The effect of intermittent vs. continuous walking on distance to fatigue in persons with multiple sclerosis.

PURPOSE: Previous studies provided evidence that persons with Multiple Sclerosis (pwMS) who walk intermittently experience less fatigue and walk longer distances than when walking continuously. However, total distance pwMS can walk in either condition is unknown. We examined time and distance to fatigability in pwMS comparing intermittent walking (IW) to continuous walking (CW). MATERIALS AND METHODS: 18 pwMS, with Expanded Disability Status Scale median of 4.75 [range = 2-6.5, IQR = 2.5] participated in this randomized crossover study. The IW condition consisted of alternating 30 s treadmill walking and 30 s seated rests. The CW condition consisted of treadmill walking without breaks. Treadmill speed (TS) was determined by an overground 2-min walk test. Walking fatigability was determined by participants walking on the treadmill, until gait fatigue was noted by patient or examiners. Total time and distance to gait fatigue, and subjective fatigue as measured by the Visual analog scale of fatigue were recorded. RESULTS: Participants had significantly longer duration and distance to fatigue in the IW condition than the CW condition (ps ≤ 0.037). No difference in VASF scores between the two conditions were noted. CONCLUSION: In this sample, IW allowed pwMS to perform a greater volume of walking and can be an option to improve walking endurance in this population.IMPLICATIONS FOR REHABILITATIONMultiple sclerosis (MS) is a disease that progressively impacts walking, resulting in a decrease in the maximum distance that a person with MS can walk.Intermittent walking has been shown to improve 6-min walk test performance in persons with MS (pwMS) compared to continuous walking, but its effects on longer and shorter walks is not known.The use of distance to fatigue should be considered a viable option for measuring walking fatigability in pwMS as it does not exclude persons based on their ability to complete a 6-min walk, nor would it be too easy for persons with pwMS with mild disability.By using distance to fatigue as an outcome measure, this study provides evidence that intermittent walking results in less fatigability regardless of walking ability.PwMS, regardless of their walking ability, can walk longer distances intermittently than continuously, suggesting that clinical treatment of walking fatigability in pwMS should utilize intermittent rather than continuous walking training.

Requirements for distinct steps of phospholipase Cgamma2 regulation, membrane-raft-dependent targeting and subsequent enzyme activation in B-cell signalling.

Studies of PLCgamma (phospholipase Cgamma) have identified a number of regulatory components required for signalling; however, molecular mechanisms and the relationship between events leading to translocation and an increase of substrate hydrolysis have not been well defined. The addition of a membrane-targeting tag to many signal transducers results in constitutive activation, suggesting that these processes could be closely linked and difficult to dissect. The present study of PLCgamma2 regulation by cross-linking of the BCR (B-cell antigen receptor) or H2O2 stress in DT40 B-cells, demonstrated that the membrane targeting is a separate step from further changes that result in enzyme activation and substrate hydrolysis. Furthermore, we have defined the roles of different domains of PLCgamma2 and, using a panel of cell lines deficient in components linked to PLCgamma2 regulation, the involvement of signalling molecules with respect to each of the steps. We have found that only the lipid-raft-targeted Lyn-PLCgamma2 construct, unlike non-specific membrane targeting, overcame the requirement for the adapter protein BLNK (B-cell linker). The stable expression of Lyn-PLCgamma2 was not accompanied by an increase in substrate hydrolysis in resting cells, which followed stimulation and specifically required the presence and/or activation of Syk, Btk, phosphoinositide 3-kinase but not BLNK, as established using deficient cell lines or specific inhibitors. Based on mutational analysis of the specific tyrosine residues [Tyr753-->Phe (Y753F)/Y759F] and SH2 (Src homology 2) domains (R564A/R672A) in the context of Lyn-PLCgamma2, we found that Tyr753/Tyr759 were essential, whereas the PLCgamma2 SH2 domains did not have an important role in the transient activation of Lyn-PLCgamma2 but may serve to stabilize an activated form in sustained activation.