Mutations in fukutin-related protein (FKRP) cause a common subset of muscular dystrophies characterized by aberrant glycosylation of alpha-dystroglycan (α-DG), collectively known as dystroglycanopathies. The clinical variations associated with FKRP mutations range from mild limb-girdle muscular dystrophy type 2I with predominantly muscle phenotypes to severe Walker-Warburg syndrome and muscle-eye-brain disease with striking structural brain and eye defects. In the present study, we have generated animal models and demonstrated that ablation of FKRP functions is embryonic lethal and that the homozygous-null embryos die before reaching E12.5. The homozygous knock-in mouse carrying the missense P448L mutation almost completely lacks functional glycosylation of α-DG in muscles and brain, validating the essential role of FKRP in the functional glycosylation of α-DG. However, the knock-in mouse survives and develops a wide range of structural abnormalities in the central nervous system, characteristics of neuronal migration defects. The brain and eye defects are highly reminiscent of the phenotypes seen in severe dystroglycanopathy patients. In addition, skeletal muscles develop progressive muscular dystrophy. Our results confirm that post-translational modifications of α-DG are essential for normal development of the brain and eyes. In addition, both the mutation itself and the levels of FKRP expression are equally critical for the survival of the animals. The exceptionally wide clinical spectrums recapitulated in the P448L mice also suggest the involvement of other factors in the disease progression. The mutant mouse represents a valuable model to further elucidate the functions of FKRP and develop therapies for FKRP-related muscular dystrophies.

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For simulated humeral neck fractures subjected to cyclic loading, locking-plate constructs demonstrated significantly greater torsional stability and similar bending stability to blade plates in a cadaveric specimen model. In contrast, these same constructs performed similarly with torsional loading when using synthetic humerus specimens. These results indicate potential advantages for locking-plate fixation. They also indicate that the synthetic specimens tested may not be appropriate for evaluating fixation stability in the humeral head, where cancellous bone fixation predominates.

The Timed 25-Foot Walk is under evaluation as a clinical tool to follow patients with MS. Several approaches have been taken to define a clinically significant change in this measurement. This study was undertaken to define the range of values expected for the Timed 25-Foot Walk and to correlate prospectively the change in walk-time that occurs during an exacerbation of MS associated with subjective difficulty walking. Five results from this study are emphasized. (1) Patients who were minimally affected by MS frequently walked 25 feet between three and five seconds. (2) the walk-time variability, defined as the ratio of the longest to the shortest walk-time, minus 1, times 100%, for three consecutive trials was generally 20% or less; (3) if the two fastest walk-times obtained in three trials were compared, the walk-time variability was almost always 10% or less; (4) for clinically stable individuals, the walk-times of single trials separated by 12 months or less generally varied less than 20%; and (5) patients who complained of difficulty walking, but who did not have changes otherwise detectable by examination, generally had a prolongation of walk-time. These results suggest that an increase of more than 20% in the Timed 25-Foot Walk may indicate a significant change in gait. Multiple Sclerosis (2000) 6 286 - 290

BackgroundMenisci play a vital role in load transmission, shock absorption and joint stability. There is increasing evidence suggesting that OA menisci may not merely be bystanders in the disease process of OA. This study sought: 1) to determine the prevalence of meniscal degeneration in OA patients, and 2) to examine gene expression in OA meniscal cells compared to normal meniscal cells.MethodsStudies were approved by our human subjects Institutional Review Board. Menisci and articular cartilage were collected during joint replacement surgery for OA patients and lower limb amputation surgery for osteosarcoma patients (normal control specimens), and graded. Meniscal cells were prepared from these meniscal tissues and expanded in monolayer culture. Differential gene expression in OA meniscal cells and normal meniscal cells was examined using Affymetrix microarray and real time RT-PCR.ResultsThe grades of meniscal degeneration correlated with the grades of articular cartilage degeneration (r = 0.672; P < 0.0001). Many of the genes classified in the biological processes of immune response, inflammatory response, biomineral formation and cell proliferation, including major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1), integrin, beta 2 (ITGB2), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), ankylosis, progressive homolog (ANKH) and fibroblast growth factor 7 (FGF7), were expressed at significantly higher levels in OA meniscal cells compared to normal meniscal cells. Importantly, many of the genes that have been shown to be differentially expressed in other OA cell types/tissues, including ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) and prostaglandin E synthase (PTGES), were found to be expressed at significantly higher levels in OA meniscal cells. This consistency suggests that many of the genes detected in our study are disease-specific.ConclusionOur findings suggest that OA is a whole joint disease. Meniscal cells may play an active role in the development of OA. Investigation of the gene expression profiles of OA meniscal cells may reveal new therapeutic targets for OA therapy and also may uncover novel disease markers for early diagnosis of OA.

: Amantadine 100 mg every morning and at noon appears an effective and safe means of reducing frequency and severity of irritability and aggression among individuals with TBI and sufficient creatinine clearance.

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Although cancer rehabilitation is considered an important area of education, quality and quantity of experiences may be improved. Several opportunities may exist to improve such exposure in anticipation of serving the functional needs for a growing population of cancer survivors.