Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsP-glycoprotein in the membranes of endothelial cells actively transports some drugs out of the brain. The theoretical effect of P-glycoprotein mediated drug efflux on the cerebral distribution volumes of drugs was examined, with particular emphasis on anaesthetic-related drugs (often characterized by moderate to high permeability across the blood brain barrier due to their lipophilicity and intermediate molecular weight). An analytical equation for the cerebral distribution volume in the presence of the efflux was derived, and validated by modelling the same system using differential equations. The efflux was shown to lower both the membrane and intracellular drug concentrations in parallel, and to reduce the time required for brain:blood equilibration. The net effect of the efflux was governed by the ratio of the P-glycoprotein drug clearance from the membrane (Pcl) and the permeability of the membrane (PS). It was therefore a balance between the rate that a drug could be pumped out of the membrane by the efflux system, and the rate that the drug leaked back in due to the permeability of the membrane for the drug. The effect of the efflux was therefore more pronounced for drugs with membrane-limited cerebral kinetics (e.g. morphine), but was nevertheless significant for drugs with more flow-limited kinetics (e.g fentanyl). The cerebral distribution volume was also influenced by the free fraction in blood and the free fraction in the intracellular space in the conventional manner. There are no theoretical limitations to the P-glycoprotein system influencing the cerebral distribution volume of moderately lipophilic anaesthetic-related drugs.http://www.aaic.net.au/Article.asp?D=200114

Interactions between proteins bound to biomembranes

We study a physical model for the interaction between general inclusions bound to fluid membranes that possess finite tension, as well as the usual bending rigidity. We are motivated by an interest in proteins bound to cell membranes that apply forces to these membranes, due to either entropic or direct chemical interactions. We find an exact analytic solution for the repulsive interaction between two similar circularly symmetric inclusions. This repulsion extends over length scales of order tens of nanometers, and contrasts with the membrane-mediated contact attraction for similar inclusions on tensionless membranes. For non circularly symmetric inclusions we study the small, algebraically long-ranged, attractive contribution to the force that arises. We discuss the relevance of our results to biological phenomena, such as the budding of caveolae from cell membranes and the striations that are observed on their coats.Comment: 22 pages, 2 figure

Cohort-level brain mapping: learning cognitive atoms to single out specialized regions

International audienceFunctional Magnetic Resonance Imaging (fMRI) studies map the human brain by testing the response of groups of individuals to carefully-crafted and contrasted tasks in order to delineate specialized brain regions and networks. The number of functional networks extracted is limited by the number of subject-level contrasts and does not grow with the cohort. Here, we introduce a new group-level brain mapping strategy to differentiate many regions reflecting the variety of brain network configurations observed in the population. Based on the principle of functional segregation, our approach singles out functionally-specialized brain regions by learning group-level functional profiles on which the response of brain regions can be represented sparsely. We use a dictionary-learning formulation that can be solved efficiently with on-line algorithms, scaling to arbitrary large datasets. Importantly, we model inter-subject correspondence as structure imposed in the estimated functional profiles, integrating a structure-inducing regularization with no additional computational cost. On a large multi-subject study, our approach extracts a large number of brain networks with meaningful functional profiles

Determination of Inflationary Observables by Cosmic Microwave Background Anisotropy Experiments

Inflation produces nearly Harrison-Zel'dovich scalar and tensor perturbation spectra which lead to anisotropy in the cosmic microwave background (CMB). The amplitudes and shapes of these spectra can be parametrized by $Q_S^2$, $r\equiv Q_T^2/Q_S^2$, $n_S$ and $n_T$ where $Q_S^2$ and $Q_T^2$ are the scalar and tensor contributions to the square of the CMB quadrupole and $n_S$ and $n_T$ are the power-lawspectral indices. Even if we restrict ourselves to information from angles greater than one third of a degree, three of these observables can be measured with some precision. The combination $130^{1-n_S}Q_S^2$ can be known to better than $\pm 0.3\%$. The scalar index $n_S$ can be determined to better than $\pm 0.02$. The ratio $r$ can be known to about $\pm 0.1$ for $n_S \simeq 1$ and slightly better for smaller $n_S$. The precision with which $n_T$ can be measured depends weakly on $n_S$ and strongly on $r$. For $n_S \simeq 1$ $n_T$ can be determined with a precision of about $\pm 0.056(1.5+r)/r$. A full-sky experiment with a $20'$beam using technology available today, similar to those being planned by several groups, can achieve the above precision. Good angular resolution is more important than high signal-to-noise ratio; for a given detector sensitivity and observing time a smaller beam provides significantly more information than a larger beam. The uncertainties in $n_S$ and $r$ are roughly proportional to the beam size. We briefly discuss the effects of uncertainty in the Hubble constant, baryon density, cosmological constant and ionization history.Comment: 28 pages of uuencoded postscript with 8 included figures. A postscript version is also available by anonymous ftp at ftp://astro.uchicago.edu/pub/astro/knox/fullsim.p

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Doppelheterodyn-Interferometrie für hochgenaue Vermessung im Nahbereich

In diesem Aufsatz wurde ein Meßsystem vorgestellt, welches sich aus der Kombination der Zweiwellenlängen-Interferometrie mit dem intensitätsunabhängigen Heterodyn-Verfahren zusammensetzt. Die resultierende Doppelheterodyn-Interferometrie vereinigt die Vorteile der beiden Verfahren. Ein großer Eindeutigkeitsbereich entsprechend der effektiven Wellenlänge A entsteht, darüberhinaus sind optisch rauhe Oberflächen als Meßobjekte zulässig; reduzierte Empfindlichkeit gegenüber Vibrationen und Umwelteinflüssen, hohe Auflösung infolge elektronischer Phasenbestimmung sowie hochgenaue Abstandsmessung in Echtzeit sind weitere Vorteile. Das Doppelheterodyn-Interferometer wird in Zukunft zu einem effektiven und dynamischen Meßinstrument zur hochgenauen Entfernungsmessung im Mikrometerbereich bis hin zu Meßdistanzen von 100 m entwickelt werden, für das sich schon jetzt zahlreiche Einsatzmöglichkeiten abzeichnen

Palliative care for the elderly - developing a curriculum for nursing and medical students

<p>Abstract</p> <p>Background</p> <p>Delivering palliative care to elderly, dying patients is a present and future challenge. In Germany, this has been underlined by a 2009 legislation implementing palliative care as compulsory in the medical curriculum. While the number of elderly patients is increasing in many western countries multimorbidity, dementia and frailty complicate care. Teaching palliative care of the elderly to an interprofessional group of medical and nursing students can help to provide better care as acknowledged by the ministry of health and its expert panels.</p> <p>In this study we researched and created an interdisciplinary curriculum focussing on the palliative care needs of the elderly which will be presented in this paper.</p> <p>Methods</p> <p>In order to identify relevant learning goals and objectives for the curriculum, we proceeded in four subsequent stages.</p> <p>We searched international literature for existing undergraduate palliative care curricula focussing on the palliative care situation of elderly patients; we searched international literature for palliative care needs of the elderly. The searches were sensitive and limited in nature. Mesh terms were used where applicable. We then presented the results to a group of geriatrics and palliative care experts for critical appraisal. Finally, the findings were transformed into a curriculum, focussing on learning goals, using the literature found.</p> <p>Results</p> <p>The literature searches and expert feedback produced a primary body of results. The following deduction domains emerged: Geriatrics, Palliative Care, Communication & Patient Autonomy and Organisation & Social Networks. Based on these domains we developed our curriculum.</p> <p>Conclusions</p> <p>The curriculum was successfully implemented following the Kern approach for medical curricula. The process is documented in this paper. The information given may support curriculum developers in their search for learning goals and objectives.</p