunit can promote dendrite growth in a manner that depends on its direct binding partner, SAP97. SAP97 is a modular scaffolding protein that ...has at least seven recognizable protein–protein interaction domains. Several complementary approaches were employed to show that the dendrite branching promoting action of full length SAP97 depends on ligand(s) that bind to the PDZ3 domain. Ligand(s) to PDZ1, PDZ2 and I3 domains also contribute to dendrite growth. The ability of PDZ3 ligand(s) to promote dendrite growth depends on localization at the plasma membrane along with GluA1 and SAP97. These results suggest that the assembly of a multi-protein complex at or near synapses is vital for the translation of AMPA-R activity into dendrite growth.
•Study domains of SAP97 that promote dendrite growth•Identify PDZ3 domain of SAP97 as branch promoting•Show GluA1 is required for SAP97's activity
Temporal lobe epilepsy is the most prevalent seizure disorder in adults. Compromised inhibitory neurotransmitter function in the hippocampus contributes to the hyperexcitability generating this ...condition, but the underlying molecular mechanisms are unknown. Combining patch-clamp recording and single-cell mRNA amplification (aRNA) techniques in single dentate granule cells, we demonstrate that expression of GABA(A) receptor subunit mRNAs is substantially altered in neurons from epileptic rats. These changes in gene expression precede epilepsy onset by weeks and correlate with profound alterations in receptor function, indicating that aberrant GABA(A) receptor expression and function has an essential role in the process of epileptogenesis.
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