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PubMed2000

A new physiologically based, segregated-flow model to explain route-dependent intestinal metabolism.

Processes of intestinal absorption, metabolism, and secretion must be considered simultaneously in viewing oral drug bioavailability. Existing models often fail to predict route-dependent intestinal metabolism, namely, little metabolism occurs after systemic dosing but notable metabolism exists after oral dosing. A physiologically based, Segregated-Flow Model (SFM) was developed to examine the influence of intestinal transport (absorption and exsorption), metabolism, flow, tissue-partitioning characteristics, and elimination in other organs on intestinal clearance, intestinal availability, and systemic bioavailability. For the SFM, blood flow to intestine was effectively segregated for the perfusion of two regions, with 10% reaching an absorptive layer-the enterocytes at the villus tips of the mucosa where metabolic enzymes and the P-glycoprotein reside, and the remaining 90% supplying the rest of the intestine (serosa and submucosa), a nonabsorptive layer. The traditional, physiologically-based model, which regards the intestine as a single, homogeneous compartment with all of the intestinal blood flow perfusing the tissue, was also examined for comparison. The analytical solutions under first order conditions were essentially identical for the SFM and traditional model, differing only in the flow rate to the absorptive/removal region. The presence of other elimination organs did not affect the intestinal clearance and bioavailability estimates, but reduced the percentage of dose metabolized by the intestine. For both models, intestinal availability was inversely related to the intrinsic clearances for intestinal metabolism and exsorption, and was additionally affected by both the rate constant for absorption and that denoting luminal loss when drug was exsorbed. However, the effect of secretion by P-glycoprotein became attenuated with rapid absorption. The difference in flow between models imparted a substantial influence on the intestinal clearance of flow-limited substrates, and the SFM predicted markedly higher extents of intestinal metabolism for oral over i.v. dosing. Thus, the SFM provides a physiological view of the intestine and explains the observation of route-dependent, intestinal metabolism.

Administration, Oral↗
PubMedDate not supplied

An educational model for explaining hospice services.

Explaining the concept and philosophy of hospice can be difficult. There is a reluctance in our society to openly address dying/death issues; there is a reluctance on the part of many health-care professionals to look beyond physical issues. The following model has been used successfully to explain hospice to both the general public and health care professionals. It is not intended to introduce hospice to a patient/family during the initial referral/assessment visit.

Health Education↗
PubMed2000

Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. KIGS International Board. Kabi International Growth Study.

It has become common practice to apply GH treatment in short Turner syndrome patients with the objective of promoting growth. The variability in response and the high costs of this treatment demand the individualization and optimization of therapy. Based on 686 prepubertal Turner patients from the Kabi International Growth Study (KIGS; Pharmacia & Upjohn, Inc. International Growth Database), we undertook a multiple regression analysis of height velocity (centimeters per yr) by using various parameters of potential relevance. Derived prediction models for the first 4 yr of GH treatment were validated with 76 additional KIGS patients and 81 patients from Tuebingen, Germany. Among the 6 predictors identified, the most influential variable for first year growth response was the natural log (ln) of the weekly GH dose. The first year growth response was also correlated with age and distance between height and target height (SD score; both negative) and body weight SD, number of GH injections per week, and oxandrolone treatment given additionally (positive). The first year model explains 46% of the variability, with 1 SD of 1.26 cm. For the second to fourth years, 5 predictors were identified: height velocity during previous years, weekly GH dose (ln), weight SD, oxandrolone therapy (all positive), and age (negative). These models explained 32%, 29%, and 30% of the variability, respectively, with SD scores of 1.1, 1.0, and 1.0 cm, respectively. When the models were applied to the other cohorts, no significant difference was noted between observed and predicted responses. Although the parameters used in our models do not entirely explain the variability in the growth response in Turner syndrome, the parameters themselves were clinically relevant to our present understanding and proved to be of high precision. Some of the tested markers, such as karyotype, do not contribute to the growth response. These variables make the models practical and suitable for planning beneficial and cost-effective therapy.

Anabolic Agents↗
PubMed1998

Psychosocial contributors to mental and physical health in patients with systemic lupus erythematosus.

OBJECTIVE: To delineate psychosocial and systemic lupus erythematosus (SLE)-related medical factors that contribute to the mental and physical health of SLE patients. METHODS: In a cross-sectional study, 44 women completed standardized instruments assessing daily hassles, social support, psychologic distress, and quality of life and underwent a physician examination to assess disease activity and disease damage. Four multiple linear regression analyses were computed to identify factors associated with the following outcomes: patient-perceived psychologic distress and global physical health and physician-assessed disease activity and damage. Variables entered into the regression analyses were: hassles severity, types of social support, SLE disease activity and damage, age, disease duration, education, ethnicity, and global psychologic distress (for the outcomes of self-perceived global physical health and disease activity and damage). RESULTS: The best model explaining global psychologic distress included hassles severity and self-esteem social support. The best model explaining patients' perceptions of their global physical health included hassles severity and tangible social support. Psychologic distress accounted for a significant proportion of variance in both disease activity and damage. CONCLUSION: High stress (assessed by hassles severity), poor social support, and psychologic distress--potentially modifiable variables--are associated with the mental and physical health of SLE patients.

Adult↗
PubMed1999

Explaining lifetime criminal arrests among clients of a psychiatric probation and parole service.

This study examines the extent to which sociodemographic characteristics, clinical characteristics, substance abuse problems, and the array of lifetime criminal behavior may explain lifetime arrests among offenders supervised by the psychiatric probation and parole service. Three hundred twenty-five clients with new cases at a psychiatric probation and parole service in a large urban center were screened for major psychiatric disorders. They were also interviewed for socio-demographic characteristics, mental health treatment history, criminal behavior, and arrest history. Hierarchical block multiple regression analysis tested a model explaining lifetime arrests. After controlling for age and other demographic variables, the number of lifetime psychiatric hospitalizations and lifetime occurrences of mania diagnosis significantly explained lifetime arrests. The total model explained about 10 percent of the variance in lifetime arrests after controlling for opportunity variables, which explained 45 percent. The explanatory power of lifetime hospitalizations and mania support the contention that symptoms, rather than diagnosis, may be the most important clinical factor in explaining criminal arrest among persons with mental illness. Implications for psychiatric services include the development of effective jail diversion programs.

Adult↗
PubMed1995

Development of factor-score-based models to explain and predict maximal box-lifting performance.

The objectives of the study were threefold: (1) to develop factor-score-based models to predict maximum mass on a box-lifting task using multiple regressions; (2) to compare predictive and explanatory powers of factor-score-based models to models derived from data-level variables; and (3) to apply these findings to ergonomic research and practical problem-solving situations. Forty-eight volunteers (25 women and 23 men) completed a maximal box-lifting task and a maximal isoinertial lifting test on an Incremental Lifting Machine (ILM). Dynamic data collected during isoinertial testing were summarized into 32 lift parameters, and then subjected to principal components analyses using the 'FACTOR PROCEDURE' from the Statistical Analysis System (SAS). Factor scores were calculated for each participant on each of the four factors comprising the final solution, and multiple regression equations for men, women and combined data were generated using the 'GENERAL LINEAR MODELS' procedure from SAS. Results revealed that prediction of box-lifting performance was optimized when regression equations were developed using numerous data-level variables as predictors, i.e., all 32 lift parameters and ILM mass. In comparison, explanation was enhanced but predictive capabilities were reduced when linear models were formed using ILM mass and the factor scores derived from analyses of isoinertial lifting. The use of variables loading on the factors gave slightly increased predictive power than did the factor-score-based models. Similar trends in predictive and explanatory powers appeared when the data were analysed according to gender. Ergonomic applications of factor-score-based models were discussed with regard to ongoing research as well as to practical problem-solving situations. It was concluded that the advantages and usefulness of factor-score-based models warranted their inclusion in future investigations of lifting performance.

Adult↗
PubMed1976

Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances.

A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Clp is the plasma clearance, Vf is the "true" volume of distribution of free drug, beta is the apparent elimination rate constant, sigma is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, kf is the intrinsic elimination rate constant for free drug, and AoTB is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Clp = Vfsigma kf; (2) beta = f kf; and Vdext = (sigma/f) Vf. Only sigma, and not f, can be measured experimentally. Dividing Clp by sigma provides an estimate of the intrinsic clearance of free drug, Vfkf. A plot of Vdext versus sigma has an intercept equal to Vf, and the ratio of the slope/intercept is an estimate of AoTB/Aof, where Aof is the initial amount of free drug (equal to Vf times initial concentration of free drug in plasma). Thus, an estimate of AoTB may be obtained. Dividing the intrinsic clearance by Vf provides an estimate of kf. Thus, theoretically, estimates of Vf, kf, AoTB and f may be obtained. The variables are not separated when beta is plotted versus sigma, and curvature of such plots is expected; no useful information is obtained from such plots.

Blood Proteins↗
PubMed2001

Anthropometric and demographic factors affecting distance hopped and limb symmetry index for the crossover hop-for-distance test in high school athletes.

STUDY DESIGN: Prospective cohort study using a random selection from an accessible population. OBJECTIVES: We examined anthropometric and demographic characteristics affecting distance hopped (DH) and limb symmetry index (LSI) in the crossover hop-for-distance test in uninjured high school athletes. BACKGROUND: Between-subject comparisons of hop test results described by DH and LSI are common in the literature and clinical practice. The effect that anthropometric traits and demographic characteristics have on these measures is uncertain but must be known to correctly interpret hop-for-distance test results in research or to determine suitability of return to sports. METHODS AND MEASURES: For 201 high school athletes (age = 15.15+/-1.45 years, mean weight = 63.67+/-14.02 kg, mean height = 167.92+/-9.58 cm) completing the crossover hop-for-distance test, we recorded maximum DH for each leg and calculated the LSI of each subject. We performed 2 separate step-wise regression analysis models to develop predictive equations for DH and LSI. RESULTS: Age (r = 0.36), weight r = 0.41), and body fat percentage (r = 0.58) were significant predictors of DH, with the regression model explaining 59% of the variability. None of the measured variables were significant predictors of LSI (r = 0.03). The regression model explained only 3% of the variability of LSI. CONCLUSIONS: The LSI for the crossover hop-for-distance test can be compared among all individuals without subdividing into groups. Subject characteristics should be as homogeneous as possible when comparing DH among subjects or groups.

Adipose Tissue↗
PubMed1993

New urodynamic model to explain micturition disorders in benign prostatic hyperplasia patients. Pressure-flow relationships in collapsable tubes, hydraulic analysis of the urethra and evaluation of urethral resistance.

How can the hydrodynamic disorders caused by benign prostatic hyperplasia (BPH) be explained? And how can they be measured in order to assess the efficiency of treatment? To answer these questions, a model based on the results of experiments performed in collapsable tubes and on a hydraulic analysis of the urethra is elaborated. A BPH combining hypertonia and/or hypertrophy, essentially leads to a rise in the opening pressure which increases bladder work before micturition, as well as a reduction in the functional caliber of the prostatic urethra. Whatever its origin, this reduction in caliber is the only explanation for the importance of the urethral resistance increase noticed in cases of BPH. Instantaneous resistance calculation, based on the pressure/maximum flow rate relationship, measured when the flow is steady (for a few seconds), would be a good experimental physical parameter. However, on a clinical basis, an exact calculation is impossible, which makes its precision and reliability not as good as they should be. In order to calculate the resistance to micturition as a whole, particularly taking into account the difficulty in urethral opening, it was suggested to include the opening pressure in the pressure/flow study. But this fits neither with fluid mechanics data nor with the results of experiments carried out in collapsable tubes. Eventually, considering that no evaluation method of the resistance to urinary flow is acknowledged to be accurate on a hydraulic basis or urodynamically applicable, one wonders whether placing more confidence in simple data obtained in a noninvasive way, and used without mathematical tricks, is not preferable.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1998

Modelling migration: the clock-and-compass model can explain the distribution of ringing recoveries.

The aim of the present study was to test whether the directional distributions found in ringing recoveries could be explained if night-migrating passerines use only a simple clock-and-compass strategy during autumn migration. I developed a mathematical model that predicts the expected directional distributions as a function of distance covered by birds using a clock-and-compass strategy. The predictions were compared with data from natural migration: all ringing recoveries of pied flycatchers, Ficedula hypoleuca, ringed in Scandinavia and recovered elsewhere in Europe and North Africa within the same autumn. The predictions of the model correlated strongly with the distribution of ringing recoveries. This suggests that at least young pied flycatchers, and perhaps night-migrating passerines in general, use a simple clock-and-compass strategy to reach their wintering area. If so, all the prerequisites (a compass and an internal clock) that they need to orient during migration seem to be known at present, at least at the behavioural level, and navigational abilities or any elusive map-sense are not needed for migration. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1994

A cellular model to explain the pathogenesis of infection by the hepatitis B virus.

The natural history of infection by the hepatitis B virus (HBV) depends on many factors, including the age and immunological status of the patient, and can range from acute transient infection to subclinical chronic hepatitis. Persistent infection often leads to the development of primary hepatocellular carcinoma. We consider a cellular model of HBV infection based on the hypothesis that the liver contains two populations of cells with contrasting responses to the virus. Our findings show that the model can be used to account for the wide variety of clinical manifestations of infection and can explain the observed age dependence of the main different outcomes of the disease.

Carcinoma, Hepatocellular↗