HSV-1 infection induces phosphorylated tau propagation among neurons via extracellular vesicles.

Extracellular vesicles (EV), key players in cell-to-cell communication, may contribute to disease propagation in several neurodegenerative diseases, including Alzheimer's disease (AD), by favoring the dissemination of neurotoxic proteins within the brain. Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htauGFP), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtauGFP. Finally, we exploited an in vivo model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer's disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.

A structured community engagement strategy to support uptake of TB active case-finding.

BACKGROUND: In Lima, Peru, a mobile TB screening program ("TB Móvil") was implemented in high TB prevalence districts to increase TB screening. Community engagement activities to promote TB Móvil were simultaneously conducted. OBJECTIVE: To describe a structured, theory-driven community engagement strategy to support the uptake of TB Móvil. METHODS: We adapted Popular Opinion Leader (POL), an evidence-based social networking intervention previously used in Peru to promote HIV testing, for TB Móvil. Community health workers, women who run soup kitchens, and motorcycle taxi drivers served as "popular opinion leaders" who disseminated information about TB Móvil in everyday conversations, aided by a multi-media campaign. Performance indicators of POL included the number/characteristics of persons screened; number of multimedia elements; and proportion of persons with abnormal radiographs hearing about TB Móvil before attending. RESULTS: Between February 2019 and January 2020, 63,899 people attended the TB Móvil program at 210 sites; 60.1% were female. The multimedia campaign included 36 videos, 16 audio vignettes, flyers, posters, community murals and "jingles." Among attendees receiving an abnormal chest X-ray suggestive of TB, 48% (6,935/14,563) reported hearing about TB Móvil before attending. CONCLUSIONS: POL promotes the uptake of TB Móvil and should be considered as a strategy for increasing TB screening uptake.

CONTEXTE: À Lima, Pérou, un programme mobile de dépistage de la TB (« TB Móvil ¼) a été mis en place dans les quartiers à forte prévalence de TB afin d'accroître le dépistage de la maladie. Des activités de mobilisation communautaire visant à promouvoir TB Móvil ont été menées en parallèle. L'objectif de ce rapport est de décrire une stratégie structurée de mobilisation communautaire, fondée sur des principes théoriques, afin de soutenir le recours au programme TB Móvil. MÉTHODES: Nous avons adapté à TB Móvil l'intervention factuelle de réseautage social appelée « Popular Opinion Leader (POL; leader d'opinion) ¼, précédemment utilisée au Pérou pour promouvoir le dépistage du VIH. Les agents de santé communautaires, les femmes responsables de la soupe populaire et les chauffeurs de mototaxis étaient des leaders d'opinion. Ils communiquaient des informations sur TB Móvil lors de leurs conversations quotidiennes, qui étaient étayées par une campagne multimédia. Les indicateurs de performance des POL comprenaient le nombre/les caractéristiques des personnes dépistées, le nombre d'éléments multimédias et le pourcentage de personnes avec cliché radiographique anormal qui avaient entendu parler de TB Móvil avant de se faire dépister. RÉSULTATS: Entre février 2019 et janvier 2020, 63 899 personnes ont pris part au programme TB Móvil dans 210 sites ; 60,1% étaient des femmes. La campagne multimédia reposait sur 36 vidéos, 16 vignettes audio, des prospectus, des posters, des peintures murales dans la communauté et des « jingles ¼. Parmi les personnes dont la radiographie pulmonaire était anormale et évocatrice de TB, 48% (6 935/14 563) ont rapporté avoir entendu parler de TB Móvil avant de venir consulter. CONCLUSIONS: L'intervention POL, qui semblait renforcer le recours au programme TB Móvil, peut donc servir d'une stratégie de promotion du dépistage de la TB.

Integrated screening and testing for TB and COVID-19 in Peru.

We describe the experience of integrating COVID-19 screening and testing into a mobile TB screening unit in Lima, Peru. All attendees received chest radiographs, which were analysed using CAD4TB and CAD4COVID; Xpert MTB/RIF Ultra was used to test for TB, and antibody and polymerase chain reaction (PCR) for SARS-CoV-2. One Xpert-positive TB case was diagnosed per 168 people screened, one person with SARS-CoV-2 antibodies per 3 people screened, and one PCR-confirmed SARS-CoV-2 infection per 8 people screened. Integrated screening can help to avoid delays in the diagnosis of both TB and COVID-19.

Nous décrivons l'expérience de l'intégration du dépistage et du test COVID-19 dans une unité mobile de dépistage de la TB à Lima, au Pérou. Toutes les personnes présentes ont reçu des radiographies pulmonaires, qui ont été analysées à l'aide de CAD4TB et CAD4COVID ; Xpert® MTB/RIF Ultra a été utilisé pour le dépistage de la TB, et les anticorps et la réaction en chaîne par polymérase (PCR) pour le SARS-CoV-2. Un cas de TB Xpert-positif a été diagnostiqué pour 168 personnes dépistées, une personne présentant des anticorps du SARS-CoV-2 pour 3 personnes dépistées et une infection du SARS-CoV-2 confirmée par PCR pour 8 personnes dépistées. Le dépistage intégré peut contribuer à éviter les retards dans le diagnostic de la TB et du COVID-19.

Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Radiculopatía compresiva C5-C6 secundaria a disección espontánea de la arteria vertebral derecha / Compressive C5-C6 radiculopathy secondary to spontaneous vertebral artery dissection

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Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

Focus on biological identity of endothelial progenitors cells.

Circulating Endothelial Progenitor Cells (EPCs) were discovered by Asahara et al in 1997 and defined as bone marrow CD34+/KDR+ cells endowed with angiogenic potentialities in vitro and in vivo. The most likely assumption is that EPCs consist of several cell subpopulations with functions targeted at accomplishing the post-natal neovascularization process in a synergic and complementary fashion. Indeed, the subsequent identification of numerous and differentiated hematic populations, characterized by the capacity to develop an endothelial phenotype, has posed a number of questions as to the real identity of EPCs. This concept does not represent a sterile speculation but rather it suggests important implications for the future practice of stem cell therapy. The aim of this report was to explore through a critical analysis the two main experimental methodologies, in vitro culture and flow cytometry, applied to EPCs, followed by a brief revaluation of the endothelial progenitors employing a globally functional approach.

Prevalence of red ear syndrome in juvenile primary headaches.

BACKGROUND: Previous studies have suggested a relationship between 'red ear syndrome' (RES) and pediatric migraine. Aims of this study were (i) to assess the frequency, specificity and sensitivity of RES in a population of pediatric migraineurs and (ii) to establish the pathophysiological mechanisms of RES associated with migraine. METHODS AND RESULTS: A total of 226 children suffering from headache (aged 4-17 years) were enrolled. One hundred and seventy-two (76.4%) were affected by migraine, the remaining 54 (23.6%) by other primary headaches. RES was followed significantly more frequently by migraine (23.3%; p < .0001), and was characterized by high specificity and positive predictive value (96.3 and 95.3%, respectively). According to the univariate statistical analysis, RES showed a statistically significant association with male gender, throbbing quality of the pain, vomiting and phonophobia. It was confirmed by a multivariate stepwise logistic regression model only for the throbbing quality of the pain, vomiting and male gender. CONCLUSIONS: Our study showed that (i) in children, RES is a highly specific sign for migraine. In addition, the evidence of an association of RES with some migraine features partially provoked by the parasympathetic system supports the hypothesis of a shared pathophysiological background (e.g. via the activation of the trigeminal-autonomic reflex).

A double-blind cross-over trial of amantadine hydrochloride in Friedreich's ataxia.

We performed a double-blind cross-over study with amantadine hydrochloride in 12 patients with Friedreich's disease and 2 with autosomal dominant cerebellar ataxia. Patients were randomly assigned to a placebo-amantadine or amantadine-placebo sequence. The interval between the treatments was two weeks. Patients were graded according to a functional ataxia scoring scale and videotaped in basal conditions and 90 min after a single oral dose of 100 mg amantadine or placebo. Three evaluators independently scored the videotapes. Statistical analysis showed no significant effect of amantadine in Friedreich's disease.