Gait variability is affected more by peripheral artery disease than by vascular occlusion

Background Patients with peripheral artery disease with intermittent claudication (PAD-IC) have altered gait variability from the first step they take, well before the onset of claudication pain. The mechanisms underlying these gait alterations are poorly understood. Aims To determine the effect of reduced blood flow on gait variability by comparing healthy older controls and patients with PAD-IC. We also determined the diagnostic value of gait variability parameters to identify the presence of PAD. Methods A cross-sectional cohort design was used. Thirty healthy older controls and thirty patients with PAD-IC walked on a treadmill at their self-selected speed in pain free walking (normal walking for healthy older controls; prior to claudication onset for PAD) and reduced blood flow (post vascular occlusion with thigh tourniquet for healthy older controls; pain for PAD) conditions. Gait variability was assessed using the largest Lyapunov exponent, approximate entropy, standard deviation, and coefficient of variation of ankle, knee, and hip joints range of motion. Receiver operating characteristics curve analyses of the pain free walking condition were performed to determine the optimal cut-off values for separating individuals with PAD-IC from those without PAD-IC. Results and discussion Patients with PAD-IC have increased amount of variability for knee and hip ranges of motion compared with the healthy older control group. Regarding the main effect of condition, reduced blood flow demonstrated increased amount of variability compared with pain free walking. Significant interactions between group and condition at the ankle show increased values for temporal structure of variability, but a similar amount of variability in the reduced blood flow condition. This demonstrates subtle interactions in the movement patterns remain distinct between PAD-IC versus healthy older controls during the reduced blood flow condition. A combination of gait variability parameters correctly identifies PAD-IC disease 70% of the time or more. Conclusions Gait variability is affected both by PAD and by the mechanical induction of reduced blood flow. Gait variability parameters have potential diagnostic ability, as some measures had 90.0% probability of correctly identifying patients with PAD-IC.

Negative Hematopoietic Scaffold Lnk Upregulates Integrin Outside-In Signaling in Platelets.

The adaptor molecule Lnk negatively regulates signaling downstream of cytokine receptors in self-renewal of hematopoietic stem cells, proliferation of B precursors and differentiation/maturation of megakaryocytes. The circulating number of platelets in Lnk-deficient mice is increased by 5-folds to control, presumably owing to its negative effects on TPO-elicited signaling. Lnk expression is maintained in platelets, however, the precise functions in platelets remain unknown. Here we report that Lnk deficiency results in the prolonged bleeding time (2-folds, p<0.01) due to, at least in part, defective the outside-in signaling from α IIbβ 3 integrin. Lnk-null platelets exhibited less activation of PAK kinase, a Rac effector in fibrinogen-adherent platelets. These were concomitant with the defect of lamellipodial formation upon adhesion to fibrinogen in the absence of Lnk, compared to control platelets (p<0.01). Defective Lnk-null platelet functions were also demonstrated by the reduced three-dimensional growth (height) of platelet thrombi on the collagen surface under whole blood flow condition with the adjusted same platelet number at high wall shear rate of 1,500 s-1 (8.1±1.4 μ m in Lnk-deficient vs. 12.1±2.2 μ m in control, p<0.001), while the two-dimensional surface coverage was not impaired. On the other hand, there was no difference between Lnk-null and control platelets in aggregation and α IIbβ 3 integrin activation in response to stimulation with thrombin or collagen. Taken together, implication of Lnk to sites of adhesion may explain the phenotype of Lnk-deficient platelet function. The findings indicate that Lnk is a unique “dual-functioning” scaffolding molecule, which upregulates thrombus formation, while suppressing cytokine-mediated signaling.