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.     

Fixed-order H∞ compensator design

A method is presented for the construction of fixed-order compensators to provide H_∞ norm constraint for linear control systems with exogenous disturbances. The method is based on the celebrated bounded-real lemma that predicates the H_∞ norm constraint via a Riccati inequality. The synthesis of fixed-order controllers whose dimensions are less than the order of a given plant, is demonstrated by a set of sufficient conditions along with a numerical algorithm.     

Sheldon H. White (1928-2005).

Sheldon "Shep" Harold White, one of developmental psychology's most distinguished scholars, died on March 17, 2005, at the age of 76. He is perhaps best remembered for his sharp intellect, generous spirit, good humor, and warm compassion. Shep's principal work lay in three intermeshed areas: children's learning and cognitive development, social programs and policies, and the history of developmental psychology. Shep White is sorely missed by his family and friends, and countless children have unknowingly benefited from his research, scholarship, and contributions to public policy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preparation of glucose oxidase immobilized in different carriers using radiation polymerization

Glucose oxidase (EC 1.1.3.4) was immobilized on different polymeric materials using different immobilization techniques (entrapping by γ‐irradiation, and covalent binding using epichlorohydrin). Studies were carried out to increase the thermal stability of glucose oxidase (GOD) for different applications. The activity and stability of the resulting biopolymers have been compared with those of free GOD. The effect of different polyvinyl alcohol/polyacrylamide (PVA/PAAm) compositions of the copolymer carrier on the enzymatic activity of the immobilized GOD was studied. The maximum enzymatic activity was obtained with the composition ratio of PVA/PAAm of 60:40. The behaviour of the free and immobilized enzyme was analysed as a function of pH. A broadening in the pH profile (5.5–8) was observed for immobilized preparations. The activity and stability of the resulting biopolymers produced by immobilization of GOD onto different carriers have been compared, in both aqueous and organic media, with those of the free GOD. The enzyme's tolerance toward both heat and organic solvent was enhanced by immobilization onto polymers. The addition of different concentrations of organic solvents (10–50%, v/v) to the enzyme at higher temperature (60 °C) was found to stabilize the enzyme molecule. The strongest stabilizing effect on the enzymatic activity was achieved at a concentration of 10%. Copyright © 2005 Society of Chemical Industry     

On the determination of boundaries to manipulator workspaces

The accumulation of two independent, broadly applicable formulations for determining the boundary to manipulator workspaces, presented elsewhere, are compared in this paper. Insights gained from one method are used to explain behavior exhibited in the other. Results are also compared and validated. A numerical formulation based on continuation methods is used to map curves that are on the boundary of a manipulator workspace. Analytical criteria based on row rank deficiency criteria of the manipulator's analytical Jacobian are used to map a family of one-dimensional solution curves on the boundary. The other formulation, based on a similar rank-deficiency criteria, yields analytic boundaries parametrized in terms of surface patches on the boundary. Results concerning the applicability of the numerical method to open- and closed-loop systems are compared with those limited to the open-loop for the analytical method. Conclusions regarding the behavior of the manipulator on geometric entities characterized by singular curves, higher-order bifurcation points, and surfaces inside the workspace are drawn. Applicability of both methods and their limitations are also addressed.     

Top-down logic design with pass-transistor cells and efficientsynthesiser

A pass-transistor based cell library containing only two types of cells is designed and a corresponding logic/circuit synthesiser developed for logic mapping of any combinational circuit. The proposed design has better performance than the recently proposed lean integration with pass transistors (LEAP) cell library. Furthermore, the modified LEAP cell library can be easily migrated to a new process technology due to the smaller number of cells     

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.     

Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta

How senile plaques and neurofibrillary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer's disease. We characterized a hippocampal neuronal culture system in which tau undergoes maturation in vivo; rat neurons maintained in culture for more than 3 weeks replicated the splicing and phosphorylation changes that tau undergoes upon maturation in situ. Using this model system, we induced an Alzheimer-like neuritic dystrophy following the application of fibrillar beta-amyloid. The dystrophy consisted of focal distortions and swellings within the neurites and an altered phosphorylation of the adult tau isoforms. Fibrillar beta-amyloid induced the concomitant activation of MAP kinase and GSK3 beta. The aberrant activation of several signaling pathways may lead to the abnormal phosphorylation of tau and neuritic degeneration.     

Novel technique for SiO2 formed by liquid-phasedeposition for low-temperature processed polysilicon TFT

A technique for SiO₂ formation by liquid-phase deposition (LPD) at nearly room temperature for low-temperature processed (LTP) polysilicon thin-film transistor (poly-Si TFT) was developed. LPD SiO₂ film with a lower P-etch rate shows a dense structure. LPD SiO₂ also exhibits good electrical characteristics. LTP poly-Si thin-film transistors (TFTs) with LPD SiO ₂ as the gate insulator have been fabricated and investigated. Their characteristics indicate performance adequate for their use as pixel transistors in liquid crystal displays (LCDs)