MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trial

High-intensity mechanical therapy for loss of knee extension for worker's compensation and non-compensation patients

<p>Abstract</p> <p>Background</p> <p>Knee flexion contractures have been associated with increased pain and a reduced ability to perform activities of daily living. Contractures can be treated either surgically or conservatively, but these treatment options may not be as successful with worker's compensation patients. The purposes of retrospective review were to 1) determine the efficacy of using adjunctive high-intensity stretch (HIS) mechanical therapy to treat flexion contractures, and 2) compare the results between groups of worker's compensation and non-compensation patients.</p> <p>Methods</p> <p>Fifty-six patients (19 women, 37 men, age = 51.5 ± 17.0 years) with flexion contractures were treated with HIS mechanical therapy as an adjunct to outpatient physical therapy. Mechanical therapy was only prescribed for those patients whose motion had reached a plateau when treated with physical therapy alone. Patients were asked to perform six, 10-minute bouts of end-range stretching per day with the ERMI Knee Extensionater^(r)(ERMI, Inc., Atlanta, GA). Passive knee extension was recorded during the postoperative visit that mechanical therapy was prescribed, 3 months after beginning mechanical therapy, and at the most recent follow-up. We used a mixed-model 2 × 3 ANOVA (group × time) to evaluate the change in passive knee extension between groups over time.</p> <p>Results</p> <p>Regardless of group, the use of adjunctive HIS mechanical therapy resulted in passive knee extension deficits that significantly improved from 10.5° ± 5.2° at the initial visit to 2.6° ± 3.5° at the 3 month visit (p < 0.001). The degree of extension was maintained at the most recent follow-up (2.0° ± 2.9°), which was significantly greater than the initial visit (p < 0.001), but did not differ from the 3 month visit (p = 0.23). The gains in knee extension did not differ between worker's compensation and non-compensation patients (p = 0.56).</p> <p>Conclusions</p> <p>We conclude that the adjunctive use of HIS mechanical therapy is an effective treatment option for patients with knee flexion contractures, regardless of whether the patient is being treated as part of a worker's compensation claim or not.</p

Clinical predictors of elective total joint replacement in persons with end-stage knee osteoarthritis

Abstract Background Arthritis is a leading cause of disability in the United States. Total knee arthroplasty (TKA) has become the gold standard to manage the pain and disability associated with knee osteoarthritis (OA). Although more than 400 000 primary TKA surgeries are performed each year in the United States, not all individuals with knee OA elect to undergo the procedure. No clear consensus exists on criteria to determine who should undergo TKA. The purpose of this study was to determine which clinical factors will predict the decision to undergo TKA in individuals with end-stage knee OA. Knowledge of these factors will aid in clinical decision making for the timing of TKA. Methods Functional data from one hundred twenty persons with end-stage knee OA were obtained through a database. All of the individuals complained of knee pain during daily activities and had radiographic evidence of OA. Functional and clinical tests, collectively referred to as the Delaware Osteoarthritis Profile, were completed by a physical therapist. This profile consisted of measuring height, weight, quadriceps strength and active knee range of motion, while functional mobility was assessed using the Timed Up and Go (TUG) test and the Stair Climbing Task (SCT). Self-perceived functional ability was measured using the activities of daily living subscale of the Knee Outcome Survey (KOS-ADLS). A logistic regression model was used to identify variables predictive of TKA use. Results Forty subjects (33%) underwent TKA within two years of evaluation. These subjects were significantly older and had significantly slower TUG and SCT times (p 2 = 0.403). Conclusions Younger patients with full knee ROM who have a higher self-perception of function are less likely to undergo TKA. Physicians and clinicians should be aware that potentially modifiable factors, such as knee ROM can be addressed to potentially postpone the need for TKA.</p

Rotational knee laxity: Reliability of a simple measurement device in vivo

<p>Abstract</p> <p>Background</p> <p>Double bundle ACL reconstruction has been demonstrated to decrease rotational knee laxity. However, there is no simple, commercially-available device to measure knee rotation. The investigators developed a simple, non-invasive device to measure knee rotation. In conjunction with a rigid boot to rotate the tibia and a force/moment sensor to allow precise determination of torque about the knee, a magnetic tracking system measures the axial rotation of the tibia with respect to the femur. This device has been shown to have acceptable levels of test re-test reliability to measure knee rotation in cadaveric knees.</p> <p>Methods</p> <p>The objective of this study was to determine reliability of the device in measuring knee rotation of human subjects. Specifically, the intra-tester reliability within a single testing session, test-retest reliability between two testing sessions, and inter-tester reliability were assessed for 11 male subjects with normal knees.</p> <p>Results</p> <p>The 95% confidence interval for rotation was less than 5° for intra-tester, test-retest, and inter-tester reliability, and the standard error of measurement for the differences between left and right knees was found to be less than 3°.</p> <p>Conclusion</p> <p>It was found that the knee rotation measurements obtained with this device have acceptable limits of reliability for clinical use and interpretation.</p

Fixation strength of biocomposite wedge interference screw in ACL reconstruction: effect of screw length and tunnel/screw ratio. A controlled laboratory study

<p>Abstract</p> <p>Background</p> <p>Primary stability of the graft is essential in anterior cruciate ligament surgery. An optimal method of fixation should be easy to insert and provide great resistance against pull-out forces.</p> <p>A controlled laboratory study was designed to test the primary stability of ACL tendinous grafts in the tibial tunnel. The correlation between resistance to traction forces and the cross-section and length of the screw was studied.</p> <p>Methods</p> <p>The tibial phase of ACL reconstruction was performed in forty porcine tibias using digital flexor tendons of the same animal. An 8 mm tunnel was drilled in each specimen and two looped tendons placed as graft. Specimens were divided in five groups according to the diameter and length of the screw used for fixation. Wedge interference screws were used. Longitudinal traction was applied to the graft with a Servohydraulic Fatigue System. Load and displacement were controlled and analyzed.</p> <p>Results</p> <p>The mean loads to failure for each group were 295,44 N (Group 1; 9 × 23 screw), 564,05 N (Group 2; 9 × 28), 614,95 N (Group 3; 9 × 35), 651,14 N (Group 4; 10 × 28) and 664,99 (Group 5; 10 × 35). No slippage of the graft was observed in groups 3, 4 and 5. There were significant differences in the load to failure among groups (ANOVA/P < 0.001).</p> <p>Conclusions</p> <p>Longer and wider interference screws provide better fixation in tibial ACL graft fixation. Short screws (23 mm) do not achieve optimal fixation and should be implanted only with special requirements.</p

Biomechanics and anterior cruciate ligament reconstruction

For years, bioengineers and orthopaedic surgeons have applied the principles of mechanics to gain valuable information about the complex function of the anterior cruciate ligament (ACL). The results of these investigations have provided scientific data for surgeons to improve methods of ACL reconstruction and postoperative rehabilitation. This review paper will present specific examples of how the field of biomechanics has impacted the evolution of ACL research. The anatomy and biomechanics of the ACL as well as the discovery of new tools in ACL-related biomechanical study are first introduced. Some important factors affecting the surgical outcome of ACL reconstruction, including graft selection, tunnel placement, initial graft tension, graft fixation, graft tunnel motion and healing, are then discussed. The scientific basis for the new surgical procedure, i.e., anatomic double bundle ACL reconstruction, designed to regain rotatory stability of the knee, is presented. To conclude, the future role of biomechanics in gaining valuable in-vivo data that can further advance the understanding of the ACL and ACL graft function in order to improve the patient outcome following ACL reconstruction is suggested

Intraarticular location predicts cartilage filling and subchondral bone changes in a chondral defect: A randomized, blind, long-term follow-up trial involving 82 rabbit knees

Open Access - This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.Background and purpose: The natural history of, and predictive factors for outcome of cartilage restoration in chondral defects are poorly understood. We investigated the natural history of cartilage filling subchondral bone changes, comparing defects at two locations in the rabbit knee. Animals and methods: In New Zealand rabbits aged 22 weeks, a 4-mm pure chondral defect (ICRS grade 3b) was created in the patella of one knee and in the medial femoral condyle of the other. A stereo microscope was used to optimize the preparation of the defects. The animals were killed 12, 24, and 36 weeks after surgery. Defect filling and the density of subchondral mineralized tissue was estimated using Analysis Pro software on micrographed histological sections. Results: The mean filling of the patellar defects was more than twice that of the medial femoral condylar defects at 24 and 36 weeks of follow-up. There was a statistically significant increase in filling from 24 to 36 weeks after surgery at both locations. The density of subchondral mineralized tissue beneath the defects subsided with time in the patellas, in contrast to the density in the medial femoral condyles, which remained unchanged. Interpretation: The intraarticular location is a predictive factor for spontaneous filling and subchondral bone changes of chondral defects corresponding to ICRS grade 3b. Disregarding location, the spontaneous filling increased with long-term follow-up. This should be considered when evaluating aspects of cartilage restoration

Reconstruction versus conservative treatment after rupture of the anterior cruciate ligament: cost effectiveness analysis

BACKGROUND: The decision whether to treat conservatively or reconstruct surgically a torn anterior cruciate ligament (ACL) is an ongoing subject of debate. The high prevalence and associated public health burden of torn ACL has led to continuous efforts to determine the best therapeutic approach. A critical evaluation of benefits and expenditures of both treatment options as in a cost effectiveness analysis seems well-suited to provide valuable information for treating physicians and healthcare policymakers. METHODS: A literature review identified four of 7410 searched articles providing sufficient outcome probabilities for the two treatment options for modeling. A transformation key based on the expert opinions of 25 orthopedic surgeons was used to derive utilities from available evidence. The cost data for both treatment strategies were based on average figures compiled by Orthopaedic University Hospital Balgrist and reinforced by Swiss national statistics. A decision tree was constructed to derive the cost-effectiveness of each strategy, which was then tested for robustness using Monte Carlo simulation. RESULTS: Decision tree analysis revealed a cost effectiveness of 16,038 USD/0.78 QALY for ACL reconstruction and 15,466 USD/0.66 QALY for conservative treatment, implying an incremental cost effectiveness of 4,890 USD/QALY for ACL reconstruction. Sensitivity analysis of utilities did not change the trend. CONCLUSION: ACL reconstruction for reestablishment of knee stability seems cost effective in the Swiss setting based on currently available evidence. This, however, should be reinforced with randomized controlled trials comparing the two treatment strategies