Dimeric Tubulin Modifies Mechanical Properties of Lipid Bilayer, as Probed Using Gramicidin A Channel.

Using the gramicidin A channel as a molecular probe, we show that tubulin binding to planar lipid membranes changes the channel kinetics-seen as an increase in the lifetime of the channel dimer-and thus points towards modification of the membrane's mechanical properties. The effect is more pronounced in the presence of non-lamellar lipids in the lipid mixture used for membrane formation. To interpret these findings, we propose that tubulin binding redistributes the lateral pressure of lipid packing along the membrane depth, making it closer to the profile expected for lamellar lipids. This redistribution happens because tubulin perturbs the lipid headgroup spacing to reach the membrane's hydrophobic core via its amphiphilic α-helical domain. Specifically, it increases the forces of repulsion between the lipid headgroups and reduces such forces in the hydrophobic region. We suggest that the effect is reciprocal, meaning that alterations in lipid bilayer mechanics caused by membrane remodeling during cell proliferation in disease and development may also modulate tubulin membrane binding, thus exerting regulatory functions. One of those functions includes the regulation of protein-protein interactions at the membrane surface, as exemplified by VDAC complexation with tubulin.

Adaptive Physical Activity for Stroke: An Early-Stage Randomized Controlled Trial in the United States.

Background. As stroke survival improves, there is an increasing need for effective, low-cost programs to reduce deconditioning and improve mobility. Objective. To conduct a phase II trial examining whether the community-based Italian Adaptive Physical Activity exercise program for stroke survivors (APA-Stroke) is safe, effective, and feasible in the United States. Methods. In this single-blind, randomized controlled trial, 76 stroke survivors with mild to moderate hemiparesis >6 months were randomized to either APA-Stroke (N = 43) or Sittercise (N = 33). APA-Stroke is a progressive group exercise regimen tailored to hemiparesis that includes walking, strength, and balance training. Sittercise, a seated, nonprogressive aerobic upper body general exercise program, served as the control. Both interventions were 1 hour, 3 times weekly, in 5 community locations, supervised by exercise instructors. Results. A total of 76 participants aged 63.9 ± 1.2 years, mean months poststroke 61.8 ± 9.3, were included. There were no serious adverse events; completion rates were 58% for APA-Stroke, 70% for Sittercise. APA-Stroke participants improved significantly in walking speed. Sample size was inadequate to demonstrate significant between-group differences. Financial and logistical feasibility of the program has been demonstrated. Ongoing APA classes have been offered to >200 participants in county Senior Centers since study completion. Conclusion. APA-Stroke shows great promise as a low-cost, feasible intervention. It significantly increased walking speed. Safety and feasibility in the US context are demonstrated. A pivotal clinical trial is required to determine whether APA-Stroke should be considered standard of care.

Neutron scattering in the biological sciences: progress and prospects.

The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation-funded workshop in February 2018, recent developments in this field are reviewed here, as well as future prospects that can be expected given recent advances in sources, instrumentation and computational power and methods. Crystallography, solution scattering, dynamics, membranes, labeling and imaging are examined. For the extraction of maximum information, the incorporation of judicious specific deuterium labeling, the integration of several types of experiment, and interpretation using high-performance computer simulation models are often found to be particularly powerful.

The actions of volatile anesthetics: a new perspective.

This article reviews recent work in applying neutron and X-ray scattering towards the elucidation of the molecular mechanisms of volatile anesthetics. Experimental results on domain mixing in ternary lipid mixtures, and the influence of volatile anesthetics and hydrostatic pressure are placed in the contexts of ion-channel function and receptor trafficking at the postsynaptic density.

Lipid nanodomains change ion channel function.

Signaling proteins and neurotransmitter receptors often associate with saturated chain and cholesterol-rich domains of cell membranes, also known as lipid rafts. The saturated chains and high cholesterol environment in lipid rafts can modulate protein function, but evidence for such modulation of ion channel function in lipid rafts is lacking. Here, using raft-forming model membrane systems containing cholesterol, we show that lipid lateral phase separation at the nanoscale level directly affects the dissociation kinetics of the gramicidin dimer, a model ion channel.

Hydrostatic Pressure Promotes Domain Formation in Model Lipid Raft Membranes.

Neutron diffraction measurements demonstrate that hydrostatic pressure promotes liquid-ordered (Lo) domain formation in lipid membranes prepared as both oriented multilayers and unilamellar vesicles made of a canonical ternary lipid mixture for which demixing transitions have been extensively studied. The results demonstrate an unusually large dependence of the mixing transition on hydrostatic pressure. Additionally, data at 28 °C show that the magnitude of increase in Lo caused by 10 MPa pressure is much the same as the decrease in Lo produced by twice minimum alveolar concentrations (MAC) of general anesthetics such as halothane, nitrous oxide, and xenon. Therefore, the results may provide a plausible explanation for the reversal of general anesthesia by hydrostatic pressure.

Community-based exercise for chronic disease management: an Italian design for the United States?

Although only a small proportion of older adults in the United States engage in recommended amounts of physical exercise, the health benefits of exercise for this population and the potential for lowering health care costs are substantial. However, access to regular exercise programs for the frail elderly and individuals with disabilities remains limited. In the context of health reform and emerging opportunities in developing integrated systems of care, the experience in Tuscany in implementing a community-based program of exercise for the elderly should be of interest.

Community-based exercise for upper limb paresis: a controlled trial with telerehabilitation.

BACKGROUND: Arm paresis remains a major impairment after stroke despite the best conventional rehabilitation. Randomized, controlled trials of intensive exercise programs have demonstrated improvements in arm function for patients with chronic stroke. However, the gains achieved have been relatively modest for the large investments in patient and therapist time. OBJECTIVE: To evaluate the safety, acceptance, adherence, and effectiveness of a community-based exercise program for upper limb paresis in patients with chronic stroke and the effects of telerehabilitation monitoring in kiosks distributed through the community. METHODS: Longitudinal cohort with geographic control group. The experimental group received devices needed for a home exercise program based on the Carr and Shepherd "Motor Learning Program" and were instructed to practice the exercises at least twice a week at the kiosk and at least 3 more days a week at home. The control group received usual care. RESULTS: Compared with the control group, patients in the experimental group demonstrated significant gains in arm function as measured by the Wolf Motor Function Test, 9-Hole Peg Test, Motricity Index, and Nottingham Extended Activities of Daily Living Questionnaire. The intervention received high satisfaction ratings and produced no adverse events. Only 30% of the subjects attended kiosks regularly. Outcomes for this group did not differ significantly from those who only practiced at home. CONCLUSIONS: Home- and community-based exercise for arm paresis is safe and effective. Telerehabilitation interventions will need additional enhancements to improve effectiveness. The optimal upper extremity exercise prescription poststroke remains to be established.

Xenon and other volatile anesthetics change domain structure in model lipid raft membranes.

Inhalation anesthetics have been in clinical use for over 160 years, but the molecular mechanisms of action continue to be investigated. Direct interactions with ion channels received much attention after it was found that anesthetics do not change the structure of homogeneous model membranes. However, it was recently found that halothane, a prototypical anesthetic, changes domain structure of a binary lipid membrane. The noble gas xenon is an excellent anesthetic and provides a pivotal test of the generality of this finding, extended to ternary lipid raft mixtures. We report that xenon and conventional anesthetics change the domain equilibrium in two canonical ternary lipid raft mixtures. These findings demonstrate a membrane-mediated mechanism whereby inhalation anesthetics can affect the lipid environment of transmembrane proteins.

Halothane changes the domain structure of a binary lipid membrane.

X-ray and neutron diffraction studies of a binary lipid membrane demonstrate that halothane at physiological concentrations produces a pronounced redistribution of lipids between domains of different lipid types identified by different lamellar d-spacings and isotope composition. In contrast, dichlorohexafluorocyclobutane (F6), a halogenated nonanesthetic, does not produce such significant effects. These findings demonstrate a specific effect of inhalational anesthetics on mixing phase equilibria of a lipid mixture.

Commentary: beyond educational initiatives: how can we change health care to improve the health of persons with disabilities?

Minihan and colleagues discuss necessary elements of an educational program to instruct generalist physicians in the care of individuals with disabilities. To support these physicians adequately in practice will require significant adaptations of health care financing, recognition of the unique medical needs of persons with disabilities, and efficient utilization of experienced clinical resources. The author outlines what remains to be addressed in the pursuit of better health for patients with disabilities as the U.S. health care system evolves.

Coverage policy for neurorehabilitation: an international perspective.

BACKGROUND: Coverage policy ultimately determines the delivery of services. This article summarizes the authors' effort to ascertain the extent of publically available information on coverage for neurorehabilitation services internationally. OBJECTIVE: Present available data on neurorehabilitation coverage and examine the needs for further research in this area. METHODS: Review of published literature, review of government Web sites, survey of World Federation of NeuroRehabilitation (WFNR) program chairs, and attendees of the 2010 World Congress of NeuroRehabilitation. RESULTS: A wide variation in coverage was found internationally. Data are not routinely accessible. CONCLUSIONS: Informed policy requires current data. There is an opportunity for the WFNR to provide leadership in policy for neurorehabilitation services by assembling and maintaining current data on coverage policy internationally.

Methodological issues in monitoring health services and outcomes for stroke survivors: a case study.

BACKGROUND: Obtaining comprehensive health outcomes and health services utilization data on stroke patients has been difficult. This research grew out of a memorandum of understanding between the NIH and the ISS (its Italian equivalent) to foster collaborative research on rehabilitation. OBJECTIVE: The purpose of this study was to pilot a methodology using administrative data to monitor and improve health outcomes for stroke survivors in Tuscany. METHODS: This study used qualitative and quantitative methods to study health resources available to and utilized by stroke survivors during the first 12 months post-stroke in two Italian health authorities (AUSL10 and 11). Mortality rates were used as an outcome measure. RESULTS: Number of inpatient days, number of prescriptions, and prescription costs were significantly higher for patients in AUSL 10 compared to AUSL 11. There was no significant difference between mortality rates. CONCLUSION: Using administrative data to monitor process and outcomes for chronic stroke has the potential to save money and improve outcomes. However, measures of functional impairment and more sensitive outcome measures than mortality are important. Additional recommendations for enhanced data collection and reporting are discussed.

Lipid-dependent effects of halothane on gramicidin channel kinetics: a new role for lipid packing stress.

We find that the sensitivity of gramicidin A channels to the anesthetic halothane is highly lipid dependent. Specifically, exposure of membranes made of lamellar DOPC to halothane in concentrations close to clinically relevant reduces channel lifetimes by 1 order of magnitude. At the same time, gramicidin channels in membranes of nonlamellar DOPE are affected little, if at all, by halothane. We attribute this difference in channel behavior to a difference in the stress of lipid packing into a planar lipid bilayer, wherein the higher stress of DOPE packing reduces the degree of halothane partitioning into the hydrophobic interior.

Community-based adaptive physical activity program for chronic stroke: feasibility, safety, and efficacy of the Empoli model.

OBJECTIVE: To determine whether Adaptive Physical Activity (APA-stroke), a community-based exercise program for participants with hemiparetic stroke, improves function in the community. METHODS: Nonrandomized controlled study in Tuscany, Italy, of participants with mild to moderate hemiparesis at least 9 months after stroke. Forty-nine participants in a geographic health authority (Empoli) were offered APA-stroke (40 completed the study). Forty-four control participants in neighboring health authorities (Florence and Pisa) received usual care (38 completed the study). The APA intervention was a community-based progressive group exercise regimen that included walking, strength, and balance training for 1 hour, thrice a week, in local gyms, supervised by gym instructors. No serious adverse clinical events occurred during the exercise intervention. Outcome measures included the following: 6-month change in gait velocity (6-Minute Timed Walk), Short Physical Performance Battery (SPPB), Berg Balance Scale, Stroke Impact Scale (SIS), Barthel Index, Hamilton Rating Scale for Depression, and Index of Caregivers Strain. RESULTS: After 6 months, the intervention group improved whereas controls declined in gait velocity, balance, SPPB, and SIS social participation domains. These between-group comparisons were statistically significant at P<.00015. Individuals with depressive symptoms at baseline improved whereas controls were unchanged (P<.003). Oral glucose tolerance tests were performed on a subset of participants in the intervention group. For these individuals, insulin secretion declined 29% after 6 months (P=.01). CONCLUSION: APA-stroke appears to be safe, feasible, and efficacious in a community setting.

Adaptive physical activity improves mobility function and quality of life in chronic hemiparesis.

This study investigated the effects of an adaptive physical activity (APA) program on mobility function and quality of life (QOL) in chronic stroke patients. Twenty subjects with chronic hemiparesis completed a 2-month, combined group, class-home exercise regimen that emphasized mobility training. APA improved Berg Balance Scale scores (35 +/- 2 vs 45 +/- 2, p = 0.001), 6-minute walk distances (114 +/- 15 vs 142 +/- 7 m, p < 0.001), and Short Physical Performance Battery scores (3.2 +/- 0.4 vs 5.2 +/- 0.6, p < 0.001). Barthel Index scores increased (75 +/- 4 vs 84 +/- 4, p < 0.001), but Lawton scores were unchanged. Geriatric Depression Scale (p < 0.01) and Stroke Impact Scale (SIS), Mobility, Participation, and Recovery improved with APA (p < 0.03). APA has the potential to improve gait, balance, and basic but not instrumental activities of daily living profiles in individuals with chronic stroke. Improved depression and SIS scores suggest APA improves stroke-specific outcomes related to QOL.