Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST–XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at −80°C for at least 60 days. M30-Apoptosense™ plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp396) was stable for 3 months at −80°C, while at 37°C it had a half-life of 80–100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited

Warming of Central European lakes and their response to the 1980s climate regime shift

Lake surface water temperatures (LSWTs) are sensitive to atmospheric warming and have previously been shown to respond to regional changes in the climate. Using a combination of in situ and simulated surface temperatures from 20 Central European lakes, with data spanning between 50 and ∼100 years, we investigate the long-term increase in annually averaged LSWT. We demonstrate that Central European lakes are warming most in spring and experience a seasonal variation in LSWT trends. We calculate significant LSWT warming during the past few decades and illustrate, using a sequential t test analysis of regime shifts, a substantial increase in annually averaged LSWT during the late 1980s, in response to an abrupt shift in the climate. Surface air temperature measurements from 122 meteorological stations situated throughout Central Europe demonstrate similar increases at this time. Climatic modification of LSWT has numerous consequences for water quality and lake ecosystems. Quantifying the response of LSWT increase to large-scale and abrupt climatic shifts is essential to understand how lakes will respond in the future

Home based exercise to improve turning and mobility performance among community dwelling older adults: protocol for a randomized controlled trial

Background: Turning is a common activity for older people, and is one of the activities commonly associated with falls during walking. Falls that occur while walking and turning have also been associated with an increased risk of hip fracture in older people. Despite the importance of stability during turning, there has been little focus on identifying this impairment in at risk older people, or in evaluating interventions aiming to improve this outcome. This study will evaluate the effectiveness of a 16 week tailored home based exercise program in older adults aged (50 years and above) who were identified as having unsteadiness during turning.Methods/Design: A single blind randomized controlled trial will be conducted, with assessors blind to group allocation. Study participants will be aged 50 years and above, living in the community and have been identified as having impaired turning ability [outside of age and gender normal limits on the Step Quick Turn (180 degree turn) task on the Neurocom® Balance Master with long plate]. After a comprehensive baseline assessment, those classified as having balance impairment while turning will be randomized to intervention or control group. The intervention group will receive a 16 week individualized balance and strength home exercise program, based on the Otago Exercise Program with additional exercises focused on improving turning ability. Intervention group will attend four visit to the assessment centre over 16 weeks period, for provision, monitoring, modification of the exercise and encourage ongoing participation. Participants in the control group will continue with their usual activities. All participants will be re-assessed on completion of the 16 week program. Primary outcome measures will be the Step Quick Turn Test and Timed-Up and Go test. Secondary outcomes will include other clinical measures of balance, psychological aspects of falls, incidence of falls and falls risk factors. Discussion: Results of this study will provide useful information for clinicians on the types of exercises to improve turning ability in older people with increased falls risk and the effectiveness of these exercises in improving outcomes

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity

Neural Correlates of Visual Motion Prediction

Predicting the trajectories of moving objects in our surroundings is important for many life scenarios, such as driving, walking, reaching, hunting and combat. We determined human subjects’ performance and task-related brain activity in a motion trajectory prediction task. The task required spatial and motion working memory as well as the ability to extrapolate motion information in time to predict future object locations. We showed that the neural circuits associated with motion prediction included frontal, parietal and insular cortex, as well as the thalamus and the visual cortex. Interestingly, deactivation of many of these regions seemed to be more closely related to task performance. The differential activity during motion prediction vs. direct observation was also correlated with task performance. The neural networks involved in our visual motion prediction task are significantly different from those that underlie visual motion memory and imagery. Our results set the stage for the examination of the effects of deficiencies in these networks, such as those caused by aging and mental disorders, on visual motion prediction and its consequences on mobility related daily activities

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation