Physical Agent Modalities in Early Osteoarthritis: A Scoping Review

Early osteoarthritis (EOA) still represents a challenge for clinicians. Although there is no consensus on its definition and diagnosis, a prompt therapeutic intervention in the early stages can have a significant impact on function and quality of life. Exercise remains a core treatment for EOA; however, several physical modalities are commonly used in this population. The purpose of this paper is to investigate the role of physical agents in the treatment of EOA. A technical expert panel (TEP) of 8 medical specialists with expertise in physical agent modalities and musculoskeletal conditions performed the review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model. The TEP searched for evidence of the following physical modalities in the management of EOA: “Electric Stimulation Therapy”, “Pulsed Electromagnetic field”, “Low-Level Light Therapy”, “Laser Therapy”, “Magnetic Field Therapy”, “Extracorporeal Shockwave Therapy”, “Hyperthermia, Induced”, “Cryotherapy”, “Vibration therapy”, “Whole Body Vibration”, “Physical Therapy Modalities”. We found preclinical and clinical data on transcutaneous electrical nerve stimulation (TENS), extracorporeal shockwave therapy (ESWT), low-intensity pulsed ultrasound (LIPUS), pulsed electromagnetic fields stimulation (PEMF), and whole-body vibration (WBV) for the treatment of knee EOA. We found two clinical studies about TENS and PEMF and six preclinical studies—three about ESWT, one about WBV, one about PEMF, and one about LIPUS. The preclinical studies demonstrated several biological effects on EOA of physical modalities, suggesting potential disease-modifying effects. However, this role should be better investigated in further clinical studies, considering the limited data on the use of these interventions for EOA patients

Cluster of travel-associated Legionnaires' disease in Lazise, Italy, July to August 2011

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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

Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged

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

Silver Oxide Coatings with High Silver-Ion Elution Rates and Characterization of Bactericidal Activity.

This paper reports the synthesis and characterization of silver oxide films for use as bactericidal coatings. Synthesis parameters, dissolution/elution rate, and bactericidal efficacy are reported. Synthesis conditions were developed to create AgO, Ag₂O, or mixtures of AgO and Ag₂O on surfaces by reactive magnetron sputtering. The coatings demonstrate strong adhesion to many substrate materials and impede the growth of all bacterial strains tested. The coatings are effective in killing Escherichia coli and Staphylococcus aureus, demonstrating a clear zone-of-inhibition against bacteria growing on solid media and the ability to rapidly inhibit bacterial growth in planktonic culture. Additionally, the coatings exhibit very high elution of silver ions under conditions that mimic dynamic fluid flow ranging between 0.003 and 0.07 ppm/min depending on the media conditions. The elution of silver ions from the AgO/Ag₂O surfaces was directly impacted by the complexity of the elution media, with a reduction in elution rate when examined in complex cell culture media. Both E. coli and S. aureus were shown to bind ~1 ppm Ag⁺/mL culture. The elution of Ag⁺ resulted in no increases in mammalian cell apoptosis after 24 h exposure compared to control, but apoptotic cells increased to ~35% by 48 and 72 h of exposure. Taken together, the AgO/Ag₂O coatings described are effective in eliciting antibacterial activity and have potential for application on a wide variety of surfaces and devices

Large community-acquired Legionnaires’ disease outbreak caused by Legionella pneumophila serogroup 1, Italy, July to August 2018

In July 2018, a large outbreak of Legionnaires\u2019 disease (LD) caused by Legionella pneumophila serogroup 1 (Lp1) occurred in Bresso, Italy. Fifty-two cases were diagnosed, including five deaths. We performed an epidemiological investigation and prepared a map of the places cases visited during the incubation period. All sites identified as potential sources were investigated and sampled. Association between heavy rainfall and LD cases was evaluated in a case-crossover study. We also performed a case\u2013control study and an aerosol dispersion investigation model. Lp1 was isolated from 22 of 598 analysed water samples; four clinical isolates were typed using monoclonal antibodies and sequence-based typing. Four Lp1 human strains were ST23, of which two were Philadelphia and two were France-Allentown subgroup. Lp1 ST23 France-Allentown was isolated only from a public fountain. In the case-crossover study, extreme precipitation 5\u20136 days before symptom onset was associated with increased LD risk. The aerosol dispersion model showed that the fountain matched the case distribution best. The case\u2013control study demonstrated a significant eightfold increase in risk for cases residing near the public fountain. The three studies and the matching of clinical and environmental Lp1 strains identified the fountain as the source responsible for the epidemic

Silver Oxide Coatings with High Silver-Ion Elution Rates and Characterization of Bactericidal Activity.

This paper reports the synthesis and characterization of silver oxide films for use as bactericidal coatings. Synthesis parameters, dissolution/elution rate, and bactericidal efficacy are reported. Synthesis conditions were developed to create AgO, Ag₂O, or mixtures of AgO and Ag₂O on surfaces by reactive magnetron sputtering. The coatings demonstrate strong adhesion to many substrate materials and impede the growth of all bacterial strains tested. The coatings are effective in killing Escherichia coli and Staphylococcus aureus, demonstrating a clear zone-of-inhibition against bacteria growing on solid media and the ability to rapidly inhibit bacterial growth in planktonic culture. Additionally, the coatings exhibit very high elution of silver ions under conditions that mimic dynamic fluid flow ranging between 0.003 and 0.07 ppm/min depending on the media conditions. The elution of silver ions from the AgO/Ag₂O surfaces was directly impacted by the complexity of the elution media, with a reduction in elution rate when examined in complex cell culture media. Both E. coli and S. aureus were shown to bind ~1 ppm Ag⁺/mL culture. The elution of Ag⁺ resulted in no increases in mammalian cell apoptosis after 24 h exposure compared to control, but apoptotic cells increased to ~35% by 48 and 72 h of exposure. Taken together, the AgO/Ag₂O coatings described are effective in eliciting antibacterial activity and have potential for application on a wide variety of surfaces and devices