Developmental parallelism in primates

The authors examined a large random sample of skulls from two species of macaques: rhesus monkeys and cynomolgus monkeys. The skulls were measured, divided into age and sex groups and thoroughly analysed using statistical methods. The analysis shows that skulls of young rhesuses are considerably more domed, i.e. have better-developed neurocrania, than their adult counterparts. Male and female skulls, on the other hand, were found to be very similar, which means that sexual dimorphism of the rhesus macaque was suppressed. Both of these patterns are known from the human evolutionary pattern. No such parallelism to the development of Homo sapiens was found in the cynomolgus monkeys. The authors conclude that mosaic hominisation trends may have featured in the evolution of all primates. This would mean that apes were not a necessary step on the evolutionary way leading to the development of Homo sapiens, who may have started to evolve at an earlier stage of monkeys

A simplified protocol for detecting two systemic bait markers (Rhodamine B and iophenoxic acid) in small mammals

We developed a method of quantifying levels of fluorescence in the whiskers of wild stoats (Mustela erminea) using fluorescence microscopy and Axiovision 3.0.6.1 software. The method allows for discrimination between natural fluorescence present in or on a whisker, and the fluorescence resulting from the ingestion of the systemic marker Rhodamine B (RB), although some visual judgement is still required. We also developed a new high performance liquid chromatography (HPLC) protocol for detecting the systemic marker iophenoxic acid (IPA) in the blood of laboratory rats (Rattus norvegicus) and wild stoats. With this method, the blood of an animal that has consumed IPA can be tested for the presence of the foreign IPA compound itself. This is a more reliable test than the previous method, which measured the raised level of natural blood protein-bound iodine correlated with IPA absorption. The quantity of blood required from animal subjects is very small (10 μl), so the testing is less intrusive and the method can be extended to smaller species. The extraction technique uses methanol, rather than acids and heavy metal salts, thereby simplifying the procedure. Recovery of IPA is quantitative, giving a highly reliable reading. In experiments on captive rats the IPA method proved successful. Of 12 positively marked carcasses, two that had not been frozen for the 24 h before blood samples were taken showed relatively lower IPA levels. The same IPA detection method, as well as the whisker analysis for RB, was applied successfully to a population of wild stoats to which both Rhodamine B and IPA were made available at bait stations. The presence of both bait markers was detectable in rats for at least 21 days and in stoats for at least 27 days

Human physiologically based pharmacokinetic model for propofol

BACKGROUND: Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol. METHODS: PKQuest, a freely distributed software routine , was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. RESULTS: The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. CONCLUSION: A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed

Anaesthetic Impairment of Immune Function Is Mediated via GABAA Receptors

GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients.We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin.Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem