An Activin A/BMP2 Chimera,AB204, Displays Bone‐Healing Properties Superior to Those of BMP2

Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10‐fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2‐like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100‐fold greater than that of BMP2. The structure also led to our identification of a single Activin A‐derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non‐union bone fractures. © 2014 American Society for Bone and Mineral Research.     

High Dietary Phosphate Intake Induces Development of Ectopic Calcifications in a Murine Model of Familial Tumoral Calcinosis

Familial tumoral calcinosis is characterized by ectopic calcifications due to persistent hyperphosphatemia. The most common genetic cause of the disease is mutations in GALNT3, encoding a glycosyltransferase involved in a posttranslational modification of fibroblast growth factor 23 (FGF23). The Galnt3 knockout mouse we developed was hyperphosphatemic due to low intact Fgf23 levels, but did not develop any apparent calcifications on a standard rodent diet. We therefore tested the hypothesis that a further challenge with a high phosphate diet could induce ectopic calcifications in Galnt3 knockout mice. Mice were fed either normal (0.6%) or high (1.65%) phosphate diet for 20 weeks beginning from weaning at 3 weeks. The high phosphate diet did not affect serum phosphorus concentration. However, regardless of the dietary phosphate contents, serum phosphorus levels were consistently elevated in Galnt3 knockout mice. The mice on the high phosphate diet had slightly low serum calcium, but significantly high alkaline phosphatase, parathyroid hormone (PTH), and calcium in the kidney. Although none of Galnt3 knockout mice on the normal phosphate diet developed calcifications, calcifications appeared in approximately one‐half of the mice on the high phosphate diet by 12 weeks. Calcified masses were most often found around the neck and on the back and as large as 9.9 mm in length. These data indicate that dietary phosphate load has major impact on the development of ectopic calcifications in tumoral calcinosis. © 2014 American Society for Bone and Mineral Research.     

Action verb comprehension in amyotrophic lateral sclerosis and Parkinson’s disease

Patients with amyotrophic lateral sclerosis (ALS) have a motor disorder and cognitive difficulties, including difficulty with action verbs. However, the basis for the action verb impairment is unknown. Thirty-six participants with ALS and 22 with Parkinson’s disease (PD) were assessed on a simple, two-alternative forced-choice associativity judgment task, where performance was untimed and did not depend on motor functioning. We probed 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns. Performance was related to T1 MRI imaging of gray matter atrophy. Patients with ALS were significantly impaired relative to healthy senior control participants only for action verbs. Patients with PD did not differ from controls for all word categories. Regression analyses related action verb performance in ALS to motor-associated cortices, but action verb judgments in PD were not related to cortical atrophy. These findings are consistent with the hypothesis that action verb difficulty in ALS is related in part to the degradation of action-related conceptual knowledge represented in motor-associated cortex.     

Physical Activity Disparities in Heterosexual and Sexual Minority Youth Ages 12–22 Years Old: Roles of Childhood Gender Nonconformity and Athletic Self-Esteem

Background

Physical activity is an important health determinant. Little is known about sexual orientation differences in physical activity and their psychosocial determinants.

Purpose

The aim of this study is to examine adolescent and young adult hours/week of moderate/vigorous physical activity (MVPA) and team sports participation by sexual orientation and investigate contributions of gender nonconformity and low athletic self-esteem to possible sexual orientation differences.

Methods

Analysis of data from 5,272 males and 7,507 females from 1999 to 2005 waves of the US Growing Up Today Study (ages 12–22 years).

Results

Sexual minorities (i.e., lesbian, gay, bisexual, mostly heterosexual) reported 1.21–2.62 h/week less MVPA (p?<?0.01) and were 46–76 % less likely to participate in team sports than same-gender heterosexuals. Gender nonconformity and athletic self-esteem accounted for 46–100 % of sexual orientation MVPA differences.

Conclusions

Physical activity contexts should be modified to welcome sexual minority males and females. Targeting intolerance of gender nonconformity and fostering athletic self-esteem may mitigate sexual orientation MVPA disparities.     

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Cocaine functions, in part, through agonist actions at sigma‐1 (σ₁) receptors, while roles played by sigma‐2 (σ₂) receptors are less established. Attempts to discriminate σ₂ receptor‐mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ₂ receptor affinity, and excellent selectivity for binding to σ₂ over σ₁ receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5‐bromo‐N‐[4‐(6,7‐dimethoxy‐3,4‐dihydro‐1H‐isoquinolin‐2‐yl)‐butyl)]‐2,3‐dimethoxy‐benzamide, 1 , a ligand shown by others to bind preferentially to σ₂ over σ₁ receptors, as well as dopamine D₂ and D₃ sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57‐fold selectivity for σ₂ receptors over the serotonin transporter, and >800‐fold selectivity for σ₂ receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD‐1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ₁ receptors or the dopamine transporter by 1 , or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ₂ receptor‐selective antagonist that is able to counteract cocaine's motor stimulatory effects. Synapse 68:73–84, 2014 . © 2013 Wiley Periodicals, Inc.     

Persistence of urothelial carcinoma of the bladder risk among former smokers: Results from a contemporary,prospective cohort study

ObjectivesCigarette smoking is a known risk factor for urothelial carcinoma (UC) of the bladder. However, the persistence of an increased risk for UC following smoking cessation is not well established. We assessed the risk of UC among former smokers using a recent, prospective cohort with a high proportion of former smokers.Materials and methodsStudy participants were members of the VITamins And Lifestyle cohort (VITAL), a group of 77,719 men and women between the ages of 50 and 76 years from western Washington State. Smoking history and other risk factors were obtained at the time of recruitment. The primary outcome was a new diagnosis of UC (n =385), as determined through linkage to a population-based cancer registry.Results and limitationsThe cohort included 8% current and 44% former smokers, and among the UC cases, 15% were current and 60% former smokers. Both the current and former smoker had an increased risk of UC compared with never smokers (hazard ratio [HRs]: 3.81; 95% confidence intervals [CI] 2.71–5.35 and 2.0; 95% CI 1.55–2.58, respectively). Among former smokers, the risk of UC increased with the pack-years smoked and decreased with the years since quitting. When both the measures of smoking were considered together, the risk of UC was similar for long-term quitters and recent quitters for a given level of pack-years. For example, for those with pack-years of 22.5–37.5, the HR of UC was 1.91 (95% CI 1.17–3.11) for the distant quitters (≥23.5 y before baseline) and HR = 1.92 (95% CI 1.26–2.94) among the recent quitters. Limitations include the small number of cases at the extremes of smoking history and errors in self-reported smoking history.ConclusionsThe risk of bladder cancer in former smokers remains elevated>32 years after quitting, even among those with moderate smoking histories. This argues that a history of smoking confers a lifelong increased risk of UC.