Along the road not taken: how many myosin heads act on a single actin filament at any instant in working muscle?

We reconsider the use of stiffness measurements to estimate N, the number of myosin heads acting (working at any instant to produce tension) on a single actin filament in vertebrate striated muscle, and give reasons for our rejection of numbers produced from such measurements. We go on to present a different approach to the problem, citing and extending a model bearing on the value of N which is derived from other physiological and biochemical data and which offers insight into the fundamental actin-myosin contractile event as an impulsive force. New experimental data accumulating over the past decade support this model, in which the myosin heads act sequentially along the actin filament (this is an example of Conformational Spread). In this model only a single myosin head acts on a single actin filament to produce an impulse at any given instant in normally-contracting muscle, either in the isometric or the isotonic mode, so N = 1. However, extra impulses occur within the same time frame after quick release of length or tension. The predictions of this sequential model are in striking agreement with a large body of recent detailed biophysical and biochemical evidence. We suggest that this warrants further in-depth experimental work, specifically to explore and test the sequential model and its implications.

Socio-economic factors and health-related quality of life in adults living with HIV.

This study examined the relationships of income, employment status and other socioeconomic characteristics with dimensions of health-related quality of life (HRQOL) for those living with HIV/AIDS, controlling for clinical characteristics. Demographic (gender, age, education, living with a partner, HIV transmission category), economic (employment status, monthly household income, volunteer experience), clinical (CD4 count, AIDS defining illness, time since diagnosis, number of HIV symptoms, and highly active antiretroviral therapy), and HRQOL measures (five Medical Outcomes Study HIV Health Survey subscales) were obtained from 308 consenting HIV clinic patients in Calgary, Canada. Multiple regression results indicate that the strongest predictor of the five QL subscales is employment status, while income was significant as an independent predictor in two of the models. Other socioeconomic characteristics were not consistently significant predictors of HRQOL subscales. The contribution of employment to HRQOL is important to explore further, and suggest the need for flexibility in income support and return-to-work programmes for those with HIV.

Muscle contraction: a new interpretation of the transient behaviour of muscle.

Piazzesi et al. [G. Piazzesi, L. Lucii, V. Lombardi, J. Physiol. 545 (2002) 145-151] made a study on the muscle transients due to step changes in force using improved time resolution and recorded filament movement and shortening velocities in the four phases. They point to Phase 2 and to Phase 4 (working muscle) and claim that their results do not contradict the swinging-cross-bridge (SCB) model which has a much-quoted constant power stroke of about 150 A (their value of 70 A was smaller). Siding with the SCB model, they nevertheless record that the power stroke decreases with load. We are pleased with this experimental result as it conforms to our theory, published in 1996, of an impulsive model with a much smaller step-size distance z (approximately 20 A). Using their data we obtain precise interval times and estimates of filament movement in Phase 2 and in working muscle. Our first result is that the time frames (interval times) for Phase 2 are the same as in working muscle. Moreover, we demonstrate that the authors' data verify the correctness of our calculated z values. There are eight active ATP events in Phase 2 in time frame t compared to one in working muscle in the same time frame t. This gives, for the first time, precise numbers for contractile events. We show that the SCB model is incorrect and our analysis supports the impulsive model with a much smaller filament (zero-load) motion, approximately 20 A per ATP split.

Muscle contraction: energy rate equations in relation to efficiency and step-size distance.

We derive the energy rate equation for muscle contraction. Our equation has only two parameters m, the maintenance heat rate and 1/S, the shortening heat coefficient. The impulsive model (previously described in earlier papers) provides a physical basis for parameter 1/S as well as for constants a and b in Hill's force-velocity equation. We develop new theory and relate the efficiency and the step-size distance to our energy rate equation. Correlation between the efficiency and the step-size distance is established. The various numbers are listed in Table 1: we use data from five different muscles in the literature. In summary, our analysis strongly supports the impulsive model as the correct model of contraction.

Muscle contraction: viscous-like frictional forces and the impulsive model.

Apart from a few experimental studies muscle viscosity has not received much recent analytical attention as a determinant of the contractile process. This is surprising, since any muscle cell is 80% water, and may undergo large shape changes during its working cycle. Intuitively, one might expect the viscosity of the solvent to be an important determinant of the physiological activity of muscle tissue. This was apparent to pioneers of the study of muscle contraction such as Hill and his contemporaries, whose putative theoretical formulations contained terms related to muscle viscosity. More recently, though, a hydrodynamic calculation by Huxley, using a solvent viscosity close to that of water, has been held to demonstrate that viscous forces are negligible in muscle contraction. We have re-examined the role of viscosity in contraction, postulating impulsive acto-myosin forces that are opposed by a viscous resistance between the filaments. The viscous force required, 10(4) times the hydrodynamic estimate, is close to recent experimental measurements, themselves 10(2)-10(3) times the hydrodynamic estimate. This also agrees with contemporary measurements of cytoplasmic viscosity in other biological cells using magnetic bead micro-rheometry. These are several orders of magnitude greater than the viscosity of water. In the course of the analysis, we have derived the force-velocity equation for an isolated half-sarcomere containing a single actin filament for the first time, and from first principles. We conclude that muscle viscosity is indeed important for the contractile process, and that it has been too readily discounted.

Muscle contraction: viscous-like frictional forces and the impulsive model.

Apart from a few experimental studies muscle viscosity has not received much recent analytical attention as a determinant of the contractile process. This is surprising, since any muscle cell is 80% water, and may undergo large shape changes during its working cycle. Intuitively one might expect the viscosity of the solvent to be an important determinant of the physiological activity of muscle tissue. This was apparent to pioneers of the study of muscle contraction such as Hill and his contemporaries, whose putative theoretical formulations contained terms related to muscle viscosity. More recently, though, a hydrodynamic calculation by Huxley, using a solvent viscosity close to that of water, has been held to demonstrate that viscous forces are negligible in muscle contraction. We have re-examined the role of viscosity in contraction, postulating impulsive acto-myosin forces that are opposed by a viscous resistance between the filaments. The viscous force required, 10(4) times the hydrodynamic estimate, is close to recent experimental measurements, themselves 10(2)-10(3) times the hydrodynamic estimate. This also agrees with contemporary measurements of cytoplasmic viscosity in other biological cells using magnetic bead micro-rheometry. These are several orders of magnitude greater than the viscosity of water. In the course of the analysis we have derived the force-velocity equation for an isolated half-sarcomere containing a single actin filament for the first time, and from first principles. We conclude that muscle viscosity is indeed important for the contractile process, and that it has been too readily discounted.

Computerized tomography cisternography of the trigeminal nerve for stereotactic radiosurgery. Case report.

A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.

Community pharmacist perspectives on HIV/AIDS and interventions for injection drug users in Canada.

In several countries, community pharmacies play a major role in the provision of HIV prevention services to injection drug users (IDUs). In this study, results from a national Canadian Survey of Community Pharmacies and HIV/AIDS Prevention are used to describe pharmacists' perspectives on HIV/AIDS and services to IDUs, and explore the relationship between personal and organizational characteristics and the level of support for HIV/AIDS prevention initiatives. A mailed questionnaire was directed to a random sample of 2,017 pharmacist owner-managers. The response rate was 84.6%. Results suggest that current services to IDUs primarily are limited to discretionary needle and syringe sales to non-diabetics, with almost three-quarters supportive. Staff safety was an important consideration in the provision of this service (77%), while remuneration was the lowest (27%). Community pharmacists were most comfortable with the provision of counselling, advice and literature (X = 2.6) and environmental and technological interventions (X = 2.4) and least supportive of provision of services as part of a programme (X = 1.6) and legalization of drugs or prescription of methadone (X = 1.9). Female pharmacists were more likely to support preventive measures such as the provision of counselling or advice, and males were more likely to promote legislative change. Pharmacists appear generally willing to expand their services in the fight against HIV/AIDS. However, it is not feasible to expect uniform programmes to be immediately introduced. While organizational, educational and policy changes may facilitate programme development, individual pharmacy and pharmacist discretion remains important.

The muscle motor: 'simultaneous' levers or sequential impulses?

We use the step-size distance equation z = u/n developed in our two previous papers (z is the step-size distance, u is the actin filament relative velocity and n is the rate of ATP splitting on a given actin filament), and introduce one additional concept: that the impulsive contractile forces developed on an actin filament should proceed sequentially along a given actin-myosin train. This enables us to elucidate some unexplained and puzzling data in the literature, and to predict the surprisingly high values of ATPase in intact muscle that have recently been found experimentally. It seems that a sequential impulsive model of the actin myosin interaction may give a better explanation of many phenomena in muscle physiology than does the current model of the action of simultaneous levers.

Comparison of functional magnetic resonance imaging for language localization and intracarotid speech amytal testing in presurgical evaluation for intractable epilepsy. Preliminary results.

A comparison is made between the results of standard intracarotid speech amytal testing and a new methodology, echoplanar blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI), in patients undergoing presurgical evaluation for intractable epilepsy. Of the 15 patients entered in the study, all had fMRIs while performing a verbal fluency task. Twelve of these patients also underwent standard intracarotid sodium amytal testing for speech and memory. Results of the fMRIs as compared to the intracarotid speech amytal testing are discussed, including agreement and disagreement between studies. Potential reasons for poor concordance are discussed, including complexity of the verbal fluency task, and motion and technical issues in MRI scan acquisition and data analysis.

The step-size distance in muscle contraction: properties and estimates.

The step-size distance in muscle contraction is obtained using the step-size distance equation z = u/n, where z is the step-size distance, u is the actin filament velocity and n is the ATPase rate of splitting. In a previous study a step-size distance of about 17 A at no load was determined for intact frog muscle. Some properties of the step-size equation are described. We have now made estimates of the step-size distance z for a variety of muscles using existing physiological and biochemical data in the literature. The estimates are listed in Tables 1 and 2. We find that the step-size distances are clustered in the range 13-17 A for nearly all muscles.

The role of policy in community pharmacies' response to injection-drug use: results of a nationwide Canadian survey.

The response rate to this survey reflects the salience of the topic and the professional concern about and interest in issues presented by HIV. The HIV/AIDS epidemic has presented pharmacists with one of the greatest challenges to their professional training, ethics, and practice. It further expedites a current re-examination that is occurring among community pharmacies concerning their roles in community health practices. In response to HIV there have been dramatic and unprecedented changes in pharmacy policy and practices. Clearly, some community pharmacies have led the way and influenced policy and practices. In view of the recent introduction of many of these policies and practices, it is likely that change will continue. Survey respondents were, in general, very comfortable with an expanded role involving counseling, health promotion, and disease prevention, consistent with a broader role for community pharmacies in general that has been recently advocated. Community pharmacies serve all areas of the country, in communities large and small; many are open seven days a week, and some provide extended hours of service. Community pharmacies may provide an important complement to community outreach programs as a source of clean needles and syringes for IDUs in most communities, and as an alternative service in some communities where more elaborate programs are not feasible. Safer needle use, as part of a health-promotion approach, is divergent from conventional practice. While major changes have occurred, it appears that there has been some polarization of attitudes and response. The explanation for this is not simple, and further analysis is required to determine the full impact from several ethical perspectives that include professional, business, and public health viewpoints. We have highlighted the role that policy has in moving toward preventive and harm-reduction approaches. From a policy perspective, we have found that support from the federal government, regulatory bodies, and professional associations may be an important catalyst to pharmacists' participation in programs. Further, it does not appear to be possible to implement such policies without professional development and continuing education, and collaboration with the community. Based on data on knowledge and educational need, we believe that our study population's lowest levels of information were in such areas as the role of methadone in HIV prevention and the availability of needle-exchange programs. As with other health-promotion campaigns, additional skills training may be important. Movement forward with expanded preventive and harm-reduction strategies by pharmacies will require careful planning. It is anticipated that change in this area will be incremental in nature, and that it is necessary to introduce programs and services into community pharmacies gradually. Successful implementation will require extensive community development and collaboration with other health professionals, public health officials, police, groups who represent IDUs, and persons living with HIV/AIDS. Careful monitoring and evaluation of these programs will be necessary to enhance their effectiveness.

Muscle contraction: the step-size distance and the impulse-time per ATP.

We derive the step-size distance, and the impulse time per ATP split, from a consideration of Hill's energy rate equation coupled with the enthalpy available per ATP split. This definition of step-size distance is model-independent, and is calculated to have a maximum of 17 A at no load and to reduce to zero at isometric tension, since it will depend on the velocity of shortening. We revisit a derivation of Hill's force-velocity equation depending on impulsive forces working against frictional forces and show that this gives a physical meaning to Hill's constants a and b. This is particularly elegant for Hill's constant b, which is directly related to the impulse time; the value of this impulse time is 1/2 ms. The question that muscle contraction may involve overlapping interactions is considered. However, we find that the step-size distance is not dependent on the possibility of overlapping interactions.

The multiconstituency approach to organizational performance assessment: a Canadian mental health system application.

This papers applies a multiconstituency approach to assessing organizational performance in Canadian general hospital psychiatric units and provincial psychiatric hospitals. In the absence of reliable and valid outcome measures, researchers and administrators have increasingly considered the views of external constituencies as a means of both defining the criteria for effective performance and actually assessing organizational performance. Key constituencies included psychiatric unit staff, psychiatric hospital administrators, and directors of community agencies providing mental health and related services. Opinions about organizational roles were found to exist among constituencies and among professional groups. Perceptions of organizational performance were highest for primary roles and substantially lowest for roles of secondary importance to the constituency. Future analyses of this type could help to validate the use of both constituency measures and more traditional performance measures. While constituency views may be seen as subjective, they are nevertheless key to building effective mental health service delivery systems.

How muscle may contract.

A new molecular model is proposed for muscle contraction, that involves the electrical charging of the long (C-terminal) alpha-helical part of the head of the myosin molecule (S1) while the head is attached to actin; as it charges the alpha-helical part moves in the radial electric field between the filaments. The alpha-helical part snaps back when the myosin molecule is discharged electrically, at the moment that ATP binds to the active enzymatic site. This snap-back model explains several puzzling phenomena in contractility, as well as providing a physical explanation for the origin of an impulsive force that drives muscle contraction.

Surgical clipping of difficult intracranial aneurysms using deep hypothermia and total circulatory arrest.

Intracranial aneurysms often present a challenging problem for the neurosurgeon. A variety of techniques have been developed to deal with these lesions. Several subspecialists are frequently involved in such treatment. We present our experience in a community hospital using a previously described technique of hypothermic cardiac arrest and barbiturate cerebral protection.

Measurement of chain tilt angle in fully hydrated bilayers of gel phase lecithins.

The tilt angle theta tilt of the hydrocarbon chains has been determined for fully hydrated gel phase of a series of saturated lecithins. Oriented samples were prepared on glass substrates and hydrated with supersaturated water vapor. Evidence for full hydration was the same intensity pattern of the low angle lamellar peaks and the same lamellar repeat D as unoriented multilamellar vesicles. Tilting the sample permitted observation of all the wide angle arcs necessary to verify the theoretical diffraction pattern corresponding to tilting of the chains towards nearest neighbors. The length of the scattering unit corresponds to two hydrocarbon chains, requiring each bilayer to scatter coherently rather than each monolayer. For DPPC, theta tilt was determined to be 32.0 +/- 0.5 degrees at 19 degrees C, slightly larger than previous direct determinations and considerably smaller than the value required by recent gravimetric measurements. This new value allows more accurate determinations of a variety of structural parameters, such as area per lipid molecule, A = 47.2 +/- 0.5 A2, and number of water molecules of hydration, nw = 11.8 +/- 0.7. As the chain length n of the lipids was increased from 16 to 20 carbons, the parameters A and nw remained constant, suggesting that the headgroup packing is at its excluded volume limit for this range. However, theta tilt increased by 3 degrees and the chain area Ac decreased by 0.5 A2. This behavior is explained in terms of a competition between a bulk free energy term and a finite or end effect term.

An examination of factors influencing the diagnosis and treatment of black patients in the mental health system.

The Civil Rights Movement, which began in the 1950s and lasted through the mid 1970s played a major role improving the quality of life for black Americans. Although much has changed since the 1950s the roots of racism are deep and change occurs slowly. Race exerts an overwhelming influence on popular ideology and medical thinking. Many researchers have speculated that a strong association exists between race and diagnosis. Understanding the sociocultural background of the patient would aid in the distinguishing culturally bound behavior from behavior that reflects actual psychopathology. This review examines the professional literature on racial and ethnic factors as they pertain to the diagnosis and treatment of black patients in the mental health system.

Dynamic stereotactic radiosurgery using a linear accelerator.

We describe a system for stereotactic radiosurgery with a linear accelerator. This technique allows treatment of small (less than 40 mm diameter) intracranial lesions, including vascular malformations, and primary and metastatic tumors that are deep within the brain or in areas not amenable to open surgery. A beam of ionizing radiation (1800 to 2500 cGy) is focused on the center of the lesion, which is determined by stereotactic localization. "Dynamic rotation" of the linac gantry and table continuously about this predetermined point ensures that only the lesion receives the full radiation dose, while the normal structures in the head receive minimal amounts of radiation. The system combines, for the first time in one place, elements of radiosurgical technique developed at various centers. Testing for accuracy compares favorably with results at other centers using linac-based systems as well as comparing favorably with the gamma knife.