Identifying patients at risk for myasthenic crisis with hemogram and inflammation-related laboratory parameters - a pilot study.

Background: Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG. Methods: We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit. Results: 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02-1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14-1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99-1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99-2.38) may indicate increased risk for a myasthenic crisis. Conclusion: This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG.

Stroke in the Time of Circadian Medicine.

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

An Assessment of Physical and N6-Cyclohexyladenosine-Induced Hypothermia in Rodent Distal Focal Ischemic Stroke.

Therapeutic hypothermia (TH) mitigates damage in ischemic stroke models. However, safer and easier TH methods (e.g., pharmacological) are needed to circumvent physical cooling complications. This study evaluated systemic and pharmacologically induced TH using the adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), with control groups in male Sprague-Dawley rats. CHA was administered intraperitoneally 10 minutes following a 2-hour intraluminal middle cerebral artery occlusion. We used a 1.5 mg/kg induction dose, followed by three 1.0 mg/kg doses every 6 hours for a total of 4 doses, causing 20-24 hours of hypothermia. Animals assigned to physical hypothermia and CHA-hypothermia had similar induction rates and nadir temperatures, but forced cooling lasted ∼6 hours longer compared with CHA-treated animals. The divergence is likely attributable to individual differences in CHA metabolism, which led to varied durations at nadir, whereas physical hypothermia was better regulated. Physical hypothermia significantly reduced infarction (primary endpoint) on day 7 (mean reduction of 36.8 mm3 or 39% reduction; p = 0.021 vs. normothermic animals; Cohen's d = 0.75), whereas CHA-induced hypothermia did not (p = 0.33). Similarly, physical cooling improved neurological function (physical hypothermia median = 0, physical normothermia median = 2; p = 0.008) and CHA-induced cooling did not (p > 0.99). Our findings demonstrate that forced cooling was neuroprotective compared with controls, but prolonged CHA-induced cooling was not neuroprotective.

Not open and shut: Complex and prolonged blood-brain barrier responses after stroke.

Blood-brain barrier dysfunction (BBB) occurs rapidly after stroke and contributes to edema, inflammation, and secondary brain injury including haemorrhage. Two recent studies shed light on the temporal extent of post-stroke BBB dysfunction as well as its consequences for drug delivery. Zhang et al. found increases in BBB permeability that persist up to one-year post-ischemia. Despite increased paracellular leakage, Stanton et al. showed that transcellular transporter systems are required to deliver therapeutics into brain parenchyma. Both studies remind us of the complexity of BBB responses after stroke and provide novel entry points for future research into the underlying mechanisms.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Posterior circulation ischaemic stroke diagnosis and management.

This narrative review provides an overview of the posterior circulation and the clinical features of common posterior circulation stroke (PCS) syndromes in the posterior arterial territories and how to distinguish them from mimics. We outline the hyperacute management of patients with suspected PCS with emphasis on how to identify those who are likely to benefit from intervention based on imaging findings. Finally, we review advances in treatment options, including developments in endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT), and the principles of medical management and indications for neurosurgery. Observational and randomised clinical trial data have been equivocal regarding EVT in PCS, but more recent studies strongly support its efficacy. There have been concomitant advances in imaging of posterior stroke to guide optimal patient selection for thrombectomy. Recent evidence suggests that clinicians should have a heightened suspicion of posterior circulation events with the resultant implementation of timely, evidence-based management.

Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

AIMS: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields. METHODS: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. RESULTS: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways. CONCLUSIONS: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.

Cerebroprotection in the endovascular era: an update.

Despite advances in clinical diagnosis and increasing numbers of patients eligible for revascularisation, ischaemic stroke remains a significant public health concern accounting for 3.3 million deaths annually. In addition to recanalisation therapy, patient outcomes could be improved through cerebroprotection, but all translational attempts have remained unsuccessful. In this narrative review, we discuss potential reasons for those failures. We then outline the diverse, multicellular effects of ischaemic stroke and the complex temporal sequences of the pathophysiological cascade during and following ischaemia, reperfusion, and recovery. This evidence is linked with findings from prior cerebroprotective trials and interpreted for the modern endovascular era. Future cerebroprotective agents that are multimodal and multicellular, promoting cellular and metabolic health to different targets at time points that are most responsive to treatment, might prove more successful.

Developing a metabolic clearance rate framework as a translational analysis approach for hyperpolarized 13C magnetic resonance imaging.

Hyperpolarized carbon-13 magnetic resonance imaging is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel perfusion formalism and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 ± 2 vs 89 ± 6 mL/100 g/min, p < 0.01, respectively) and pigs (139 ± 12 vs 95 ± 5 mL/100 g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 ± 5 vs 4 ± 2%, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 ± 0.007 vs 0.017 ± 0.02/s, p = 0.03, respectively) and a decrease in mean transit time (31 ± 8 vs 60 ± 2 s, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

Reinventing the Penumbra - the Emerging Clockwork of a Multi-modal Mechanistic Paradigm.

The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. ï»¿Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain's central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

The neurovascular unit and systemic biology in stroke - implications for translation and treatment.

Ischaemic stroke is a leading cause of disability and death for which no acute treatments exist beyond recanalization. The development of novel therapies has been repeatedly hindered by translational failures that have changed the way we think about tissue damage after stroke. What was initially a neuron-centric view has been replaced with the concept of the neurovascular unit (NVU), which encompasses neuronal, glial and vascular compartments, and the biphasic nature of neural-glial-vascular signalling. However, it is now clear that the brain is not the private niche it was traditionally thought to be and that the NVU interacts bidirectionally with systemic biology, such as systemic metabolism, the peripheral immune system and the gut microbiota. Furthermore, these interactions are profoundly modified by internal and external factors, such as ageing, temperature and day-night cycles. In this Review, we propose an extension of the concept of the NVU to include its dynamic interactions with systemic biology. We anticipate that this integrated view will lead to the identification of novel mechanisms of stroke pathophysiology, potentially explain previous translational failures, and improve stroke care by identifying new biomarkers of and treatment targets in stroke.

Neuroprotection in Acute Ischemic Stroke: A Brief Review.

The goal of effective neuroprotection in acute ischemic stroke remains elusive. Despite decades of experimental preclinical and clinical experience with innumerable agents, no strategy has proven to be beneficial in humans. As endovascular therapies mature and approach the limits of speed and efficacy, neuroprotection will become the next frontier of acute stroke care. This review will briefly summarize the history, preclinical and clinical triumphs and failures, and future directions of cerebral neuroprotection.

Circadian Biology and Stroke.

Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review/perspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke. Accounting for the complex and multifactorial effects of circadian rhythm may improve translational opportunities for stroke diagnostics and therapeutics.

Gender parity in scientific authorship in a National Institute for Health Research Biomedical Research Centre: a bibliometric analysis.

OBJECTIVE: Scientific authorship is a vital marker of achievement in academic careers and gender equity is a key performance metric in research. However, there is little understanding of gender equity in publications in biomedical research centres funded by the National Institute for Health Research (NIHR). This study assesses the gender parity in scientific authorship of biomedical research. DESIGN: Descriptive, cross-sectional, retrospective bibliometric study. SETTING: NIHR Oxford Biomedical Research Centre (BRC). DATA: Data comprised 2409 publications that were either accepted or published between April 2012 and March 2017. The publications were classified as basic science studies, clinical studies (both trial and non-trial studies) and other studies (comments, editorials, systematic reviews, reviews, opinions, book chapters, meeting reports, guidelines and protocols). MAIN OUTCOME MEASURES: Gender of authors, defined as a binary variable comprising either male or female categories, in six authorship categories: first author, joint first authors, first corresponding author, joint corresponding authors, last author and joint last authors. RESULTS: Publications comprised 39% clinical research (n=939), 27% basic research (n=643) and 34% other types of research (n=827). The proportion of female authors as first author (41%), first corresponding authors (34%) and last author (23%) was statistically significantly lower than male authors in these authorship categories (p<0.001). Of total joint first authors (n=458), joint corresponding authors (n=169) and joint last authors (n=229), female only authors comprised statistically significant (p<0.001) smaller proportions, that is, 15% (n=69), 29% (n=49) and 10% (n=23) respectively, compared with male only authors in these joint authorship categories. There was a statistically significant association between gender of the last author with gender of the first author (p<0.001), first corresponding author (p<0.001) and joint last author (p<0.001). The mean journal impact factor (JIF) was statistically significantly higher when the first corresponding author was male compared with female (Mean JIF: 10.00 vs 8.77, p=0.020); however, the JIF was not statistically different when there were male and female authors as first authors and last authors. CONCLUSIONS: Although the proportion of female authors is significantly lower than the proportion of male authors in all six categories of authorship analysed, the proportions of male and female last authors are comparable to their respective proportions as principal investigators in the BRC. These findings suggest positive trends and the NIHR Oxford BRC doing very well in gender parity in the senior (last) authorship category. Male corresponding authors are more likely to publish articles in prestigious journals with high impact factor while both male and female authors at first and last authorship positions publish articles in equally prestigious journals.

Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro.

Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7-10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 µM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFß) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling.

Markers of achievement for assessing and monitoring gender equity in a UK National Institute for Health Research Biomedical Research Centre: A two-factor model.

BACKGROUND: The underrepresentation of women in academic medicine at senior level and in leadership positions is well documented. Biomedical Research Centres (BRC), partnerships between leading National Health Service (NHS) organisations and universities, conduct world class translational research funded by the National Institute for Health Research (NIHR) in the UK. Since 2011 BRCs are required to demonstrate significant progress in gender equity (GE) to be eligible to apply for funding. However, the evidence base for monitoring GE specifically in BRC settings is underdeveloped. This is the first survey tool designed to rank and identify new GE markers specific to the NIHR BRCs. METHODS: An online survey distributed to senior leadership, clinical and non-clinical researchers, trainees, administrative and other professionals affiliated to the NIHR Oxford BRC (N = 683). Participants ranked 13 markers of GE on a five point Likert scale by importance. Data were summarised using frequencies and descriptive statistics. Interrelationships between markers and underlying latent dimensions (factors) were determined by exploratory and confirmatory factor analyses. RESULTS: The response rate was 36% (243 respondents). Respondents were more frequently female (55%, n = 133), aged 41-50 years (33%, n = 81), investigators (33%, n = 81) affiliated to the BRC for 2-7 years (39.5%, n = 96). Overall participants ranked 'BRC senior leadership roles' and 'organisational policies on gender equity', to be the most important markers of GE. 58% (n = 141) and 57% (n = 139) respectively. Female participants ranked 'organisational policies' (64.7%, n = 86/133) and 'recruitment and retention' (60.9%, n = 81/133) most highly, whereas male participants ranked 'leadership development' (52.1%, n = 50/96) and 'BRC senior leadership roles' (50%, n = 48/96) as most important. Factor analyses identified two distinct latent dimensions: "organisational markers" and "individual markers" of GE in BRCs. CONCLUSIONS: A two-factor model of markers of achievement for GE with "organisational" and "individual" dimensions was identified. Implementation and sustainability of gender equity requires commitment at senior leadership and organisational policy level.