Analysis and application of an equilibrium model for in vitro bioassay systems with three components: Receptor, hormone and hormone-binding-protein

A simple theoretical framework is presented for bioassay studies using three component in vitro systems. An equilibrium model is used to derive equations useful for predicting changes in biological response after addition of hormone-binding-protein or as a consequence of increased hormone affinity. Sets of possible solutions for receptor occupancy and binding protein occupancy are found for typical values of receptor and binding protein affinity constants. Unique equilibrium solutions are dictated by the initial condition of total hormone concentration. According to the occupancy theory of drug action, increasing the affinity of a hormone for its receptor will result in a proportional increase in biological potency. However, the three component model predicts that the magnitude of increase in biological potency will be a small fraction of the proportional increase in affinity. With typical initial conditions a two-fold increase in hormone affinity for its receptor is predicted to result in only a 33% increase in biological response. Under the same conditions an Ii-fold increase in hormone affinity for receptor would be needed to produce a two-fold increase in biological potency. Some currently used bioassay systems may be unrecognized three component systems and gross errors in biopotency estimates will result if the effect of binding protein is not calculated. An algorithm derived from the three component model is used to predict changes in biological response after addition of binding protein to in vitro systems. The algorithm is tested by application to a published data set from an experimental study in an in vitro system (Lim et al., 1990, Endocrinology 127, 1287-1291). Predicted changes show good agreement (within 8%) with experimental observations. (C) 1998 Academic Press Limited.

Contradiction of quantum mechanics with local hidden variables for quadrature phase amplitude measurements

We demonstrate a contradiction of quantum mechanics with local hidden variable theories for continuous quadrature phase amplitude (position and momentum) measurements. For any quantum state, this contradiction is lost for situations where the quadrature phase amplitude results are always macroscopically distinct. We show that for optical realizations of this experiment, where one uses homodyne detection techniques to perform the quadrature phase amplitude measurement, one has an amplification prior to detection, so that macroscopic fields are incident on photodiode detectors. The high efficiencies of such detectors may open a way for a loophole-free test of local hidden variable theories.

Epidermal iontophoresis: II. Application of the ionic mobility-pore model to the transport of local anesthetics

Purpose, An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. Methods. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. Results. The logarithm of the iontophoretic permeability coefficient (log PCj,iont) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PCj,iont was best defined by ionic mobility (and its determinants: conductivity, pK(a) and MW) and MW. Conclusions. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pK(a)) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.

Predictors of local recurrence after treatment of ductal carcinoma in situ - A meta-analysis

lBACKGROUND. Management of patients with ductal carcinoma in situ (DCIS) is a dilemma, as mastectomy provides nearly a 100% cure rate but at the expense of physical and psychologic morbidity. It would be helpful if we could predict which patients with DCIS are at sufficiently high risk of local recurrence after conservative surgery (CS) alone to warrant postoperative radiotherapy (RT) and which patients are at sufficient risk of local recurrence after CS + RT to warrant mastectomy. The authors reviewed the published studies and identified the factors that may be predictive of local recurrence after management by mastectomy, CS alone, or CS + RT. METHODS. The authors examined patient, tumor, and treatment factors as potential predictors for local recurrence and estimated the risks of recurrence based on a review of published studies. They examined the effects of patient factors (age at diagnosis and family history), tumor factors (sub-type of DCIS, grade, tumor size, necrosis, and margins), and treatment (mastectomy, CS alone, and CS + RT). The 95% confidence intervals (CI) of the recurrence rates for each of the studies were calculated for subtype, grade, and necrosis, using the exact binomial; the summary recurrence rate and 95% CI for each treatment category were calculated by quantitative meta-analysis using the fixed and random effects models applied to proportions. RESULTS, Meta-analysis yielded a summary recurrence rate of 22.5% (95% CI = 16.9-28.2) for studies employing CS alone, 8.9% (95% CI = 6.8-11.0) for CS + RT, and 1.4% (95% CI = 0.7-2.1) for studies involving mastectomy alone. These summary figures indicate a clear and statistically significant separation, and therefore outcome, between the recurrence rates of each treatment category, despite the likelihood that the patients who underwent CS alone were likely to have had smaller, possibly low grade lesions with clear margins. The patients with risk factors of presence of necrosis, high grade cytologic features, or comedo subtype were found to derive the greatest improvement in local control with the addition of RT to CS. Local recurrence among patients treated by CS alone is approximately 20%, and one-half of the recurrences are invasive cancers. For most patients, RT reduces the risk of recurrence after CS alone by at least 50%. The differences in local recurrence between CS alone and CS + RT are most apparent for those patients with high grade tumors or DCIS with necrosis, or of the comedo subtype, or DCIS with close or positive surgical margins. CONCLUSIONS, The authors recommend that radiation be added to CS if patients with DCIS who also have the risk factors for local recurrence choose breast conservation over mastectomy. The patients who may be suitable for CS alone outside of a clinical trial may be those who have low grade lesions with little or no necrosis, and with clear surgical margins. Use of the summary statistics when discussing outcomes with patients may help the patient make treatment decisions. Cancer 1999;85:616-28. (C) 1999 American Cancer Society.

Targeting local tissues by transdermal application: Understanding drug physicochemical properties that best exploit protein binding and blood flow effects

The targeting of topically applied drug molecules into tissues below a site of application requires an understanding of the complex interrelationships between the drug, its formulation, the barrier properties of the skin, and the physiological processes occurring below the skin that are responsible for drug clearance from the site, tissue, and/or systemic distribution and eventual elimination. There is still a certain amount of controversy over the ability of topically applied drugs to penetrate into deeper tissues by diffusion or whether this occurs by redistribution in the systemic circulation. The major focus of our work in this area has been in determining how changes in drug structure and physicochemical properties, such as protein binding and lipophilicity, affect drug clearance into the local dermal microcirculation and lymphatics, as well as subsequent distribution into deeper tissues below an application site. The present study outlines our recent thinking on the drug molecule optimal physical attributes, in terms of plasma and tissue partitioning behaviour, that offer the greatest potential for deep tissue targeting. Drug Dev. Res. 46:309-315, 1999. (C) 1999 Wiley-Liss, Inc.

Life tables of the processionary caterpillar Ochrogaster lunifer Herrich-Schaffer (Lepidoptera : Thaumetopoeidae) at local and regional scales

A major ongoing debate in population ecology has surrounded the causative factors underlying the abundance of phytophagous insects and whether or not these factors limit or regulate herbivore populations. However, it is often difficult to identify mortality agents in census data, and their distribution and relative importance across large spatial scales are rarely understood. Were, we present life tables for egg batches and larval cohorts of the processionary caterpillar Ochrogaster lunifer Herrich-Schaffer, using intensive local sampling combined with extensive regional monitoring to ascertain the relative importance of different mortality factors at different localities. Extinction of entire cohorts (representing the entire reproductive output of one female) at natural localities was high, with 82% of the initial 492 cohorts going extinct. Mortality was highest in the egg and early instar stages due to predation from dermestid beetles, and while different mortality factors (e.g. hatching failure, egg parasitism and failure to establish on the host) were present at many localities, dermestid predation, either directly observed or inferred from indirect evidence, was the dominant mortality factor at 89% of localities surveyed. Predation was significantly higher in plantations than in natural habitats. The second most important mortality factor was resource depletion, with 14 cohorts defoliating their hosts. Egg and larval parasitism were not major mortality agents. A combination of predation and resource depletion consistently accounted for the majority of mortality across localities, suggesting that both factors are important in limiting population abundance. This evidence shows that O. lunifer is not regulated by natural enemies alone, but that resource patches (Acacia trees) ultimately, and frequently, act together to limit population growth.

Coupled experimental and thermodynamic modeling studies for metallurgical smelting and coal combustion slag systems

An extensive research program focused on the characterization of various metallurgical complex smelting and coal combustion slags is being undertaken. The research combines both experimental and thermodynamic modeling studies. The approach is illustrated by work on the PbO-ZnO-Al2O3-FeO-Fe2O3-CaO-SiO2 system. Experimental measurements of the liquidus and solidus have been undertaken under oxidizing and reducing conditions using equilibration, quenching, and electron probe X-ray microanalysis. The experimental program has been planned so as to obtain data for thermodynamic model development as well as for pseudo-ternary Liquidus diagrams that can be used directly by process operators. Thermodynamic modeling has been carried out using the computer system FACT, which contains thermodynamic databases with over 5000 compounds and evaluated solution models. The FACT package is used for the calculation of multiphase equilibria in multicomponent systems of industrial interest. A modified quasi-chemical solution model is used for the liquid slag phase. New optimizations have been carried out, which significantly improve the accuracy of the thermodynamic models for lead/zinc smelting and coal combustion processes. Examples of experimentally determined and calculated liquidus diagrams are presented. These examples provide information of direct relevance to various metallurgical smelting and coal combustion processes.

Experimental study of phase equilibria in the systems Fe-Zn-O and Fe-Zn-Si-O at metallic iron saturation

The reported experimental work on the systems Fe-Zn-O and Fe-Zn-Si-O in equilibrium with metallic iron is part of a wider research program that combines experimental and thermodynamic computer modeling techniques to characterize zinc/lead industrial slags and sinters in the system PbO-ZnO-SiO2-CaO-FeO-Fe2O3. Extensive experimental,investigations using high-temperature equilibration and quenching techniques followed by electron probe X-ray microanalysis (EPMA) were carried out. Special experimental; procedures were developed to enable accurate measurements in these ZnO-containing systems to be performed in equilibrium with metallic iron; The systems Fe-Zn-O and FeZn-Si-O were experimentally investigated in equilibrium with metallic iron in the temperature ranges 900 degreesC to 1200 degreesC (1173 to 1473 K) and from 1000 degreesC to 1350 degreesC (1273 to 1623 K), respectively. The liquidus surface in the system Fe-Zn-Si-O in equilibrium with metallic iron was characterized in the composition ranges 0 to 33 wt pet ZnO and 0 to 40 wt pet SiO2. The wustite (Fe,Zn)O, zincite (Zn,Fe)O, willemite (Zn,Fe)(2)SiO4, arid fayalite: (Fe,Zn)(2)SiO4 solid solutions in equilibrium with metallic iron were measured.

Experimental study of phase equilibria in the PbO-MgO-SiO2 system

Equilibrium phase relations in the PbO-Al2O3-SiO2 system have been investigated experimentally by means of high-temperature equilibration, quenching, and electron probe X-ray microanalysis (EPMA). The system has 21 primary phase fields including three monoxides (PbO, Al2O3, and SiO2), seven binary compounds (Al6Si2O13, PbAl2O4, PbAl12O19, Pb2Al2O5, PbSiO3, Pb2SiO4, and Pb4SiO6), and eleven ternary compounds (PbAl2Si2O8, Pb3Al10SiO20, Pb4Al2Si2O11, Pb4Al4SiO12, Pb4Al4Si3O16, Pb4Al4Si5O20, Pb5Al2Si10O28, Pb6Al2Si6O21, Pb8Al2Si4O19, Pb12Al2Si17O49, and Pb12Al2Si20O55). Three new ternary compounds, Pb4Al4SiO12, Pb4Al4Si5O20, and Pb12Al2Si17O49, were observed and characterized by EPMA. No extensive solid solution in any of the compounds was found in the present study. The liquidus isotherms were experimentally determined in most of the primary phase fields in the temperature range from 923 to 1873 K, and the ternary phase diagram of the PbO-Al2O3-SiO2 System has been constructed.

Exploratory research: Citizen participation, local government and sustainable development in Australia

Exploratory research reported in this paper was undertaken in Adelaide, Australia during 1998/99. The purpose of the research is to explore local development practice as evidenced through the experiences and actions of local citizens, community based groups and local government (Neuman, 1994). Results from this first stage research suggest that sustainability initiatives in Australia might best be implemented through a collaborative approach at the local community level involving local citizens working in partnership with local government. Copyright (C) 2002 John Wiley & Sons, Ltd and ERP Environment.

Evolution of local recruitment and its consequences for marine populations

Advantages of dispersal on the scales that are possible in a long pelagic larval period are not apparent, even for benthic species. An alternative hypothesis is that wide dispersal may be an incidental byproduct of an ontogenetic migration from and then back to the parental habitat. Under this hypothesis, the water column is a better habitat than the bottom for early development. Because the parental area is often an especially favorable habitat for juveniles and adults, selection may even favor larval retention or larval return rather than dispersal. Where larval capabilities and currents permit, a high percentage of recruits may then be produced from local adults. Expected consequences of a high proportion of local recruitment are stronger links between stock and recruitment, greater vulnerability to recruitment overfishing and local modifications of habitat, greater local benefits from fishery reserves, and possibly more localized adaptation within populations. Export of some larvae is consistent with a high proportion of retained or returning larvae, could stabilize populations linked by larval exchange, and provide connectivity between marine reserves. Even a small amount of larval export could account for the greater gene flow, large ranges, and long evolutionary durations seen in species with long pelagic larval stages.

Local-global processing in early-onset schizophrenia: Evidence for an impairment in shifting the spatial scale of attention

In this study we report the results of two experiments on visual attention conducted with patients with early-onset schizophrenia. These experiments investigated the effect of irrelevant spatial-scale information upon the processing of relevant spatial-scale information, and the ability to shift the spatial scale of attention, across consecutive trials, between different levels of the hierarchical stimulus. Twelve patients with early-onset schizophrenia and matched controls performed local-global tasks under: (1) directed attention conditions with a consistency manipulation and (2) divided-attention conditions. In the directed-attention paradigm, the early-onset patients exhibited the normal patterns of global advantage and interference, and were not unduly affected by the consistency manipulation. Under divided-attention conditions, however, the early-onset patients exhibited a local-processing deficit. The source of this local processing deficit lay in the prolonged reaction time to local targets, when these had been preceded by a global target, but not when preceded by a local target. These findings suggest an impaired ability to shift the spatial scale of attention from a global to a local spatial scale in early-onset schizophrenia. (C) 2003 Elsevier Science (USA). All rights reserved.

Sources of variation in larval quality for free-spawning marine invertebrates: Egg size and the local sperm environment

There has been growing interest in the effects of variation in larval quality on the post-larval performance of adult marine invertebrates. Variation in egg/larval size is an obvious source of variation in larval quality but sources of variation have received little attention. For broadcast spawners, larval size may vary according to the local sperm environment but the generality of this result is unclear. Here, we show that, for a solitary ascidian, a polychaete and an echinoid, larval size is affected by the concentration of sperm present during fertilization. Larvae that are produced at high sperm concentrations are smaller than larvae that are produced from eggs exposed to low sperm concentrations. We also show that for three ascidians and an asteroid, egg size increases with maternal body size. These differences in larval size are likely to affect larval and subsequent adult performance in the field. Given that sperm concentrations in the field can fluctuate widely, it is likely that larval quality in free-spawning marine invertebrates will also vary widely.

Spatial aspects of trade liberalization in Colombia: A general equilibrium approach

This paper offers some preliminary steps in the marriage of some of the theoretical foundations of new economic geography with spatial computable general equilibrium models. Modelling the spatial economy of Colombia using the traditional assumptions of computable general equilibrium (CGE) models makes little sense when one territorial unit, Bogota, accounts for over one quarter of GDP and where transportation costs are high and accessibility low compared to European or North American standards. Hence, handling market imperfections becomes imperative as does the need to address internal spatial issues from the perspective of Colombia`s increasing involvement with external markets. The paper builds on the Centro de Estudios de Economia Regional (CEER) model, a spatial CGE model of the Colombian economy; non-constant returns and non-iceberg transportation costs are introduced and some simulation exercises carried out. The results confirm the asymmetric impacts that trade liberalization has on a spatial economy in which one region, Bogota, is able to more fully exploit scale economies vis--vis the rest of Colombia. The analysis also reveals the importance of different hypotheses on factor mobility and the role of price effects to better understand the consequences of trade opening in a developing economy.