Biomedical subjects

T D Jones

Publications and source records attributed to T D Jones.

At least 37 records · Page 2Linked to original sources

PubMed1999

Shielding from solar particle event exposures in deep space.

The physical composition and intensities of solar particle event exposures of sensitive astronaut tissues are examined under conditions approximating an astronaut in deep space. Response functions for conversion of particle fluence into dose and dose equivalent averaged over organ tissues are used to establish significant fluence levels and the expected dose and dose rates of the most important events from past observations. The BRYNTRN transport code is used to evaluate the local environment experienced by sensitive tissues and used to evaluate bioresponse models developed for use in tactical nuclear warfare. The present results will help to clarify the biophysical aspects of such exposure in the assessment of RBE and dose rate effects and their impact on design of protection systems for the astronauts. The use of polymers as shielding material in place of an equal mass of aluminum would provide a large safety factor without increasing the vehicle mass. This safety factor is sufficient to provide adequate protection if a factor of two larger event than has ever been observed in fact occurs during the mission.

Bone Marrow↗

PubMed1999

Pseudomonas aeruginosa outer-membrane protein F epitopes are highly immunogenic in mice when expressed on a plant virus.

A synthetic peptide (peptide 10) representing a surface-exposed, linear B cell epitope from outer-membrane (OM) protein F of Pseudomonas aeruginosa was shown previously to afford protection in mice from P. aeruginosa infection. This peptide was expressed in tandem with the protein F peptide 18 on each of the two coat proteins of cowpea mosaic virus (CPMV). The chimaeric virus particles (CVPs) expressing the peptides on the S (small) coat protein (CPMV-PAE4) and L (large) coat protein (CPMV-PAE5) were used to immunize mice. Following subcutaneous immunization in Freund's and QuilA adjuvants, CPMV-PAE4 induced antibodies predominantly against peptide 18, whereas CPMV-PAE5 produced antibodies exclusively against peptide 10, indicating that the site of peptide expression on CPMV influences its immune recognition. The anti-peptide antibodies elicited by CPMV-PAE5 were predominantly of the IgG2a isotype, indicating a highly polarized TH1-type response. The peptide-specific IgG2a strongly recognized the whole F protein, but more importantly, recognized protein F in all seven Fisher-Devlin immunotypes of P. aeruginosa. Furthermore, the peptide-specific IgG2a in CVP/QS-21 adjuvant-immunized mice was shown to bind complement and to augment phagocytosis of P. aeruginosa by human neutrophils in vitro. The ability of CPMV-PAE5 to induce P. aeruginosa-specific opsonic IgG2a gives it potential for further development as a protective vaccine against P. aeruginosa.

Animals↗

PubMed1999

Chimeric plant virus particles administered nasally or orally induce systemic and mucosal immune responses in mice.

The humoral immune responses to the D2 peptide of fibronectin-binding protein B (FnBP) of Staphylococcus aureus, expressed on the plant virus cowpea mosaic virus (CPMV), were evaluated after mucosal delivery to mice. Intranasal immunization of these chimeric virus particles (CVPs), either alone or in the presence of ISCOM matrix, primed CPMV-specific T cells and generated high titers of CPMV- and FnBP-specific immunoglobulin G (IgG) in sera. Furthermore, CPMV- and FnBP-specific IgA and IgG could also be detected in the bronchial, intestinal, and vaginal lavage fluids, highlighting the ability of CVPs to generate antibody at distant mucosal sites. IgG2a and IgG2b were the dominant IgG subclasses in sera to both CPMV and FnBP, demonstrating a bias in the response toward the T helper 1 type. The sera completely inhibited the binding of human fibronectin to the S. aureus FnBP. Oral immunization of the CVPs also generated CPMV- and FnBP-specific serum IgG; however, these titers were significantly lower and more variable than those generated by the intranasal route, and FnBP-specific intestinal IgA was undetectable. Neither the ISCOM matrix nor cholera toxin enhanced these responses. These studies demonstrate for the first time that recombinant plant viruses have potential as mucosal vaccines without the requirement for adjuvant and that the nasal route is most effective for the delivery of these nonreplicating particles.

Adhesins, Bacterial↗

PubMed1998

Atherosclerotic risks from chemicals: part I. Toxicological observations and mechanisms of atherosclerosis.

Atherosclerosis is a common disease, primarily of the large arteries, that begins in childhood and progresses with advancing age. Atherosclerosis leads to coronary heart disease, the major cause of death in the United States. Several risk factors affect atherosclerosis, but high LDL cholesterol is the most important risk factor. In addition, high levels of lipoprotein (a) appear to be associated with increased atherosclerosis and myocardial infarction. The level of lipoprotein (a) is genetically determined and is not affected by diet or exercise. Studies on the pathogenesis of atherosclerosis suggest that several steps are involved, including endothelial injury, increased arterial permeability to plasma lipoproteins, smooth muscle cell proliferation, and platelet aggregation. Atherosclerotic plaques are benign neoplasms of the arterial wall that result from the monoclonal proliferation of a single mutated smooth muscle cell. Abnormal proliferation of smooth muscle cells is the key event in the initiation and progression of atherosclerosis. Endothelial injury is another major contributory factor. Many factors associated with an increased risk of cancer are also associated with atherosclerosis. Cancer and atherosclerosis go through the same stages of initiation, promotion, and complication. Both inflammatory and immune reactions play important roles in the progressions of the two diseases. Smooth muscle cells and endothelial cells produce and respond to several cytokines and growth factors, which may influence the initiation, progression, and complication of the atherosclerotic lesions. Many studies have shown that the production of nitric oxide is decreased in atherosclerosis-reduction in the bioavailability of nitric oxide in the arterial wall may lead to leukocyte adhesion and platelet aggregation. It should be noted additionally, nitric oxide is a mutagenic agent involved in the origin of neoplastic diseases. Atherosclerotic plaques express genes for products not found in the normal arterial wall. As with carcinogenesis, there may be more than one mechanism that promotes atherosclerotic lesions and there may be common mechanistic similarities between the two diseases. The purpose of this study is to establish an exploratory scientific hypothesis that will permit the use of standardized toxicological test data to evaluate different chemicals. The companion paper that follows will use a method of relative toxicological potencies to develop tentative risk coefficients based on relative potency. These papers, in combination, provide both a conceptual and a quantitative hypothesis that can be tested with data from forthcoming epidemiological studies or animal test models.

Animals↗

PubMed1998

Atherosclerotic risks from chemicals: part II. A RASH analysis of in vitro and in vivo bioassay data to evaluate 45 potentially hazardous compounds.

As reviewed in the Part I companion manuscript by Basavaraju and Jones (Arch Environ Contam Toxicol), atherosclerosis and carcinogenesis may share some common mechanisms of toxicological action. On that hypothesis, standardized test data taken from the Registry of Toxic Effects of Chemical Substances (RTECS) were used to compute relative potency factors for chemical compounds associated with increased risk of atherosclerosis to humans. Potencies of the different compounds were computed relative to each of six reference compounds comprised of benzo(a)pyrene, nicotine, cisplatin, adriamycin, estrogen, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Reference-specific potencies were all converted to a common numerical scale adjusted to unit potency for B(a)P. Because the list of compounds contained several antibiotics, amino acids, hormones, chemotherapeutic agents, polynuclear aromatics, alkaloids, metals, and vitamins, the standardized estimates of potency varied significantly depending on which of the six reference compounds are considered as standards of comparison. For the n - 1 other substances. Estimates of relative potency, risk coefficients, and generalized risk equations are estimated for cigarette smoke condensate, dietary cholesterol, ethanol, and carbon disulfide. From data on atherosclerosis as a result of cigarette smoking, a tentative risk was estimated as Increased Relative Risk = S (mg/kg-day)-1 x dose (mg/kg-day) x RP, where the dose is chronic intake per kilogram of body weight per day, RP is the potency of the compound of interest relative to that of benzo(a)pyrene, and S is 0.83, 0.25, 0.20, or 13 depending on whether cigarette smoke, cholesterol, ethanol, or carbon disulfide epidemiological data were used as a standard of comparison.

Animals↗

PubMed1998

MAVIS: a non-invasive instrument to measure area and volume of wounds. Measurement of Area and Volume Instrument System.

Accurate measurement of the physical size of wounds is vital for assessment of the progress of healing. An instrument has been developed to measure area and volume of skin wounds, ulcers, and pressure sores. MAVIS--Measurement of Area and Volume Instrument System-is based on the principle of colour coded structured light. A set of parallel stripes of alternating colours is projected onto the wound area at an angle of approximately 45 degrees and is recorded by a CCD camera. From the known position of the focal points of projector and camera, and from the observed intersection points of the stripes of light with the wound surface, a computer calculates a three-dimensional map of the observed wound. The volume of the wound is defined as the volume of the region sandwiched between the observed surface and the original healthy skin surface which is simulated by cubic spline interpolation. This paper compares the performance of the instrument with three traditional wound measurement techniques using results obtained from a clinical trial involving 50 patients. Traditional area measurement techniques such as transparency tracings produce results with standard deviations between 4% (large wounds) and up to 20% (small wounds) of the measured mean value. MAVIS measurements reduce these standard deviations by 3-5%. Measuring the wound volume by alginate casts produces errors in volume figures between 5% and 40%. Standard deviations of MAVIS results are 5% smaller on average. The results demonstrate that MAVIS yields more reproducible results with a minimum of inter-observer error. The instrument does not make contact with the wound, provided visual records and measurements are made in less then 5 min. It is not suitable for undermined, very deep or very large wounds.

Humans↗

PubMed1998

A preliminary cell kinetics model of thrombocytopenia after radioimmunotherapy.

UNLABELLED: Thrombocytopenia is often the dose-limiting toxicity for radionuclide therapy. Prediction of platelet counts after therapy is important for treatment planning. Simple prediction methods based on linear correlation between radiation dose and blood count nadir have been insufficient because they have not considered time, because of the complicated hierarchical structure of the hematopoietic system in which platelets are not directly injured by low dose rate radiation and because of changing radiation dose rates to marrow with time. This study addresses these problems using a cell kinetics model. METHODS: The model consists of compartments for progenitor cells, megakaryocytes, platelets and stromal cells. A linear quadratic formula was used for progenitor cell survival. Stromal cells were described by a model based on a maximum likelihood estimate for cellular damage, repair and proliferation. Reported values for murine cellular turnover rates and radiosensitivity of progenitor cells were used in the model calculations. Experimental mice received 4 Gy of external beam radiation for tumor implantation and 12.4-23.3 MBq 67Cu-2-iminothiolane-BAT-Lym-1 (BAT = 6-[p-(bromoacetamido) benzyl]-1,4,8,11-tetra-azacyclotetradecane-N,N',N'',N'''-tetraacet ic acid) 19-30 days later. Blood counts were measured three times each week. RESULTS: The model predicted the severity of thrombocytopenia, and the time of the nadir corresponded to measured values in mice. For a dose of 14.2 MBq 67Cu-2-iminothiolane-BAT-Lym-1 that induced a platelet nadir of 20% of baseline (Grade II), the model predicted that at least 20 days were needed before a second 14.2-MBq injection if a subsequent nadir of <10% of baseline (Grade IV) was to be avoided. CONCLUSION: The nadir and duration of thrombocytopenia predicted by the model were similar to those observed in the mice. Predicted information could be useful for planning the dose and timing of fractionated radionuclide therapy. This model provides a stepping stone for future development of a predictive model for patients.

Animals↗

PubMed1997

Plant-derived vaccine protects target animals against a viral disease.

The successful expression of animal or human virus epitopes on the surface of plant viruses has recently been demonstrated. These chimeric virus particles (CVPs) could represent a cost-effective and safe alternative to conventional animal cell-based vaccines. We report the insertion of oligonucleotides coding for a short linear epitope from the VP2 capsid protein of mink enteritis virus (MEV) into an infectious cDNA clone of cowpea mosaic virus and the successful expression of the epitope on the surface of CVPs when propagated in the black-eyed bean, Vigna unguiculata. The efficacy of the CVPs was established by the demonstration that one subcutaneous injection of 1 mg of the CVPs in mink conferred protection against clinical disease and virtually abolished shedding of virus after challenge with virulent MEV, demonstrating the potential utility of plant CVPs as the basis for vaccine development. The epitope used occurs in three different virus species-MEV, canine parvovirus, and feline panleukopenia virus- and thus the same vaccine could be used in three economically important viral hosts-mink, dogs, and cats, respectively.

Amino Acid Sequence↗

PubMed1997

Neutron RBEs for cytopenia and repopulation of stroma and hematopoietic stem cells: mathematical models of marrow cell kinetics.

The objectives of this study were to (a) extend previous bone-marrow cell kinetics models that have been published for ionizing photons to include neutron radiations, and (b) provide Relative Biological Effectiveness (RBE) values for time-specific cell killing (cytopenia) and compensatory cellular proliferation (repopulation in response to toxic injury) for neutron doses ranging from 0.01 to 4.5 Gy delivered uniformly over one minute, hour, day, week, and month. RBEs for cytopenia of a cell lineage were based on ratios of protocol-specific doses that determined the same cell population nadir, whereas the RBEs for repopulation of a lineage were based on the ratios of protocol-specific doses that corresponded to the same total number of cells killed over the radiation treatments, and which should be replaced for long-term survival of the animal. Time-dependent RBEs were computed for neutron exposures relative to the effect of 60Co gamma rays given as a prompt dose. By the use of these RBE factors, low or variable dose rates, dose fractionations given over long periods of time, and different protocols involving several radiation qualities can be converted realistically, and by standard convention, into an equivalent dose of a reference radiation comprised of x or gamma rays given either as a pulse or at any other reference dose rate for which risk information based on epidemiological or animal dose-response data are available. For stromal tissues irradiated by fission neutrons, time-dependent RBEs for cytopenia were computed to range from 4.24 to 0.70 and RBEs for repopulation varied from a high of 6.88 to a low of 2.24. For hematopoietic stem cells irradiated by fission neutrons, time-dependent RBEs for cytopenia were computed to range from 5.02 to 0.22 and RBEs for repopulation varied from a high of 5.02 to a low of 1.98. RBEs based on tissue-kerma-free-in-air would be about twofold lower for isotropic cloud or rotational exposure geometries because marrow dose from isotropic neutron fields suffer factor-of-two greater attenuation than the gamma doses from gamma photons. For certain doses and dose rates, the RBE values computed for compensatory cellular proliferation clearly demonstrate the behavior that is commonly referred to as an inverse dose-rate effect, i.e., protraction of exposure may-under certain conditions-increase the magnitude of the dose response. Furthermore, because of non-linear rates for repair and repopulation, the highest RBEs are not necessarily found for the lowest doses nor the lowest RBEs always found at the highest doses.

Animals↗

PubMed1997

MarCell software for modeling bone marrow radiation cell kinetics.

Differential equations were used to model cellular injury, repair, and compensatory proliferation in the irradiated bone marrow. Recently, that model was implemented as MarCell, a user-friendly MS-DOS computer program that allows users from a variety of technical disciplines to evaluate complex radiation exposure. The software allows menu selections for different sources of ionizing radiation. Choices for cell lineages include progenitor, stroma, and malignant, and the available species include mouse, rat, dog, sheep, swine, burro, and man. An attractive feature is that any protracted irradiation can be compared with an equivalent prompt dose (EPD) in terms of cell kinetics for either the source used or for a reference such as 250 kVp x rays or 60Co. EPD is used to mean a dose rate for which no meaningful biological recovery occurs during the period of irradiation. For human as species, output from MarCell includes: risk of 30-day mortality; risk of whole-body cancer and leukemia based either on radiation-induced cytopenia or compensatory cell proliferation; cell survival and repopulation plots as functions of time or dose; and 4-week recovery following treatment.

Animals↗

PubMed1997

Clinical comparison of magnetic resonance imaging and nuclear emission imaging in cervical-facial trauma patients.

This retrospective study examined 20 consecutively treated trauma patients who reported a chief complaint of earache or trauma preauricular pain. These individuals were examined with magnetic resonance imaging (MRI), emission study using single photon emission, computerized tomography, and joints auscultation using Doppler sound magnification. There are no statistically significant correlations between clinical findings and imaging studies in trauma patients with complaints of earaches and preauricular pain.

Adolescent↗

PubMed1996

A RASH analysis of National Toxicology Program data: predictions for 30 compounds to be tested in rodent carcinogenesis experiments.

Relative potencies for 30 compounds scheduled for carcinogenic testing in the 2-year rodent bioassays were estimated based on comparisons with a wide variety of bioassay data for benzo[a]pyrene, nicotine, cisplatin, aflatoxin B1, and cyclophosphamide. Potential for oncogenic transformation of each of the compounds was estimated from short-term bioassays. Promoting strength was assigned on the basis of comparisons of the product of relative potency and test dose with the distribution of similar products obtained for 67 common compounds in the data-base of Gold et al. A potency class for promotion was assigned on the basis of whether the potency-adjusted test dosage was > 2 sigma below the mean, > 1 sigma below the mean, within +/- sigma of the mean, > sigma above the mean, or > 2 sigma above the mean, as determined from the 67 compounds. The underlying hypothesis is that a weak test dose may have a low probability of revealing a potential carcinogen, whereas a strong dose may have a high probability of producing false-positive results. Predictions are therefore directed at the central 68% of the log-normal frequency distribution according to the assumption that +/- sigma represents the ideal test dose.

Animals↗

PubMed1996

Potential of chimaeric plant virus particles as novel, stable vaccines.

Technology has been developed for the expression of multiple copies of epitopes from human and animal pathogens on the surface of assembled particles of a plant virus (cowpea mosaic virus). The technology, termed the Chimaeric Virus Particle (CVP) Technology, can be exploited for the production of vaccines in plants. Each chimaeric virus particle contains 60 copies of the foreign peptide which are expressed in highly exposed positions on the surface of the virus particle. Viral and bacterial epitopes have been expressed as CVPs in an immunologically active form. CPMV is stable at temperatures up to 65 degrees C and a chimaera expressing an HIV epitope survives exposure to a protease and to pH values as low as 1.0.

AIDS Vaccines↗

PubMed1995

Toxicological potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin relative to 100 other compounds: a relative potency analysis of in vitro and in vivo test data.

A common definition of relative potency is the dose of a reference compound required to cause a particular incidence of a specific toxic response divided by the dose of a test compound needed to cause an equal incidence of that same effect. In this simple manner, toxicological assessments for a chemical of concern can be made in terms of another compound about which much is known from a human health perspective. Relative potency factors were used to compare 2,3,7,8-tetrachlorodibenzo-p-dioxin CAS # 1746-01-6 (TCDD) with 100 other compounds both individually and collectively. All results were standardized to a common scale that spanned many orders of magnitude and was indexed to an arbitrary potency of unity for benzo(a)pyrene [B(a)P]. From comparisons between 2,771 pairs of bioassay results (i.e., matched experimental design conditions) for TCDD compared with the 100 other compounds, it was found that TCDD is about 600 times as toxic as B(a)P (interquartile range of 130 to 1,900). The distribution of relative potency values is fitted accurately with a log-normal distribution function having an untransformed mean of 550 and an untransformed slope (i.e., the inverse of the standard deviation of the distribution) of 140. These factors combined with (a) a reference lifetime carcinogenic risk level of 1/100,000 and (b) a universal, potency-dependent risk coefficient (estimated from the collection of epidemiologically-based carcinogens) yielded estimates that equally toxic concentrations for TCDD should be in the range of 13 pg/m3 and 7 pg/L in air and water, respectively.

Animals↗

PubMed1995

Use of bioassays in assessing health hazards from complex mixtures: a rash analysis.

The Finney harmonic mean model for joint toxicity of ingredients in mixtures can be used to estimate the toxicity of the neat compound if each component can be substituted in potency-adjusted-doses for any of the other components. Chemical analysis of constituent substances and their associated concentrations and relative toxicological potency values (computed according to the RApid Screening of Hazard (RASH) method) were used to compare the toxicities as predicted from ingredients of cigarette smoke, PAHs in diesel exhaust, asphalt, coal tar, pitch, and creosote with the measured toxicities of the corresponding neat mixtures. Accuracy for cigarette smoke condensate, coal tar, pitch, and creosote were within a factor of three based on the PAH fraction; asphalt was within a factor of 18; but the PAH fraction of diesel particulate was again found to be inadequate to describe the composite toxicity of diesel emissions.

Animals↗

PubMed1994

Bone marrow equivalent prompt dose from two common fallout scenarios.

A cell-kinetics model for radiation-induced myelopoiesis has been derived for mice, rats, dogs, sheep, swine, and burros. The model was extended to humans after extensive comparisons with molecular and cellular data from biological experiments and an assortment of predictive/validation tests on animal mortality, cell survival, and cellular repopulation following irradiations. One advantage of the model is that any complex pattern of protracted irradiation can be equated to its equivalent prompt dose. Severity of biological response depends upon target-organ dose, dose rate, and dose fractionation. Epidemiological and animal data are best suited for exposures given in brief periods of time. To use those data to assess risk from protracted human exposures, it is obligatory to model molecular repair and compensatory proliferation in terms of prompt dose. Although the model is somewhat complex both mathematically and biologically, this note describes simple numerical approximations for two common exposure scenarios. Both approximations are easily evaluated on a simple pocket calculator by a health physicist or emergency management officer.

Animals↗

PubMed1994

Dose-rate RBE factors for photons: hematopoietic syndrome in humans vs. stromal cell cytopenia.

Traditionally, dose-response modeling has been on a strict experiment-by-experiment basis. Such an approach greatly restricts understanding of complex biological systems affected by numerous confounding factors that individually vary from experiment to experiment. In contrast, work described in this manuscript relies on a new analytical process (that considers both pooled and experiment-specific considerations) that was used to jointly analyze the bone marrow cell kinetics from a large data base on six species of test animals irradiated by protracted schedules of ionizing photon radiations. From this approach, we have modeled how the human LD50 may vary with dose protraction and how the dose rate efficiency or RBE factors for x rays, 137Cs, and 60Co change for irradiations given at constant rate over one minute, hour, day, week, and month.

Animals↗

PubMed1994

Clinical comparison of temporomandibular joint sound auscultation and emission imaging studies.

Single photon-emission computerized tomography scintigraphy was used to examine 250 patients who previously had temporomandibular joint sounds auscultated and recorded with a Doppler machine. Patients were divided into four groups based on the presence of joint sounds: no sound, reciprocal clicks, reciprocal clicks with crepitus, and crepitus. Statistically significant differences between the groups and the single photon-emission computerized tomography scintigraphy results were determined. There was no correlation between these results and the no sound and crepitus groups, but significant correlation was established between positive results and crepitant joints with reciprocal clicks and noncrepitant clicking joints.

Analysis of Variance↗