Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Histomorphologic Characterization of Noncarious and Caries-Affected Dentin/Adhesive Interfaces

PURPOSE: The purpose of this study was to compare the dentin/adhesive interfacial characteristics when bonding to noncarious as well as caries-affected dentin. MATERIALS AND METHODS: Seven extracted, unerupted, third molars were sectioned into halves. Artificial caries was created on one-half of each tooth, leaving the other half as a control. Dentin surfaces were treated with UNO adhesive according to the manufacturer's instructions for the wet-bonding technique and under environmental conditions present in the oral cavity. Dentin/adhesive interface sections of each half-tooth were stained with Goldner's trichrome, a classic bone stain, and examined using light microscopy. The width of exposed collagen was measured directly from photomicrographs, and adhesive penetration was analyzed qualitatively. RESULTS: The degree and extent to which the adhesive encapsulated the demineralized dentin matrix were reflected in the color difference in the stained sections with the noncarious dentin sections showing a degree of collagen encapsulation superior to that of the caries-affected dentin sections. The overall mean widths of exposed collagen were significantly (p < or = .05) greater at the caries-affected dentin/adhesive interface, 8.6 (1.7) microm, as compared with those at the noncarious dentin/adhesive interface, 6.0 (1.5) microm. CONCLUSIONS: The morphologic characteristics of the caries-affected dentin/interface suggest an increase in the exposed collagen zone and a decrease in the quality of the adhesive infiltration when compared with noncarious dentin. The evidence suggests that dentin substrate characteristics have a significant effect on the dentin/adhesive interface structure.     

Comparison of parent and teacher reports of attention-deficit/hyperactivity disorder symptoms from two placebo-controlled studies of atomoxetine in children.

BACKGROUND: The validity of parent reports regarding children's attention-deficit/hyperactivity disorder (ADHD) symptoms has been questioned. This study assessed whether parent reports were as sensitive as teacher reports to document change in ADHD symptoms during clinical trials with atomoxetine. METHODS: Data were compared from two randomized, double-blind, placebo-controlled clinical trials of atomoxetine using different versions (parent or teacher) of the same rating scale (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV [parent or teacher] Version: Investigator Administered and Scored - ADHD RS). Exclusion criteria included history of bipolar disorder, psychosis, seizures, alcohol abuse, or positive drug screen. Patients (6-16 years old) were treated with atomoxetine (titrated to a maximum dose of 1.8 mg/kg/day) administered once daily for up to 7 weeks. Parent and teacher ratings were compared using an analysis of covariance (ANCOVA) model. RESULTS: The analysis (n = 318) showed that treatment effects (mean change, baseline to endpoint) were similar between parent and teacher ratings (total, p = .762; inattention, p = .519; hyperactive/impulsive, p = .955). Effect sizes also were similar based on total scores (parent ratings = .69; teacher ratings = .63). CONCLUSIONS: Parent reports are as sensitive as teacher reports in assessing the efficacy of long-acting pharmacologic treatment for ADHD in children during clinical trials using the nonstimulant atomoxetine.     

Socioeconomic determinants of health related quality of life in childhood and adolescence: results from a European study

Socioeconomic determinants of health related quality of life in childhood and adolescence: results from a European study . von Rueden , U. , Gosch , A. , Rajmil , L. , Bisegger , C. , Ravens-Sieberer , U. , the European KIDSCREEN group ( 2006 ) Journal of Epidemiology and Community Health , 60 , 130 – 135 .     

On the Edge: a drama‐based mental health education programme on early psychosis for schools

Aims: On the Edge is a mental health education programme designed to support early intervention by increasing knowledge and understanding of early psychosis, reducing the stigma associated with mental health issues and improving awareness of avenues of help. The target audience was young people aged 14–22 years in schools and colleges. Methods: An interactive drama programme was developed through collaborative working across psychiatry, applied drama and those with direct experience of psychosis. A national tour engaged 2500 students in 71 performances that took place in 51 schools and colleges. The programme was evaluated against its aims with data collected both during and after the tour. Results: Quantitative and qualitative evaluation found significant gains with respect to all three aims. Thirty‐one schools developed supportive links with local mental health services. Conclusions: This programme shows the value and effectiveness of delivering health education on early psychosis through the medium of applied drama, and offers a model for a programme that can be incorporated into early intervention services. Lessons learned through delivering this programme are a valuable contribution towards future developments of mental health education programmes for schools.     

Gated myocardial perfusion single photon emission computed tomography in the clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial, Veterans Administration Cooperative study no. 424

Background  Stress gated myocardial perfusion single photon emission computed tomography (gSPECT) is increasingly used before and after intercurrent therapeutic intervention and is the basis for ongoing evaluation in the Department of Veterans Affairs clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial. Methods and Results  The COURAGE trial is a North American multicenter randomized clinical trial that enrolled 2287 patients to aggressive medical therapy vs percutaneous coronary intervention plus aggressive medical therapy. Three COURAGE nuclear substudies have been designed. The goals of substudy 0 are to examine the diagnostic accuracy of the extent and severity of inducible ischemia at baseline in COURAGE patients compared with patient symptoms and quantitative coronary angiography and to explore the relationship between inducible ischemia and the benefit from revascularization when added to medical therapy. Substudy 1 will correlate the extent and severity of provocative ischemia with the frequency, quality, and instability of recurrent symptoms in postcatheterization patients. Substudy 2 (n _ 300) will examine the usefulness of sequential gSPECT monitoring 6 to 18 months after therapeutic intervention. Together, these nuclear substudies will evaluate the role of gSPECT to determine the effectiveness of aggressive risk-factor modifications, lifestyle interventions, and anti-ischemic medical therapies with or without revascularization in reducing patients’ ischemic burdens. Conclusions  The unfolding of evidence on the application of gSPECT in trials such as COURAGE defines a new era for nuclear cardiology. We hope the evidence that emerges from the COURAGE trial will further establish the role of nuclear imaging in the evidence-based management of patients with stable coronary disease. The COURAGE trial was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development in collaboration with the Canadian Institutes of Health Research. Unrestricted research grants were obtained from Merck & Co; Pfizer Pharmaceuticals; Bristol-Myers Squibb Medical Imaging; Astellas Pharma; Kos Pharmaceuticals; Data Scope; Astra Zeneca Pharmaceuticals; Astra-Zeneca-Canada; Schering-Plough Coorporation, Ltd; Sanofi-Aventis, Inc; First Horizon; and GE Healthcare. All industrial funding for this trial was directed through the Department of Veterans Affairs. Additional funding for this substudy was provided by grants to the Department of Veterans Affairs and Canadian Institutes of Health Research from Astellas Pharma and Bristol-Myers-Squibb Medical Imaging.     

Neurological disorders and violence: a systematic review and meta-analysis with a focus on epilepsy and traumatic brain injury

The objectives of this study were to systematically review and meta-analyze the research literature on the association of common neurological disorders and violence. Keywords relating to neurological disorders and violence were searched between 1966 and August 2008. Case–control and cohort studies were selected. Odds ratios of violence risk in particular disorders compared with controls were combined using fixed-effects meta-analysis with the data presented in forest plots. Sensitivity analyses were conducted to identify possible differences in risk estimates across surveys. Information on risk factors for violence was extracted if replicated in more than one study. Nine studies were identified that compared the risk of violence in epilepsy or traumatic brain injury compared with unaffected controls. For the epilepsy studies, the overall pooled odds ratio for violent outcomes was 0.67 [95% confidence interval (CI) 0.46–0.96]. For traumatic brain injury, the odds ratio was 1.66 (95% CI 1.12–2.31). An additional 11 case–control studies investigated factors associated with violence in epilepsy and traumatic brain injury. It was not possible to meta-analyze these data. Comorbid psychopathology was associated with violence. Data on other neurological conditions was limited and unreplicated. In conclusion, although the evidence was limited and methodological quality varied, epilepsy and traumatic brain injury appeared to differ in their risk of violence compared with control populations. Longitudinal studies are required to replicate this review’s provisional findings that epilepsy is inversely associated with violence and that brain injury modestly increases the risk, and further research is needed to provide information on a broader range of risk factors.