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Levels of adult distress and ad lib alcohol consumption following interactions with child confederates were investigated in parents of children with no diagnosable psychiatric disorders. Sixty parents (20 married couples and 20 single mothers) interacted with boys trained to enact behaviors characteristic of either normal children or "deviant" children with externalizing behavior disorders--attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD). Relative to the normal child role, interactions with deviant confederates were rated as significantly more unpleasant, resulted in feelings of role inadequacy, and produced significantly more anxiety, depression, and hostility. After the interactions, parents were given the opportunity to drink as much of their preferred alcoholic beverage as they desired while anticipating a second interaction with the same child. The participants consumed more alcohol following exposure to deviant as opposed to normal confederates. [ABSTRACT FROM AUTHOR]

Background: Sclerosteosis, a severe autosomal recessive sclerosing skeletal dysplasia characterised by excessive bone formation, is caused by absence of sclerostin, a negative regulator of bone formation that binds LRP5/6 Wnt co-receptors. Current treatment is limited to surgical management of symptoms arising from bone overgrowth. This study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis., Methods: Recombinant wild type mouse sclerostin (mScl) and novel mScl fusion proteins containing a C-terminal human Fc (mScl hFc), or C-terminal human Fc with a poly-aspartate motif (mScl hFc PD), were produced and purified using mammalian expression and standard chromatography methods. In vitro functionality and efficacy of the recombinant proteins were evaluated using three independent biophysical techniques and an in vitro bone nodule formation assay. Pharmacokinetic properties of the proteins were investigated in vivo following a single administration to young female wild type (WT) or SOST knock out (SOST -/- ) mice. In a six week proof-of-concept in vivo study, young female WT or SOST -/- mice were treated with 10 mg/kg mScl hFc or mScl hFc PD (weekly), or 4.4 mg/kg mScl (daily). The effect of recombinant sclerostin on femoral cortical and trabecular bone parameters were assessed by micro computed tomography (μCT)., Results: Recombinant mScl proteins bound to the extracellular domain of the Wnt co-receptor LRP6 with high affinity (nM range) and completely inhibited matrix mineralisation in vitro . Pharmacokinetic assessment following a single dose administered to WT or SOST -/- mice indicated the presence of hFc increased protein half-life from less than 5 min to at least 1.5 days. Treatment with mScl hFc PD over a six week period resulted in modest but significant reductions in trabecular volumetric bone mineral density (vBMD) and bone volume fraction (BV/TV), of 20% and 15%, respectively., Conclusion: Administration of recombinant mScl hFc PD partially corrected the high bone mass phenotype in SOST -/- mice, suggesting that bone-targeting of sclerostin engineered to improve half-life was able to negatively regulate bone formation in the SOST -/- mouse model of sclerosteosis., The Translational Potential of This Article: These findings support the concept that exogenous sclerostin can reduce bone mass, however the modest efficacy suggests that sclerostin replacement may not be an optimal strategy to mitigate excessive bone formation in sclerosteosis, hence alternative approaches should be explored., Competing Interests: MS, CD, KG, MP, PC, AK, HZK and GH are/have been employees of UCB Pharma and may hold UCB Pharma shares and/or stock options. TD and VN declare no competing interests., (© 2021 The Authors.)

Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by pathogenic immunoglobulin G (IgG) autoantibodies that bind to platelets, causing their phagocytic removal and leading to reductions in platelet number. The neonatal Fc receptor (FcRn) selectively salvages and recycles IgG, including pathogenic IgG, thereby extending the half-life of IgG in plasma. Two anti-mouse FcRn monoclonal antibodies (mAb) (4470 and 4464) were generated to evaluate the effect of inhibiting IgG recycling. Statistically significant reductions in plasma IgG concentration were observed upon administration of 4470 (10, 30 and 100 mg/kg) in wild-type mice. In a passive mouse model of ITP, 4464 alleviated the reduction in platelet number and/or preserved newly produced platelets when dosed prophylactically as well as in a therapeutic dosing regimen once platelet numbers had already been reduced. These results support the investigation of anti-FcRn therapy as a potential treatment for ITP., (Copyright © 2018. Published by Elsevier B.V.)

Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

Administration of antibodies to sclerostin (Scl-Ab) has been shown to increase bone mass, bone mineral density (BMD) and bone strength by increasing bone formation and decreasing bone resorption in both animal studies and human clinical trials. In these studies, the magnitude and rate of increase in bone formation markers is attenuated upon repeat dosing with Scl-Ab despite a continuous and progressive increase in BMD. Here, we investigated whether the attenuation in the bone formation response following repeated administration of Scl-Ab was associated with increased expression of secreted antagonists of Wnt signalling and determined how the circulating marker of bone formation, P1NP, responded to single, or multiple doses, of Scl-Ab four days post-dosing. Female Balb/c mice were treated with Scl-Ab and we demonstrated that the large increase in serum P1NP observed following the first dose was reduced following administration of multiple doses of Scl-Ab. This dampening of the P1NP response was not due to a change in the kinetics of the bone formation marker response, or differences in exposure to the drug. The abundance of transcripts encoding several secreted Wnt antagonists was determined in femurs collected from mice following one or six doses of Scl-Ab, or vehicle treatment. Compared with vehicle controls, expression of SOST, SOST-DC1, DKK1, DKK2, SFRP1, SFRP2, FRZB, SFRP4 and WIF1 transcripts was significantly increased (approximately 1.5-4.2 fold) following a single dose of Scl-Ab. With the exception of SFRP1, these changes were maintained or further increased following six doses of Scl-Ab and the abundance of SFRP5 was also increased. Up-regulation of these Wnt antagonists may exert a negative feedback to increased Wnt signalling induced by repeated administration of Scl-Ab and could contribute to self-regulation of the bone formation response over time. After an antibody-free period of four weeks or more, the P1NP response was comparable to the naïve response, and a second phase of treatment with Scl-Ab following an antibody-free period elicited additional gains in BMD. Together, these data demonstrate that the rapid dampening of the bone formation response in the immediate post-dose period which occurs after repeat dosing of Scl-Ab is associated with increased expression of Wnt antagonists, and a treatment-free period can restore the full bone formation response to Scl-Ab., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to assess the implementation of a novel ED model of care, which combines clinical streaming, team-based assessment and early senior consultation to reduce length of stay., Methods: A pre-post-intervention study was used to compare ED performance following an extensive clinical redesign programme. Clinical teams and work sequences were reconfigured to promote the role of the staff specialist, with a focus on earlier decisions regarding disposition. Primary outcome measures were ED length of stay and National Emergency Access Target (NEAT) compliance. Secondary outcomes included referral and workup times, wait times by triage category, ambulance offload times, ward discharges and unit transfers within 24 h of admission, representation within 48 h, and Medical Emergency Response Team (MERT) calls within 24 h of admission., Results: Two seasonally matched 26 week intervals were compared with adjustment for demographics, triage category and arrival by ambulance. Overall, there was an 18.4% rise in NEAT performance (95% confidence interval (CI): 17.7-19.1) while ED length of stay decreased by a total of 86.8 min (95% CI: 83.6-90.1). Time series analysis did not suggest any preexisting trends to explain these results. The average time to referral decreased by 74.7 min (95% CI: 69.8-79.6) and waiting times decreased across all triage categories. Rates of MERT activation and unplanned representation were unchanged., Conclusion: A facilitated team leader role for senior doctors can help to reduce length of stay by via early disposition, without significant risks to the patient., (© 2017 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Purpose: This research investigated a first step in implementing the dynamic assessment (DA) component of Triadic Gaze Intervention (Olswang, Feuerstein, Pinder, & Dowden, 2013; Olswang et al., 2014), an evidence-based protocol for teaching early signals of communication to young children with physical disabilities. Clinician attitudes about adopting external evidence into practice and implementation fidelity in DA protocol delivery were examined following training., Method: Seven early intervention clinicians from multiple disciplines were trained to deliver the four essential elements of the DA protocol: (a) provide communication opportunity, (b) recognize child's potentially communicative signal, (c) shape child's signal toward triadic gaze, and (d) reinforce with play. Clinician attitude regarding adopting evidence into practice was measured at baseline and follow-up, with the Evidence-Based Practice Attitude Scale (Aarons, 2004). Implementation fidelity in delivering the protocol was measured for adherence (accuracy) and competence (quality) during trial implementation., Results: Clinicians' attitudes about trying new evidence that at first was perceived as incongruent with their practice improved over the course of the research. Clinicians demonstrated strong adherence to the DA protocol; however, competence varied across clinicians and appeared related to child performance., Conclusions: The results provided insight into moving Triadic Gaze Intervention into practice and yielded valuable information regarding the implementation process, with implications for future research.

We hypothesized that exudates collected at the beginning of the resolution phase of inflammation might be enriched for tissue protective molecules; thus an integrated cellular and molecular approach was applied to identify novel chondroprotective bioactions. Exudates were collected 6 h (inflammatory) and 24 h (resolving) following carrageenan-induced pleurisy in rats. The resolving exudate was subjected to gel filtration chromatography followed by proteomics, identifying 61 proteins. Fractions were added to C28/I2 chondrocytes, grown in micromasses, ions with or without IL-1β or osteoarthritic synovial fluids for 48 h. Three proteins were selected from the proteomic analysis, α1-antitrypsin (AAT), hemopexin (HX), and gelsolin (GSN), and tested against catabolic stimulation for their effects on glycosaminoglycan deposition as assessed by Alcian blue staining, and gene expression of key anabolic proteins by real-time PCR. In an in vivo model of inflammatory arthritis, cartilage integrity was determined histologically 48 h after intra-articular injection of AAT or GSN. The resolving exudate displayed protective activities on chondrocytes, using multiple readouts: these effects were retained in low m.w. fractions of the exudate (46.7% increase in glycosaminoglycan deposition; ∼20% upregulation of COL2A1 and aggrecan mRNA expression), which reversed the effect of IL-1β. Exogenous administration of HX, GSN, or AAT abrogated the effects of IL-1β and osteoarthritic synovial fluids on anabolic gene expression and increased glycosaminoglycan deposition. Intra-articular injection of AAT or GSN protected cartilage integrity in mice with inflammatory arthritis. In summary, the strategy for identification of novel chondroprotective activities in resolving exudates identified HX, GSN and AAT as potential leads for new drug discovery programs., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Purpose: This randomized controlled study investigated whether a supplemental treatment designed to teach triadic gaze (TG) as a signal of coordinated joint attention would yield a significantly greater increase in TG in the experimental versus control group., Method: Eighteen 10- to 24-month-old children with severe motor impairments were randomly assigned to an experimental ( n = 9) or control group ( n = 9). For approximately 29 sessions over 17 weeks, experimental participants received TG treatment twice weekly with a speech-language pathologist in addition to standard practice. Control participants received only standard practice from birth-to-three therapists. Coders who were masked to group assignment coded TG productions with an unfamiliar speech-language pathologist at baseline, every 3 weeks during the experimental phase, and at the final measurement session., Results: TG increased across groups from baseline to final measurement, with the experimental group showing slightly greater change. Performance trends were examined using experimental phase moving averages. Comparisons revealed significant differences between groups at 2 time points (at 12 weeks, r = .30, a medium effect, and at the end of the phase, r = .50, a large effect)., Conclusion: The results suggest the promise of a short-term, focused treatment to teach TG as a behavioral manifestation of coordinated joint attention to children with severe physical disabilities.

The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N- and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins.

We studied whether children with severe developmental disabilities (SDDs) who have a comorbid behavioral disorder also have higher rates of special healthcare needs (SHCNs). We used a matched-comparison control group design to establish whether SHCNs were higher in children with SDDs with behavioral disorders versus children with SDDs without behavioral disorders. Thirty-six children were matched for age (mean 12 y 6 mo; range 5 y 2 mo-18 y 8 mo), sex (24 males, 12 females), ethnicity (22 non-white), mental retardation level (22 moderate, eight severe, six profound), and Diagnostic and Statistical Manual of Mental Disorders, 4th edition axis I diagnosis (18 autism spectrum disorder, 10 specified syndrome, eight mental retardation not otherwise specified). Measures included the Achenbach Child Behavior Checklist, behavioral observation, health status examination, and Childhood Health Questionnaire (CHQ). Children with SDDs with behavioral disorders had significantly higher levels of SHCN, as measured by the CHQ and health status examination. Children with SDDs with behavioral disorders had a twofold higher incidence of SHCNs than children with SDDs without behavioral disorders. No difference was observed in the number or types of prescription medication that children received. The findings suggest that SHCNs contribute to the occurrence and/or intensity of behavioral disorders in children with SDD and may require interdisciplinary care coordination.

Distress and ad lib alcohol consumption after interactions with child confederates were investigated in parents of children with externalizing disorders--attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), or oppositional defiant disorder (ODD). Sixty subjects interacted with boys trained to act like either normal children or children with ADHD/CD/ODD. Interactions with deviant confederates resulted in feelings of inadequacy and produced negative affect but had no effect on alcohol consumption. Post hoc analyses showed that parents with a family history of alcohol problems (FH+) showed increased drinking after interaction with a deviant confederate, compared with FH+ parents who interacted with the normal confederate. FH- parents showed the opposite pattern of results.

Objective: Diacerhein, an anti-osteoarthritic agent, was tested for its ability to suppress synthesis of proinflammatory cytokines in a model of granuloma-induced cartilage breakdown., Design: 50 TO mice received a subcutaneous implant of cotton-wrapped rat femoral head cartilage for a period of 2 weeks. Animals (N = 10/group) were dosed daily with either 6 mg/kg p.o. diclofenac or diacetylrhein at 5, 15 or 50 mg/kg p.o. in 0.1.ml 1% gum tragacanth which served as a control. Implanted cartilages were assayed for glycosaminoglycan (GAG) and hydroxyproline content. The surrounding granulomas were assayed for interleukin-1 alpha (IL-1 alpha), tumour necrosis factor-alpha (TNF-alpha) and IL-6. Statistical analysis was by Mann-Whitney U test., Results: Diclofenac had no significant effect on GAG or hydroxyproline content of implanted cartilage or on granuloma cytokine concentrations. Diacerhein protected implanted cartilages against hydroxyproline loss, implanted control cartilages contained 220 micrograms hydroxyproline compared with diacerhein at 5, 15 and 50 mg/kg which produced a 21, 16 and 59% decrease in hydroxyproline loss compared with non-implanted controls (P < 0.05, 0.05 and 0.001) respectively. Diacerhein also protected against GAG loss at 5 mg/kg and 50 mg/kg, control cartilages contained 134 micrograms GAG compared with diacerhein at 5 mg/kg and 50 mg/kg which produced a 24 and 38% decrease in GAG loss respectively (P < 0.05 for both). Diacerhein significantly reduced granuloma interleukin-1 alpha content at 5 mg/kg (control level of 2.4 micrograms/ml reduced by 58%; P < 0.05), reduced TNF-alpha at 5 mg/kg and 15 mg/kg (reduced by 61%: P < 0.01 and 49%: P < 0.05 respectively; control level of 469 pg/ml) and reduced IL-6 at 15 mg/kg and 50 mg/kg (control level of 537 pg/ml reduced by 60 and 51%, respectively; P < 0.01 for both)., Conclusions: The mechanism of the chondroprotective effects of diacerhein is not understood but may be explained by a reduction in the concentrations of proinflammatory cytokines.

Ratings were collected on a rating scale comprised of the DSM-III-R diagnostic criteria for disruptive behavior disorders. Teacher ratings were obtained for 931 boys in regular classrooms in grades K through 8 from around North America. Means and standard deviations for attention-deficit hyperactivity disorder (ADHD), oppositional-defiant disorder (ODD), and conduct disorder (CD) scales are reported by age. Frequencies of DSM-III-R symptoms are reported by age, and suggested diagnostic cutoffs are discussed. A factor analysis revealed three factors: one reflecting ODD and several CD symptoms, one on which ADHD symptoms of inattention loaded, and one comprised of ADHD impulsivity/overactivity symptoms. Conditional probability analyses revealed that several hallmark symptoms of ADHD had very poor predictive power, whereas combinations of symptoms from the two ADHD factors had good predictive power. Combinations of ODD symptoms also had very high predictive power. The limited utility of teacher ratings in assessing symptoms of conduct disorder in this age range is discussed.

Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind, placebo-controlled, crossover evaluation of the efficacy of standard methylphenidate twice a day and comparable doses every morning of a sustained-release preparation of methylphenidate (SR-20 Ritalin), a sustained-release form of dextroamphetamine (Dexedrine Spansule), and pemoline. The children were participating in a summer treatment program in which they engaged in recreational and classroom activities. Dependent measures include evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Results revealed generally equivalent and beneficial effects of all four medications. Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication. The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion, and the effects lasted for 9 hours. The implications of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed.