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PubMed1989

A model to explain the pharmacological effects of snake venom phospholipases A2.

Snake venom phospholipase A2 enzymes induce a wide variety of pathological symptoms in animals, despite sharing a common catalytic activity and similar structural features with nontoxic mammalian pancreatic enzymes. A hypothetical model is described to explain how specific pharmacological effects, such as presynaptic neurotoxicity, cardiotoxicity, myotoxicity, anticoagulant and platelet effects are exhibited by venom PLA2 enzymes. The model is an effort to elucidate many controversial and contradictory observations which have previously been difficult to interpret. The essential feature of the model is the targeting of venom PLA2 enzymes to the specific tissue or cell due to their affinity towards specific proteins, rather than lipid domains. After the initial binding, PLA2 enzymes induce various pharmacological effects by mechanisms which are either dependent or independent of their enzymatic activity. The model and its predicted target proteins thus provide a new focus for toxin research.

Blood Coagulation↗
PubMed1990

The stereospecificities of seven dehydrogenases from Acholeplasma laidlawii. The simplest historical model that explains dehydrogenase stereospecificity.

Stereospecificities are reported for seven dehydrogenases from Acholeplasma laidlawii, an organism from an evolutionarily distinct branch of life which has not previously been studied from a stereochemical point of view. Three of the activities examined (alcohol dehydrogenase, lactate dehydrogenase, and alanine dehydrogenase) catalyze the transfer of the pro-R (A) hydrogen from NADH. Four other activities (3-hydroxy-3-methylglutaryl-CoA reductase, glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, and NADH oxidase) catalyze the transfer of the pro-S (B) hydrogen from NAD(P)H. The stereospecificity of hydroxymethylglutaryl-CoA reductase is notable because it is the opposite of that of hydroxymethylglutaryl-CoA reductases from yeast and rat. These data are used to derive the simplest historical model capable of explaining available experimental facts.

Acholeplasma laidlawii↗
PubMed1990

Determinants of health-promoting lifestyle in ambulatory cancer patients.

The Health Promotion Model was tested as an explanatory framework for health-promoting lifestyle in a sample of 385 ambulatory cancer patients undergoing treatment in 13 clinical sites in the midwestern United States. The aim of this study was to determine the extent to which cognitive/perceptual and modifying variables identified in the Health Promotion Model explain the occurrence of health-promoting behaviors in adults with cancer. A secondary aim was to determine the potential of illness-specific cognitive/perceptual and modifying variables for further explaining the occurrence of health-promoting behaviors in adults with cancer. Multiple regression analyses revealed that 23.5% of the variance in health-promoting lifestyle was explained by the model cognitive/perceptual variables definition of health, perceived health status and perceived control of health and the modifying variables education, income, age and employment. When illness-specific variables were included in the analysis, initial reaction to the diagnosis of cancer was found to be a significant contributor to the regression. Study results support the importance of both general health-related and cancer-specific cognitive/perceptual factors in explaining the occurrence of health-enhancing behaviors among ambulatory cancer patients; these factors may therefore be suitable targets for interventions to encourage adoption of healthy lifestyles.

Adult↗
PubMed1978

A tunnelling model to explain the reduction of ferricytochrome c by H and OH radicals.

The kinetics of the reaction of OH radicals with ferricytochrome c was studied in the time range 1 microsecond to 1 s by means of pulse radiolysis. The OH radicals reduce ferricytochrome c by 40% +/- 10%. The time course of the reduction is explained by a mechanism whereby a radical formed after hydrogen has been abstracted from the outer surface of the protein reduces the iron by electron tunnelling. We have calculated that the reducing electron in the radical is bound with an energy of at least 1.75 eV and that the frequency factor of the tunnelling process is v=10(11.5)s-1. This model accounts for the observed absorbance change in time range 5 . 10(-6)--10(-1)s. The time course of the reduction of ferricytochrome c by H radicals (Lichtin, N.N., Shafferman A. and Stein, G. (1974) Biochim. Biophys. Acta 357, 386--398) is explained by the same model.

Calorimetry↗
PubMed1990

A bivariate negative binomial model to explain traffic accident migration.

The phenomenon of "regression to the mean" is now widely known in the study of the effectiveness of remedial treatment of traffic accident blackspots. What happens is that the criterion used for selection of sites at which treatment is to be applied gives rise to bias in the estimate of the effectiveness: the conditional expectation of the after frequency is less than the true mean, even if the treatment is totally ineffective. It has been reported in some previous studies that accident "migration" has been observed. This is the phenomenon whereby the accident rate apparently rises at sites that are untreated but that are neighbours to treated sites. If this were a genuine effect, it would have serious implications for the assessment of remedial treatments. This paper aims to explain this migration effect in purely probabilistic terms, without recourse to the concept of physical migration. The model used is a new bivariate negative binomial distribution, incorporating spatial correlation between the true mean site accident rates. As with the regression to mean effect, the migration effect can then be explained in terms of the conditioning implicit in the selection process.

Accidents, Traffic↗
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↗
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↗
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↗
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↗
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↗
PubMed1979

A multivariate analysis of interstate variation in fertility of teenage girls.

A multiple regression model was used to determine the correlates of state-to-state variation in fertility of teenage girls. The independent variables were the abortion-t0-live birth ratio, contraception/conception ratio, racial composition, adult personal income, per cent urban population, and adult educational attainment. The model explained 69 per cent of the interstate variation in 1974 fertility. Both the racial composition and the abortion ratio were significantly (p less than .01) correlated with fertility. With 1970--1974 change in fertility as the dependent variable, the model explained 80 per cent of the variation, with income as the most strongly correlated variable. The contraception/conception ratio was also significant (p less than .01), as was racial composition (p less than .05). Factor analysis of the independent variables showed that the six variables were well accounted for by three factors representing culture/education status, abortion availability, and contraception availability. The analysis showed that utilization of both contraception and abortion was important in determining the fertility of a state's teenagers. Increased availability of publicly subsidized contraception in low income areas and increased availability of abortion in low income and rural areas might be expected to result in decreased fertility of teenage girls.

Abortion, Induced↗
PubMed1991

Development of a semiquantitative food frequency questionnaire to assess food, energy and nutrient intake in Denmark.

Foods to be included in a Danish self-administered semiquantitative food frequency questionnaire were identified from food tables developed, together with data collected, for the survey 'Dietary habits in Denmark, 1985'. The questionnaire was to be used in a prospective study on diet, cancer and health, and the aim was to rank individuals with regard to intake of 19 different nutrients considered of prime importance in human carcinogenesis. The questionnaire for the dietary survey included 247 foods and recipes. From stepwise multiple regression analyses with the intake of each of the 19 nutrients as the dependent variable and the intake of the 247 foods and recipes as independent variables, the foods in the models explaining 90% of the between-person variability were considered for the final questionnaire. All relevant analyses were performed for the study group as a whole, for men and women separately, and in each gender for subgroups of energy intake. Taken together, the models explaining 90% of the between-person variability identified a total of 74 foods or recipes, which were important predictors of the intake of one or more of the nutrients considered. A few foods were excluded and a few foods were added to the final questionnaire based on common biological background information, and on information on foods providing important amounts of given nutrients, but which failed to contribute to regression analyses. The 92 foods and recipes, which were included in the final questionnaire provided altogether 81% of the average total supply of the nutrients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

A hypothetical model to explain the 'termination' of chronic myeloid leukemia into blastic crisis.

Chronic myeloid leukemia is characterised by two discrete phases, a 'benign' phase which terminates into an 'acute' phase. Various explanations have been given to explain the cause of 'blastic' crisis in CML. But the consistency and regularity with which blast crisis occurs and the irregularity with which the factors which are ascribed to cause it (e.g. additional chromosomal abnormalities, change in bcr/abl rearrangement, etc. occur, suggests that CML-BC is not a stochastic process in the natural history of CML but is predetermined at the time of the first mutation in the stem cell. A hypothetical model is put forward proposing this. Different points supporting the model are discussed. The most important implication of this model would be to provide an insight that should lead to the development of more selective and appropriate treatment strategies for this disease.

Blast Crisis↗
PubMed1989

A model that explains the varying frequency of aneuploid children with maternal age (J-shaped curve) as well as aneuploidy of paternal origin.

A compromised microcirculation could account for aneuploidy incidence in women of any reproductive age, the frequency varying with the probability of events leading to reduced development and/or function of the critical perifollicular capillary bed. This would explain the J-shaped curve of changing frequency of Down syndrome children with maternal age (Erickson, 1978). The seminiferous tubule of the testis, like the follicle, has no internal circulation, so small localized regions of reduced circulation could occur and result in aneuploidy. From all that we know about the deficiency of regional microcirculation in tumors (see Hall, 1978), it is reasonable to speculate that reduced pH could be responsible for some of the aneuploidy that is seen in practically all advanced tumors. As a first step in testing the model proposed here, we are beginning studies with mouse oocytes, on the assumption that ovarian conditions are responsible for the maternal age effect rather than uterine conditions (reduced rejection of trisomic fetuses). Should our model for aneuploidy induction in both germ and somatic cells prove to be correct, the molecular mechanism(s) would still have to be ascertained.

Aneuploidy↗