Intraclinician Variability in Force Application During Anteroposterior Mobilization of the Ankle Joint

Objective: The purpose of this study was to quantify the variability in the force applied during 20 cycles of Maitland's grade IV anteroposterior ankle mobilization measured on 2 occasions. Methods: Thirteen healthy adults (mean age, 25 ± 5 years; height, 170 ± 7 cm; weight, 71 ± 16 kg) received 20 cycles of Maitland's grade IV ankle mobilization on 2 sessions separated by 1 week. A force transducer was used to measure the peak force, loading rate, and impulse applied during each load cycle. Mean within-session coefficient of variation, standard error of measurement, and 95% level of agreement were estimated during each mobilization session. Results: The mean peak force during the anteroposterior mobilization technique was 70 ± 12 N and 58 ± 10 N during sessions 1 and 2, respectively. The mean within-session coefficients of variation in peak force, loading rate, and impulse applied during 20 loading cycles were 10% to 13%, 15%, and 21% to 43%, respectively. There was a significant difference between sessions in mean peak force (−17%, t12 = 2.445, P = .031) and impulse (−51%, t12 = 2.306, P = .040), with large 95% levels of agreement in applied peak force (±33 N) and impulse (±128 N s) compared to their mean values (approximately ±50% and 110%, respectively). Conclusion: The peak force and loading rate applied by an experienced practitioner during a Maitland's grade IV anteroposterior talar mobilization session varied over 20 loading cycles. Variability between repeated mobilization sessions by the same practitioner was even greater, with respect to peak applied force and loading rate. The large variability in force applied during a Maitland's grade IV talar mobilization may underpin differential clinical effects reported in the joint-mobilization literature. The findings of this study highlight the need for strategies that standardize the application of force during talar mobilization.</p

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype