Unimpaired Neuropsychological Performance and Enhanced Memory Recall in Patients with Sbma: A Large Sample Comparative Study.

Peculiar cognitive profile of patients with SBMA has been described by fragmented literature. Our retrospective study reports the neuropsychological evaluations of a large cohort of patients in order to contribute towards the understanding of this field. We consider 64 neuropsychological evaluations assessing mnesic, linguistic and executive functions collected from 2013 to 2015 in patients attending at Motor Neuron Disease Centre of University of Padova. The battery consisted in: Digit Span forwards and backwards, Prose Memory test, Phonemic Verbal fluency and Trail making tests. ANCOVA statistics were employed to compare tests scores results with those obtained from a sample of healthy control subjects. Multiple linear regressions were used to study the effect on cognitive performance of CAG-repeat expansion, the degree of androgen insensitivity and their interaction to cognitive performance. Statistical analyses did not reveal altered scores in any neuropsychological tests among those adopted. Interestingly, patients performed significantly better in the Prose Memory test's score. No relevant associations were found with genetic, hormonal or clinical patients' profile. Results inconsistent with previous studies have been interpreted according to the phenomenon of somatic mosaicism. We suggest a testosterone-related and the mood state-dependant perspectives as two possible interpretations of the enhanced performances in the Prose Memory test. Further studies employing more datailed tests batteries are encouraged

Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure.

The G protein-coupled receptor kinase-2 (GRK2 or beta-ARK1) regulates beta-adrenergic receptors (beta-ARs) in the heart, and its cardiac expression is elevated in human heart failure (HF). We sought to determine whether myocardial levels and activity of GRK2 could be monitored using white blood cells, which have been used to study cardiac beta-ARs. Moreover, we were interested in determining whether GRK2 levels in myocardium and lymphocytes may be associated with beta-AR dysfunction and HF severity.In myocardial biopsies from explanted failing human hearts, GRK activity was inversely correlated with beta-AR-mediated cAMP production (R(2)=-0.215, P<0.05, n=24). Multiple regression analysis confirmed that GRK activity participates with beta-AR density to regulate catecholamine-sensitive cAMP responses. Importantly, there was a direct correlation between myocardial and lymphocytes GRK2 activity (R(2)=0.5686, P<0.05, n=10). Lymphocyte GRK activity was assessed in HF patients with various ejection fractions (EFs) (n=33), and kinase activity was significantly higher in patients with lower EFs and was higher with increasing NYHA class (P<0.001).Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of beta-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF

PPARγ is a Major Driver of the Accumulation and Phenotype of Adipose-Tissue TregT_{reg} Cells

Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T $(T_{reg})$ cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the ‘master regulator’ of adipocyte differentiation, as a crucial molecular orchestrator of VAT $T_{reg}$ cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT $T_{reg}$ cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of $T_{reg}$ cells with unique functions can be precisely targeted to therapeutic ends

Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis

Objectives To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). Methods Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). Results BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p1 joint 10.6 (95% CI 1.9 to 60.4, p<0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1–132.8, p<0.01). Conclusions In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in >1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis

Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients.

Increased levels of G protein coupled receptor kinase GRK2 appear to participate in hypertension presumably through the desensitization of beta adrenergic receptors (betaARs) that mediate vasodilatation. There are contrasting data on the occurrence of betaAR desensitization in the vasculature, we therefore investigated betaAR vasodilatation and desensitization in normotensives and in hypertensive humans. In blood lymphocytes, we assessed betaAR signaling and GRK2 expression and found betaAR signaling alterations and, consistent with desensitization, ncreased GRK2 levels in hypertensives. We studied in vivo vasodilatation to the betaAR agonist isoproterenol (ISO) injected in the brachia artery in control conditions and during the concomitant infusion of heparin, a known in vitro nonspecific GRK inhibitor. ISO induced a dose-dependent vasorelaxation that was attenuated in hypertensives indicating a loss of betaAR signaling. Intra-arterial infusion of heparin nhibited lymphocyte GRK2 activity and prevented desensitization of betaAR vasodilatation in normotensives. In hypertensives, heparin restored vasodilatation to ISO, to levels observed in normotensives. Our results suggest that betaAR desensitization does indeed occur at the vascular levels in vivo, and that heparin by acting as a GRK inhibitor prevents this in normotensives and restores impaired betaAR vasodilation in hypertensives. We conclude that desensitization participates to impaired betaAR vasodilation in hypertension

AKT participates in endothelial dysfunction in hypertension.

In hypertension, reduced nitric oxide production and blunted endothelial vasorelaxation are observed. It was recently reported that AKT phosphorylates and activates endothelial nitric oxide synthase and that impaired kinase activity may be involved in endothelial dysfunction.To identify the physiological role of the kinase in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), we used adenoviral vectors to transfer the human AKT1 gene selectively to the common carotid endothelium. In vitro, endothelial vasorelaxations to acetylcholine, isoproterenol, and insulin were blunted in control carotids from SHR compared with WKY rats, and human AKT1 overexpression corrected these responses. Similarly, blood flow assessed in vivo by Doppler ultrasound was reduced in SHR compared with WKY carotids and normalized after AKT1 gene transfer. In primary cultured endothelial cells, we evaluated AKT phosphorylation, activity, and compartmentalization and observed a mislocalization of the kinase in SHR.We conclude that AKT participates in the settings of endothelial dysfunction in SHR rats by impaired membrane localization. Our data suggest that AKT is involved in endothelium dysfunction in hypertension

VOC 202012/01 Variant Is Effectively Neutralized by Antibodies Produced by Patients Infected before Its Diffusion in Italy

The coronavirus disease 2019 (Covid-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and presents a global health emergency that needs urgent intervention. Viruses constantly change through mutation, and new variants of a virus are expected to occur over time. In the United Kingdom (UK), a new variant called B.1.1.7 has emerged with an unusually large number of mutations. The aim of this study is to evaluate the level of protection of sera from 12 patients infected and later healed in Apulia Region (Italy) with Covid-19 between March and November 2020, when the English variant was not circulating in this territory yet, against the new VOC 202012/01 variant by seroneutralization assay. The sera of patients had already been tested before, using a virus belonging to the lineage B.1 and showed an antibody neutralizing titer ranging between 1:160 and 1:320. All the 12 sera donors confirmed the same titers of neutralizing antibodies obtained with a strain belonging to the lineage B.1.1.7 (VOC 202012/01). These data indicate that antibodies produced in subjects infected with variants of Sars-CoV-2 strain before the appearance of the English one, seem to have a neutralizing power also against this variant

Comparative life cycle environmental and economic assessment of anaerobic membrane bioreactor and disinfection for reclaimed water reuse in agricultural irrigation: A case study in Italy

Supplementary data are available online at https://www.sciencedirect.com/science/article/pii/S0959652621004212#appsec1 .Reuse of treated wastewater for irrigation purposes is a measure to reduce water stress and overexploitation of freshwater resources. This study aims to investigate the environmental and economic impacts of a current conventional wastewater treatment plant (WWTP) in Peschiera Borromeo (Milan, Italy), and compare possible scenarios to enable reclaimed water reuse for agriculture. Accordingly, we propose alternative disinfection methods (i.e. enhanced UV, peracetic acid) and replace conventional activated sludge (CAS) with upflow anaerobic sludge blanket (UASB) for biological treatment and use anaerobic membrane bioreactor (AnMBR) as the tertiary treatment. Life cycle assessment (LCA) and life cycle costing (LCC) were implemented on the existing full-scale wastewater treatment line and the hypothetical scenarios. In most cases, the impact categories are primarily influenced by fertilizer application and direct emissions to water (i.e. nutrients and heavy metals). The baseline scenario appears to have the largest environmental impact, except for freshwater eutrophication, human ecotoxicity and terrestrial ecotoxicity. As expected, water depletion is the most apparent impact category between the baseline and proposed scenarios. The UASB + AnMBR scenario gives relatively higher environmental benefits than the other proposed scenarios in climate change (−28%), fossil fuel depletion (−31%), mineral resource depletion (−52%), and terrestrial ecotoxicity compared to the baseline. On the other hand, the highest impact on freshwater eutrophication is also obtained by this scenario since the effluent from the anaerobic processes is rich in nutrients. Moreover, investment and operational costs vary remarkably between the scenarios, and the highest overall costs are obtained for the UASB + AnMBR line mostly due to the replacement of membrane modules (24% of the total cost). The results highlighted the importance of the life cycle approach to support decision making when considering possible upgrading scenarios in WWTPs for water reuse.This study was carried out within the framework of the ‘Digital-Water.City - DWC’ Innovation Action which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 820954. Alessia Foglia kindly acknowledges the Fondazione Cariverona for funding her PhD scholarship