Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway.

Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the research has focused on electrophilic Nrf2 activators, but there is increasing interest in non-electrophilic modulators of Nrf2. This Digest examines the current selection of small molecules that modulate Nrf2 through non-electrophilic mechanisms, and it highlights new opportunities for this important therapeutic target.

HIV transmission risks of females and males in paired partner relationships.

As the HIV/AIDS epidemic has evolved, heterosexual behaviors have come to be an increasingly important mode of transmission and rates of infection have increased faster among women generally and minority women in particular. Most of what we known about heterosexual risk taking is based on survey data collected from either women or men. These data have been useful for helping to understand different levels and types of risk taking by women and men. However, they provide little information about the levels of risk taking that exist for paired partners in main partner relationships, the types of risks each partner brings to the relationship and how the contribution of partner risks varies. Using data from the pretest of a pilot project designed to test a behavioral intervention to reduce HIV/AIDS transmission among main sex partners, the authors developed four subscales of sexual risk taking for each partner. The association between subscales within and between genders are examined and the subscales are combined to obtain measures of couple risks. Particular attention is given to the gender contribution of partners to couple risk and the differential contribution of types of risk to total risk. The data suggest that, even though men bring relatively higher risks to their main partner relationship than women, this varies inversely with the level of couple risk.

The industry manipulation attitudes of smokers and nonsmokers.

A cross-sectional random sample was obtained of Florida youth between the ages of 12-17. Data were collected through a telephone survey after obtaining parent and child consent. Industry manipulation attitudes of three groups (self-identified nonsmokers who did not use cigarettes in the past 30 days, self-identified nonsmokers who used cigarettes in the past 30 days, and self-identified smokers who used cigarettes in the past 30 days) were compared. Constraints resulting from the method of data collection resulted in a conservative estimate of the strength of the association between industry manipulation attitudes and smoking behavior.

A compartmental model for oxygen-carbon dioxide coupled transport in the microcirculation.

We present a multicompartmental model for an oxygen-carbon dioxide transport system. The compartmental equations and their lumped parameters are derived through space averaging of the corresponding distributed model. The model can predict compartmental distributions of oxygen and carbon dioxide partial pressures, oxygen-hemoglobin saturation, and pH. Other unique features include the effects of the radial distribution of partial pressures and the difference in metabolic rates between vessel wall and tissue. A model for the cat brain, based on this formulation, is compared with results of experiments and with two types of earlier models: one without space averaging and one without carbon dioxide transport. The results suggest that space averaging the convective terms significantly affects the behavior of the model. This is consistent with conclusions from our earlier oxygen-only model. Our observations also demonstrate, however, significant differences between the results from the oxygen-carbon dioxide model and the oxygen-only model. For instance, at low blood flow rates or at low level of oxygen input, predicted oxygen partial pressures can differ by as much as 30% between the two models. Results obtained from the present model are supported by available experimental findings.

A mathematical model of G time-tolerance.

We propose a model to explain experimentally observed effects of Gz onset rates and levels on the time of occurrence of loss of vision and/or consciousness. The model is based on the existence of two generally accepted parameters: a G limit beyond which cerebral perfusion ceases, and a buffer time between loss of perfusion and loss of function. When applied to ramp onset G profiles, the model predicts a generally hyperbolic locus of endpoints, similar to the well-known Stoll curve, except for the dip. The advantage of the model is its applicability to any G onset profile. Data from the literature support the assumptions of the model and its results, including the absence of the dip in the locus for a ramp onset. The results call into question some concepts used to design G avoidance inflight strategies and the usefulness of some experimental centrifuge methods. The model may enable an increase in the accuracy of predictions of the time of visual or cerebral loss of function under various G profiles.

Contributions of oxygen dissociation and convection to the behavior of a compartmental oxygen transport model.

We previously derived a compartmental model for oxygen transport in vascular blood in which lumped terms, representing convective and oxygen dissociative effects, were obtained from a distributed model by space averaging. In this paper, we compare the results of this model and those of another compartmental model from the literature in which these terms were selected arbitrarily. The use of space-averaged parameters resulted in a more distinct difference in calculated partial pressures of oxygen between capillary and venule compartments, more accurate distribution patterns for partial pressures of oxygen through the venule compartments, and a capability to simulate conditions under which mean oxygen partial pressure in tissue is higher than in the venules. These results are supported by available experimental findings. Results also showed that the employment of space-averaged convective terms had a greater effect on the distribution of compartmental partial pressures than did the use of the cross-sectional averaged oxygen-hemoglobin binding function. The latter produced significant changes only for certain compartments, and only under extreme physiologic conditions. The results demonstrate our model's ability to reflect relationships among capillary, venule, and tissue compartmental partial pressures under varying conditions.

Incorporating vessel taper and compliance properties in Navier-Stokes based blood flow models.

A popular and useful technique used to model blood flow in cardiovascular simulations is to divide each blood vessel into a series of segments, each with its own lumped resistance, inertance, and compliance parameters. The values of these parameters are usually obtained through a simplification of the Navier-Stokes equations for fluid flow. However, the simplification often ignores the nonlinear and convective terms of the equations, resulting in errors in the parameter values, especially in the value found for resistance per unit length. We report a new method for the calculation of vessel resistance per unit length which takes into account the effects of vessel taper and wall compliance. It is shown that these effects can be addressed by the addition of two time-varying terms to the calculation of resistance per unit length. One term, due to vessel taper, is proportional to volumetric flow rate Q. The other term, due to vessel compliance, is proportional to delta p/delta t. These variables are readily available in computer simulations of blood flow in lumped parameter systems. Using data for the descending aorta, the new parameter values, when averaged over a cardiac cycle, compare favorably with results in the literature.

Performance optimization of left ventricular assistance. A computer model study.

Performance of temporary parallel left ventricular assistance was investigated and the theoretic conditions leading to optimal behavior of the mechanical system were explored. Computer models of nonpulsatile and pulsatile left ventricular assist devices (LVADs) were incorporated into a previously reported closed-loop simulation of the canine cardiovascular system. Assuming the assisted heart was capable of recovery, LVAD performance was assessed based on both myocardial oxygen balance and cardiac output. With a synchronous LVAD, and operating in a counterpulsation mode, these variables were sensitive to the phasing of pump ejection. Maximum reduction in cardiac oxygen consumption, maximum increase in oxygen availability, and maximum increase in cardiac output with the atrio-aortic device were obtained when pump ejection immediately followed aortic valve closure. These variables were directly proportional to the magnitude of bypass volume. The pulsatile asynchronous and nonpulsatile LVAD models affected oxygen balance in a similar manner, but neither performed so well as the synchronous model when equal bypass volumes were used. Ventricular uptake of blood provided a further 27% decrease in oxygen consumption and further 78% increase in oxygen availability than atrial uptake. In summary, the model predicted that the pulsatile synchronous LVAD, filling from the ventricle during heart systole and ejecting into either the ascending or descending aorta just after ventricular systole, would be most beneficial to both myocardial oxygen balance and cardiac output.

Optimal controller for intraaortic balloon pumping.

An optimal control algorithm was adapted to identify and track the optimal deflation time of the intraaortic balloon pump (IABP). Routines for handling physiologically imposed constraints were added to the algorithm which was implemented in a computer-controlled system. The system was designed to provide real time optimization for the clinical setting. The controller continuously maximizes a performance index while observing the constraints. The index is composed of clinically available hemodynamic variables which indicate changes in myocardial energy balance. Proper values for the algorithm parameters were determined and the system was tested in animal experiments. The results indicate that controlling deflation time relative to the R wave, which precedes the next ejection phase, reduces the time required for optimization when the heart rate varies.

Optimal control system for the intra-aortic balloon pump.

An optimal control system for the intra-aortic balloon pump (IABP) is presented. Control of the IABP is based on a performance index formulated to reflect a tradeoff between maximising cardiac oxygen supply and minimising cardiac oxygen consumption. In the performance index, mean diastolic pressure (MDP) was used to represent oxygen availability and peak systolic pressure (PSP) was used to represent oxygen consumption. An algorithm, implemented using an 8-bit microcomputer, changes the deflation time of the IABP to maximise this performance index by using an optimisation technique that employs both a search and an approximation. The search produces three equally spaced points which define a region that includes the maximum of the performance index. From these points, the optimum deflation time is estimated by a quadratic approximation. The algorithm has been successfully tested using performance index curves generated by computer simulations.

Cardiovascular model for studying circulatory impairment under acceleration.

A model of the cardiovascular system developed for use in the study of cardiovascular responses to acceleration of the type encountered by pilots of high-performance aircraft is described. The model includes simulations of the heart; arterial, venous, and peripheral circulations; and physiological compensatory mechanisms important to acceleration studies. It can predict blood pressure and flow in any part of the circulation under conditions of G(z) stress and with the application of G-protection techniques. Predictions of the model have been used to analyze the cause of loss of pilot function under G forces, and to design an improved anti-G suit.

Cardiac energy considerations during intraaortic balloon pumping.

Cardiac oxygen availability and oxygen consumption were used in a theoretical study as indexes of myocardial energy supply and utilization, respectively. A detailed computer simulation of the closed-loop canine cardiovascular system was utilized to study the dependence of these indexes on timing of the intraaortic balloon pump. Oxygen availability exhibited higher sensitivity to balloon timing than oxygen utilization. While maximum augmentation of oxygen availability was 58 percent, oxygen consumption could be reduced by only 13 percent. Animal experiments were initiated to validate the theoretical results. The results of both the animal experiments and the computer simulation suggested that neither balloon timing which maximizes oxygen availability nor timing which minimizes oxygen consumption correlates with timing which minimizes aortic end diastolic pressure. Thus, end diastolic pressure, presently used as a determinant of proper timing in patients undergoing cardiac assistance, was found to be a poor index of ventricular energy consumption. A performance index comprised of clinically available variables, was formulated to reflect myocardial energy balance. In this performance index, mean diastolic pressure was used to represent energy availability and peak systolic pressure was used as an index of oxygen consumption. Their relationship to oxygen balance and their dependence on timing were studied using the computer simulation of the canine cardiovascular system and animal experiments. Theoretical and experimental results suggest that such an index is capable of representing O2 balance and can be used to control phasing of the device.

Computer simulation of the mechanically-assisted failing canine circulation.

A model of the cardiovascular system is presented. The model includes representations of the left and right ventricles, a nonlinear multielement model of the aorta and its main branches, and lumped models of the systemic veins and the pulmonary circulation. A simulation of the intra-aortic balloon pump and representations of physiological compensatory mechanisms are also incorporated in the model. Parameters of the left ventricular model were set to simulate either the normal or failing canine circulation. Pressure and flow waveforms throughout the circulation as well as ventricular pressure and volume were calculated for the normal, failing, and assisted failing circulation. Cardiac oxygen supply and consumption were calculated from the model. They were used as direct indices of cardiac energy supply and utilization to assess the effects of cardiac assistance.

An experimental microcomputer controlled system for synchronized pulsating anti-gravity suit.

An experimental system to deliver synchronized external pressure pulsations to the lower body is described in this technical note. The system is designed using a microcomputer with a real time interface and an electro-pneumatic subsystem capable of delivering pressure pulses to a modified anti-G suit at a fast rate. It is versatile, containing many options for synchronizing, phasing and sequencing of the pressure pulsations and controlling the pressure level in the suit bladders. Details of its software and hardware are described along with the results of initial testing in a Dynamic Flight Simulator on human volunteers.

Control of intraaortic balloon pumping: theory and guidelines for clinical applications.

The effectiveness of intraaortic balloon pumping was investigated by using a lumped parameter model of the cardiovascular/assist device system. The model consists of a time-varying elastance left ventricular simulation, a 2-element windkessel arterial simulation, and an RC venous return and pulmonary simulation. The four major hemodynamic variables, stroke volume (SV), aortic mean diastolic pressure (MDP), tension time index (TTI), and aortic end diastolic pressure (EDP), were divided into two categories related to system energy supply and demand: "external" and "internal" variables. The effects of balloon pumping on these variables can be described by closed-form equations that yield an optimal solution. The model prediction suggests that, in the ideal case, optimization of balloon pumping calls for instantaneous inflation of the balloon to maximum volume at end systole and instantaneous complete deflation at end diastole. For finite inflation/deflation rates, the optimal time for the start of inflation is end systole. Deflation timing, however, involves a tradeoff between maximizing the external variables and minimizing the internal variables. These predictions were tested using a nonlinear digital computer model. The results also suggest that when SV is not being monitored, optimal inflation timing can be controlled from the measurements of TTI or pulmonary venous pressure; optimal deflation timing can be controlled by a weighted combination of MDP and EDP.

A cardiovascular model for studying impairment of cerebral function during +Gz stress.

A digital computer model of the human cardiovascular system has been developed which can be used for studying impairment of cerebral function during +Gz stress. The model includes simulation of the arterial and venous systems, the heart, baroreceptor control of heart rate, control of venous tone, and the effect of gravity. Model predictions suggest that, for unprotected subjects, carotid pressure at eye level decreases to 50 mm Hg (beginning of peripheral light loss) at approximately 2.7 Gz. The pressure decreases to 20 mm Hg (beginning of central light loss) at approximately 3.6 Gz. An anti-G suit provides an extra 1.1 to 1.5 Gz protection. Even though blood pressure supplying retinal vessels drops significantly at the above G levels, cerebral blood flow is maintained due to protective and compensatory mechanisms. These observations compare favorably with results reported in the literature. The results suggest that this model can be used to improve our understanding of the cardiovascular system's response to +Gz stress.