The current clinically relevant findings on COVID-19 pandemic

The emergence of a novel coronavirus and coronavirus disease 2019 (COVID-19) represents a challenge to global healthcare. In the past 20 years, this is the third coronavirus that jumped the species barrier and infected humans. It is highly contagious but associated with low pathogenicity. First identified in Wuhan, China, a city of over 11 million, the disease has since spread to every continent except Antarctica. About 15 to 20 of all cases may be called severe, and it is believed many cases are asymptomatic. The average age of a person with COVID has been reported as 49 years. Worse outcomes are associated with geriatric populations and those with un-derlying diseases such as cardiovascular, respiratory disorders, and/or diabetes. The coronavirus, like other coronaviruses, is highly contagious and has a latency period of about 14 days. Most patients present with fever and a dry cough, but fever may be absent. Differential diagnosis can be challenging since influenza may present with similar symptoms. Chest radiography or computed to-mography may be used to find evidence of secondary pneumonia. Nosocomial infection is of concern, and it has been reported that 3.8 of all cases with COVID-19 in that country involve healthcare workers in China. Most patients have mild disease, and supportive care suffices. A variety of repurposed and investigational drugs are being evaluated. There are currently no antiviral therapies or vaccines, even if many therapies are proposed. Hand hygiene, social distancing, and scientifically sound information are the best strategies at the moment to combat this epidemic. © 2020, Author(s)

Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations

Guiding Principles for Chronic Total Occlusion Percutaneous Coronary Intervention.

Outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have improved because of advancements in equipment and techniques. With global collaboration and knowledge sharing, we have identified 7 common principles that are widely accepted as best practices for CTO-PCI.  1. Ischemic symptom improvement is the primary indication for CTO-PCI.  2. Dual coronary angiography and in-depth and structured review of the angiogram (and, if available, coronary computed tomography angiography) are key for planning and safely performing CTO-PCI.  3. Use of a microcatheter is essential for optimal guidewire manipulation and exchanges.  4. Antegrade wiring, antegrade dissection and reentry, and the retrograde approach are all complementary and necessary crossing strategies. Antegrade wiring is the most common initial technique, whereas retrograde and antegrade dissection and reentry are often required for more complex CTOs.  5. If the initially selected crossing strategy fails, efficient change to an alternative crossing technique increases the likelihood of eventual PCI success, shortens procedure time, and lowers radiation and contrast use.  6. Specific CTO-PCI expertise and volume and the availability of specialized equipment will increase the likelihood of crossing success and facilitate prevention and management of complications, such as perforation.  7. Meticulous attention to lesion preparation and stenting technique, often requiring intracoronary imaging, is required to ensure optimum stent expansion and minimize the risk of short- and long-term adverse events. These principles have been widely adopted by experienced CTO-PCI operators and centers currently achieving high success and acceptable complication rates. Outcomes are less optimal at less experienced centers, highlighting the need for broader adoption of the aforementioned 7 guiding principles along with the development of additional simple and safe CTO crossing and revascularization strategies through ongoing research, education, and training

Exploring the Connection Between Sleep and Cluster Headache : A Narrative Review

Cluster headache is a rare form of headache associated with sleep and even speculated to be a manifestation of a sleep disorder rather than a primary headache. Cluster headache exhibits both circadian and circannual rhythmicity. While attacks often occur during sleep, the implication that cluster headaches might be involved with rapid eye movement (REM) sleep phases has neither been fully established nor refuted. The regulatory mechanisms governing sleep including hypothalamic activity and the autonomic nervous system response may play a role. Hypothalamic activation has been observed in cluster headache patients during positron emission tomography testing, but only during attacks. While sleep apnea is associated with morning headaches in general, the link between sleep-disordered respiration and cluster headache remains elusive. Hypoarousal during sleep and periods of hypoxia are associated with cluster headache, the latter likely involving inflammatory processes rather than apnea. Further study is needed, as cluster headaches represent a serious primary cephalgia that is incompletely understood

COVID-19 and NSAIDS : A Narrative Review of Knowns and Unknowns

Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. NSAID use must also be categorized by whether the drugs are relatively low-dose over-the-counter oral products taken occasionally versus higher-dose or parenteral NSAIDs. Even if evidence emerged arguing for or against NSAIDs in this setting, it is unclear if this evidence would apply to all NSAIDs at all doses in all dosing regimens. Paracetamol (acetaminophen) has been proposed as an alternative to NSAIDs but there are issues with liver toxicity at high doses. There are clearly COVID-19 cases where NSAIDs should not be used, but there is no strong evidence that NSAIDs must be avoided in all patients with COVID-19; clinicians must weigh these choices on an individual basis

Etudes précliniques de candidats vaccins contre le paludisme (analyses immuno-épidémiologiques et validation d'un test fonctionnel de chimiluminescence)

Un vaccin contre Plasmodium falciparum est une grande priorité. Il est difficile de tester les candidats vaccins en essai clinique, et sans un bon modèle animal, des tests fonctionnels d anticorps in vitro sont nécessaires pour choisir les meilleurs candidats. Ce travail décrit un test mesurant l activation des neutrophiles (poussée respiratoire) et la phagocytose des mérozoïtes en présence d anticorps anti-mérozoïte, par chimiluminescence. Ce test est reproductible et relié à la protection clinique en zone d endémie. Les anticorps spécifiques de PfMSP1p19 et PfMSP4p20 exprimé en baculovirus sont fonctionnels dans ce test. Avec une reproductibilité confirmée ailleurs, il pourrait devenir un outil de référence. Une autre approche immuno-épidémiologique démontre une corrélation entre le taux d anticorps anti-PfMSP1p19 ou anti-PfMSP5 et la protection clinique.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy

NMDA receptors (NMDAR), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course, and increases single channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes over-activation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient’s epileptic phenotype as well as cerebral atrophy