The role of endorphins in animal learning and behavior.

The present review examined the influence of endorphins in animal learning and behavior. It was suggested that in learning paradigms involving stress, the stressor elicits the release of endorphins. Given the evidence on endorphin-mediated, stress-induced analgesia, it was further suggested that the stress-induced release of endorphins modulates the aversiveness of the stressor, and as such, affects the learning based on this stressor. A number of learning paradigms, e.g., the conditioned emotional response, preference for signaled shock, conditioned taste aversions, and learned helplessness, were presented in support of this mediation of learning by the endorphins. A possible interaction between the endorphins and adrenocorticotropic hormone was offered as a physiological basis for this mediation.

Risk of thromboembolic events in patients with atrial flutter.

Based on multiple studies, clear, guided anticoagulation therapy is recommended for patients with atrial fibrillation. The value of anticoagulation therapy in patients with atrial flutter, however, is less well established. Little is known about the incidence of thromboembolism in patients with atrial flutter. We evaluated the risk of thromboembolism in 191 consecutive unselected patients referred for treatment of atrial flutter. A history of embolic events was noted in 11 patients. Acute embolism (<48 hours) occurred in 4 patients (3 after direct current cardioversion, 1 after catheter ablation). During follow-up of 26+/-18 months, 9 patients experienced thromboembolic events. During the follow-up, the overall embolic event rate (including acute embolism and thromboembolic events during follow-up) was 7 % in this patient population. Risk indicators for an embolic event in an univariate analysis were organic heart disease (p = 0.037), depressed left ventricular function (p = 0.02), history of systemic hypertension (p = 0.004), and diabetes mellitus (p = 0.0038). Using multivariate analysis, a history of hypertension was the only independent predictor for elevated embolic risk in this patient population (odds ratio = 6.5; 95% confidence intervals 1.5 to 45). Thus, the thromboembolic risk is higher than previously recognized for patients with atrial flutter. Anticoagulation therapy may decrease this risk.

Rats learn to like the taste of morphine.

When rats are forced to drink a morphine solution as their only source of fluid, they eventually reverse their initial preference and drink more morphine than water in a two-bottle preference test. The cause of this shift in preference was examined with the taste reactivity test which involves the analysis of fixed action patterns elicited by taste solutions infused into rats' mouths. Three morphine concentrations and two levels of motivation were studied. A greater percentage of ingestive taste reactivity responses occurred to the oral morphine infusion in morphine-raised rats than in water-raised rats. These data argue against the idea that enhanced morphine ingestion is caused by anticipation of positive consequences. Instead, they support the idea that rats come to "like" the flavor of the morphine solution; in other words, the palatability evaluation of the morphine changes, possibly through an association between the flavor and the hedonically positive effects of the morphine.

Individualized drug dosage in patients treated with continuous hemofiltration.

BACKGROUND: Subtherapeutic drug dosing may be even more dangerous than overdosage, especially for intensive care patients requiring hemofiltration. PROPOSAL: According to Dettli's fundamental equation, body clearance of any drug (Cl) is a linear function of creatinine clearance (Cl = Cl anur + a x C(Cr)), with [a = (Cl norm - Cl anur)/C(Cr), norm]. We propose to individualize drug dosage during high-flux hemofiltration by basing it on Dettli's equation and on total C(Cr) (C(Cr) tot = C(Cr) ren + C(Cr) filt). Using this approach, drug clearance will eventually be overestimated for drugs with substantial tubular secretion and for high-efficiency hemofiltration (C(Cr) tot > 30 ml/min). CONCLUSION: In patients undergoing hemofiltration, the total C(Cr) approach might be a practical alternative to standardized dosing schemes for deriving an individualized dosage from published pharmacokinetic data and functions.

The Sézary syndrome. A case with fetal-type glycogen and lymphocytic lymphoma.

A patient had Sézary syndrome and lymphocytic lymphoma. Cytoplasmic inclusions within the Sézary cells were demonstrated by histochemistry and electron microscopy to be composed of fetal-type glycogen. Results of tests for the presence of virus were negative. It is suggested that the Sézary cell represents a reversion of metabolic systems to more youthful types. Previously reported differences in diastase reactivity of the PAS-positive cytoplasmic inclusions are probably based on whether the glycogen is in fetal or mature configuration.

Effects of eating abnormalities and gender on perceptions of desirable body shape.

Men and women differ when choosing the figure drawings that most resemble (a) their own current figures (CURRENT), (b) their ideal figures (IDEAL), and (c) the figure thought most attractive to the opposite sex (OPPOSITE) (Fallon & Rozin, 1985). In the present experiment, women with high Eating Attitude Test (EAT) scores, indicating abnormal eating patterns, choose differently from those with low scores. All women's IDEAL and OPPOSITE figures are thinner than their CURRENT figures, whereas men rate all three nearly identically. Only the high-scoring women choose an IDEAL figure thinner than their OPPOSITE. This suggests that whereas men are satisfied with their figures, women desire to be thinner than they think they are, and women with abnormal eating behaviors desire to be even thinner than what they think men find attractive.

Color affects perceived odor intensity.

In Experiment 1, some odorous solutions (e.g., strawberry) were rated as smelling stronger when colored (e.g., red) than when colorless. Experiment 2 showed this effect to be due to a perceptual change rather than a response to experimental demand characteristics. Experiment 3 showed that the color-induced increase in odor intensity is not due to subjects' preexperimental experience with particular color-odor combinations, because the increase occurred with novel ones. We conclude that color induces a weak olfactory percept that combines with odorant-induced percepts. The effect may be due to conditioning or may be the result of residual intersensory neural connections left over from infancy.

Effect of temperature and expectations on liking for beverages.

Three experiments investigated the influence of expectation on liking ratings of beverages at different temperatures. The first confirmed the general belief that people like certain beverages at certain familiar temperatures and dislike them at others. In the second experiment, subjects tasted and rated how much they liked four beverages (chicken bouillon, red wine, fruit punch and water) at three different temperatures (hot, room temperature, and cold) with their eyes closed (beverages not identified by the experimenter) and with their eyes open (beverages identified by the experimenter). They then rated how much they thought they would like these same beverages plus a number of new beverages at the three temperatures. Subjects rated the tastes of the beverages at unfamiliar temperatures (e.g., cold bouillon) when tasting them better than they thought they would. However, even after a few opportunities to taste a beverage at an unfamiliar temperature, expectations about its taste did not change. Experiment 3 successfully altered liking ratings of beverages by changing expectations concerning the temperature at which an unfamiliar beverage is typically consumed. The results argue for an important role for culture-based expectations in determining preferred temperatures for foods.

Opiate withdrawal: the result of conditioning or physiological mechanisms?

Although it has been suggested that opiate withdrawal responses might be conditioned compensatory responses elicited by drug-associated stimuli, the present results do not support such a view. Withdrawal, as measured by an aversion to a saccharin solution following the termination of morphine administration, occurred independent of the presence of morphine-paired environmental or temporal cues. These results suggest that withdrawal is most likely the result of some physiological mechanism, rather than the result of conditioning.

The effect of post-conditioning exposure to morphine on the retention of a morphine-induced conditioned taste aversion.

In the following experiment, multiple injections of morphine sulfate following the acquisition of a morphine-induced taste aversion had no effect on the retention of the previously acquired aversion. Post-conditioning injections of morphine resulted in the development of physical dependence to morphine and led to a decrement in the ability of morphine to induce a subsequent aversion to a second novel taste. This failure of post-conditioning exposures to morphine to affect a previously acquired morphine-induced taste aversion even though tolerance to morphine had occurred was discussed in the context of Rescorla's event-memory model of conditioning.

Synthesis of pharmacokinetic parameters of vancomycin via bootstrap methods.

OBJECTIVE: For the adjustment of individual vancomycin dosages, we estimate the important pharmacokinetic quantities half-life, clearance, and volume of distribution. MATERIAL: To obtain reliable information 293 observations from 244 patients were extracted from 23 published studies on vancomycin. Information about vancomycin's pharmacokinetics out of different sources represents an increase in sample size and, therefore, interpretive power. METHODS: Once the whole of the data had been stratified into a small number of homogeneous clusters based on cofactors, different (robust) estimators (mean, median, Winsorized, and trimmed mean) were calculated for the expected value of the pharmacokinetic parameters of vancomycin within the clusters. Measures of the statistical accuracy such as standard error, bias, mean square error, and confidence interval were estimated via bootstrap methods from large bootstrap sample sizes to compare the quality of the estimators. RESULTS: Due to the homogenization of the data all individual estimator functions yield very similar results and the empirical mean works fairly well as an estimate. The most frequently used estimator with the smallest estimated mean square error was the Winsorized mean.

Dosage adjustment of antiinfective therapy in patients with renal impairment.

Schematic dosage adjustments for aminoglycosides, vancomycin, and ciprofloxacin were derived from published data on the prolongation of elimination half-lives in patients with renal impairment. Therapeutic drug monitoring was retrospectively evaluated with 84 severely ill patients, 29 of whom needed renal replacement therapy (35%). Mortality (n = 27) and antiinfective failures were high (n = 23). Toxicity was suspected in 5 patients, though it was demonstrated only in 1 case. As compared to the patients with normal renal function, patients with renal impairment exhibited peak levels that tended to be lower, although their trough levels tended to be higher; the aminoglycoside troughs even were significantly elevated in renal replacement patients (1.0 mg/l (0.6-1.4) versus 0.6 mg/l (0.3-0.8)). Seen in relation to toxicity, antiinfective failure was by far the greater problem even with dosage adjustments at high trough levels. Multivariate analysis showed antiinfective failure to be significantly correlated to 10 canonical variables (age, weight, leucocyte count, peak level, trough level, initial creatinine, increase in creatinine, fever, change of dosage, and renal replacement therapy). Among these variables, it were neither drug levels nor renal replacement, but only persistent fever and deteriorating renal function that independently contributed to antiinfective failure. For adjustment of antiinfective therapy, paradoxically we conclude that trough concentrations higher than normal must be allowed for to avoid underdosage in renal replacement patients.

Unifying concept of pharmacokinetics derived from drug distribution and elimination in renal failure.

We are in the process of establishing a pharmacokinetic database for drug dosage adjustment to impaired renal function. To meet these demands, the system needs a unifying pharmacokinetic concept. Drug clearance is the common parameter that allows for intersecting the different pharmacokinetic approaches. In addition, two parameters are essentially needed for the concept, either the area-derived volume and the dominant elimination half-life or the moment-derived volume and the mean residence time. For drugs where the area-derived volume decreases with renal impairment, it can be shown that compartment-derived parameters are explicitly convertible into moment-derived parameters and vice versa.

Relationship between pharmacokinetic half-life and pharmacodynamic half-life in effect-time modeling.

A pharmacodynamic parameter relating time-dependent changes of the effect with time-dependent changes of concentrations has yet to be developed. In pharmacokinetics, half-lives (T1/2kin) are used to describe the relation between concentration (C) and time (t). In pharmacodynamics, often the sigmoid Emax model and the Hill equation are used (E = Emax CH/(EC50H + CH)) to describe the relation between effect (E) and concentration (C). To describe the correlation between effect (E) and time (t), a pharmacodynamic half-life (T1/2dyn) could be estimated if the use of the term half-life is not restricted only to log-linear first order processes. To bisect the drug effect a variable time (t1-2 = t2-t1) will be required for this nonlinear process. The bisection of the effect (E2 = 1/2 E1) is associated with a decrease in concentrations (C2 = C1 exp(-0.693 t1-2/T1/2kin)). A mathematical relationship can be derived between pharmacodynamic half-life (T1/2dyn = t1-2) and pharmacokinetic half-life (T1/2dyn = T1/2kin (ln (1 + ln(a)/ln(2))/H ) with (a = (EC50H + C1H)/(EC50H + C2H)). For concentrations in the range of the EC50 value with the Hill coefficient (H = 1), the pharmacodynamic half-life will be 1.6-2.0 times the kinetic half-life (T1/2dyn < or = 2.0 T1/2kin). For high concentrations (C1 > EC50), the dynamic half-life will grow much longer than the kinetic half-life, consequently the effect of a drug will not increase but it will last longer. The pharmacodynamic half-life turns out to be a specific estimate for the effect time relation, being a concentration-dependent function of the kinetic half-life.

PK-PD curve-fitting problems with the Hill equation? Try one of the 1-exp functions derived from Hodgkin, Douglas or Gompertz.

UNLABELLED: Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each I of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. CONCLUSION: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.

Blastic transformation of splenic marginal zone B-cell lymphoma.

To our knowledge, blastic transformation of splenic marginal zone lymphoma, a recently characterized low-grade lymphoproliferative disorder, has not been reported previously. In this regard, we report the unique case of a 70-year-old woman whose untreated splenic marginal zone lymphoma underwent blastic transformation 3 years after diagnosis. Her hematologic medical history started in 1988 as thrombocytopenia refractory to steroids associated with atypical lymphoid infiltrate in the bone marrow. She underwent splenectomy in 1989, which revealed splenic marginal zone lymphoma. One year later, the patient developed lymphadenopathy noted in the chest, axillary, abdominal, and retroperitoneal lymph nodes. Because she was asymptomatic, treatment was limited to a conservative supportive regimen. The nodal lymphoma cells had features associated with marginal zone lymphoma and expressed B-cell monotypic kappa light chain. She was readmitted for the last time 2 years later with findings of 16% blasts in the peripheral blood and massive infiltration of the bone marrow by large blastoid cells. The blasts showed dispersed chromatin and prominent nucleoli, and possessed a moderate amount of clear cytoplasm. The blasts, like the previous nodal and splenic lymphomas, had a CD20-, CD19-, IgM-positive phenotype, but lacked reactivity for CD5, CD10, and CD23. The patient displayed clinical remission after treatment with vincristine and prednisone, but died of aspiration pneumonia 1 month later. These observations suggest that, similar to the other low-grade lymphoproliferative disorders, an untreated splenic marginal zone lymphoma may undergo high-grade blastic transformation.

Structured data entry for reliable acquisition of pharmacokinetic data.

A pharmacokinetic database was constructed that is as free of errors as possible. Pharmacokinetic parameters were derived from the literature using a text-processing system and a database system. A random data sample from each system was compared with the original literature. The estimated error frequencies using statistical methods differed significantly between the two systems. The estimated error frequency in the text-processing system was 7.2%, that in the database system 2.7%. Compared with the original values in the literature, the estimated probability of error for identical pharmacokinetic parameters recorded in both systems is 2.4% and is not significantly different from the error frequency in the database. Parallel data entry with a text-processing system and a database system is, therefore, not significantly better than structured data entry for reducing the error frequency.

A SAS macro for sample size re-estimation.

The assessment of sample size in clinical trials comparing means requires a variance estimate of the main efficacy variable. If no reliable information about the variance of the key response is available at the beginning of a clinical trial, the use of data from the first 'few' patients entered in the trial ('internal pilot') may be appropriate to estimate the variance and thus to recalculate the required sample size. A SAS macro that implements the EM algorithm for carrying out and simulating such interim power evaluations without unblinding the treatment status is presented.

Standardized structure and modular design of a pharmacokinetic database.

BACKGROUND: The accumulated knowledge on drugs can be used for an individual drug dosage adjustment if it is placed at our disposal in an informatically structured form. THEORY AND METHODS: We have started building up a pharmacokinetic database aimed at adjusting drug dosages, in exemplary form, to patients with renal impairment. Parameters needed for the three dosage adjustment rules (Dettli, Kunin, Holford) and the most general concept of pharmacokinetics constituted the theoretical basis. TWO PROCESSES PERTAIN TO ALL DRUGS: Distribution and elimination. Total drug clearance and at least two parameters representing distribution and elimination processes are closely interdependent in mathematical terms (clearance = volume of distribution*rate of elimination). This relation yields the unifying concept that serves as a prerequisite for a structured recording of 30 assigned pharmacokinetic and pharmacodynamic parameters within an informatic database. SOLUTIONS AND RESULTS: The information is retrieved and referenced from 2383 original publications by means of a standardized input module. The complete database at present contains 15,397 records for 1573 drugs. A programmed meta-analytic algorithm is used to calculate the statistical measures for the central value and variance--as available--from the pooled values of primary records. The statistically standardized parameters are extracted for 6601 pharmacokinetic parameters, and placed at the users disposal with the output module. PRACTICAL UTILITY: Following meta-analysis, published pharmacokinetics can be used as statistical estimates of population parameters. The statistical estimates with variances permit an individual drug dosage adjustment by applying the Bayesian approach or neural networks.

The effect of color intensity and appropriateness on color-induced odor enhancement.

Coloring solutions has been shown to increase perceived odor intensity. In Experiment 1, subjects rated the odor intensity of red strawberry and green mint solutions that had four levels of color intensity. Ratings of strawberry odor peaked at the medium color intensity and ratings of mint odor increased monotonically with color intensity. Thus, color-induced odor enhancement can increase with increasing color intensity but need not. Experiment 2 found that the color intensities producing maximum odor enhancement in Experiment 1 are not always the ones perceived as most appropriate for the odorants. Using different odors, Experiment 3 found that color intensity has some influence on the strength of the color-induced odor enhancement and color appropriateness has little. The presence or absence of color in the solution seems to be the most important variable.