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Biomedical subjects

A Gelman

Publications and source records attributed to A Gelman.

At least 19 recordsLinked to original sources
PubMed1996

Adenovirus-mediated gene transfer in the transplant setting: early events after orthotopic transplantation of liver allografts expressing TGF-beta1.

We hypothesized that adenovirus mediated gene transfer of TGF-beta1 into liver grafts would enhanced local expression of this recombinant protein and down-regulate inflammatory and alloreactive immune response. A full length DNA encoding the murine TGF-beta1 was used to replaced the E1 region of adenovirus type 5 (AdmTGF-beta1). Expression and protein production of biologically active murine TGF-beta1 was tested in AdmTGF-beta1-transduced Hep G2 cells and TGF-beta-sensitive MV1 cells. In the transplant setting, the replication-defective vector was used to perfused cold preserved ACI liver allograft prior to transplantation into Lewis recipients. Control livers were similarly perfused with cold lactated Ringer's solution and were followed without immunosuppression. Animals were sacrificed at 1, 3, and 5 days after transplantation. Intragraft cytokine levels of TNFalpha, and IFNgamma were determined using ELISA and quantitative PCR. TGF-beta1 ELISA of culture supernatants from AdmTGF-beta1 transduced hepatocyte cell line Hep G2 excreted TGF-beta1 in quantities directly correlated with multiplicity of infection (MOI, vector:hepatic cell ratio). The biological activity of the excreted recombinant protein was confirmed by growth inhibition of MV1 TGF-beta-sensitive cells. Enhanced production of TGF-beta1 in transduced allografts was associated with decreased levels of TNFalpha and IFNgamma when compared with nonimmunosuppressed controls. Adenovirus-mediated gene transfer of murine TGF-beta1 into hepatic cells results in the expression of biologically active protein. Transduction of allografts with TGF-beta1 down-regulates TNFalpha and IFNgamma production early after orthotopic transplantation. Graft transduction with TGF-beta1 offers a novel approach to study the effects of single immune modulator on alloreactive immune response, T cell function, and cytokine cascade.

Adenoviridae↗
PubMed1996

Population toxicokinetics of tetrachloroethylene.

In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments.

Administration, Inhalation↗
PubMed1996

Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity.

A variable region gene of the T-cell receptor, V beta 8.2, is rearranged, and its product is expressed on pathogenic T cells that induce experimental autoimmune encephalomyelitis (EAE) in H-2u mice after immunization with myelin basic protein (MBP). Vaccination of these mice with naked DNA encoding V beta 8.2 protected mice from EAE. Analysis of T cells reacting to the pathogenic portion of the MBP molecule indicated that in the vaccinated mice there was a reduction in the Th1 cytokines interleukin-2 (IL-2) and interferon-gama. In parallel, there was an elevation in the production of IL-4, a Th2 cytokine associated with suppression of disease. A novel feature of DNA immunization for autoimmune disease, reversal of the autoimmune response from Th1 to Th2, may make this approach attractive for treatment of Th1-mediated diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1996

Bayesian prediction of mean indoor radon concentrations for Minnesota counties.

Past efforts to identify areas with higher than average indoor radon concentrations by examining the statistical relationship between local mean concentrations and physical parameters such as the soil radium concentration have been hampered by the variation in local means caused by the small number of homes monitored in most areas. In this paper, indoor radon data from a survey in Minnesota are analyzed to minimize the effect of finite sample size within counties, to determine the true county-to-county variation of indoor radon concentrations in the state, and to find the extent to which this variation is explained by the variation in surficial radium concentration among counties. The analysis uses hierarchical modeling, in which some parameters of interest (such as county geometric mean radon concentrations) are assumed to be drawn from a single population, for which the distributional parameters are estimated from the data. Extensions of this technique, known as random effects regression and mixed effects regression, are used to determine the relationship between predictive variables and indoor radon concentrations; the results are used to refine the predictions of each county's radon levels, resulting in a great decrease in uncertainty. The true county-to-county variation of geometric mean radon levels is found to be substantially less than the county-to-county variation of the observed geometric means, much of which is due to the small sample size in each county. The variation in the logarithm of surficial radium content is shown to explain approximately 80% of the variation of the logarithm of geometric mean radon concentration among counties. The influences of housing and measurement factors, such as whether the monitored home has a basement and whether the measurement was made in a basement, are also discussed. The statistical method can be used to predict mean radon concentrations, or applied to other geographically distributed environmental parameters.

Air Pollution, Indoor↗
PubMed1996

Markov chain Monte Carlo methods in biostatistics.

Appropriate models in biostatistics are often quite complicated. Such models are typically most easily fit using Bayesian methods, which can often be implemented using simulation techniques. Markov chain Monte Carlo (MCMC) methods are an important set of tools for such simulations. We give an overview and references of this rapidly emerging technology along with a relatively simple example. MCMC techniques can be viewed as extensions of iterative maximization techniques, but with random jumps rather than maximizations at each step. Special care is needed when implementing iterative maximization procedures rather than closed-form methods, and even more care is needed with iterative simulation procedures: it is substantially more difficult to monitor convergence to a distribution than to a point. The most reliable implementations of MCMC build upon results from simpler models fit using combinations of maximization algorithms and noniterative simulations, so that the user has a rough idea of the location and scale of the posterior distribution of the quantities of interest under the more complicated model. These concerns with implementation, however, should not deter the biostatistician from using MCMC methods, but rather help to ensure wise use of these powerful techniques.

Algorithms↗
PubMed1995

Preservation of surface-dependent properties of viral antigens following immobilization on particulate ceramic delivery vehicles.

B-cell stimulation for the purpose of evoking an effective neutralizing humoral immune response is a surface phenomenon that is exquisitely specific to antigen conformation. Consequently, successful delivery of antigen, such as would be desired in a vaccine, entails preservation of an antigen's apparent native surface (conformational) properties. Prior to testing the actual vaccinating efficacy of delivered antigens, the surface properties could be assessed through a variety of in vitro and in vivo assays in which the measurement standard would be the properties of the antigens in their native state (whole virus). Using surface modified nanocrystalline carbon and calcium-phosphate ceramic particulates (carbon ceramics and brushite), we evaluated the surface activity of immobilized non-nuclear material extracted from HIV-1. Physical characterization showed that the particles with immobilized antigen ("HIV decoys") measured 50 nm in diameter (HIV = 50-100 nm) and exhibited the same zeta potentials as whole (live) HIV. In vitro testing showed that the HIV decoys were recognized by both conformationally nonspecific and specific monoclonal antibodies, were recognized by human IgG from HIV antibody-positive patients, and could promote surface agglomeration among malignant T-cells similar to live HIV. Last, in vivo testing in three vaccinated animal species showed that the HIV decoys elicited humoral and cellular immune responses similar to that evoked by whole (live) HIV.

Animals↗
PubMed1994

Surface-modified nanocrystalline ceramics for drug delivery applications.

Drug delivery systems comprised of various types of carriers have long been the object of pharmacological investigation. The search has been stimulated by the belief that carriers will lead to reduced drug toxicity, dosage requirements, enhanced cellular targeting and improved shelf-life. Among the carriers investigated are complex polymeric carbohydrates, synthetic proteins and liposomal structures. For the past four years, we have been experimenting with a radically new class of carriers comprised of surface-modified nanocrystalline ceramics. While the ceramics provide the structural stability of a largely immutable solid, the surface modification creates a glassy molecular stabilization film to which pharmacological agents may be bound non-covalently from an aqueous phase with minimal structural denaturation. As a consequence of maintained structural integrity and owing to concentration effects afforded by the surfaces of the nanocrystalline materials, drug activity following surface immobilization is preserved. We have used successfully surface-modified nanocrystalline ceramics to deliver viral antigens for the purpose of evoking an immune response, oxygenated haemoglobin for cell respiration and insulin for carbohydrate metabolism. The theoretical principles, technical details and experimental results are reviewed. Surface-modified nanocrystalline materials offer an exciting new approach to the well-recognized challenges of drug delivery.

Animals↗
PubMed1994

Cross linking encapsulated hemoglobin with solid phase supports: lipid enveloped hemoglobin adsorbed to surface modified ceramic particles exhibit physiological oxygen lability.

To reduce hemoglobin toxicity, a cross linking agent is generally used. To preserve hemoglobin function, an allosteric modifier is generally used. Historically, the use of one has precluded the use of the other. A potential solution to this problem was investigated. Hemoglobin AO was adsorbed irreversibly to carbohydrate coated nanosized diamond particles and then encapsulated in a standard mixture of phospholipids. Endotoxin free preparations with concentrations of bound hemoglobin near 10 g/dl were achieved with as little as 0.1 g/dl of free hemoglobin and remained stable over a 48 hour period. By transmission electron microscopy these particles appeared roughly spherical and measured approximately 75 nanometers well below that of alveolar capillary vessels. In shallow pH gradients, liquid electrophoresis demonstrated that such constructs exhibit Bohr effect behavior by the induction of a dramatic surface charge inversion at around pH 6.8. To evaluate oxygen lability, oxygen saturation trials were conducted in isosmolar physiological salts. Normal sigmoidal binding behavior of O2 over a typical pO2 gradient could be modulated by systemic levels of pyridoxyl-5-phosphate. Constructs with a P50 as low as 12 mm Hg could be increased to 37 mm Hg with the allosteric effector. Viscosity and bio distribution studies are to follow. The use of solid phase nanocrystalline supports to cross link hemoglobin may reduce the toxicity of free hemoglobin while still enabling the use of allosteric modifiers.

Adsorption↗
PubMed1991

The precision of positron emission tomography: theory and measurement.

The limits of quantitation with positron emission tomography (PET) are examined with respect to the noise propagation resulting from radioactive decay and other sources of random error. Theoretical methods for evaluating the statistical error have been devised but seldom applied to experimental data obtained on human subjects. This paper extends the analysis in several ways: (1) A Monte Carlo method is described for tracking the propagation of statistical error through the analysis of in vivo measurements; (2) Experimental data, obtained in phantoms, validating the Monte Carlo method and other methods are presented; (3) A difference in activation paradigm, performed on regional CBF (rCBF) data from five human subjects, was analyzed on 1.6-cm diameter regions of interest to determine the mean fractional statistical error in PET tissue concentration and in rCBF before and after stereotactic transformation; and (4) A linear statistical model and calculations of the various statistical errors were used to estimate the magnitude of the subject-specific fluctuations under various conditions. In this specific example, the root mean squared (RMS) noise in flow measurements was about three times higher than the RMS noise in the concentration measurements. In addition, the total random error was almost equally partitioned between statistical error and random fluctuations due to all other sources.

Brain↗
PubMed1989

The thermal properties of intestinal alkaline phosphatase of three kinds of deep-water fish.

1. The thermal properties of intestinal alkaline phosphatase were investigated with three species of deep-water fish in the temperature range of 0-70 C. 2. A relationship was found between the thermal stability of the enzyme and the fish origin. 3. Maximum activity of alkaline phosphatase of the fish that originated in tropical water, namely, Aphanopus carbo and Epigonus telescopus was 60 C, whereas the respective maximum enzyme activity of Etmopterus princeps that originated in the burial zone was 30 C. 4. A breakpoint at 10 degrees C in the Arrhenius plot of emzyme activity in the case of A. carbo and a lack of a break point in the case of E. telescopus and E. princeps, are in accordance with the stenothermic nature of the former and the everythermic nature of the two latter fish species.

Alkaline Phosphatase↗
PubMed1978

Starvation---an interesting model for the study of the renin-angiotensin-aldosterone system.

Five obese subjects were studied during prolonged starvation. Then renin aldosterone system and urinary aldosterone excretion were studied during prolonged starvation and refeeding in five obese subjects. An uniform increase in aldosterone urinary excretion was observed in all subjects studied. A progressive increase in renin plasma activity was found in all patients along the starvation period with a striking additional increase after refeeding. The possible factors involved are discussed.

Adolescent↗
PubMed1978

[Effect of hematocrit variation on the urinary sodium excretion in normal and uremic dogs (author's transl)].

The effect of progressive increase in hematocrit on urinary sodium excretion was studied in normal and uremic dogs submitted to expansion of the extracellular fluid volume. In normal dogs concomitant with hematocrit increases it was observed a decrease in urinary sodium excretion. On the other hand in uremic dogs submitted to the same experimental conditions it was verified an increase in urinary sodium excretion.

Animals↗