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At least 109 records · Page 6Linked to original sources
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↗
PubMed1991

A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs.

To account for experimental data showing increased onset time with increased potency of neuromuscular blocking drugs, a pharmacokinetic-pharmacodynamic model is presented. It is characterized by a finite concentration of receptors (R) in the effect compartment. Transfer from central to effect compartment is linearly related to concentration gradient. A sigmoid Emax model is used to describe the relationship between receptor occupancy and effect. Plasma concentrations found in the literature are used. Differential equations are solved numerically for equipotent doses of drugs of different potencies. Because the density of receptors constitutes a significant drain of drug molecules for potent drugs, the model predicts an inverse relationship between speed of onset and potency. The concentration of receptors in the effect compartment R which best fits experimental data obtained in humans is 0.28 mumol/L. With this value of R, onset times are prolonged when the ED95 (dose for 95% blockade) is less than 0.1 mumol/kg. It is concluded that, in the development of a short-acting nondepolarizing neuromuscular blocking drug, agents having an ED95 of 0.1 mumol/kg or greater appear more promising.

Dose-Response Relationship, Drug↗
PubMed1995

LTP--a structural model to explain the inconsistencies.

One of the major controversies in neuroscience concerns whether the expression of long-term potentiation (LTP) is a pre- or postsynaptic phenomenon, with apparently contradictory data being the norm. The model that is outlined in this article combines anatomical and electrophysiological evidence to allow apparently contradictory data to be compatible. Development of LTP involves both influx of Ca2+ through NMDA receptors, and activation of another factor, perhaps the metabotropic glutamate receptor. These two processes might result, respectively, in the insertion of activation of additional postsynaptic receptors, and the growth of microfilaments that could split simple synapses into perforated synapses, consisting of multiple active zones. Whether the latter occurred, and at what rate, would be likely to depend on multiple factors, such as temperature, the metabolic state of the cell, buffering of Ca2+, and the concentration of factors such as nitric oxide. These subtle experimental variables would thus determine whether the dominant effect observed was pre- or postsynaptic.

Long-Term Potentiation↗
PubMed1998

Using the health belief model to explain clinic appointment-keeping for the management of a chronic disease condition.

Broken appointments have untoward repercussions for patients' health and well-being. Although the literature on missed appointments has been largely atheoretical, several studies have tested the Health Belief Model (HBM) in this context. Those studies have found HBM dimensions are not predictive of keeping appointments for the management of a chronic condition. Given several limitations that characterize these studies, questions can be raised about the validity of this conclusion. This study investigated the utility of HBM for explaining appointment-keeping for Systemic Lupus Erythematosus (SLE), a potentially fatal chronic disease. A questionnaire, operationalizing HBM dimensions and exhibiting acceptable psychometric properties, was developed for this research and administered to 153 SLE patients enrolled at an outpatient clinic of a major teaching hospital. In addition to measuring intention to keep appointments, data were abstracted from medical records regarding actual appointment-keeping during 12 months prior to and 6 months following questionnaire completion. Regression analysis indicated that general health motivation and perceived severity of SLE were uniquely associated in the theoretically predicted direction with, respectively, intent and the percentage of scheduled appointments kept (PSAK) during the 12 month retrospective period. Perceived costs was associated in the expected direction with intent, 12 month retrospective and 6 month prospective PSAK. Typical of HBM research the effect sizes uncovered were modest in magnitude. Questions for future investigation are discussed.

Adult↗
PubMed1990

A model to explain the osmotic pressure behavior of hemoglobin and serum albumin.

Previously published osmotic pressure data on hemoglobin and bovine serum albumin were used to determine the osmotically unresponsive solvent volume per unit dry mass of protein. A model is presented that accounts for the osmotic pressure of globular proteins based on a surface-associated osmotically unresponsive solvent volume. The model also accounts for changes in the osmotically unresponsive solvent volume owing to changes in pH, cosolute salt concentration, protein conformation, and protein aggregation.

Hemoglobins↗
PubMed2000

Modelling the influence of age, body size and sex on maximum oxygen uptake in older humans.

The purpose of this study was to describe the influence of body size and sex on the decline in maximum oxygen uptake (O2,max) in older men and women. A stratified random sample of 152 men and 146 women, aged 55-86 years, was drawn from the study population. Influence of age on O2,max, independent of differences in body mass (BM) or fat-free mass (FFM), was investigated using the following allometric model: O2,max = BMb (or FFMb) exp(a + (c ' age) + (d ' sex)) [epsilon]. The model was linearised and parameters identified using standard multiple regression. The BM model explained 68.8 % of the variance in O2,max. The parameters (+/- s.e.e., standard error of the estimate) for lnBM (0.563 +/- 0.070), age (-0.0154 +/- 0.0012), sex (0.242 +/- 0.024) and the intercept (-1.09 +/- 0.32) were all significant (P < 0.001). The FFM model explained 69.3 % of the variance in O2,max, and the parameters (+/- s.e.e) lnFFM (0.772 +/- 0.090), age (-0.0159 +/- 0.0012) and the intercept (-1.57 +/- 0.36) were significant (P < 0.001), while sex (0.077 +/- 0.038) was significant at P = 0.0497. Regardless of the model used, the age-associated decline was similar, with a relative decline of 15 % per decade (0.984 exp(age)) in O2,max in older humans being estimated. The study has demonstrated that, for a randomly drawn sample, the age-related loss in O2,max is determined, in part, by the loss of fat-free body mass. When this factor is accounted for, the loss of O2,max across age is similar in older men and women.

Aged↗
PubMed1992

Relation between the convergence temperatures Th* and Ts* in protein unfolding.

A challenge in understanding the thermodynamics of protein unfolding is to explain the 1979 puzzle posed by Privalov. Why do values of the specific enthalpy and specific entropy of unfolding both converge to common values at approximately the same temperature (Th* approximately equal to Ts*) when extrapolated linearly versus temperature? In 1986, a liquid hydrocarbon model gave an explanation for convergence of the specific entropies at Ts*: it happens because the contribution of the hydrophobic effect to the entropy of unfolding goes to zero at Ts*. The reason for convergence of the specific enthalpies at Th* and for the equality Th* approximately equal to Ts* has remained, however, a matter for speculation; recently, some explanations have been given that are based on models for polar interactions in protein folding. We show here that the relation Th* approximately equal to Ts* can be derived straightforwardly without making any assumptions either about polar interactions or about splitting the hydrophobic interaction into two terms--one for the "hydrophobic hydration" and the other for the residual effect, as suggested recently. Thus, the liquid hydrocarbon model explains both halves of Privalov's puzzle. A similar conclusion has been reached independently by A. Doig and D. H. Williams (personal communication). It has been proposed recently that a correction should be made for the relative sizes of a hydrocarbon solute and water when computing the thermodynamic properties of the hydrophobic interaction from a solvent transfer experiment. This correction affects the temperature at which the entropy of transfer equals zero, and it is important to evaluate its effect on the convergence temperature Ts*. We show that making the size correction does not change the conclusion, reached earlier, that the liquid hydrocarbon model explains the convergence of the specific entropies of protein unfolding.

Mathematics↗
PubMed1997

Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives.

The (thio)carboxanilide derivatives are potent and selective inhibitors of HIV-1 reverse transcriptase (RT) and have a favourable antiviral activity spectrum. To understand better their mode of action, and to provide a structural basis for further improvement, models of RT complexed with four (thio)carboxanilide inhibitors (UC781, UC10, UC38 and UC84) have been constructed based on the X-ray structure of RT complexed with 9-chloro-TIBO. In the models, the protein conformation is similar to that of the RT-TIBO complex and the complexes are stabilised by hydrogen bonding between the inhibitors and the main chain oxygen of Lys101. Significant hydrophobic interactions include those with Leu100, Val106, Val179, Tyr188, Phe227, Leu234, and His235. The thiocarboxanilides UC781 and UC10 also make important hydrophobic interactions with Trp229. The models are consistent with the inhibitors' relative antiviral potencies and the observed resistance data. They further predict that mutations to Phe227, Trp229, or Leu234 might confer resistance. Since these are not observed, some constraining structural or functional role for these residues in the active enzyme is suggested.

Anilides↗
PubMed1996

A three-compartment open pharmacokinetic model can explain variable toxicities of cobra venoms and their alpha toxins.

The pharmacokinetic profiles of labelled Naja melanoleuca, Naja nivea, Naja nigricollis and Naja haje venoms and their alpha neurotoxins were determined following rapid i.v. injection into rabbits. The data obtained fitted a triexponential equation characteristic of a three-compartment open pharmacokinetic model comprising a central compartment 'blood', a rapidly equilibrating 'shallow' tissue compartment and a slowly equilibrating 'deep' tissue compartment. The distribution half-lives for the shallow compartment ranged from 3.2 to 5 min, reflecting the rapid uptake of venoms and toxins compared with 22-47 min for the deep tissue compartment denoting much slower uptake. The overall elimination half-lives, t1/2 beta, ranged from 15 to 29 hr, indicating a slow body elimination. Peak tissue concentration was reached within 15-20 min in the shallow tissue compartment. The corresponding values for the deep tissue compartment were 120 min for N. melanoleuca and N. nigricollis venoms and their toxins and 240 min for N. nivea and N. haje venoms and their toxins. Steady-state distribution between the shallow tissue compartment and the blood gave values of 0.50 and 0.92 (N. melanoleuca), 1.64 and 1.05 (N. nivea), 0.78 and 0.92 (N. nigricollis) and 1.70 and 1.03 (N. haje) for the venoms and their toxins, respectively. The corresponding values for the deep tissue compartment gave ratios of 3.31 and 3.44 (N. melanoleuca), 2.99 and 1.68 (N. nivea), 3.74 and 3.79 (N. nigricollis) and 1.39 and 2.46 (N. haje) for the venoms and their toxins, respectively. Ratios lower than unity indicate lower venom and toxin concentrations in the tissues than in the blood, while larger ratios denote higher tissue concentrations. The values thus reflect a higher affinity of the venoms and their toxins for the central than the shallow tissue compartment and for the deep tissue than the central compartment. The sites of action of the venoms seem to be located in the deep tissue compartment since most of the pharmacological, biochemical and electrocardiographic effects of the venoms started 30-60 min after i.v. injection. The mean residence time in the body, MRTb, ranged from 20.8 to 51.8 hr, which correlated well with the long duration of the pharmacological and biochemical effects induced by the venoms. The tissue distribution of the venoms and toxins was similar, with the highest uptake being in the kidneys, followed by the stomach, lungs, liver, spleen, intestine, heart and diaphragm. Very high radioactivity was found in the stomach contents, which reached values higher than the kidneys. Some of the biochemical markers were significantly changed by one or more venoms but the grouped parameters did not reflect significant changes in cardiac, renal, hepatic or electrolyte profiles as a function of time. It is concluded that antivenom, even if injected several hours after a cobra bite, is still capable of neutralizing the slowly eliminating venom. To speed up neutralization of the venom effects, doses of antivenom higher than the calculated in vitro neutralizing dose ought to be injected to compensate for the slow rate of transfer of antivenom to the tissues.

Animals↗
PubMed1994

Models to explain dose-response relationships that exhibit a downturn phase.

Over a broad dose (or concentration) range, dose-response relationships frequently display a bell-shaped form. Mechanisms leading to this phenomenon may be manifold, but so far they have not been adequately identified. In this article, Vladimir Pliska discusses two models that are based on multiple-state cell-signaling pathways and enable an estimate of generally applicable descriptors. These can be used for expression of drug potency and for similar purposes.

Algorithms↗