β2-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations

Background: The NF-kappa B signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic beta(2)-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic beta(2)-adrenergic receptors and the TNF-alpha induced inflammatory gene program. Methods: Proinflammatory conditions were generated by the administration of TNF-alpha. Genes that are susceptible to astrocytic crosstalk between beta(2)-adrenergic receptors (stimulated by clenbuterol) and TNF-alpha were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-alpha in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-alpha administration. Results: Parallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic beta(2)-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of beta(2)-adrenergic receptor agonists and TNF-alpha on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-alpha co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance. Conclusions: Our results show that astrocytic beta(2)-adrenergic receptors are potent regulators of astrocytic TNF-alpha-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic beta(2)-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses

Neurological manifestations and neuro-invasive mechanisms of the severe acute respiratory syndrome coronavirus type 2

Background and purpose Infections with coronaviruses are not always confined to the respiratory tract and various neurological manifestations have been reported. The aim of this study was to perform a review to describe neurological manifestations in patients with COVID-19 and possible neuro-invasive mechanisms of Sars-CoV-2. Methods PubMed, Web of Science and COVID-dedicated databases were searched for the combination of COVID-19 terminology and neurology terminology up to 10 May 2020. Social media channels were followed up between 15 March and 10 May 2020 for postings with the same scope. Neurological manifestations were extracted from the identified papers and combined to provide a useful summary for the neurologist in clinical practice. Results Neurological manifestations potentially related to COVID-19 have been reported in large studies, case series and case reports and include acute cerebrovascular diseases, impaired consciousness, cranial nerve manifestations and autoimmune disorders such as the Guillain-Barre syndrome often present in patients with more severe COVID-19. Cranial nerve symptoms such as olfactory and gustatory dysfunctions are highly prevalent in patients with mild to moderate COVID-19 even without associated nasal symptoms and often present in an early stage of the disease. Conclusion Physicians should be aware of the neurological manifestations in patients with COVID-19, especially when rapid clinical deterioration occurs. The neurological symptoms in COVID-19 patients may be due to direct viral neurological injury or indirect neuroinflammatory and autoimmune mechanisms. No antiviral treatments against the virus or vaccines for its prevention are available and the long-term consequences of the infection on human health remain uncertain especially with regard to the neurological system

A clinician’s perspective on yellow fever vaccine-associated neurotropic disease

Yellow fever (YF) causes high fever, liver dysfunction, renal failure, hypercoagulopathy and platelet dysfunction and can lead to shock and death with a case-fatality ratio of 20-50%. YF vaccination results in long-lasting protective immunity. Serious adverse events (SAEs), such as YF vaccine-associated neurotropic disease (YEL-AND) are rare. We present a case of a 56-year-old Caucasian man with fever, headache, cognitive problems at the emergency department. He received a primary YF vaccination 4 weeks prior to symptom onset. Cerebrospinal fluid tested positive (POS) for YF virus by reverse transcriptase polymerase chain reaction and confirmed diagnosis of YEL-AND. The patient recovered with symptomatic treatment. We reviewed published clinical reports on YEL-AND indexed for MEDLINE. We identified and analyzed 53 case reports. Forty-five patients were male and eight were female. Twenty-nine cases met criteria for definite YEL-AND and twenty-four for suspected YEL-AND according to YF Vaccine Safety Working Group. We applied the Brighton Collaboration diagnostic criteria to assess the diagnostic accuracy of the clinical diagnoses and found meningoencephalitis in 38 reported YEL-AND cases, Guillain Barre Syndrome (GBS) in seven, Acute Disseminated Encephalomyelitis (ADEM) in six and myelitis in five. Thirty-five patients recovered or improved; however, not all cases had a complete follow-up. The prognosis of YEL-AND presenting with GBS, ADEM or myelitis was poor. Fourteen patients received therapy (corticosteroids, intravenous immunoglobulins and/or plasmapheresis). In conclusion, YF vaccine-associated neurotropic disease is a very rare but SAE after YF vaccination. We described a case of YEL-AND and propose a standardized clinical workup of this condition based on a review of the literature. Centralized registration of complications of YF vaccination is encouraged

Deciphering the morphology of motor evoked potentials

Motor Evoked Potentials (MEPs) are used to monitor disability progression in multiple sclerosis (MS). Their morphology plays an important role in this process. Currently, however, there is no clear definition of what constitutes a normal or abnormal morphology. To address this, five experts independently labeled the morphology (normal or abnormal) of the same set of 1,000 MEPs. The intra- and inter-rater agreement between the experts indicates they agree on the concept of morphology, but differ in their choice of threshold between normal and abnormal morphology. We subsequently performed an automated extraction of 5,943 time series features from the MEPs to identify a valid proxy for morphology, based on the provided labels. To do this, we compared the cross-validation performances of one-dimensional logistic regression models fitted to each of the features individually. We find that the approximate entropy (ApEn) feature can accurately reproduce the majority-vote labels. The performance of this feature is evaluated on an independent test set by comparing to the majority vote of the neurologists, obtaining an AUC score of 0.92. The model slightly outperforms the average neurologist at reproducing the neurologists consensus-vote labels. We can conclude that MEP morphology can be consistently defined by pooling the interpretations from multiple neurologists and that ApEn is a valid continuous score for this. Having an objective and reproducible MEP morphological abnormality score will allow researchers to include this feature in their models, without manual annotation becoming a bottleneck. This is crucial for large-scale, multi-center datasets. An exploratory analysis on a large single-center dataset shows that ApEn is potentially clinically useful. Introducing an automated, objective, and reproducible definition of morphology could help overcome some of the barriers that are currently obstructing broad adoption of evoked potentials in daily care and patient follow-up, such as standardization of measurements between different centers, and formulating guidelines for clinical use

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

Background: Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS. Methods/Design: The FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography. Discussion: The FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS

Cerebral correlates of explicit sequence learning

peer reviewedUsing positron emission tomography (PET) and regional cerebral blood flow (rCBF) measurements, we investigated the cerebral correlates of consciousness in a sequence learning task through a novel application of the Process Dissociation Procedure, a behavioral paradigm that makes it possible to separately assess conscious and unconscious contributions to performance. Results show that the metabolic response in the anterior cingulate/mesial prefrontal cortex (ACC/MPFC) is exclusively and specifically correlated with the explicit component of performance during recollection of a learned sequence. This suggests a significant role for the ACC/MPFC in the explicit processing of sequential material. © 2003 Elsevier Science B.V. All rights reserved

Etude de l'impact de techniques non-pharmacologiques (auto-hypnose/auto-bienveillance) sur les plaintes cognitives de patients atteints d'un cancer

Cancer diagnosis generates a number of physical, psychological and cognitive impairments such as memory, attentional and informational processing deficits that can undermine patients’ quality of life (QoL). Self-hypnosis combined to self-care learning have been used in the past years to treat these symptoms, at the moment of diagnosis, during and/or after the cancer treatments. However, the impact of self-hypnosis/self-care upon cognitive difficulties has not been investigated yet.The aim of this study is to better understand the impact of self hypnosis/self-care upon the cognitive functions by means of the Functional Assessment of Cancer Therapy-Cognitive Function1 (FACT-COG).Etude de l'impact de techniques non-pharmacologiques (autohypnose/ auto-bienveillance) sur le bien-être, les plaintes cognitives et le retour/maintien au travail de personnes atteintes d'un cance