Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.     

An experimental and numerical investigation of ductile crack growth characteristics in surface cracked specimens under combined loading

Fracture mechanics tests have been performed in the upper shelf region of a steel on large surface cracked plate (SCT) specimens and on small compact tension (CT) specimens. Some of the SCT specimens were subjected to combined tension and bending in such a way that the loading was strongly non-proportional. Crack growth characteristics were compared between the specimens in order to assess possible influences of geometry and nonproportional loading. The differences observed could unambiguously be reduced to and correlated with differences in constraint. Constraint parameters were evaluated by detailed three-dimensional finite element computations and quantities for growing cracks were interpreted on the basis of deformation theory considerations, in analogy with the commonly used J _R-philosophy. It was noted that the initiation of ductile crack growth along a three-dimensional crack front appears to be independent of the degree of local constraint. However, the increase in toughness for a growing crack was markedly affected by the degree of local constraint. Some estimates of the constraints effects regarding stability considerations were also made.     

The association of gonorrhoea and syphilis with premature birth and low birthweight

The indications and results of single and double lung transplantation are described on the basis of 66 operations performed by the authors and on the background of the world literature. Lung transplantation is considered a new and promising therapeutic mode for treating patients with end-stage pulmonary failure related to fibrosis, emphysema, infective conditions, and pulmonary hypertension yielding satisfactory early results. The long-term prognosis of patients undergoing lung transplantation, like that of any other organ transfer, remains guarded.     

Sociopolitical effects on personality research.

Comments on L. R. Goldberg's (see record 1993-17546-001) history of the Big Five framework of personality traits and elaborated on its use. The reasons why industrial/organizational psychologists de-emphaszied the impact of personality on the job peformance in the late 1960s and 1970s and re-emphasized it in the 1980s are addressed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tribological properties of oil-soluble polyolefins

Translated from Khimiya i Tekhnologiya Topliv i Masel, No. 11, pp. 17–18, 23, November, 1993.     

A multivariate mixed linear model for meta-analysis.

A multivariate mixed-effects approach for meta-analysis is presented. The approach (a) incorporates as outcomes multiple effect sizes per study; (b) allows different studies to have different subsets of effect sizes; and (c) treats each study's effect sizes as random realizations from a population of possible effect sizes. Application is illustrated via reanalysis of data from studies assessing the effects of coaching on verbal and mathematical subtests of the Scholastic Aptitude Test. Covariance components are estimated via restricted maximum likelihood (REML); inferences about regression coefficients and specific study effect sizes are based on their joint conditional distribution given the REML covariance component estimates. The approach can be implemented via now-standard software for unbalanced hierarchical data. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the Possibility of Observing Third Sound on 3He

This paper focuses on the hydrodynamics of third sound on a superfluid ³ He film. We solve the hydrodynamical equations in the limit of thick films with weak interaction with the substrate. The surface tension at the free interface is shown to have a large effect on the third sound velocity and on the attenuation for frequencies larger than 1Hz. In the case of a diffusely scattering substrate a ripplon-like dispersion relation is found for this frequency range.     

The role of perspective in the accessibility of goals during reading.

An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)