Intra-Articular Hybrid Hyaluronic Acid Injection Treatment in Overweight Patients with Knee Osteoarthritis: A Single-Center, Open-Label, Prospective Study

Abstract: Background: A BMI > 25 is the most decisive, albeit modifiable, risk factor for knee osteoarthritis (KOA). This study aimed at assessing the efficacy of intra-articular injections of hybrid hyaluronic acid (HA) complexes (Sinovial® H-L) for the treatment of KOA in overweight patients in terms of disease severity, cardiocirculatory capacity, and quality of life. Materials: In this single-site, open-label, prospective trial, 37 patients with symptomatic knee OA were assessed at baseline and 3 months after ultrasound-guided intra-articular injection of hybrid HA complexes (Sinovial® H-L). Results: Primary variables displaying a statistically significant improvement after treatment were pain (VAS), disease severity (WOMAC), and cardiopulmonary capacity (6 min walk test). Among secondary variables, quality of life (SF-12) improved significantly, as did analgesic intake for pain control. No statistically significant difference was observed in body fat and muscle mass percentage measured by bioelectrical impedance analysis. Conclusions: Intra-articular hybrid HA injections are significantly effective in improving OA-related disease severity, cardiopulmonary function, and analgesic intake. This supports the role of hybrid HA viscosupplementation as a nonpharmacological treatment to relieve pain, reduce disability, improve quality of life, and limit the risk of polypharmacy in overweight patients with knee OA

NUDT2 initiates viral RNA degradation by removal of 5′-phosphates.

While viral replication processes are largely understood, comparably little is known on cellular mechanisms degrading viral RNA. Some viral RNAs bear a 5 '-triphosphate (PPP-) group that impairs degradation by the canonical 5 '-3 ' degradation pathway. Here we show that the Nudix hydrolase 2 (NUDT2) trims viral PPP-RNA into monophosphorylated (P)-RNA, which serves as a substrate for the 5 '-3 ' exonuclease XRN1. NUDT2 removes 5 '-phosphates from PPP-RNA in an RNA sequence- and overhang-independent manner and its ablation in cells increases growth of PPP-RNA viruses, suggesting an involvement in antiviral immunity. NUDT2 is highly homologous to bacterial RNA pyrophosphatase H (RppH), a protein involved in the metabolism of bacterial mRNA, which is 5 '-tri- or diphosphorylated. Our results show a conserved function between bacterial RppH and mammalian NUDT2, indicating that the function may have adapted from a protein responsible for RNA turnover in bacteria into a protein involved in the immune defense in mammals. RNA of some viruses is protected from degradation by a 5 ' triphosphate group. Here the authors identify nudix hydrolase 2 (NUDT2) as novel antiviral defense protein that dephosphorylates viral RNA and thereby enables its degradation.We thank the core facility of the MPI of biochemistry for support

Characterization of the mode of action of a potent dengue virus capsid inhibitor

Dengue viruses (DV) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. In spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of DV infection. We have previously reported the identification of ST-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against DV in vitro and in vivo (C. M. Byrd et al., Antimicrob. Agents Chemother. 57:15–25, 2013, doi:10 .1128/AAC.01429-12). In the present study, we investigated the mode of action of this promising compound by using a combination of biochemical, virological, and imaging-based techniques. We confirmed that ST-148 targets the capsid protein and obtained evidence of bimodal antiviral activity affecting both assembly/release and entry of infectious DV particles. Importantly, by using a robust bioluminescence resonance energy transfer-based assay, we observed an ST-148-dependent increase of capsid self-interaction. These results were corroborated by molecular modeling studies that also revealed a plausible model for compound binding to capsid protein and inhibition by a distinct resistance mutation. These results suggest that ST-148-enhanced capsid protein self-interaction perturbs assembly and disassembly of DV nucleocapsids, probably by inducing structural rigidity. Thus, as previously reported for other enveloped viruses, stabilization of capsid protein structure is an attractive therapeutic concept that also is applicable to flaviviruses

Computational cluster validation for microarray data analysis: experimental assessment of Clest, Consensus Clustering, Figure of Merit, Gap Statistics and Model Explorer

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

An international trial of quantitative PCR for monitoring Legionella in artificial water systems

To perform an international trial to derive alert and action levels for the use of quantitative PCR (qPCR) in the monitoring of Legionella to determine the effectiveness of control measures against legionellae. Laboratories (7) participated from six countries. Legionellae were determined by culture and qPCR methods with comparable detection limits. Systems were monitored over ≥10 weeks. For cooling towers (232 samples), there was a significant difference between the log mean difference between qPCR (GU l −1) and culture (CFU l −1) for Legionella pneumophila (0·71) and for Legionella spp. (2·03). In hot and cold water (506 samples), the differences were less, 0·62 for Leg. pneumophila and 1·05 for Legionella spp. Results for individual systems depended on the nature of the system and its treatment. In cooling towers, Legionella spp. GU l −1 always exceeded CFU l −1, and usually Legionella spp. were detected by qPCR when absent by culture. The pattern of results by qPCR for Leg. pneumophila followed the culture trend. In hot and cold water, culture and qPCR gave similar results, particularly for Leg. pneumophila. There were some marked exceptions with temperatures ≥50°C, or in the presence of supplementary biocides. Action and alert levels for qPCR were derived that gave results comparable to the application of the European Guidelines based on culture. Algorithms are proposed for the use of qPCR for routine monitoring. Action and alert levels for qPCR can be adjusted to ensure public health is protected with the benefit that remedial actions can be validated earlier with only a small increase in the frequency of action being required. This study confirms it is possible to derive guidelines on the use of qPCR for monitoring the control of legionellae with consequent improvement to response and public health protection

Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial

BACKGROUND AND AIM: Low plasma vitamin D levels have been associated with heart failure (HF). This research attempts to explain the role of vitamin D supplementation on myocardial function in elderly patients with HF. METHODS AND RESULTS: Twenty-three chronic HF patients were randomized in a small parallel group, double-blind, placebo-controlled trial. All patients, with a mean age of 74 years and vitamin D levels <30 ng/mL, received 800,000 IU (4000 IU/daily) of cholecalciferol or placebo for 6 months. The outcomes measured at baseline and after 6 months were ejection fraction (EF) and other echocardiography parameters, carboxyterminal propeptide of procollagen type I (PIP), natriuretic peptides, lipid profile, renin, parathyroid hormone, blood pressure, and body mass index (BMI). In 13 patients under active treatment for 6 months, mean plasma 25-hydroxy vitamin D concentrations (15.51 vs. -1.40 ng/mL, p < 0.001) and plasma calcium (from 9.3 to 9.6 mmol/L, p < 0.05) increased significantly. However, other biomarkers of bone metabolism did not differ between the treatment and placebo groups. EF increased significantly in the intervention group (6.71 vs. -4.3%; p < 0.001), and the serum concentration of PIP increased only in the placebo group after 6 months (1140.98 vs. -145 mcg/L; p < 0.05). Systolic blood pressure was lower after 6 months of cholecalciferol treatment (from 129.6 to 122.7 mm Hg, p < 0.05). No significant variations were observed for other parameters. CONCLUSIONS: Six months of vitamin D supplementation significantly improves EF in elderly patients with HF and vitamin D deficiency

Dengue Virus Non-structural Protein 1 Modulates Infectious Particle Production via Interaction with the Structural Proteins

Non-structural protein 1 (NS1) is one of the most enigmatic proteins of the Dengue virus (DENV), playing distinct functions in immune evasion, pathogenesis and viral replication. The recently reported crystal structure of DENV NS1 revealed its peculiar three-dimensional fold; however, detailed information on NS1 function at different steps of the viral replication cycle is still missing. By using the recently reported crystal structure, as well as amino acid sequence conservation, as a guide for a comprehensive site-directed mutagenesis study, we discovered that in addition to being essential for RNA replication, DENV NS1 is also critically required for the production of infectious virus particles. Taking advantage of a trans-complementation approach based on fully functional epitope-tagged NS1 variants, we identified previously unreported interactions between NS1 and the structural proteins Envelope (E) and precursor Membrane (prM). Interestingly, coimmunoprecipitation revealed an additional association with capsid, arguing that NS1 interacts via the structural glycoproteins with DENV particles. Results obtained with mutations residing either in the NS1 Wing domain or in the β-ladder domain suggest that NS1 might have two distinct functions in the assembly of DENV particles. By using a trans-complementation approach with a C-terminally KDEL-tagged ER-resident NS1, we demonstrate that the secretion of NS1 is dispensable for both RNA replication and infectious particle production. In conclusion, our results provide an extensive genetic map of NS1 determinants essential for viral RNA replication and identify a novel role of NS1 in virion production that is mediated via interaction with the structural proteins. These studies extend the list of NS1 functions and argue for a central role in coordinating replication and assembly/release of infectious DENV particles

Progenitori endoteliali circolanti ed apoptosi in pazienti con scompenso cardiaco

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