Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome

: Rett syndrome is a rare genetic neurodevelopmental disease, affecting 1 in over 10,000 females born worldwide, caused by de novo mutations in the X-chromosome-located methyl-CpG-binding protein 2 (MeCP2) gene. Despite the great effort put forth by the scientific community, a therapy for this devastating disease is still needed. Here, we tested the therapeutic effects of a painless mutein of the Nerve Growth Factor, called human NGF painless (hNGFp), via a non-invasive intranasal delivery in female MeCP2+/- mice. Of note, previous work had demonstrated a broad biodistribution of hNGFp in the mouse brain by the nasal delivery route. We report that (1) the long-term lifelong treatment of MeCP2+/- mice with hNGFp, starting at 2 months of age, increased the chance of survival while also greatly improving behavioral parameters. Furthermore, when we assessed the phenotypic changes brought forth by (2) a short-term 1-month-long hNGFp-treatment, starting at 3 months of age (right after the initial presentation of symptoms), we observed the rescue of a well-known neuronal target population of NGF, cholinergic neurons in the medial septum. Moreover, we reveal a deficit in microglial morphology in MeCP2+/- mice, completely reversed in treated animals. This effect on microglia is in line with reports showing microglia to be a TrkA-dependent non-neuronal target cell population of NGF in the brain. To understand the immunomodulatory activity of hNGFp, we analyzed the cytokine profile after hNGFp treatment in MeCP2+/- mice, to discover that the treatment recovered the altered expression of key neuroimmune-communication molecules, such as fractalkine. The overall conclusion is that hNGFp delivered intranasally can ameliorate symptoms in the MeCP2+/- model of Rett syndrome, by exerting strong neuroprotection with a dual mechanism of action: directly on target neurons and indirectly via microglia

Protecting the historic centre of Venice. A coordinated analysis of the physical and perceived wear processes to define mitigating actions

The research aims to identify "physical" and "perceptual" wear factors of the historic center of Venice (with particular attention to the effects of anthropogenic pressure related to the phenomenon of tourism) and to assess the damages they could produce to identify criteria and tools of mitigation and control. Research is part of the Action Plan "Protection and conservation of the heritage", established by the Plan of Management for the UNESCO Site of Venice and its Lagoon. Through a systemic reading and analysis of the forces of change in place, this study identifies the " macro-emergencies", i.e. the main factors that adversely affect the site’s safeguarding. The research project "Evaluation of wear processes and critical factors of the City of Venice and its lagoon, and its impact on the site’s protection" is part of the actions set out by the Management Plan of the UNESCO site of Venice and its Lagoon. The main objective of the project is the identification of physical and perceptual factors of wear, which threaten the conservation of the historical and artistic heritage of the historic center of Venice, with a particular focus on the effects of anthropogenic pressure linked to tourism, and the evaluation of their level of danger. A further objective is the recognition of measurable parameters (indicators) for monitoring and, subsequently, mitigation strategies for the most significant phenomena

Psychological aspects in the management of patients with essential hypertension

The hypertensive patient is the most stable phenotype in psychosomatic medicine. Hypertensive patients represent a vulnerable population that deserves special attention from health care providers and systems, and psychosomatic medicine may be an important tool in the management of high blood pressure. Depression, anxiety disorders and personality features are often associated with elevated blood pressure (BP) and they may have a role in the development of mild high-renin essential hypertension. Besides, "white coat" hypertension and "masked" hypertension demonstrate how clinic blood pressure could be strongly related to trait anxiety. Hypertension is largely asymptomatic, and patients often have little understanding of the importance of achieving BP control. Medication adverse effects may become an important factor in poor adherence to the treatment and the antidepressant use increases the risk of hypertension. So, the challenge in the management of hypertensive patients is the adherence to non-pharmacological and behavioural treatments for hypertension

Combined search for the standard model Higgs boson decaying to a bb pair using the full CDF data set

We combine the results of searches for the standard model Higgs boson based on the full CDF Run II data set obtained from sqrt(s) = 1.96 TeV p-pbar collisions at the Fermilab Tevatron corresponding to an integrated luminosity of 9.45/fb. The searches are conducted for Higgs bosons that are produced in association with a W or Z boson, have masses in the range 90-150 GeV/c^2, and decay into bb pairs. An excess of data is present that is inconsistent with the background prediction at the level of 2.5 standard deviations (the most significant local excess is 2.7 standard deviations).Comment: To be published in Phys. Rev. Lett (v2 contains minor updates based on comments from PRL

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

Regional food trade and policy in West Africa in relation to structural adjustment

Drell-Yan lepton pairs are produced in the process $p\bar{p} \rightarrow e^+e^- + X$ through an intermediate $\gamma^*/Z$ boson. The lepton angular distributions are used to provide information on the electroweak-mixing parameter $sin^2\theta_W$ via its observable effective-leptonic $sin^2\theta_W$, or $sin^2\theta^{lept}_{eff}$. A new method to infer $sin^2\theta_W$, or equivalently, the W-boson mass M_W, is developed and tested using a previous CDF Run II measurement of angular distributions from electron pairs in a sample corresponding to 2.1 fb-1 of integrated luminosity from $p\bar{p}$ collisions at a center-of-momentum energy of 1.96 TeV. The value of $sin^2\theta^{lept}_{eff}$ is found to be 0.2328 +- 0.0011. Within a specified context of the standard model, this results in $sin^2\theta_W$ = 0.2246 +- 0.0011 which corresponds to a W-boson mass of 80.297 +- 0.055 GeV/c^2, in agreement with previous determinations in electron-position collisions and at the Tevatron collider

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon