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Biomedical subjects

D Shepard

Publications and source records attributed to D Shepard.

At least 19 recordsLinked to original sources
PubMed2001

Improving alcoholism treatment across the spectrum of services.

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The chair was Michael E. Hilton. The presentations were (1) The effects of brief advice and motivational enhancement on alcohol use and related variables in primary care, by Stephen A. Maisto, Joseph Conigliaro, Melissa McNiel, Kevin Kraemer, Mary E. Kelley, and Rosemarie Conigliaro; (2) Enhanced linkage of alcohol dependent persons to primary medical care: A randomized controlled trial of a multidisciplinary health evaluation in a detoxification unit, by Jeffrey H. Samet, Mary Jo Larson, Jacqueline Savetsky, Michael Winter, Lisa M. Sullivan, and Richard Saitz; (3) Cost-effectiveness of day hospital versus traditional alcohol and drug outpatient treatment in a health maintenance organization: Randomized and self-selected samples, by Constance Weisner, Jennifer Mertens, Sujaya Parthasarathy, Charles Moore, Enid Hunkeler, Teh-Wei Hu, and Joe Selby; and (4) Case monitoring for alcoholics: One year clinical and health cost effects, by Robert L. Stout, William Zywiak, Amy Rubin, William Zwick, Mary Jo Larson, and Don Shepard.

Alcoholism↗
PubMed2000

The effect of user-defined variables on dosimetry consistency in Gamma Knife planning.

We report a dosimetric variation caused by a user-defined variable for the Leksell Gamma Knife planning system. Treatment plans of 31 randomly selected patients were studied retrospectively to determine the dosimetric effects in the dose prescription and computation as a result of dose matrix positioning in the Leksell Gamma Plan (LGP, Version 4.12). Phantom studies with ion chamber measurements were carried out to validate the accuracy of the computation results. An average overdose of 2% was found due to the variations in the user-defined dose matrix position for the studied cases. In the extreme, the overdose value was as high as 5% with an over-treatment time exceeding 2 min. The phantom measurements were found to agree with the LGP calculation within 0.5%. An adaptive method was developed and demonstrated in this study to eliminate such dosimetry variations.

Biophysical Phenomena↗
PubMed1999

Tomotherapy.

Tomotherapy is delivery of intensity-modulated, rotational radiation therapy using a fan-beam delivery. The NOMOS (Sewickley, PA) Peacock system is an example of sequential (or serial) tomotherapy that uses a fast-moving, actuator-driven multileaf collimator attached to a conventional C-arm gantry to modulate the beam intensity. In helical tomotherapy, the patient is continuously translated through a ring gantry as the fan beam rotates. The beam delivery geometry is similar to that of helical computed tomography (CT) and requires the use of slip rings to transmit power and data. A ring gantry provides a stable and accurate platform to perform tomographic verification using an unmodulated megavoltage beam. Moreover, megavoltage tomograms have adequate tissue contrast and resolution to provide setup verification. Assuming only translational and rotational offset errors, it is also possible to determine the offsets directly from tomographic projections, avoiding the time-consuming image reconstruction operation. The offsets can be used to modify the leaf delivery pattern to match the beam to the patient's anatomy on each day of a course of treatment. If tomographic representations of the patient are generated, this information can also be used to perform dose reconstruction. In this way, the actual dose distribution delivered can be superimposed onto the tomographic representation of the patient obtained at the time of treatment. The results can be compared with the planned isodose on the planning CT. This comparison may be used as an accurate basis for adaptive radiotherapy whereby the optimized delivery is modified before subsequent fractions. The verification afforded tomotherapy allows more precise conformal therapy. It also enables conformal avoidance radiotherapy, the complement to conformal therapy, for cases in which the tumor volume is ill-defined, but the locations of sensitive structures are adequately determined. A clinical tomotherapy unit is under construction at the University of Wisconsin.

Dose Fractionation, Radiation↗
PubMed1997

The stabilization and encapsulation of human growth hormone into biodegradable microspheres.

PURPOSE: To produce and evaluate sustained-acting formulations of recombinant human growth hormone (rhGH) made by a novel microencapsulation process. METHODS: The protein was stabilized by forming an insoluble complex with zinc and encapsulated into microspheres of poly (D,L-lactide co-glycolide) (PLGA) which differed in polymer molecular weight (8-31 kD), polymer end group, and zinc content. The encapsulation procedure was cryogenic, non-aqueous, and did not utilize surfactants or emulsification. The rhGH extracted from each of these microsphere formulations was analyzed by size-exclusion, ion-exchange and reversed-phase chromatography, SDS-polyacrylamide gel electrophoresis, peptide mapping, and cell proliferation of a cell line expressing the hGH receptor. In addition, the in vivo release profile was determined after subcutaneous administration of the microspheres to rats and juvenile rhesus monkeys. RESULTS: Protein and bioactivity analyses of the rhGH extracted from three different microsphere formulations showed that the encapsulated protein was unaltered relative to the protein before encapsulation. In vivo, microsphere administration to rats or monkeys induced elevated levels of serum rhGH for up to one month, more than 20-fold longer than was induced by the same amount of protein injected subcutaneously as a solution. The rate of protein release differed between the three microsphere formulations and was determined by the molecular weight and hydrophobicity of the PLGA. The serum rhGH profile, after three sequential monthly doses of the one formulation examined, was reproducible and showed no dose accumulation. CONCLUSIONS: Using a novel process, rhGH can be stabilized and encapsulated in a solid state into PLGA microspheres and released with unaltered properties at different rates.

Administration, Cutaneous↗
PubMed1996

A month-long effect from a single injection of microencapsulated human growth hormone.

An injectable sustained-release form of human growth hormone (hGH) was developed by stabilizing and encapsulating the protein, without altering its integrity, into biodegradable microspheres using a novel cryogenic process. A single injection of microspheres in monkeys resulted in elevated serum levels of recombinant hGH (rhGH) for more than one month. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP-3, both of which are induced by hGH, were also elevated for four weeks by the rhGH containing microspheres to a level greater than that induced by the same amount of rhGH administered by daily injections. These results show that, by using appropriate methods of stabilization and encapsulation, the advantages of sustained-release formulations previously demonstrated for low-molecular-weight drugs can now be extended to protein therapeutics.

Animals↗
PubMed1995

Structural studies on human rhinovirus 14 drug-resistant compensation mutants.

Structures have been determined of three human rhinovirus 14 (HRV14) compensation mutants that have resistance to the antiviral capsid binding compounds WIN 52035 and WIN 52084. In addition, the structure of HRV14 is reported, with a site-directed mutation at residue 1219 in VP1. A spontaneous mutation occurs at the same site in one of the compensation mutants. Some of the mutations are on the viral surface in the canyon and some lie within the hydrophobic binding pocket in VP1 below the ICAM footprint. Those mutant virus strains with mutations on the surface bind better to cells than does wild-type virus. The antiviral compounds bind to the mutant viruses in a manner similar to their binding to wild-type virus. The receptor and WIN compound binding sites overlap, causing competition between receptor attachment and antiviral compound binding. The compensation mutants probably function by shifting the equilibrium in favor of receptor binding. The mutations in the canyon increase the affinity of the virus for the receptor, while the mutations in the pocket probably decrease the affinity of the WIN compounds for the virus by reducing favorable hydrophobic contacts and constricting the pore through which the antiviral compounds are thought to enter the pocket. This is in contrast to the resistant exclusion mutants that block compounds from binding by increasing the bulk of residues within the hydrophobic pocket in VP1.

Antiviral Agents↗
PubMed1995

Dietary calorie restriction in the Emory mouse: effects on lifespan, eye lens cataract prevalence and progression, levels of ascorbate, glutathione, glucose, and glycohemoglobin, tail collagen breaktime, DNA and RNA oxidation, skin integrity, fecundity, and cancer.

The Emory mouse is the best model for age-related cataract. In this work we compare the effects of feeding a control diet (C) with a diet restricted (R) by 40% relative to C animals. In the R animals, median lifespan was extended by 40%. The proportion of R mice with advanced cataract was lower than C mice as early as 5 months of age. The mean grade of cataract was lower in R animals, beginning at 11 months and continuing until the end of the study. Ascorbate levels in R plasma and liver were 41-56% of C animals. There was no difference between diet groups with respect to lens ascorbate. Aging was associated with a decrease in ascorbate in lenses and kidneys in C and R mice. By 22 months, R animals had 48% higher liver glutathione levels than C mice. Liver glutathione levels were maximal at 12 months. Plasma glucose levels were > 27% lower in R animals at 6.5 and 22 months, and there was a 14% increase in glucose levels upon aging for both diet groups. In R mice, glycohemoglobin levels were 51% lower and tail collagen breaktime was decreased by 40%, even in younger animals. Collagen breaktime increased > 360% upon aging for both diet groups. Rates of production of urinary oxo8dG and oxo8G were higher in R animals compared with C animals, and increased upon aging. C animals exhibited more cancer and dermatological lesions, but less tail tip necrosis and inflamed genitals than R mice. These data allow evaluation of several theories of aging.

Animals↗
PubMed1993

Relationships between acetone, cataracts, and ascorbate in hairless guinea pigs.

Acetone is one of the most commonly used industrial solvents. Recent literature indicated that in guinea pigs, but not rabbits, acetone is cataractogenic and that elevated acetone exposure is also associated with depressed aqueous ascorbate levels. Other work indicated that aqueous and lens levels of ascorbate are closely linked and that depressed ascorbate status is related to cataract. Taken together, these papers suggested that acetone exposure, depressed ascorbate levels, and cataract are related, possibly causally. While the possibility that acetone is cataractogenic presented a major health concern, it also presented an opportunity to develop a new model of cataract in which hypotheses regarding anticataractogenic effects of ascorbate could be tested. Albino hairless guinea pigs are immunocompetent animals derived from albino Hartley guinea pigs. Animals were fed diets containing low (4.9 mg/day) and high (55 mg/day) levels of ascorbate. This resulted in distinct groups of animals, one with high tissue ascorbate levels and the other with low, but nonscorbutic ascorbate levels. The tissue levels of ascorbate and the relationship between tissue ascorbate levels and dietary intake indicate that with respect to ascorbate uptake, transport, and concentration, these animals are identical to the standard albino Hartley animals. Daily exposure to acetone was extended for 6 months, with a total applied dose of 65 ml. Absorption of the solvent was maximized by the use of hairless animals. Despite exposure of the animals to higher levels of acetone, in no case (n = 20) were cataracts observed over a 2-year period. This is consistent with results using rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗
PubMed1993

An animal model for pharyngocutaneous fistulas.

Postoperative pharyngocutaneous fistula is not an uncommon complication. Although the frequency of postoperative fistulae has decreased with the use of perioperative broad-spectrum antibiotics, it remains a complication with significant morbidity and expense. We present an animal model for postoperative pharyngocutaneous fistulae based on increasing wound tension. The New Zealand white rabbit was used to assess the rate of wound breakdown in the thyrohyoid membrane. The animals were assigned to one of seven groups according to the width of tissue resected. After tissue resection, the pharyngeal wounds were repaired, as were the overlying skin wounds. Animals were monitored postoperatively up to 14 days, at which time they were killed and underwent autopsy. Statistically significant results were achieved that demonstrate an increasing incidence of pharyngeal wound breakdown associated with increasing width of tissue resected and, therefore, closure tension. The procedure and results will be presented in detail. We propose that this model may be used to assess postoperative wounds as well as substances or methods touted as promoters of wound healing.

Animals↗
PubMed1991

Relationship in humans between ascorbic acid consumption and levels of total and reduced ascorbic acid in lens, aqueous humor, and plasma.

The relationships between plasma, aqueous humor and lens ascorbic acid levels are examined in 131 samples from 127 patients. Mean ascorbate intake for nonsupplemented individuals was 148 mg/day or over two times the recommended daily allowance. A subset of 44 patients participated in a trial to assess the impact of vitamin C supplementation of 2 grams per day on aqueous and lens ascorbic acid levels. Such supplementation significantly increased both total and reduced ascorbic acid levels in plasma and aqueous and total ascorbic acid in the lens. Correlation coefficients relating total and reduced ascorbic acid levels in the three tissues ranged from 0.42 to 0.19 (p less than 0.05 for all correlation coefficients). Over 60% of the ascorbate was present in the reduced form in plasma and aqueous, and about 50% of the lens ascorbate was in the reduced form.

Adult↗
PubMed1990

Effects of systemic atropine sulfate administration on the frequency content of the cat sensorimotor EEG during sleep and waking.

Sensorimotor electroencephalogram (EEG) frequencies in cats were evaluated with power spectral analysis before and after 3 doses of atropine sulfate. All doses of atropine tested caused enhanced EEG slow waves (0-7 Hz) and spindles (8-15 Hz) during waking immobility, and postdrug frequency profiles during slow-wave sleep and waking immobility were identical. With 0.75 mg/kg atropine, movement (head movement, locomotion) resulted in EEG desynchronization and reduced power in all frequencies less than 24 Hz. After 1.5 or 3.0 mg/kg atropine, power in low frequencies remained elevated during movement, but power in spindle frequencies was significantly reduced compared with other states. During active REM sleep after 1.5 mg/kg atropine, power in spindle frequencies was significantly lower than that during quiet REM sleep. These results indicate that the sensorimotor cortical EEG in cats is under the control of multiple systems. At least 1 of these systems is active during movement, and its actions are resistant to muscarinic receptor blockade.

Animals↗
PubMed1990

Effect of amiodarone on the expression of myosin isoforms and cellular growth of cardiac muscle cells in culture.

The effect of amiodarone on the expression of myosin isoforms and the growth of neonatal rat cardiac muscle cells in culture was studied by native gel electrophoresis, assays of DNA and protein synthesis, and electron microscopy. Cardiac myocytes exposed to amiodarone in the absence of triiodothyronine (T3) showed predominant V1. When cardiac myocytes were exposed to amiodarone in the presence of T3, they expressed prevalent isomyosin V3, or both V3 and V1 equally. Supraphysiological concentration of T3 counteracted the effect of amiodarone on myocytes, showing the expression of predominant isomyosin V1. Amiodarone has inhibitory effects on DNA synthesis and differentiation of cardiac myocytes. Myocytes treated with amiodarone showed maximum labeling index with 11% labeled cells after day 1. Subsequently, the labeling indexes declined and on the third day ceased, as opposed to the control culture, which attained a peak in labeling index with 60% labeled myocytes on the third day. The labeling indexes declined, showing 11% labeled myocytes at the terminal time point. Myocytes treated with amiodarone lost most of the well-organized myofibrils and other organelles, and instead contained sparse, scattered segments of myofibrils, free myofilaments, many mitochondria with disrupted cristae, and autophagic vacuoles. The results demonstrated that amiodarone has a direct influence on the expression of isomyosin by cardiac myocytes. Furthermore, this drug has inhibitory and degrading effects on the growth and differentiation of cardiac myocytes.

Amiodarone↗
PubMed1989

Relationship between dietary intake and tissue levels of reduced and total vitamin C in the nonscorbutic guinea pig.

The objective of this study was to determine the effect of a broad range of dietary intake levels of ascorbate on the distribution of both total and reduced ascorbate in guinea pig tissues. Young male Hartley guinea pigs were fed for 2 mo a modified Reid-Briggs purified diet containing five different levels of total ascorbate that provided 0.8-52 mg ascorbate/d. We also fed aged guinea pigs two different levels of ascorbic acid (1.5 or 60 mg/d) for 2 mo. Reduced and total ascorbate was measured in eye lens and aqueous humor, liver, kidney and plasma. The data indicate that it is possible to markedly enhance the level of ascorbate in tissues above that obtained by feeding a diet that contains only enough ascorbate to prevent scurvy. In all tissues, as the level of total ascorbate present in the tissue increased, so did the proportion present in the reduced form. In old guinea pigs, the eye lens was the only tissue in which both reduced and total ascorbate were significantly lower than in the young guinea pigs at both high and low intake levels.

Animals↗
PubMed1986

Antibodies to immune response gene products inhibit the IgM and IgG antibody response but not the development of resistance to Toxoplasma gondii.

We have examined the effects of a monoclonal antibody directed against immune response gene products on the appearance of antibodies and development of resistance to Toxoplasma gondii. In vivo administration of a single dose of anti-I-Ak antibody to C3H/He (H-2k) and not BALB/c (H-2d) mice suppressed both the IgM and IgG response to two different strains of Toxoplasma. Administration of anti-I-Ak antibody to mice 5 days before and 10 days after infection resulted in complete inhibition of IgM and a more pronounced inhibition of IgG response to Toxoplasma. Under these experimental conditions, development of resistance against a subsequent challenge with a virulent strain of Toxoplasma was not affected. The microbicidal and tumoricidal activities of macrophages obtained from anti-I-Ak-treated, Toxoplasma-infected mice and mice infected with Toxoplasma alone were equivalent. Mice treated with anti-I-Ak antibody demonstrated a decreased proliferative response to lipopolysaccharide, a B-cell mitogen. Enumeration of B-cell numbers in anti-I-Ak-treated mice revealed a pronounced decrease in B-cell counts.

Animals↗