SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Acknowledgements We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Umeå University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Umeå university hospital, and the Medical Faculty at Umeå University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.Peer reviewedPublisher PD

Non-neural phenotype of spinal and bulbar muscular atrophy: Results from a large cohort of Italian patients

Objective: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. \ua9 2016 Published by the BMJ Publishing Group Limited

A case report of Parry Romberg Syndrome initially presenting as periodontitis

Parry Romberg Syndrome (PRS) is a rare disorder of progressive hemifacial atrophy, involving soft tissues, fat and occasionally bone. It can co-exist with presentations of Morphea. We describe an unusual case of persistent periodontal and alveolar destruction associated with PRS. A 56-year-old African female initially presented with persistent periodontal destruction, which showed minimal response to conventional periodontal treatment. After non-surgical treatment, surgical debridement followed by extraction of the two right maxillary incisor teeth was required to halt the periodontal destruction. Atrophy was not limited to the periodontal tissues. Multidisciplinary care and extensive investigations were required to diagnose PRS. Once the PRS has stabilised, adipose tissue transplants will be required to improve the facial appearance. We highlight the need for extensive investigations and a multidisciplinary approach to diagnose rare systemic causes for recalcitrant periodontal disease

Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets

Musculoskeletal discipline science plan

Life sciences research in the musculoskeletal discipline must identify possible consequences of weightlessness on this system, understand the mechanisms of these effects, and develop effective and operationally practical countermeasures to protect crewmembers. The musculoskeletal system is highly plastic in that is possesses the inherent capability to adapt its structural and functional properties in accordance with the type and degree of stimuli imposed on it. Prolonged space travel is essentially a period of significant unloading of the musculoskeletal system. This results in adaptive responses in the structure and function of this system, placing it on the low end of a continuum from one of complete disuse to one of maximal use. There is a high probability that the musculoskeletal system is functionally impaired with increasing duration of weightlessness. The purpose of this Discipline Science Plan is to provide a conceptual strategy for NASA's Life Sciences division research and development activities in the area of musculoskeletal function. This document summarizes the current status of the program, outlines available knowledge, establishes goals and objectives, identifies science priorities, and defines research opportunities, which encompass critical questions in the subdiscipline areas (e.g., muscle, bone, and other musculoskeletal connective tissues). These science activities include ground-based and flight; basic, applied, and operational; and animal and human research and development. This document contains a general plan that will be used by both NASA Headquarters Program Offices and the field centers to review and plan basic, applied, and operational intramural and extramural research and development activities in this area

Effects of Sex and Gender on Adaptation to Space: Musculoskeletal Health

There is considerable variability among individuals in musculoskeletal response to long-duration spaceflight. The specific origin of the individual variability is unknown but is almost certainly influenced by the details of other mission conditions such as individual differences in exercise countermeasures, particularly intensity of exercise, dietary intake, medication use, stress, sleep, psychological profiles, and actual mission task demands. In addition to variations in mission conditions, genetic differences may account for some aspect of individual variability. Generally, this individual variability exceeds the variability between sexes that adds to the complexity of understanding sex differences alone. Research specifically related to sex differences of the musculoskeletal system during unloading is presented and discussed

Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness

Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. 

In vivo nuclear magnetic resonance imaging

A number of physiological changes have been demonstrated in bone, muscle and blood after exposure of humans and animals to microgravity. Determining mechanisms and the development of effective countermeasures for long duration space missions is an important NASA goal. The advent of tomographic nuclear magnetic resonance imaging (NMR or MRI) gives NASA a way to greatly extend early studies of this phenomena in ways not previously possible; NMR is also noninvasive and safe. NMR provides both superb anatomical images for volume assessments of individual organs and quantification of chemical/physical changes induced in the examined tissues. The feasibility of NMR as a tool for human physiological research as it is affected by microgravity is demonstrated. The animal studies employed the rear limb suspended rat as a model of mucle atrophy that results from microgravity. And bedrest of normal male subjects was used to simulate the effects of microgravity on bone and muscle

NASA Light Emitting Diode Medical Applications from Deep Space to Deep Sea

This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program. LED-technology developed for NASA plant growth experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. We present the results of LED-treatment of cells grown in culture and the effects of LEDs on patients’ chronic and acute wounds. LED-technology is also biologically optimal for photodynamic therapy of cancer and we discuss our successes using LEDs in conjunction with light-activated chemotherapeutic drugs

The Design of Mechanically Compatible Fasteners for Human Mandible Reconstruction

Mechanically compatible fasteners for use with thin or weakened bone sections in the human mandible are being developed to help reduce large strain discontinuities across the bone/implant interface. Materials being considered for these fasteners are a polyetherertherketone (PEEK) resin with continuous quartz or carbon fiber for the screw. The screws were designed to have a shear strength equivalent to that of compact/trabecular bone and to be used with a conventional nut, nut plate, or an expandable shank/blind nut made of a ceramic filled polymer. Physical and finite element models of the mandible were developed in order to help select the best material fastener design. The models replicate the softer inner core of trabecular bone and the hard outer shell of compact bone. The inner core of the physical model consisted of an expanding foam and the hard outer shell consisted of ceramic particles in an epoxy matrix. This model has some of the cutting and drilling attributes of bone and may be appropriate as an educational tool for surgeons and medical students. The finite element model was exercised to establish boundary conditions consistent with the stress profiles associated with mandible bite forces and muscle loads. Work is continuing to compare stress/strain profiles of a reconstructed mandible with the results from the finite element model. When optimized, these design and fastening techniques may be applicable, not only to other skeletal structures, but to any composite structure