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.

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.

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 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.

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.

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.

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.

Rules for rehabilitation: an agenda for research.

Rehabilitation services have grown tremendously in the United States over the past 2 decades. Rules originally designed to guide Medicare reimbursement policies have had substantial effects in shaping the design of clinical services. This article traces the development of the most significant federal rules regarding rehabilitation, outlines the existing empirical evidence to support these rules, and discusses an agenda for research to improve the evidence for future policy development.

Stroke rehabilitation in Switzerland versus the United States: a preliminary comparison.

This article compares the structure and process of rehabilitation for stroke patients at 2 internationally recognized rehabilitation hospitals, Klinik Valens ("Valens") in Switzerland and the William Donald Schaeffer Rehabilitation Hospital at Kernan ("Kernan") in the United States. Although the patient mix, structure, and process of rehabilitation were similar in many regards, there were some important differences. Most notably, on average, patients at the U.S. hospital were discharged from rehabilitation at approximately the same day poststroke that rehabilitation began in Switzerland. Patients remained in an inpatient setting an average of 40 days longer in Switzerland (for the combination of acute care and rehabilitation) and had significantly higher levels of functioning at discharge when compared to their U.S. counterparts. The authors' findings suggest that Europe may offer opportunities for rehabilitation research that would be difficult to duplicate in the United States and highlight policy-relevant questions for future studies aimed at developing efficient managed care systems for stroke survivors.

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.

Integrated health system for chronic disease management: lessons learned from France.

Rated number one in overall health system performance by the World Health Organization, the French spend less than half the amount on annual health care per capita that the United States spends. One contributing factor may be the attention given to chronic care. Since the mid-1900s, the French have developed regional community-based specialty systems for patients with chronic respiratory insufficiency or failure. COPD is the major cause of respiratory failure, the fourth leading cause of death in the United States, and its prevalence is increasing. Despite the clinical success of home mechanical ventilation and the potential for cost savings, providing such services in the United States remains a challenge. Lessons from France can inform the development of cost-effective chronic care models in the United States In this article, we review the French experience in the context of the United States Supreme Court's Olmstead decision, mandating that people in "more restrictive settings" such as nursing homes be offered community-based supports. We suggest that regional demonstration projects for patients with chronic respiratory failure or insufficiency can provide an important step in the development of effective chronic care systems in the United States

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Narrative and procedural discourse production by severely aphasic patients.

Five cbronically aphasic subjects were trained on a computerized iconographic communication system (C-VIC). Their performance in producing single sentences scripts. and narratives was assessed using both spoken English and C-VIC. The requisite vocabulary necessary and the narrative complexity of the target productions were controlled. Subject performance using C-VIC indicates that the ability to construct discourse at the macrostructural level is largely intact. Despite significant improvements in spoken production after C-VIC training, especially at the single sentence level, the subjects' spoken discourse remains severely impaired by their failures at the microlinguistic level. These results point to the limits of currently available approaches to the remediation of aphasia and suggest avenues for future research.

Timing, intensity, and duration of rehabilitation for hip fracture and stroke: report of a workshop at the National Center for Medical Rehabilitation Research.

This article summarizes the proceedings of an NIH workshop on timing, intensity, and duration of rehabilitation for acute stroke and hip fracture. Participants concentrated on methodological issues facing investigators and suggested priorities for future research in this area.

Brain-computer interface technology: a review of the Second International Meeting.

This paper summarizes the Brain-Computer Interfaces for Communication and Control, The Second International Meeting, held in Rensselaerville, NY, in June 2002. Sponsored by the National Institutes of Health and organized by the Wadsworth Center of the New York State Department of Health, the meeting addressed current work and future plans in brain-computer interface (BCI) research. Ninety-two researchers representing 38 different research groups from the United States, Canada, Europe, and China participated. The BCIs discussed at the meeting use electroencephalographic activity recorded from the scalp or single-neuron activity recorded within cortex to control cursor movement, select letters or icons, or operate neuroprostheses. The central element in each BCI is a translation algorithm that converts electrophysiological input from the user into output that controls external devices. BCI operation depends on effective interaction between two adaptive controllers, the user who encodes his or her commands in the electrophysiological input provided to the BCI, and the BCI that recognizes the commands contained in the input and expresses them in device control. Current BCIs have maximum information transfer rates of up to 25 b/min. Achievement of greater speed and accuracy requires improvements in signal acquisition and processing, in translation algorithms, and in user training. These improvements depend on interdisciplinary cooperation among neuroscientists, engineers, computer programmers, psychologists, and rehabilitation specialists, and on adoption and widespread application of objective criteria for evaluating alternative methods. The practical use of BCI technology will be determined by the development of appropriate applications and identification of appropriate user groups, and will require careful attention to the needs and desires of individual users.

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.