Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.

Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.

Denosumab improves density and strength parameters as measured by QCT of the radius in postmenopausal women with low bone mineral density.

BACKGROUND: Bone strength is determined by both cortical and trabecular bone compartments and can be evaluated radiologically through measurement of bone density and geometry. Quantitative computed tomography (QCT) separately assesses cortical and trabecular bone reliably at various sites, including the distal radius where there is a gradation of cortical and trabecular bone. We evaluated the effect of denosumab, a fully human monoclonal antibody that inhibits RANK ligand, on distal radius QCT in women with low bone mass to assess the impact of this novel therapy separately on trabecular and cortical bone. METHODS: Postmenopausal women (n=332) with spine areal bone mineral density (BMD) T-scores between -1.0 and -2.5 received denosumab 60 mg or placebo every 6 months during the 24-month study. QCT measurements along the distal radius were made using a whole-body computed tomography scanner and were used to determine the percentage change from baseline in volumetric BMD; volumetric bone mineral content (BMC); cortical thickness; volume; circumference; and density-weighted polar moment of inertia (PMI), a derived index of bone strength. RESULTS: Denosumab treatment significantly increased total BMD and BMC along the radius (proximal, distal, and ultradistal sections). At 24 months, the ultradistal region had the greatest percentage increase in total BMD (4.7% [95% CI, 3.6-5.7]; P<0.001) and total BMC (5.7% [95% CI, 4.8-6.6]; P<0.001) over placebo. When cortical and trabecular bone at the proximal and distal regions were separately assessed, cortical bone had significant (P<0.001) increases in BMD, BMC, and thickness, and trabecular bone had a significant increase in BMD relative to placebo (P<0.05). Bone strength, estimated by density-weighted PMI, significantly increased compared with placebo after 6 months of treatment, with the largest percentage increase occurring at 24 months in the ultradistal region (6.6% [95% CI, 5.6-7.6]; P<0.0001). CONCLUSIONS: QCT measurements demonstrated that denosumab significantly increased BMD, BMC, and PMI along the radius over 24 months. Additionally, denosumab prevented the decrease in QCT-measured cortical thickness observed in the placebo group. These data extend the evidence from previous dual-energy X-ray absorptiometry studies for a positive effect of denosumab on both the cortical and trabecular bone compartments and propose a possible mechanism for the reduction in fracture risk achieved with denosumab therapy.

Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass.

INTRODUCTION: Arzoxifene, a benzothiophene estrogen agonist/antagonist, is being developed for prevention and treatment of osteoporosis and for risk reduction of invasive breast cancer in postmenopausal women. METHODS: The effects of arzoxifene 20 mg/d on bone mineral density (BMD), uterine safety, and overall safety were studied in the FOUNDATION study, a 2-yr randomized, placebo-controlled trial including 331 postmenopausal women with normal to low bone mass. RESULTS: Compared to placebo, arzoxifene significantly increased lumbar spine (+2.9%) and total hip (+2.2%) BMD. Arzoxifene decreased biochemical markers of bone metabolism compared to placebo. Changes in breast density were neutral or slightly decreased in the arzoxifene vs. placebo group. There was no evidence of endometrial hyperplasia or carcinoma in the arzoxifene group as assessed by central review of baseline and follow-up endometrial biopsies. There was no significant change between the groups in endometrial thickness assessed by transvaginal ultrasound. The incidence of uterine polyps and vaginal bleeding was not significantly different between the groups. Vulvovaginal mycotic infection was the only adverse event significantly increased in the arzoxifene vs. placebo group. Hot flushes were not significantly different between the groups. CONCLUSION: In postmenopausal women with normal to low bone mass, arzoxifene 20 mg/d increased BMD at the spine and hip and had a neutral effect on the uterus and endometrium.

A simple and compressive splint for palmar skin grafting in young children with burns.

A simple, compressive, and easily applied splint which is suitable even for fearful and uncooperative patients after skin grafting for paediatric deep palmar burns is described. The hand, including the wrist and the forearm, is inserted between the palmar and dorsal plates of the splint and thus compression and immobilization act to decrease flexion contracture and dysfunction of the digits. Compression can be easily controlled by the use of leather bands.

Predictors of success in the EMG biofeedback training of hyperactive male children.

EMG biofeedback training is continuing to evolve as a promising treatment of hyperactivity. But while research on its application suggests that this technique induces significantly lower EMG levels in experimental samples as a whole, it also discloses that some children evidence but limited reductions. Most likely, this variability is introduced by differences in subject attributes. This study assessed that prospect by examining whether four common subject characteristics correlated with the extent of decrease in EMG level achieved by 59 hyperactive school-aged boys. Those variables were pretreatment EMG level, age degree of hyperactivity, and locus of control. Number of applications or training sessions was included as the fifth predictor. A multiple regression analysis determined that only locus of control was predictive of success in EMG training; however, it accounted for 72% of the variance. Implications of these findings are discussed.

The effects of EMG-assisted relaxation training on the academic performance, locus of control, and self-esteem of hyperactive boys.

This study investigated effects of EMG-assisted relaxation training on the academic performance, locus of control, and self-esteem of hyperactive junior high school-age boys. Twenty-four subjects each were randomly assigned to the treatment and control condition. Treatment consisted of six 20 to 25-minute sessions conducted biweekly. Pretreatment frontalis EMG, math, reading, and language performance, locus of control, and self-esteem were assessed for both groups. Outcome measures were again obtained on these dependent variables 2 weeks after the last treatment session. Experimental subjects demonstrated significantly higher posttreatment reading and language performance. Math performance gain did not reach statistical significance. A significant internal shift in locus of control was observed; however, self-esteem did not improve to that level. These outcomes correlated with significantly lower posttreatment frontalis EMG in the experimental group. EMG level did not change during the course of this study for control subjects. Implications of these findings are discussed in terms of existent research.

Biofeedback-induced relaxation training as an alternative for the elementary school learning-disabled child.

This study examined the effects of biofeedback-induced relaxation training on attention to task, impulsivity, and locus of control among 32 learning-disabled children between the ages of 8 and 11 years. Attention to task and impulsivity were measured by the Matching Familiar Figures Test and locus of control was measured by the Nowicki-Strickland Scale. Participants were randomly assigned to experimental (N = 16) and control (N = 16) groups. The study spanned a total of 8 weeks, with the experimental treatment consisting of three sessions spaced approximately 2 weeks apart. The treatment included EMG biofeedback training used with relaxation tapes. Univariate F values and discriminant analysis procedures revealed that the attention to task and impulsivity measures proved to be valid discriminators, respectively beyond the .01 and .05 levels of significance. Experimental group subjects had significantly fewer number of errors on the attention to task measure and significantly lower impulsivity scores. It was concluded that the biofeedback-induced relaxation training affords promise in assisting learning-disabled children in reaching their education potentials. It was recommended that future research examine the long-term efficacy and the transfer to school-related tasks of this intervention.