The impact of medetomidine on the protein-binding characteristics of MK-467 in canine plasma.

This study determined the unbound fraction of the peripheral α2 -adrenoceptor antagonist MK-467 alone and combined with medetomidine. MK-467 (0.1, 1 and 10 µm) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with α1-acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (fu ) of MK-467. Unbound fractions (fu ) of MK-467 in canine plasma (mean ± standard deviation) were 27.6 ± 3.5%, 26.6 ± 0.9% and 42.4 ± 1.2% at 0.1, 1.0 and 10 µm concentrations, respectively. In the presence of medetomidine, fu were 27.5 ± 0.4%, 26.6 ± 0.9% and 41.0 ± 2.4%. The fu of MK-467 in HSA were 50.1 ± 2.5% at 0.1 µm, 49.4 ± 1.2% at 1.0 µm and 56.7 ± 0.5% at 10 µm. fu of MK-467 in AGP was 56.3 ± 3.7% at 0.1 µm, 54.6 ± 5.6% at 1.0 µm and 65.3 ± 0.4% at 10 µm. Protein binding of MK-467 was approximately 70% between 0.1 and 1.0 µm. Medetomidine had no apparent effect on the protein binding of MK-467.

Rapid screening of commercially available herbal products for the inhibition of major human hepatic cytochrome P450 enzymes using the N-in-one cocktail.

Self-administration of complementary products concurrently with conventional medication is increasingly common. The potential for cytochrome P450 (CYP) inhibition requires investigation. The N-in-one assay with ten probe substrates for nine CYPs was used with human liver microsomes to investigate ten products. CYP inhibition was measured in a single liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis. Estimated IC(50)-values were determined for the extracts that produced significant inhibition (less than 100 microg ml(-1)). Inhibition of CYP2C19 by dong quai (IC(50) = 13.7-14.3 microg ml(-1) for the methanolic extract) and CYP2D6 by goldenseal (IC(50) = 6.7 and 6.3 microg ml(-1) for the aqueous and methanolic extracts, respectively), are of particular concern as the potential for adverse interactions is high. The inhibition of CYP2C8 by horsetail (IC(50) = 93 microg ml(-1) for the aqueous extract) requires further investigation, as the potential for concurrent use with products that require CYP2C8 for metabolism is significant. CYP3A4 inhibition varied depending on the probe reaction being monitored. The earlier reported findings of inhibition by black cohosh, goldenseal and gotu kola were confirmed. The present work has shown that the N-in-one cocktail is a rapid and reliable method that can be used as an initial screen to help prioritize products that require more detailed investigations and it can also be applied to monitor product variability.

Calculation of beta-ray dose distributions from ophthalmic applicators and comparison with measurements in a model eye.

Dose distributions throughout the eye, from three types of beta-ray ophthalmic applicators, were calculated using the EGS4, ACCEPT 3.0, and other Monte Carlo codes. The applicators were those for which doses were measured in a recent international intercomparison [Med. Phys. 28, 1373 (2001)], planar applicators of 106Ru-106Rh and 90Sr-90Y and a concave 106Ru-106Rh applicator. The main purpose was to compare the results of the various codes with average experimental values. For the planar applicators, calculated and measured doses on the source axis agreed within the experimental errors (<10%) to a depth of 7 mm for 106Ru-106Rh and 5 mm for 90Sr-90Y. At greater distances the measured values are larger than those calculated. For the concave 106Ru-106Rh applicator, there was poor agreement among available calculations and only those calculated by ACCEPT 3.0 agreed with measured values. In the past, attempts have been made to derive such dose distributions simply, by integrating the appropriate point-source dose function over the source. Here, we investigated the accuracy of this procedure for encapsulated sources, by comparing such results with values calculated by Monte Carlo. An attempt was made to allow for the effects of the silver source window but no corrections were made for scattering from the source backing. In these circumstances, at 6 mm depth, the difference in the results of the two calculations was 14%-18% for a planar 106Ru-l06Rh applicator and up to 30% for the concave applicator. It becomes worse at greater depths. These errors are probably caused mainly by differences between the spectrum of beta particles transmitted by the silver window and those transmitted by a thickness of water having the same attenuation properties.

Using multicriteria methods in environmental planning and management.

In environmental planning and decision processes several alternatives are analyzed in terms of multiple noncommensurate criteria, and many different stakeholders with conflicting preferences are involved. Based on our experience in real-life applications, we discuss how multicriteria decision aid (MCDA) methods can be used successfully in such processes. MCDA methods support these processes by providing a framework for collecting, storing, and processing all relevant information, thus making the decision process traceable and transparent. It is therefore possible to understand and explain why, under several conflicting preferences, a particular decision was made. The MCDA framework also makes the requirements for new information explicit, thus supporting the allocation of resources for the process.

Chaotic or periodic variation? Looking at Crustacea hearts.

A simple relationship between the burst length of the trigger neurons of the Crustacea cardiac ganglion and the length of the heartbeat, is shown to lead to chaotic heart rate. Interestingly, the same type of relationship is also capable of generating complex periodic deviations from steady heart rhythm. Real Crustacea hearts are not likely to follow strictly either suite. The general procedure of analysis, however, is applicable to various biological rhythms, and explains how variation around the mean value can occasionally show up as intricate patterns which repeat themselves with accuracy.

Visual simulations, artificial animals and virtual ecosystems.

This review is about a field that does not traditionally belong to biological sciences. A branch of computer animation has its mission to create active self-powered objects living artificial lives in the theoretical biology zone. Selected work, of particular interest to biologists, is presented here. These works include animated simulations of legged locomotion, flexible-bodied animals swimming and crawling, artificial fish in virtual ecosystems, automated learning of swimming and the evolution of virtual creatures with respect to morphology, locomotion and behaviour. The corresponding animations are available for downloading via the Internet. I hope that watching these intriguing pieces of visual simulation will stimulate digitally oriented biologists to seize the interactive methods made possible by ever-increasing computing power.

Thermal role of a blood vessel running through a temperature gradient.

A mathematical model of a blood vessel running through a linearly varying temperature field suggests that if the Graetz number of the flow is between 1 and 10, small variations in the flow rate result in large differences in blood temperature drop. Single separate blood vessels of the right Graetz number may have substantial thermoregulatory capabilities.

Temperature regulation of marine mammals.

A mathematical model of heat loss from an aquatic animal to the surrounding water is presented. Heat is generated in metabolically active tissues and distributed by circulating blood and by conduction. The time dependent radial temperature profile of the animal is numerically solved from heat transfer equations by a computer. The model is applied to large whales, porpoises, and seals. For the whales, blood circulation to the dermal layer below appendage and body skin surfaces proved to be essential for sufficient heat dissipation. When decreasing the blood flow below a certain value (dependent on sea temperature and whale activity) the large whales would overheat. Blubber thickness was found to be of minor importance in whale thermoregulation, because the blubber coat can be bypassed by blood circulation. On the other hand, it is in general not possible for small porpoises and seals to stay warm in the coldest waters using normal mammalian resting metabolic rates, even if the peripheral circulation is shut off (or artery-vein heat exchangers used). Heat loss can be reduced if the outermost tissue layers are allowed to cool. This is achieved by minimizing convective radial heat flow via the circulation. (For large whales even minute radial blood flow raises the muscle temperatures to the core temperature level.) Seasonal acclimatization of harbour seals is explained by changes in their effective insulation thickness. Differences in whale activity induce changes in the temperature profile mainly within the first few centimeters from the skin surface. These superficial temperatures, if known, could be used to estimate whale metabolic rates. Since they drop close to the sea water temperature within minutes after whale death, the measurements should be done of live whales.

A two-fluid model for hematocrit distribution in microvascular networks.

A new theoretical network model for evaluating discharge hematocrits, explicitly based on plasma skimming at branches, is introduced. The particular network geometry chosen simulates bat wing microvasculature. Blood in vessels is approximated to be a two fluid with red cell suspension as the core and a plasma layer surrounding it. The plasma layer width depends on hematocrit, which leads to nonlinear hydrodynamic equations solved by iteration. Discharge hematocrit distributions are calculated by a computer for five generations of vessels. Dispersion of hematocrit values was found to be correlated to plasma skimming at branches. Contrary to previous suggestions, plasma skimming did not result in lowered mean hematocrit towards the capillaries. Network structure was found to be an important factor affecting the hematocrits. Mean discharge hematocrit remained steady against changes in vessel dimensions, capillary resistances, red cell concentration in plasma layer, and shape of the separation surface defining the streamlines entering the side branch. This high stable mean hematocrit is based on symmetry of the model network. Enhanced asymmetry tended to lower the hematocrit.

Theoretical model of phase separation of erythrocytes, platelets, and plasma at branches.

Analytical expressions for the changes of the erythrocyte and platelet concentration are calculated as blood flows through a single bifurcation. The effect of the separation surface, which divides the blood into the two daughter vessels, upon the concentration changes is studied. Numerical fitting to the experimental data shows that both the erythrocyte and platelet distributions across the vessel are nonuniform. The maximum of the erythrocyte concentration is in the core, and of the platelet concentration, in the vicinity of the wall. A separation surface that is convex towards the axis of the vessel yields better fit to the experimental data than a concave one. Together with other studies, this suggests that flow-divider geometry depends on flow conditions and the vessel diameters. The results can be used for estimation of the distribution of erythrocytes and platelets in the microvasculature.

The size of the largest land animal.

The upper mass limit to terrestrial animals is studied using physical arguments and allometric laws for bone and muscle strength and animal locomotion. The limit is suggested to lie between 10(5) and 10(6) kg. A possibility for a still higher mass, in case of new adaptations, is not excluded.