Physiological models of body composition and human obesity

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Detection of Massive Forming Galaxies at Redshifts Greater than One

The complex problem of when and how galaxies formed has not until recently been susceptible of direct attack. It has been known for some time that the excessive number of blue galaxies counted at faint magnitudes implies that a considerable fraction of the massive star formation in the universe occurred at z < 3, but, surprisingly, spectroscopic studies of galaxies down to a B magnitude of 24 found little sign of the expected high-z progenitors of current massive galaxies, but rather, in large part, small blue galaxies at modest redshifts z \sim 0.3. This unexpected population has diverted attention from the possibility that early massive star-forming galaxies might also be found in the faint blue excess. From KECK spectroscopic observations deep enough to encompass a large population of z > 1 field galaxies, we can now show directly that in fact these forming galaxies are present in substantial numbers at B \sim 24, and that the era from redshifts 1 to 2 was clearly a major period of galaxy formation. These z > 1 galaxies have very unusual morphologies as seen in deep HST WFPC2 images.Comment: 10 pages LaTeX + 5 PostScript figures in uuencoded gzipped tar file; aasms4.sty, flushrt.sty, overcite.sty (the two aastex4.0 and overcite.sty macros are available from xxx.lanl.gov) Also available (along with style files) via anonymous ftp to ftp://hubble.ifa.hawaii.edu/pub/preprints . E-print version of paper adds citation cross-references to other archived e-prints, where available. To appear in Nature October 19, 199

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

External sources of clean technology: evidence from the clean development mechanism

New technology is fundamental to sustainable development. However, inventors from industrialized countries often refuse technology transfer because they worry about reverse-engineering. When can clean technology transfer succeed? We develop a formal model of the political economy of North–South technology transfer. According to the model, technology transfer is possible if (1) the technology in focus has limited global commercial potential or (2) the host developing country does not have the capacity to absorb new technologies for commercial use. If both conditions fail, inventors from industrialized countries worry about the adverse competitiveness effects of reverse-engineering, so technology transfer fails. Data analysis of technology transfer in 4,894 projects implemented under the Kyoto Protocol’s Clean Development Mechanism during the 2004–2010 period provides evidence in support of the model

Heterogeneity of human adipose blood flow

BACKGROUND: The long time pharmacokinetics of highly lipid soluble compounds is dominated by blood-adipose tissue exchange and depends on the magnitude and heterogeneity of adipose blood flow. Because the adipose tissue is an infinite sink at short times (hours), the kinetics must be followed for days in order to determine if the adipose perfusion is heterogeneous. The purpose of this paper is to quantitate human adipose blood flow heterogeneity and determine its importance for human pharmacokinetics. METHODS: The heterogeneity was determined using a physiologically based pharmacokinetic model (PBPK) to describe the 6 day volatile anesthetic data previously published by Yasuda et. al. The analysis uses the freely available software PKQuest and incorporates perfusion-ventilation mismatch and time dependent parameters that varied from the anesthetized to the ambulatory period. This heterogeneous adipose perfusion PBPK model was then tested by applying it to the previously published cannabidiol data of Ohlsson et. al. and the cannabinol data of Johansson et. al. RESULTS: The volatile anesthetic kinetics at early times have only a weak dependence on adipose blood flow while at long times the pharmacokinetics are dominated by the adipose flow and are independent of muscle blood flow. At least 2 adipose compartments with different perfusion rates (0.074 and 0.014 l/kg/min) were needed to describe the anesthetic data. This heterogeneous adipose PBPK model also provided a good fit to the cannabinol data. CONCLUSION: Human adipose blood flow is markedly heterogeneous, varying by at least 5 fold. This heterogeneity significantly influences the long time pharmacokinetics of the volatile anesthetics and tetrahydrocannabinol. In contrast, using this same PBPK model it can be shown that the long time pharmacokinetics of the persistent lipophilic compounds (dioxins, PCBs) do not depend on adipose blood flow. The ability of the same PBPK model to describe both the anesthetic and cannabinol kinetics provides direct qualitative evidence that their kinetics are flow limited and that there is no significant adipose tissue diffusion limitation

Game theory of mind

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution

Effectiveness of cidofovir intralesional treatment in recurrent respiratory papillomatosis

To present the results of recurrent respiratory papillomatosis (RRP) treatment with surgical excision and adjuvant anti-viral cidofovir intralesional use and to examine the correlation between the cidofovir effectiveness and the patient previous history of multiple larynx procedures, age, extension of lesion and dose. 32 patients with laryngeal papillomas were treated with cidofovir in our Department between I.2009 and I.2011. The number of previous RRP debulking procedures ranged from 1 to 100. The intensity of papillomatosis differed from one anatomic site and moderate growth to four or five localizations with heavy extension. The number of injections per patient varied from 1 to 7, and the total volume of 5 mg/ml solution varied from 2 to 33 ml. The injections were combined with laser debulking of the lesions. In disperse papillomata, the injections were administered in particular anatomical sites in 4–6 weeks intervals, in massive lesions injections were repeated in the same anatomical site in 2–4 weeks. Complete remission was observed in 18 out of 32 patients. 13 patients showed remission in a place of cidofovir injection. One patient did not react to the drug. In four patients, new changes in injection places appeared. In two patients, hepatic toxic side effects were observed. Intralesional cidofovir injection has been shown to be an effective and safe therapy for laryngeal papillomatosis and should be considered in those patients who experienced disease relapse