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Biomedical subjects

J W Wilson

Publications and source records attributed to J W Wilson.

At least 91 records · Page 5Linked to original sources
PubMed1999

Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle.

We have previously shown that glucocorticoids inhibit mitogen-stimulated proliferation of human cultured airway smooth muscle (ASM) cells. The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 microM), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.

Androstadienes↗
PubMed1999

Effectiveness of antipsychotic therapy in a naturalistic setting: a comparison between risperidone, perphenazine, and haloperidol.

BACKGROUND: Therapeutic ineffectiveness and noncompliance with antipsychotic agents are major contributors to rehospitalization in patients with psychotic disorders. It is unknown whether risperidone's favorable side effect profile compared with that of the conventional antipsychotics results in improved compliance and reduced hospitalizations in a naturalistic setting. The purpose of this study was to test the hypothesis that treatment with risperidone reduces readmission rates and associated costs when compared with treatment with perphenazine or haloperidol. METHOD: Inpatients prescribed either risperidone, perphenazine, or haloperidol between January 1, 1995, and December 31, 1995, as a single oral antipsychotic at discharge were retrospectively identified. Data were collected for that index hospitalization and for a 1-year follow-up period. Primary outcome measures included re-admission rates, changes in antipsychotic therapy, anticholinergic drug use, and costs. RESULTS: There were 202 evaluable patients (81 treated with risperidone, 78 with perphenazine, and 43 with haloperidol). Baseline demographics were similar between groups except that more patients in the risperidone group had a primary diagnosis of psychotic disorder or had been hospitalized in the year prior to study. The percentage of patients readmitted during the 1-year follow-up period was similar among drug groups (41% risperidone, 26% perphenazine, and 35% haloperidol) when controlled for baseline differences in diagnosis and hospitalization history (p = .32). Anticholinergic drug use was more common in the haloperidol group (p = .004). Mean yearly cost (drug + hospitalization) in the risperidone group was $20,317, nearly double that in the other treatment groups (p < .001). CONCLUSION: The results from this naturalistic study indicate that the high cost of risperidone is not offset by a reduction in readmission rates when compared with conventional antipsychotics.

Adolescent↗
PubMed1999

A Phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy.

Vitamin D is a steroid hormone best known for its activity in regulating calcium and bone metabolism. Epidemiological evidence suggests that vitamin D may play a role in inhibiting the development of colon and prostate cancer. Vitamin D receptors are expressed in many types of malignant cells; in vitro and in vivo vitamin D and vitamin D analogues are active in suppressing the development and inhibiting the growth of numerous human and animal tumors. The major toxicity of the active form of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), is the induction of hypercalcemia. There are no data indicating the maximum tolerated dose of calcitriol administered every other day (QOD) s.c. We hypothesized that this route and schedule would permit administration of higher doses of calcitriol, which might have anticancer activity. We conducted a Phase I trial of calcitriol given s.c. QOD in patients with advanced solid tumors. Thirty-six patients were entered at doses ranging from 2 to 10 microg QOD; dose-limiting toxicity (hypercalcemia) occurred in three of three patients entered at the 10-microg QOD dose. Hypercalciuria occurred at all dose levels examined. No other toxicity was seen. Assessment of serum calcitriol concentrations by a RIA revealed a decrease in concentration-time curves on day 7 compared to day 1 of therapy. A dose-dependent increase in peak serum level and estimated area under the concentration-time curve was seen. The maximum serum levels occurred at the 10-microg QOD dose: 288 +/- 74 and 321 +/- 36 pg/ml at days 1 and 7, respectively. The normal range of calcitriol serum concentration, determined using this assay, is 16-56 pg/ml. Serum calcitriol levels were maintained at near peak concentrations for at least 8 h following s.c. injection. This study indicates that substantial doses of calcitriol can be administered via this route with tolerable toxicity. Studies to explore approaches to ameliorate the hypercalcemia induced by calcitriol and to explore alternative schedules and interactions with other agents are warranted.

Adenocarcinoma↗
PubMed1999

The lure of unconventional therapy for rheumatic disease: how powerful is it?

Patients who suffer rheumatologic disease are known to try unconventional therapies in addition to, or instead of, medical therapy prescribed by their provider. Reasons for this include the chronic nature of their illness, the adverse effects of conventional medications, and widespread publicity about the purported efficacy of unconventional therapies. We undertook this study to assess the types of unconventional therapies used by patients in one rheumatology practice. A survey comprising nine questions and a cover letter was mailed to 300 patients in the practice, asking them to rank, in order of perceived effectiveness, unconventional therapies they had used and the treatments provided by the rheumatologist. We determined that the prevalence of unconventional therapy use was 44% (response rate, 45% [135 patients]). Patients' faith, attributes of the physician, and medications prescribed by the physician were ranked more highly effective in the healing process than all other unconventional therapies. We conclude that, although unconventional therapies were utilized by patients in this practice, they valued the physician's medical treatment plan and efforts most.

Adolescent↗
PubMed1998

Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors.

Age of host and transplantation-site microenvironment influence the tumorigenic potential of neoplastically transformed liver epithelial cells. Tumorigenic BAG2-GN6TF rat liver epithelial cells consistently form tumors at ectopic sites, but differentially express tumorigenicity or hepatocytic differentiation in the liver depending on host age and route of cell transplantation into the liver. Direct inoculation into host livers concentrates tumor cells locally, resulting in undifferentiated tumors near the transplantation site in both young (3-month-old) and old (18-month-old) rats. Transplantation-site tumors regress within 1 month in the livers of young rats, but grow progressively in old rats. However, inoculation of cells into the spleen distributes transplanted cells individually throughout the liver, resulting in hepatocytic differentiation by tumor cells with concomitant suppression of their tumorigenicity in young rats. When transplanted into livers of old rats by splenic inoculation, or when young hepatic-transplant recipients are allowed to age, hepatocytic progeny of BAG2-GN6TF cells proliferate to form foci, suggesting that the liver microenvironment of old rats incompletely regulates the proliferation and differentiation of tumor cell-derived hepatocytes. Upon removal from the liver, BAG2-GN6TF-derived hepatocytes revert to an undifferentiated, aggressively tumorigenic phenotype. We posit that the spectrum between normal differentiation and malignant potential of these cells reflects the dynamic interaction of the specific transformation-related genotype of the cells and the characteristics of the tissue microenvironment at the transplantation site. Changes in the tissue milieu, such as those that accompany normal aging, may determine the ability of a genetically aberrant cell to produce a tumor.

Aging↗
PubMed1998

Radial distribution of electron spectra from high-energy ions.

The average track model describes the response of physical and biological systems using radial dose distribution as the key physical descriptor. We report on an extension of this model to describe the average distribution of electron spectra as a function of radial distance from an ion. We present calculations of these spectra for ions of identical linear energy transfer (LET), but dissimilar charge and velocity to evaluate the differences in electron spectra from these ions. To illustrate the usefulness of the radial electron spectra for describing effects that are not described by electron dose, we consider the evaluation of the indirect events in microdosimetric distributions for ions. We show that folding our average electron spectra model with experimentally determined frequency distributions for photons or electrons provides a good representation of radial event spectra from high-energy ions in 0.5-2 microm sites.

Dose-Response Relationship, Radiation↗
PubMed1998

Radiation-induced p53 and p21WAF-1/CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest.

p53-dependent expression of p21WAF-1/CIP1 has been studied in murine intestinal epithelium after exposure to ionizing radiation. In un-irradiated small intestine, neither p53 nor p21WAF-1/CIP1 could be detected by immunohistochemistry. After irradiation (8 Gy), there was a time- and dose-dependent increase in the expression of both proteins. In the small bowel, the positional expression of p53 and p21WAF-1/CIP1 was similar but not coincident. Both proteins could be observed throughout the crypts with greatest frequency of expression over the first 15 cell positions, which includes the stem cell population (approximately positions 3 to 5) and the proliferating, transit cell population (approximately positions 5 to 15). p53-positive cells were primarily distributed toward the base of the crypt relative to p21WAF-1/CIP1. Subdivision of the p53-positive cell population revealed that the cells with strongest p53 immunoreactivity were positioned farther toward the base of the crypt, and their distribution was approximately coincident with the frequency distribution of apoptotic cells. Cells that were either weakly or moderately immunoreactive for p53 were located toward the middle of the crypt and were approximately coincident with the distribution of p21WAF-1/CIP1. The numbers of both p53- and p21WAF-1/CIP1-positive cells declined steadily with time, and by 6 days after irradiation there were very few immunoreactive cells to observe. Radiation-induced increase in p53 and p21WAF-1/CIP1 expression was not detected in mice homozygously null for p53. Expression of p21WAF-1/CIP1 and incorporation of tritiated thymidine were found to be mutually exclusive. In the large bowel, p21WAF-1/CIP1 and p53 expression were observed along the entire length of the colonic crypts after irradiation (8 Gy), and, unlike in the small intestine, this expression was not only maintained but increased over 72 hours. p21WAF-1/CIP1 immunoreactivity was detected in large intestine epithelium up to 6 days after irradiation. The differential expression of p21WAF-1/CIP1, observed between the large and small bowel and within the small intestinal crypts, is discussed.

Animals↗
PubMed1998

Nuclear absorption cross sections using medium modified nucleon-nucleon amplitudes.

We extract the in-medium nucleon-nucleon amplitudes from the available proton-nucleus total reaction cross sections data. The retrieval of the information from the experiment makes these estimates very reliable. Simple expressions are then given for the in-medium nucleon-nucleon amplitudes for any system of colliding nuclei as a function of energy. Excellent agreement is demonstrated in ion-nucleus absorption cross sections.

Aluminum↗
PubMed1998

Assessment and requirements of nuclear reaction databases for GCR transport in the atmosphere and structures.

The transport properties of galactic cosmic rays (GCR) in the atmosphere, material structures, and human body (self-shielding) are of interest in risk assessment for supersonic and subsonic aircraft and for space travel in low-Earth orbit and on interplanetary missions. Nuclear reactions, such as knockout and fragmentation, present large modifications of particle type and energies of the galactic cosmic rays in penetrating materials. We make an assessment of the current nuclear reaction models and improvements in these model for developing required transport code data bases. A new fragmentation data base (QMSFRG) based on microscopic models is compared to the NUCFRG2 model and implications for shield assessment made using the HZETRN radiation transport code. For deep penetration problems, the build-up of light particles, such as nucleons, light clusters and mesons from nuclear reactions in conjunction with the absorption of the heavy ions, leads to the dominance of the charge Z = 0, 1, and 2 hadrons in the exposures at large penetration depths. Light particles are produced through nuclear or cluster knockout and in evaporation events with characteristically distinct spectra which play unique roles in the build-up of secondary radiation's in shielding. We describe models of light particle production in nucleon and heavy ion induced reactions and make an assessment of the importance of light particle multiplicity and spectral parameters in these exposures.

Aerospace Medicine↗
PubMed1998

Transport of light ions in matter.

A recent set of light ion experiments are analyzed using the Green's function method of solving the Boltzmann equation for ions of high charge and energy (the GRNTRN transport code) and the NUCFRG2 fragmentation database generator code. Although the NUCFRG2 code reasonably represents the fragmentation of heavy ions, the effects of light ion fragmentation requires a more detailed nuclear model including shell structure and short range correlations appearing as tightly bound clusters in the light ion nucleus. The most recent NUCFRG2 code is augmented with a quasielastic alpha knockout model and semiempirical adjustments (up to 30 percent in charge removal) in the fragmentation process allowing reasonable agreement with the experiments to be obtained. A final resolution of the appropriate cross sections must await the full development of a coupled channel reaction model in which shell structure and clustering can be accurately evaluated.

Carbon↗
PubMed1998

Microscopic fragmentation model for galactic cosmic ray studies.

We describe theoretical considerations for developing models of heavy ion fragmentation appropriate for galactic cosmic ray studies. Previous models have been based on parametric fits to limited experimental data or models that ignored some aspects of the reaction dynamics, including nuclear cluster effects. The abrasion-ablation description of the fragmentation process is re-formulated to describe the excitation spectrum of pre-fragment nuclei. The resulting spectrum is shown to be related to the many-body response of the nuclear ground-state and excited states, and an approach to simplify this function is discussed. An analytic solution to the nuclear de-excitation process is described which includes a realistic level spectrum of the GCR nuclei (A < 60). Comparisons are made to experiments for fragmentation of 24Mg, 32S, and 56Fe beams on several targets and results are discussed.

Cosmic Radiation↗
PubMed1998

Cosmic ray hit frequencies in critical sites in the central nervous system.

One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells and 55 thousand out of 1.8 million thalamus cell nuclei would be directly hit by iron ions at least once on such a mission for space travelers inside a simple pressure vessel. Also, roughly 20 million out of 43 million hippocampal cells and 230 thousand out of 1.8 million thalamus cell nuclei would be directly hit by one or more particles with z > or = 15 on such a mission.

Basal Ganglia↗
PubMed1998

Validation of a comprehensive space radiation transport code.

The HZETRN code has been developed over the past decade to evaluate the local radiation fields within sensitive materials on spacecraft in the space environment. Most of the more important nuclear and atomic processes are now modeled and evaluation within a complex spacecraft geometry with differing material components, including transition effects across boundaries of dissimilar materials, are included. The atomic/nuclear database and transport procedures have received limited validation in laboratory testing with high energy ion beams. The codes have been applied in design of the SAGE-III instrument resulting in material changes to control injurious neutron production, in the study of the Space Shuttle single event upsets, and in validation with space measurements (particle telescopes, tissue equivalent proportional counters, CR-39) on Shuttle and Mir. The present paper reviews the code development and presents recent results in laboratory and space flight validation.

Algorithms↗
PubMed1998

Evaluation of risk from space radiation with high-energy heavy ion beams.

The most challenging radiation in space consists of fully ionized atomic elements with high energy for which only the few lowest energy ions can be stopped in shielding materials. The health risk from exposure to these ions and their secondary radiations generated in shield materials is poorly understood since there are few human data and a systematic study in relevant animal model systems has not been made. The accuracy of risk prediction is described as the major limiting factor in the management of space radiation risk. The expected impact of systematic studies is examined using the limited available biological data and models. Given the limitations of current predictions, models must be developed that are able to incorporate the required fundamental scientific data into accurate risk estimates. The important radiation components that can be provided for laboratory testing are identified. The use of ground-based accelerator beams to simulate space radiation is explained and quantitative scientific constraints on such facilities are derived. Three facilities, one each in the United States, in Germany and in Japan, currently have the partial capability to satisfy these constraints. A facility has been proposed using the Brookhaven National Laboratory Booster Synchrotron in the United States; in conjuction with other on-site accelerators, it will be able to provide the full range of heavy ion beams and energies required.

Aerospace Medicine↗
PubMed1997

Abrasion-ablation model for neutron production in heavy ion collisions.

In intermediate energy nucleus-nucleus collisions, neutron production at forward angles is observed to occur with a Gaussian shape that is centered near the beam energy and extends to energies well above that of the beam. This paper presents an abrasion-ablation model for making quantitative predictions of the neutron spectrum. To describe neutrons produced from the abrasion step of the reaction where the projectile and target overlap, we use the Glauber model and include effects of final-state interactions. We then use the prefragment mass distribution from abrasion with a statistical evaporation model to estimate the neutron spectrum resulting from ablation. Measurements of neutron production from Ne and Nb beams are compared with calculations, and good agreement is found.

Cosmic Radiation↗
PubMed1997

Synthesis and protein kinase C inhibitory activities of balanol analogs with replacement of the perhydroazepine moiety.

Balanol is a potent protein kinase C (PKC) inhibitor that is structurally composed of a benzophenone diacid, a 4-hydroxybenzamide, and a perhydroazepine ring. A number of balanol analogs in which the perhydroazepine moiety is replaced have been synthesized and their biological activities evaluated against both PKC and cAMP-dependent kinase (PKA). The results suggested that the activity and the isozyme/kinase selectivity of these compounds are largely related to the conformation about this nonaromatic structural element of the molecules.

Azepines↗
PubMed1997

Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium.

In rapidly proliferating tissues the stringent control of cell proliferation and cell death by apoptosis is central to the maintenance of tissue homeostasis. In the gastrointestinal tract most work studying the control of tissue cell number has traditionally focused on the growth factor control of proliferation, and the changes that occur during carcinogenesis. However, in recent years it has become increasingly apparent that the control of apoptosis is also crucial. Apoptosis is an important mechanism for eliminating both excess normal cells and those cells which have sustained damage; therefore maintaining a tissue, i.e., stem cells with preserved DNA integrity. In this review the incidence of apoptosis in the stem cells of both the small and large intestine will be discussed in relation to the expression of a number of apoptosis regulating genes (e.g. p53, Bcl-2, bax) within these cells. The importance of apoptosis as a means of controlling stem cell number (and therefore cellular output) will be addressed, as will the mechanisms by which any alterations to this process may contribute to malignancy.

Animals↗