Balloon aortic valvuloplasty in adults: failure of procedure to improve long-term survival.

OBJECTIVES: This study sought to determine the long-term outcome of adult patients undergoing percutaneous balloon aortic valvuloplasty. BACKGROUND: Percutaneous balloon aortic valvuloplasty has been offered as an alternative to aortic valve replacement for selected patients with valvular aortic stenosis. Although balloon aortic valvuloplasty produces an immediate reduction in the transvalvular aortic gradient, a high incidence of restenosis frequently leads to recurrent symptoms. Therefore, it is unclear whether balloon aortic valvuloplasty impacts on the long-term outcome of these patients. METHODS: Clinical, hemodynamic and echocardiographic data were collected at baseline in 165 patients undergoing balloon aortic valvuloplasty and examined for their ability to predict long-term outcome. RESULTS: The median duration follow-up was 3.9 years (range 1 to 6). Ninety-nine percent follow-up was achieved. During this 6-year period, 152 patients (93%) died or underwent aortic valve replacement, and 99 (60%) died of cardiac-related causes. The probability of event-free survival (freedom from death, aortic valve replacement or repeat balloon aortic valvuloplasty) 1, 2 and 3 years after valvuloplasty was 40%, 19% and 6%, respectively. In contrast, the probability of survival 3 years after balloon aortic valvuloplasty in a subset of 42 patients who underwent subsequent aortic valve replacement was 84%. Survival after aortic valvuloplasty was poor regardless of the presenting symptom, but patients with New York Heart Association functional class IV congestive heart failure had events earliest. Univariable predictors of decreased event-free survival were younger age, advanced congestive heart failure symptoms, lower ejection fraction, elevated left ventricular end-diastolic pressure, presence of coronary artery disease and increased left ventricular internal diastolic diameter. Stepwise multivariable logistic regression analysis found that only younger age and a lower left ventricular ejection fraction contributed independent adverse prognostic information (chi-square 14.89, p = 0.0006). CONCLUSIONS: Long-term event-free and actuarial survival after balloon aortic valvuloplasty is dismal and resembles the natural history of untreated aortic stenosis. Aortic valve replacement may be performed in selected subjects with good results. However, the prognosis for the remainder of patients who are not candidates for aortic valve replacement is particularly poor.

Left ventricular performance improves late after aortic valve replacement in patients with aortic stenosis and reduced ejection fraction.

EF in patients with aortic stenosis and reduced EF who underwent aortic valve replacement did not improve by 1 week postoperatively despite rectification of afterload mismatch. By 6 months, however, EF significantly improved without any further change in ventricular loading conditions. This implies that the benefit from aortic valve replacement (when measured by LV ejection performance) may not be evident until late postoperatively.

Protein and fat utilization in shock.

A previous study demonstrated that in the dog, shock, regardless of its etiology, resulted in increased oxidative utilization of substrates which form lactate and pyruvate as intermediary metabolites. The study implied a concomitant decrease in free fatty acid oxidation, as the oxidative pathway of the latter does not involve the lactate-pyruvate step. To test this hypothesis, free fatty acid metabolism was investigated by infusing carbon-14 labelled fatty acid in 12 normal dogs, in nine animals in shock due to controlled cardiac tamponade, and in six animals with endotoxin shock. The shock state was characterized by significant (p less than 0.05) decrease both in arterial fatty acid concentration and in free fatty acid turnover. In addition, both the rate of free fatty acid oxidation and the percentage of the total CO2 derived from free fatty acid oxidation were significantly (p less than 0.05) diminished. In contrast, urea production rates were higher in shock, and the calculated maximum contribution of protein oxidation to total CO2 production rose from 23% in the control animals to 50% in the test groups.

Asthma therapy from the practice perspective: changes in the wind.

The management of asthma presents a challenge to practicing primary care physicians, which is about to escalate considerably. First, it is becoming crystal clear that asthma is a heterogeneous condition that continues to be more prevalent in the community. This makes objective data (FEV1, PEFR, etc.) as essential as the care taken to work with patients so that they not only understand their disease but also how to properly use the medications they have been prescribed. Second, the number of new classes of agents will increase in the next decade far faster than an understanding of the asthmatic process, making it imperative for the physician to return to the basic principles of therapeutics.

Plasma levels of nicotine and safety of smokers wearing transdermal delivery systems during multiple simultaneous intake of nicotine and during exercise.

Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration-time curves from 0 to 24 hours (AUC0-24) for nicotine were 453 +/- 120 ng.hr/mL (day 2), 489 +/- 143 ng.hr/mL (day 3), and 485 +/- 143 ng.hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20-minute exercise period, nicotine plasma levels increased by 13 +/- 9% for Nicoderm and 30 +/- 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise-induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short-lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.

Modeling the acute neurotoxicity of styrene.

Styrene is a widely used industrial solvent associated with acute neurotoxicity. To investigate the relationships between exposure, blood concentrations, and the appearance of neurotoxic effects, four healthy males were exposed to styrene concentrations of 5-200 ppm in four different exposure-time profiles. A digit recognition test and P300 event-related evoked potential were used to measure neurologic function. A physiologically based kinetic (PBK) model generated close predictions of measured styrene blood concentrations, in the range of 0.01-12 mg/L, from this and 21 previous studies. Simulated peak brain concentration, durationXaverage exposure, and peak exposure level were predictive of toxicity. Central nervous system effects were expected at a blood concentration near 2.4 mg/L. A standard of 20 ppm was expected to protect styrene-exposed workers from acute central nervous system toxicity under light work conditions.

Partition coefficients between human blood or adipose tissue and air for aromatic solvents.

OBJECTIVES: The partitioning of lipophilic toxicants into blood and into adipose tissue plays an important role in the physiological distribution and toxicology of these substances. The partition coefficients between blood and air and adipose tissue and air were determined for widely used aromatic solvents in an in vitro test system using human tissue samples. METHODS: Samples of whole venous blood (N = 35) were drawn from 10 subjects. In addition, samples of perirenal and epididymal adipose tissue were obtained from F344 rats, along with subcutaneous, omental, or inguinal adipose tissue from 43 patients who had undergone surgery. Portions of each tissue were injected into vials for equilibration with atmospheres containing deuterated and nondeuterated organic solvents. Gas chromatographic headspace analysis was then used to determine the partition coefficients between blood and air and adipose tissue and air. RESULTS: The mean partition coefficients between human blood and air or adipose tissue and air were 334 (SE 11) (adipose tissue) for benzene; 1764 (SE 49) (adipose tissue) for ethylbenzene; 3184 (SE 84) (adipose tissue) for styrene; 18.3 (SE 0.24) (blood) and 962 (SE 32) (adipose tissue) for toluene; 35.2 (SE 0.45) (blood) and 2460 (SE 63) (adipose tissue) for O-xylene; 31.9 (SE 0.45) (blood) and 1919 (SE 53) (adipose tissue) for m-xylene; and 39.0 (SE 0.70) (blood) and 2019 (SE 102) for p-xylene. Regression analyses revealed coefficients of determination of 0.88 (human) and 0.98 (rat) between blood and air and log tissue and air. A value of 0.98 was found for partition coefficients between rat and human adipose tissue. CONCLUSIONS: The partition coefficients between blood and air and adipose tissue and air were strongly correlated. The partitioning of aromatic solvents into rat adipose tissue is predictive of partitioning into human adipose tissue.

Effects of different delay of reinforcement procedures on variable-interval responding.

Two experiments studied responding in the rat when the first bar press after a variable period of time produced a cue light that remained on for either 10, 30, or 100 sec and terminated with the delivery of food. In Experiment I, response rate decreased and time to the first response after reinforcement increased as the delay of reinforcement increased. Similar results were obtained whether the delay consisted of retracting the lever during the delay, a fixed delay with no scheduled consequence for responding, or every response during the delay restarted the delay interval. In Experiment II, fixed-delay and fixed-interval schedules of the same duration during the delay period had no differential effect on either response rate or time to the first response after reinforcement, but differentially controlled responding during the delay periods.

Improving job performance of Neighborhood Youth Corps aides in an urban recreation program.

In most federal job training and employment programs, trainees' pay is not contingent on job performance, but upon physical presence. This study sought to increase the job performance of seven Neighborhood Youth Corps workers being paid an hourly wage for serving as aides in an urban recreation program. When thorough job descriptions and threatened termination of employment were insufficient to maintain adequate job performance, an attempt was made to make the hourly wage (required by the Neighborhood Youth Corps program) more contingent on job performance. When the number of hours credited the workers on their payroll sheets was proportional to their rating on a simple checklist of job performance, rather than to the number of hours they were present, their job performance was maintained at near-perfect levels. Although this simple semantic shift in emphasis-from "hours worked" to "hours worked"-was still interpreted as meeting the Neighborhood Youth Corps requirements for hourly pay, its behavioral effects were substantial. This simple procedure might be used in other training programs handicapped by hourly wage requirements.

Recreation as a reinforcer: increasing membership and decreasing disruptions in an urban recreation centre.

It is presumed that recreation activities have a variety of functions for people, from tension reduction to citizenship development; however, a recreation activity's most empirically obvious function is as a reinforcer. This study demonstrates how two recurrent problems of urban recreation programs-recruitment of members and reduction of disruptive behaviors within the program-can be handled simply by contingently adjusting the amount of time the recreation activities are available. When extra time in the recreation center was provided to those youths who brought new members, dramatic increases in membership were achieved. On the other hand, when the closing time for each evening's recreation program was publicly moved forward by a few minutes for each offense, disruptive behaviors were nearly eliminated. Recreation used as a reinforcer can thus improve the basic operation of a recreation center and might similarly enhance other presumed and desired functions of recreation.

A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men.

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h+/-34 L/h, 117 L/h+/-23 L/h, and 129 L/h+/-33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3+/-10.2 h for para-xylene, 33.0+/-11.7 h for meta-xylene and 38.5+/-18.2 h for ortho-xylene. Significant isomeric differences were found (p<0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.

Styrene in adipose tissue of nonoccupationally exposed persons.

Given a styrene tissue/blood partition coefficient of ca. 39 and a relatively low perfusion rate of ca. 0.03 ml/min-g tissue, adipose tissue provides a useful physiologically damped integrative measure of environmental exposure. Styrene in the adipose tissue of nonoccupationally exposed individuals was measured for the first time. Tissue samples obtained from elective surgery patients and postmortem donors were analyzed by capillary gas chromatography and found to contain 1.12 +/- 1.06 (mean +/- SD) ppm styrene. Using these measured tissue levels and an apparent clearance of styrene (defined as the ratio of blood clearance to adipose tissue/blood partition coefficient), environmental intake of styrene was estimated to be 2.23 mg/hr, corresponding to an inhaled concentration of 1.96 mg/m3 (476 ppb). This value is two to three orders of magnitude higher than typical breathing zone air measurements, indicating additional undiscovered sources of styrene exposure.

The action of 10 mg famotidine versus 200 mg cimetidine: onset and magnitude of antisecretory action within the first 2 hours after administration.

The introduction of over-the-counter histamine2 -receptor antagonists (H2 -RAs) makes it important to characterize these agents in terms of their different times to onset of action and magnitude of effect. The time to onset of action and the degree of gastric acid inhibition of the H2 -RAs famotidine and cimetidine at dosage levels approved for over-the-counter use (10 mg famotidine and 200 mg cimetidine) were compared. Twenty-four subjects with a history of heartburn of at least 2 months duration received 10 mg famotidine, 200 mg cimetidine, or placebo in a randomly assigned sequence of three treatment periods. Each period began with an overnight fast, followed by insertion of an intragastric pH probe during a 1-hour baseline monitoring phase, and, 1 hour later, administration of the test medications and monitoring of intragastric pH for an additional 2-hour period. The onset of acid inhibition occurred approximately 35 minutes after administration of either famotidine or cimetidine. Famotidine provided a significantly greater degree of efficacy on all three parameters monitored: percentage of time that gastric pH values were greater than 3.0, mean area-under-the-pH-curve-versus-time curve, and median pH (obtained at 5-minute intervals). Clearly, the over-the-counter dosage of famotidine (10 mg) provided gastric pH elevations that were as rapid and of superior degree than those induced by cimetidine 200 mg.

Lactate metabolism in the dog during shock from hemorrhage, cardiac tamponade or endotoxin.

The elevated arterial lactate concentration in shock was investigated by measuring lactate production and clearance rate using a constant infusion of 14C-labeled lactate. In addition, the pathways of lactate metabolism were characterized by determining the percentage of lactate under-going oxidation and the percentage of the total carbon dioxide production which was derived from lactate. These measurements were performed on 16 normal dogs and on 23 dogs in a state of shock. Shock was induced by hemorrhage in ten, by controlled cardiac tamponade in seven and by endotoxin injection in six. In all of the dogs in a state of shock, there was a statistically significant increase in both the arterial lactate concentration and lactate turnover, while the lactate clearance decreased significantly. The percentage of the arterial lactate which underwent oxidation remained normal. The percentage of the total carbon dioxide production which was derived from lactate increased significantly, p less than 0.05, from 4.7 per cent in the normal dogs to 22.7 per cent in the dogs in a state of shock. Since both oxygen uptake and carbon dioxide production remain unchanged in shock, these data are consistent with an increased metabolism of substrates which from pyruvate and lactate as intermediary metabolites, that is, carbohydrates and certain amino acids, with a concomitant decrease in the metabolism of substrates which do not form pyruvate, that is, free fatty acids. In both the normal and shocked dogs, the arterial lactate concentration rose as the lactate production rate increased. Therefore, the elevated arterial lactate in shock was due to an increase in the lactate production and not to a lack of oxygen.

Methylmercury distribution in the pregnant rat and embryo during early midbrain organogenesis.

BACKGROUND: The period of neurogenesis represents a window of susceptibility for in utero methylmercury (MeHg) exposure. This study examined the toxicokinetics of potentially neurotoxic doses of MeHg during neurogenesis in the developing rat to provide additional information in the areas of mercury speciation and inter-study variability. METHODS: Pregnant Sprague-Dawley rats were dosed s.c. with 5-22 mg/kg MeHg on Day 11 of gestation to target rapidly dividing cells of the developing midbrain. Maternal liver, kidney, skin, blood, placenta, and the embryonic body and brain were evaluated for total and inorganic mercury content at 24, 48, and 72 hr after dosing. Tissue Hg partitioning ratios derived from our data were then compared to those derived from previous studies. RESULTS: Mercury was present in all tissues examined by 24 hr after dosing, and levels remained relatively stable over the subsequent 2 days in most tissues. The exceptions were the maternal blood and kidney, in which total mercury decreased significantly over the three days after dosing. Inorganic mercury concentrations were similarly stable over time. At maternal MeHg doses above 12 mg/kg, non-linearities were observed in mercury accumulation in the embryo, placenta and maternal liver. The mercury tissue partitioning coefficients ranged from 0.09 for maternal blood:embryo to 1.97 for maternal blood:kidney. CONCLUSIONS: Our observations at the 5 mg/kg dose were consistent with those of previous studies that involved evaluations at slightly later gestational times. The estimates of tissue partitioning coefficients we derived using multiple studies provide valuable insight into the effects of inter-study variability.

Biological monitoring of controlled toluene exposure.

OBJECTIVES: Widespread exposure to toluene occurs in the printing, painting, automotive, shoemaking, and speaker-manufacturing industries. The relationship between air concentrations and the absorbed dose is confounded by dermal exposure, personal protective devices, movement throughout the workplace, and interindividual differences in toluene uptake and elimination. METHODS: To determine the best biological indicator of exposure we examined the blood and alveolar breath concentrations of toluene as well as the urinary excretion rates of hippuric acid and of o-, m-, and p-cresols from 33 controlled human inhalation exposures to 50 ppm for 2 h. RESULTS: Among the metabolites, o-cresol was least influenced by background contributions, whereas the p-cresol and hippuric acid rates were obscured by endogenous and dietary sources. Toluene levels in alveolar breath proved to be the most accurate and noninvasive indicator of the absorbed dose. A physiologic model described blood and breath data using four measured anthropometric parameters and the fit values of extrahepatic metabolism and adipose-tissue blood flow. CONCLUSIONS: After breathing rate and extrahepatic metabolism had been set to conservative (protective) values (the 97.5th and 2.5th percentiles, respectively) the model predicted that pre-final-shift breath levels of < or =10 micromol/m3 and post-final-shift levels of < or =150 micromol/m3 corresponded to average workplace exposure levels of < or =50 ppm toluene. Alternately, we used the distributions and covariances of the measured and fit model parameters to yield conservative pre-final-shift levels of < or =7.3 micromol/m3 and post-final-shift breath levels of < or =120 micromol/m3 that were reflective of workplace exposure levels of < or =50 ppm toluene.

Individual prior information in a physiological model of 2H8-toluene kinetics: an empirical Bayes estimation strategy.

Physiologically-based toxicokinetic (PBTK) models are widely used to quantify whole-body kinetics of various substances. However, since they attempt to reproduce anatomical structures and physiological events, they have a high number of parameters. Their identification from kinetic data alone is often impossible, and other information about the parameters is needed to render the model identifiable. The most commonly used approach consists of independently measuring, or taking fom literature sources, some of the parameters, fixing them in the kinetic model, and then performing model identification on a reduced number of less certain parameters. This results in a substantial reduction of the degrees of freedom of the model. In this study, we show that this method results in final estimates of the free parameters whose precision is overestimated. We then compared this approach with an empirical Bayes approach, which takes into account not only the mean value, but also the error associated with the independently determined parameters. Blood and breath 2H8-toluene washout curves, obtained in 17 subjects, were analyzed with a previously presented PBTK model suitable for person-specific dosimetry. Model parameters with the greatest effect on predicted levels were alveolar ventilation rate QPC, fat tissue fraction VFC, blood-air partition coefficient Kb, fraction of cardiac output to fat Qa/co and rate of extrahepatic metabolism Vmax-p. Differences in the measured and Bayesian-fitted values of QPC, VFC and Kb were significant (p < 0.05), and the precision of the fitted values Vmax-p and Qa/co went from 11 +/- 5% to 75 +/- 170% (NS) and from 8 +/- 2% to 9 +/- 2% (p < 0.05) respectively. The empirical Bayes approach did not result in less reliable parameter estimates: rather, it pointed out that the precision of parameter estimates can be overly optimistic when other parameters in the model, either directly measured or taken from literature sources, are treated as known without error. In conclusion, an empirical Bayes approach to parameter estimation resulted in a better model fit, different final parameter estimates, and more realistic parameter precisions.

Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model.

Recent applications of physiologically band toxicokinetic (PBTK) models have used animal to human scaling, the hypothetical average man, and Monte Carlo techniques to estimate human exposure to toxicants. Our study built a PBTK model suitable for person-specific dosimetry. Individual measurements of age, ventilation rate, blood/air partition coefficient, body weight, and adipose tissue fraction were made on 26 male subjects exposed to 50 ppm 2H8-toluene and 50 ppm toluene for 2 hr at rest, with collection of venous blood samples for 120 hr postexposure. Fitted lung metabolism was a novel feature of the PBTK model, used to explain a systemic clearance of 2H8-toluene well in excess of hepatic blood flow. A 10-fold interindividual range in venous concentrations was found. Subject-specific modeling explained 91% of the observed data variability, compared to 53% using literature values for model parameters. Body weight, adipose tissue fraction, and blood/air partition coefficient were correlated with terminal half-life, steady-state volume of distribution, and terminal volume of distribution. Lung metabolism was correlated with systemic clearance and terminal half-life. Interindividual differences in lung metabolism resulted in divergent predicted fractions of 2H8-toluene in the body at 2 and 100 hr. An increased adipose fraction led to lower blood concentrations up to 8 hr postexposure, and simulations showed that at 98 hr, adipose tissue contained 97-99% of 2H8-toluene in the body. Use of subject-specific model parameters greatly improved model fit and demonstrated interindividual differences in toxicokinetics.