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.     

Densification involved in the UV-based photosensitivity of silicaglasses and optical fibers

A comprehensive survey of photosensitivity in silica glasses and optical fiber is reviewed. Recent work on understanding the mechanisms contributing to germanium or aluminum doped fiber photosensitivity is discussed within the framework of photoelastic densification models     

The lattice dynamics of the Fe(tpa) (NCS)2 complex : light-induced excited spin state trapping effect

A light-induced excited spin state trapping (LIESST) experiment for a thermal gradual spin crossover complex, Fetris (2-pyridylmethyl) amine(NCS)2 or Fe(tpa) (NCS)2, was attempted for the first time. The high spin (HS) state after light inducement stayed metastable over a period of days without relaxation at 10 K. Intersystem relaxation from a high to a low spin (LS) complex occurred at 50 K after bleaching at 10 K. Investigation of the Mossbauer spectra of the LIESST and relaxation experiment indicated that the Debye–Waller factor was a correlation parameter of the HS fraction and that the co-operative effect played a role in the relaxation process for such a solid compound. This revised version was published online in November 2006 with corrections to the Cover Date.     

STRESS INTENSITY FACTORS AND WEIGHT FUNCTIONS FOR SEMI-ELLIPTICAL SURFACE CRACKS IN FINITE-THICKNESS PLATES UNDER TWO-DIMENSIONAL STRESS DISTRIBUTION

Abstract— A Fourier series approach is proposed to calculate stress intensity factors using weight functions for semi-elliptical surface cracks in flat plates subjected to two-dimensional stress distributions. The weight functions were derived from reference stress intensity factors obtained by three-dimensional finite element analyses. The close form weight functions derived are suitable for the calculation of stress intensity factors for semi-elliptical surface cracks in flat plates under two-dimensional stress distributions with the crack aspect ratio in the range of 0.1 ≤ a/c ≤ 1 and relative depth in the range of 0 ≤ a/t ≤ 0.8. Solutions were verified using several two-dimensional non-linear stress distributions; the maximum difference being 6%.     

Inhibitory effect of ganciclovir on the HSV1-tk positive subcutaneous tumors transplanted with human ovarian cancer in nude mice

OBJECTIVE: To investigate the inhibitory effect in vivo of ganciclovir (GCV) on the growth of human ovarian cancer cells (AO) transducted with the thymidine kinase gene of herpes simplex virus I type (HSV1-tk). METHODS: Tumors were induced in nude mice by subcutaneous injection of AO cells and AO cells carried with HSV1-tk gene from China strain (AO/HSV1-tk cells). When the growing tumors were visible, GCV was injected daily into the peritoneum of the nude mice. RESULTS: The average weights of survived AO/HSV1-tkc tumors and AO tumors treated with GCV were 0.087 +/- 0.036 g and 0.661 +/- 0.260 g respectively. Most of the survived AO/HSV1-tkc cells treated with GCV were characterized by hypertrophy and necrosis, but their nuclear chromatins predominantely took the forms of heterchromatins. CONCLUSIONS: GCV could effectively inhibit the growth of HSV1-tk positive human ovarian cancer cells in vivo, but the nuclei of the survival tumor cells appeared to proliferate actively. As the same results of in vitro experiments, this may suggest that HSV1-tk/GCV gene therapeutic system might be combined with S-phase chemotherapy to increase the long-term effect.     

On the reliability of Landsat TM for estimating forest variables byregression techniques: a methodological analysis

In order to build models that relate thematic mapper (TM) imagery to field forest variables, several regression techniques, such as the ones based on the Mallows' C_p and the adjusted R² statistics, were applied. Nevertheless, although the best created models had good fittings (R²>0.65) apparently supported by a clear statistical significance (p<0.0001), later trials tested with additional plots showed that these models were, in fact, nonrobust models (models with very low-predictive capabilities). Two factors were pointed out as causes of these inconsistencies between predicted and observed values: a relatively small number of available field plots and a relatively high number of possible independent variables. Actually, different trials suggested much lower fittings for the expected “really” predictive models. Some restrictions of TM satellite data, such as its radiometric, spectral, and spatial limitations, together with restrictions arising from gathering and processing of field data, might have led to these poor relations. This study shows the need for guarantees stronger than the usual ones before concluding that there is a clear possibility of using satellite information to estimate forest parameters by means of regression techniques