A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes

Toxoplasma gondii is unable to synthesize purines de novo, instead salvages them from its environment, inside the host cell, for which they need high affinity carriers. Here, we report the expression of a T. gondii Equilibrative Nucleoside Transporter, Tg244440, in a Trypanosoma brucei strain from which nucleobase transporters have been deleted. Tg244440 transported hypoxanthine and guanine with similar affinity (K_m ~1 µM), while inosine and guanosine displayed K_i values of 4.05 and 3.30 µM, respectively. Low affinity was observed for adenosine, adenine, and pyrimidines, classifying Tg244440 as a high affinity oxopurine transporter. Purine analogues were used to probe the substrate-transporter binding interactions, culminating in quantitative models showing different binding modes for oxopurine bases, oxopurine nucleosides, and adenosine. Hypoxanthine and guanine interacted through protonated N1 and N9, and through unprotonated N3 and N7 of the purine ring, whereas inosine and guanosine mostly employed the ribose hydroxy groups for binding, in addition to N1H of the nucleobase. Conversely, the ribose moiety of adenosine barely made any contribution to binding. Tg244440 is the first gene identified to encode a high affinity oxopurine transporter in T. gondii and, to the best of our knowledge, the first purine transporter to employ different binding modes for nucleosides and nucleobases.     

Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation

PURPOSE: To review the treatment of cirrhotic patients with hepatocellular carcinoma in the era of liver transplantation and to determine the most appropriate approach to the treatment of patients at different stages of disease. DATA SOURCES: A MEDLINE search of English-language articles published between 1981 and 1997 and the clinical experience of the Mount Sinai Liver Transplant Program. STUDY SELECTION: Selected studies were 1) original articles reporting results of resection and transplantation in the treatment of hepatocellular carcinoma in cirrhotic patients and 2) initial reports from major transplantation centers of multimethod therapies combining chemotherapy with transplantation. DATA EXTRACTION: Study designs were assessed with careful attention to methods and aims. Relevant data on patient population, tumor stage distribution, treatment, survival, and rate of recurrent disease were extracted and analyzed. DATA SYNTHESIS: Options for the treatment of hepatocellular carcinoma in cirrhotic patients vary according to tumor stage and severity of underlying liver disease. Resection remains an important method primarily in eastern countries, where the screening of high-risk populations has been associated with early detection of small asymptomatic lesions. Long-term survival after resection, however, is low. In western countries, liver transplantation is becoming the treatment of choice in patients with advanced cirrhosis and small, unresectable lesions; resection is reserved for cirrhotic patients with small, peripheral lesions and preserved hepatic function. Minimally invasive procedures (such as percutaneous ethanol injection and transarterial chemoembolization) have been developed to treat unresectable tumors. Transarterial chemoembolization may also be effective in patients with advanced cirrhosis and unresectable lesions who are awaiting transplantation. CONCLUSIONS: The efficacy of liver transplantation for hepatocellular carcinoma has been proven mainly in patients with advanced cirrhosis and small lesions. Future studies may clarify the role of approaches combining neoadjuvant chemotherapy with transplantation for large (stage III) tumors.     

Switching tasks and attention policies.

The determinants and costs of control were studied in 6 experiments examining the performance costs of changing stimulus dimension (digit value/number of elements) or attention strategies (speed/accuracy) on the first trial after task transition. Costs were compared for task shift and reconsideration only. Preparation ability was studied by presenting all transition information at the beginning of a 2-part block or only prior to each part. Results showed pronounced first-trial transition costs. Different factors were associated with stop-start and task-switching requirements. Transition costs were separate from those of basic task performance. Costs were sensitive to global control considerations and were larger for task dimension changes than for attention strategy shifts. Costs involving task dimension change, but not strategy shifts, were reduced with advanced preparation. These results are discussed in relation to contemporary models of control. A new distinction is proposed between activation and execution of control strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterizing patterns of drug-taking behavior with a multiple drug regimen in an AIDS clinical trial

OBJECTIVE: To characterize drug-taking behavior using continuous electronic monitoring in an AIDS clinical trial. SETTING: This was a substudy of AIDS Clinical Trials Group (ACTG) protocol 175, a phase II/III study of dideoxynucleoside monotherapy versus combination therapy in asymptomatic HIV-positive subjects. Participants were required to comply with regimens containing zidovudine, zalcitabine and didanosine, or matching placebos; the total daily pill count was 16. DESIGN: For participants at two ACTG 175 sites, electronic devices were used to monitor drug-taking behavior of all study medications over a period of approximately 90 days. MEASUREMENTS: Four indices of drug-taking behavior were calculated and their distributions and relationship to the prescribed regimen were examined. RESULTS: Data from 41 subjects were analyzed. Of the prescribed doses of zidovudine, zalcitabine and didanosine, 88, 84 and 82%, respectively, were taken. Of these, 55, 66 and 79%, respectively, were taken at the prescribed dosing frequency. The median percentage of days on which participants failed to take any of the doses was 2-5%. There was a trend towards lower adherence in the combination therapy arms compared with those assigned to receive monotherapy. In this analysis, older patients demonstrated better adherence, although patient characteristics, in general, were poorly predictive of adherence. CONCLUSION: Drug-taking behavior for all three active study medications differed from that prescribed. One result of this erratic adherence was that study participants sustained little antiretroviral effect during more than 25% of the monitoring period.     

Measurements of pollen grain dispersal in still air and stationary, near homogeneous, isotropic turbulence

The dispersal of ragweed, pine and corn pollen as well as polystyrene spheres in still air and stationary, near homogeneous, isotropic turbulence (HIT) was investigated using high-speed, digital inline holographic cinematography enabling Lagrangian tracking of the particles. Mean still air settling velocities were similar as reported literature values. Small discrepancies were most likely related to species/size differences and water content of the grains. Near-HIT was generated by loudspeakers mounted on the corners of a 40 cm³ chamber and the turbulent flow field at the center of the chamber was validated using stereoscopic Particle Image Velocimetry (PIV). Results showed near homogeneity and near isotropy with mean velocities 5–10 times smaller than the corresponding rms values of velocity fluctuations. The turbulent kinetic energy dissipation rate was determined from the PIV data sets and used to calculate the Kolmogorov scales and Taylor microscales. Experiments were carried out for two different loudspeaker amplifications corresponding to Taylor microscale Reynolds numbers, R_λ=144 and 162, respectively. The mean settling velocity in turbulent conditions was in all cases higher than the corresponding still air value, the difference becoming smaller as particle Stokes numbers increased. For the present conditions, the still air particle settling velocity was lower than the rms values of air fluctuating velocities. As a result, dispersion was dominated by inertia and for a given R_λ, particle fluctuating velocity autocorrelations fell more rapidly as the particle Stokes number decreased; corresponding particle diffusion coefficients also decreased. Transverse particle diffusion coefficients were lower than those in the direction of gravity in agreement with the continuity effect. Under the present range of experimental parameters, results showed that inertial particles (0.6<St<11) in highly turbulent conditions disperse more effectively than the air.     

Advanced computer programs for drug dosing that combine pharmacokinetic and symbolic modeling of patients.

In this paper, we describe our design for advanced drug dosing programs that "reason" using a combination of Bayesian pharmacokinetic modeling and symbolic modeling of patient status and drug response. Our design is similar to the design of the Digitalis Therapy Advisor program, but extends this previous work by incorporating a Bayesian pharmacokinetic model, performing a "meta-level" analysis of drug concentrations to identify sampling errors and changes in pharmacokinetics, and including the results of this analysis in reasoning for dosing and therapeutic monitoring recommendations. The design has been implemented in a program for aminoglycoside antibiotics called Aminoglycoside Therapy Manager. The program is user-friendly and runs on low-cost general-purpose hardware. The initial validation study showed that the program was as accurate in predicting future drug concentrations as an expert using commercial Bayesian forecasting software and that its dosing recommendations were similar to those of an expert.     

Photochemistry of molecules at confined environment: CD3Br/O/Ru(001) and CO2@Ice

The photochemistry of molecules constrained within a confining environment on surfaces has been studied. Orientation of methyl bromide could be controlled methyl down or up by varying the pre-adsorbed oxygen coverage due to electrostatic interactions on Ru(001) under UHV conditions. Irradiation of the coadsorption system at 193 nm has shown that the resulting photochemical activity is sensitive to the molecular orientation. Photodesorption and dissociation cross sections were 1.0·10⁻¹⁹ cm⁻² for methyl-down and 3.0·10⁻¹⁹ cm⁻² for the methyl-up configurations. This observation represents the first report of the steric effect in electron-molecule interaction due to the dissociative electron attachment mechanism of photochemical processes on surfaces. A second system of CO₂ molecules caged within ice has also been studied. Here the trapped carbon dioxide molecules cannot leave the surface at their normal desorption temperature near 100 K, but are explosively desorbing at the onset of ice evaporation near 165 K. Upon UV irradiation, enhanced dissociation to adsorbed CO and oxygen is recorded. In addition, a new reactivity channel is observed to form H₂CO, tentatively identified as formaldehyde. The relevance of photochemistry of caged molecules within ice to interstellar hydrocarbon formation as a possible route for the origin of life is discussed.     

Population modelling in drug development

In this paper we discuss the vital role that population (hierarchical) modelling can play within the drug development process. Specifically, population pharmacokinetic/pharmacodynamic models can provide reliable predictions of an individualized dose-exposure-response relationship. A predictive model of this kind can be used to simulate and hence design clinical trials, find initial dosage regimens satisfying an optimality criterion on the population distribution of responses, and individualized regimens satisfying such a criterion conditional on individual features, such as sex, age, etc. Throughout we emphasize prediction and advocate mechanistic as opposed to empirical modelling, and argue that the Bayesian approach is particularly natural in this setting.     

A new compact microwave spectroradiometer-ozonometer

A new-generation mobile microwave spectroradiometer intended for studying the Earth’s ozone layer is described. The device receives thermal radio-frequency emission of the stratospheric ozone at the frequency of its rotational transition (110 836 MHz) in a 240-MHz frequency band. The spectral resolution at the O3 line center is 1 MHz. The effective noise temperature of the uncooled receiver in the single-sideband mode is ∼2000 K. The ozonometer is equipped with a computer-aided data measurement, calibration, and preprocessing control system. The device is intended to obtain an ozone profile in a 20- to 60-km altitude interval within 15–20 min.     

Improving drug dosing in hospitalized patients: automated modeling of pharmacokinetics for individualization of drug dosage regimens

Many clinical useful drugs have a narrow range of blood concentrations which are both safe and efficacious. Inter-individual and intra-individual variations in drug disposition are important factors causing blood concentrations of drug to fall outside of the therapeutic range. Modeling of the pharmacokinetics of the individual offers an effective approach to the problem of variation in drug disposition. Previous approaches for the modeling of individual pharmacokinetics have required either extensive computations or access to computer software and hardware in the clinical environment, and special expertise to interpret the results. This paper describes a prototype computer program, PK Monitor, which can, when connected with an appropriate interface, automatically monitor drug dosing and recommend changes that may be required to obtain blood concentrations in the therapeutic range. The software can also detect the occurrence of change in drug disposition which will lead to concentrations outside of the therapeutic range, identify potentially erroneous blood concentration measurements, and assess the need for further blood concentration measurements. This program will be an integral part of the MENTOR therapeutic monitoring system of programs. PK Monitor awaits a complete evaluation with the rest of the MENTOR system, but preliminary simulations suggest reasonable sensitivity and specificity in monitoring for unexpected data and change.