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Biomedical subjects

J M Benson

Publications and source records attributed to J M Benson.

At least 19 recordsLinked to original sources
PubMed2003

Short-term inhalation of particulate transition metals has little effect on the electrocardiograms of dogs having preexisting cardiac abnormalities.

There is growing epidemiological evidence for statistical associations between increases in air pollution, especially particulate matter, and increases in cardiovascular morbidity and mortality. Laboratory studies have shown that transition metals contribute strongly to the effects of high lung doses of model particles on changes in the electrocardiograms of animals. The present study evaluated the effects of short-term inhalation exposure to respirable particles of specific oxide and sulfate forms of transition metals on heart rate and the electrocardiogram of old dogs having preexisting cardiac abnormalities. Conscious beagle dogs were exposed by oral inhalation for 3 h on each of 3 successive days to aerosols of manganese, nickel, vanadium, iron, and copper oxides, and nickel and vanadium sulfates as single compounds at concentrations of 0.05 mg/m(3). Electrocardiograms were recorded and evaluated for exposure-related changes in heart rate, heart rate variability, and abnormalities of waveforms. Although the electrocardiograms of this population of dogs having potential age and cardiovascular susceptibility factors reflected their underlying clinical abnormalities, no significant effect of exposure to the transition metal aerosols was observed.

Administration, Inhalation↗
PubMed2001

Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit.

CD4+ T cells are believed to play a central role in the initiation and perpetuation of autoimmune diseases such as multiple sclerosis. In the murine model for multiple sclerosis, experimental autoimmune encephalomyelitis, pathogenic T cells exhibit a Th1-like phenotype characterized by heightened expression of proinflammatory cytokines. Systemic administration of "regulatory" cytokines, which serve to counter Th1 effects, has been shown to ameliorate autoimmune responses. However, the inherent problems of nonspecific toxicity limit the usefulness of systemic cytokine delivery as a potential therapy. Therefore, we used the site-specific trafficking properties of autoantigen-reactive CD4+ T cells to develop an adoptive immunotherapy protocol that provided local delivery of a Th1 cytokine antagonist, the p40 subunit of IL-12. In vitro analysis demonstrated that IL-12 p40 suppressed IFN-gamma production in developing and effector Th1 populations, indicating its potential to modulate Th1-promoted inflammation. We have previously demonstrated that transduction of myelin basic protein-specific CD4+ T cells with pGC retroviral vectors can result in efficient and stable transgene expression. Therefore, we adoptively transferred myelin basic protein-specific CD4+ T cells transduced to express IL-12 p40 into mice immunized to develop experimental autoimmune encephalomyelitis and demonstrated a significant reduction in clinical disease. In vivo tracking of bioluminescent lymphocytes, transduced to express luciferase, using low-light imaging cameras demonstrated that transduced CD4+ T cells trafficked to the central nervous system, where histological analysis confirmed long-term transgene expression. These studies have demonstrated that retrovirally transduced autoantigen-specific CD4+ T cells inhibited inflammation and promoted immunotherapy of autoimmune disorders.

3T3 Cells↗
PubMed2001

Americans' views on the use and regulation of dietary supplements.

This article presents the views of Americans on what the government's future role should be in regulating or overseeing the growing sales of dietary supplements for health purposes. Based on results of multiple national opinion surveys, including the views of both users and nonusers of supplements, we found that a substantial percentage of Americans surveyed reported that they regularly take dietary supplements as a part of their routine health regimen. However, they reported that they do not discuss the use of dietary supplements with their physicians because they believe that the physicians know little or nothing about these products and may be biased against them. Many users felt so strongly about the potential health benefits of some of these products that they reported that they would continue to take them even if they were shown to be ineffective in scientifically conducted clinical studies. However, there also was broad public support for increased government regulation of these products. We found that a majority of Americans surveyed supported the following: to require that the Food and Drug Administration review the safety of new dietary supplements prior to their sale; to provide increased authority to remove from sale those products shown to be unsafe; and to increase government regulation to ensure that advertising claims about the health benefits of dietary supplements are true.

Adolescent↗
PubMed2001

Uptake, tissue distribution, and fate of inhaled carbon tetrachloride: comparison of rat, mouse, and hamster.

Carbon tetrachloride is hepatotoxic in rats, mice, and hamsters. However, rats are less sensitive to the hepatotoxic effects of CCl(4) than the other two species. The purpose of this study was to compare the uptake, tissue distribution, and elimination of CCl(4) by these three rodent species. Groups of 20 F344/Crl BR rats, B6C3F(1) mice, and Syrian hamsters were exposed by nose-only inhalation for 4 h to 20 ppm (14)C-labeled CCl(4). The fate of (14)C was followed in tissues, excreta, and exhaled breath for 48 h after the exposure. At the end of the exposure, concentrations of CCl(4) equivalents (CE) in tissue were highest in liver of rats and mice, but highest in fat for rats. The liver received the highest dose of CCl(4) equivalents with the following species ranking: mouse > hamster > rat. Patterns of CE elimination were species and tissue dependent, with the majority of elimination occurring within 48 h after exposure. Rats eliminated less radioactivity associated with metabolism ((14)CO(2), urine and feces) and more radioactivity associated with parent compound (exhaled activity trapped on charcoal) than did mice or hamsters. The results indicate that ranking of species sensitivity to the hepatotoxic effects of inhaled CCl(4) correlates with CE dose to liver and with the ability to metabolize CCl(4).

Animals↗
PubMed2001

MTBE inhaled alone and in combination with gasoline vapor: uptake, distribution, metabolism, and excretion in rats.

The purpose of these studies was to extend previous evaluation of methyl tert-butyl ether (MTBE)* tissue distribution, metabolism, and excretion in rats to include concentrations more relevant to human exposure (4 and 40 ppm) and to determine the effects of coinhalation of the volatile fraction of unleaded gasoline on the tissue distribution, metabolism, and excretion of MTBE. Groups of male F344 rats were exposed nose-only for 4 hours to 4, 40, or 400 ppm 14C-MTBE or to 20 or 200 ppm of the light fraction of unleaded gasoline (LFG) containing 4 or 40 ppm 14C-MTBE, respectively. To evaluate the effects of repeated inhalation of LFG on MTBE tissue distribution, metabolism, and excretion, rats were exposed for 4 hours on each of 7 consecutive days to 20 or 200 ppm LFG with MTBE (4 or 40 ppm) followed on the eighth day by a similar exposure to LFG containing 14C-MTBE. Subgroups of rats were evaluated for respiratory parameters, initial body burdens, rates and routes of excretion, and tissue distribution and elimination. The concentrations of MTBE and its chief metabolite, tert-butyl alcohol (TBA), were measured in blood and kidney immediately after exposure, and the major urinary metabolites-2-hydroxyisobutyric acid (IBA) and 2-methyl-1,2-propanediol (2MePD)-were measured in urine. Inhalation of MTBE alone or as a component of LFG had no concentration-dependent effect on respiratory minute volume. The initial body burdens of MTBE equivalents achieved after 4 hours of exposure to MTBE did not increase linearly with exposure concentration. MTBE equivalents rapidly distributed to all tissues examined, with the largest percentages distributed to liver. The observed initial body burden did not increase linearly between 4 and 400 ppm. At 400 ppm, elimination half-times of MTBE equivalents from liver increased and from lung, kidney, and testes decreased compared with the two smaller doses. Furthermore, at 400 ppm the elimination half-time for volatile organic compounds (VOCs) in breath was significantly shorter and the percentage of the initial body burden of MTBE equivalents eliminated as VOCs in breath increased significantly. These changes probably reflect a saturation of blood with MTBE at 400 ppm and strongly suggest that the uptake and fate of MTBE are notably different at exposure concentrations above and below 400 ppm. Single and repeated coexposure to 20 and 200 ppm LFG with MTBE had opposite effects on the total body burden of MTBE equivalents present at the end of exposures compared with those achieved after 4 and 40 ppm MTBE exposures: 20 ppm LFG increased and 200 ppm LFG significantly decreased the burdens of MTBE equivalents present. The effects of coexposure to LFG on blood levels of MTBE equivalents paralleled the effects on body burden. These differences in overall uptake of MTBE equivalents cannot be attributed to alterations of minute volume. The reason for the increase in overall uptake after 20-ppm LFG exposure is not clear. Decreased MTBE absorption (uptake) after single and repeated coexposure to 200 ppm LFG may be due to a decrease in solubility of MTBE in blood caused by inhalation of other hydrocarbons. Investigations on the blood/air partition coefficient of MTBE in the absence and presence of LFG would be needed to confirm this hypothesis. Single and repeated coexposure to either 20 or 200 ppm LFG significantly decreased the percentage of the initial body burden from MTBE equivalents in tissues, including liver, kidney, and testes, immediately and 72 hours after

Air Pollutants↗
PubMed2001

Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism.

Thrombophilia is a multigenic disease in which the combination of genetic polymorphisms increases the risk of deep vein thrombosis (DVT). The rapid identification of these genetic combinations requires high-throughput analysis of single nucleotide polymorphisms (SNPs). The TaqMan fluorogenic 5'-->*3' nuclease assay (PE/Applied Biosystems, Foster City, CA) with custom-designed primers, probes and controls has provided a highly efficient platform for high throughput. This assay was used to rapidly detect two SNPs, FV Leiden (G1691A) and FV A4070G (R2 allele), in a study of 6295 subjects. With one thermal cycler, we completed sample set-up, PCR and analysis on 84 samples in 3 h with an additional 12 wells containing 4 "no template controls" (NTC), 4 "allele-1 controls", and 4 "allele-2 controls" in a 96-well plate. When additional thermal cyclers were used and more assays were set up while the initial sets of reactions were in the PCR machines, the output could correspondingly be increased. The TaqMan assay was extremely accurate, avoided contamination by using uracil-N-glycolase (UNG) in a single, closed tube, and offered the possibility for additional automation with robotic equipment to implement the PCR. This TaqMan assay facilitates high throughput to screen large populations quickly and economically while utilizing a simple protocol that requires minimal expenditure of personnel time. Our results demonstrated a prevalence of the R2 allele of 11.9% in U.S. Caucasians, 5.6% in African-Americans, 13.4% in Asian or Pacific Islanders and 11.3% in Hispanics. No association between venous thromboembolism and the R2 allele was noted, and furthermore no interaction with FV Leiden was observed.

Alleles↗
PubMed2000

Comparative metabolism of carbon tetrachloride in rats, mice, and hamsters using gas uptake and PBPK modeling.

No study has comprehensively compared the rate of metabolism of carbon tetrachloride (CCl4) across species. Therefore, the in vivo metabolism of CCl4 was evaluated using groups of male animals (F344 rats, B6C3F1 mice, and Syrian hamsters) exposed to 40-1800 ppm CCl4 in a closed, recirculating gas-uptake system. For each species, an optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants Km (affinity) and Vmax (capacity) using a physiologically based pharmacokinetic (PBPK) model. The results show that the mouse has a slightly higher capacity and lower affinity for metabolizing CCl4 compared to the rat, while the hamster has a higher capacity and lower affinity than either rat or mouse. A comparison of the Vmax to Km ratio, normalized for milligrams of liver protein (L/h/mg) across species, indicates that hamsters metabolize more CCl4 than either rats or mice, and should be more susceptible to CCl4-induced hepatotoxicity. These species comparisons were evaluated against toxicokinetic studies conducted in animals exposed by nose-only inhalation to 20 ppm 14C-labeled CCl4 for 4 h. The toxicokinetic study results are consistent with the in vivo rates of metabolism, with rats eliminating less radioactivity associated with metabolism (14CO2 and urine/feces) and more radioactivity associated with the parent compound (radioactivity trapped on charcoal) compared to either hamsters or mice. The in vivo metabolic constants determined here, together with in vitro constants determined using rat, mouse, hamster, and human liver microsomes, were used to estimate human in vivo metabolic rates of 1.49 mg/h/kg body weight and 0.25 mg/L for Vmax and Km, respectively. Normalizing the rate of metabolism (Vmax/Km) by milligrams liver protein, the rate of metabolism of CCl4 differs across species, with hamster > mouse > rat > human.

Administration, Inhalation↗
PubMed2000

Targeting rare populations of murine antigen-specific T lymphocytes by retroviral transduction for potential application in gene therapy for autoimmune disease.

CD4+ T cells are important mediators in the pathogenesis of autoimmunity and would therefore provide ideal candidates for lymphocyte-based gene therapy. However, the number of Ag-specific T cells in any single lesion of autoimmunity may be quite low. Successful gene transfer into autoantigen-specific CD4+ T cells would serve as an ideal vehicle for site-targeted gene therapy if it were possible to transduce preferentially the small number of autoantigen-specific T cells. In this study we have demonstrated that retroviral infection of CD4+ lymphocytes from either autoantigen-stimulated TCR transgenic mice, or Ag-activated immunized nontransgenic mice, with a retroviral vector (pGCIRES), resulted in the transduction of only the limited number of Ag-reactive CD4+ T cells. In contrast, polyclonal activation of the same cultures resulted in transduction of non-antigen-specific lymphocytes. Transduction of Ag-reactive CD4+ T cells with pGCIRES retrovirus encoding the regulatory genes IL-4 (IL4) and soluble TNF receptor (STNFR) resulted in stable integration and long-term expression of recombinant gene products. Moreover, expression of the pGCIRES marker protein, GFP, directly correlated with the expression of the upstream regulatory gene. Retroviral transduction of CD4+ T cells targeted specifically Ag-reactive cells and was cell cycle-dependent and evident only during the mitosis phase. These studies suggest that retroviral transduction of autoantigen-specific murine CD4+ T cells, using the pGCIRES retroviral vector, may provide a potential method to target and isolate the low frequency of autoantigen-specific murine CD4+ T cells, and provides a rational approach to gene therapy in animal models of autoimmunity.

3' Untranslated Regions↗
PubMed2000

Cytochrome P450 2E1 is the primary enzyme responsible for low-dose carbon tetrachloride metabolism in human liver microsomes.

We examined which human CYP450 forms contribute to carbon tetrachloride (CCl(4)) bioactivation using hepatic microsomes, heterologously expressed enzymes, inhibitory antibodies and selective chemical inhibitors. CCl(4) metabolism was determined by measuring chloroform formation under anaerobic conditions. Pooled human microsomes metabolized CCl(4) with a K(m) of 57 microM and a V(max) of 2.3 nmol CHCl(3)/min/mg protein. Expressed CYP2E1 metabolized CCl(4) with a K(m) of 1.9 microM and a V(max) of 8.9 nmol CHCl(3)/min/nmol CYP2E1. At 17 microM CCl(4), a monoclonal CYP2E1 antibody inhibited 64, 74 and 83% of the total CCl(4) metabolism in three separate human microsomal samples, indicating that at low CCl(4) concentrations, CYP2E1 was the primary enzyme responsible for CCl(4) metabolism. At 530 microM CCl(4), anti-CYP2E1 inhibited 36, 51 and 75% of the total CCl(4) metabolism, suggesting that other CYP450s may have a significant role in CCl(4) metabolism at this concentration. Tests with expressed CYP2B6 and inhibitory CYP2B6 antibodies suggested that this form did not contribute significantly to CCl(4) metabolism. Effects of the CYP450 inhibitors alpha-naphthoflavone (CYP1A), sulfaphenazole (CYP2C9) and clotrimazole (CYP3A) were examined in the liver microsome sample that was inhibited only 36% by anti-CYP2E1 at 530 microM CCl(4). Clotrimazole inhibited CCl(4) metabolism by 23% but the other chemical inhibitors were without significant effect. Overall, these data suggest that CYP2E1 is the major human enzyme responsible for CCl(4) bioactivation at lower, environmentally relevant levels. At higher CCl(4) levels, CYP3A and possibly other CYP450 forms may contribute to CCl(4) metabolism.

Acetonitriles↗
PubMed2000

Deep cervical fasciitis in a child.

Deep cervical infections in children are relatively uncommon and often require prolonged antibiotic therapy. The organism may not be isolated, in which case it is necessary to cover Gram-negative and Gram-positive organisms as well as anaerobes. During treatment continued vigilance is required to detect abscess formation, with ultrasound providing a useful tool for this purpose.

Cephalexin↗
PubMed2000

Particle clearance and histopathology in lungs of C3H/HeJ mice administered beryllium/copper alloy by intratracheal instillation.

Beryllium/copper (BeCu) alloys are commonly used in the electronics, automotive, consumer, defense, and aerospace industries. Some individuals exposed occupationally to BeCu alloys have developed chronic beryllium disease. However, little is known of the toxicity and fate of BeCu alloys in the respiratory tract. To begin to address this question, we investigated the pulmonary toxicity and clearance of BeCu alloy (2% Be; 98% Cu) in mice. Groups of 40 female C3H/HeJ mice were administered 12.5, 25, and 100 microg BeCu alloy or 2 and 8 microg Be metal by intratracheal instillation. Mice were sacrificed at 1 h and 1, 7, 14, and 28 days postinstillation. Left lungs were evaluated for histopathological change. Right lungs were analyzed for Be and Cu content. Twenty-five percent of the high-dose BeCu mice and 7.5% of the mid-dose BeCu mice died within 24 h of dosing. Acute pulmonary lesions included acute alveolitis and interstitial inflammation. Type II epithelial cell hyperplasia and centriacinar fibrosis were present by 7 days after dosing. Lesions persisted through 28 days after instillation. No lesions attributable to alloy exposure were present in liver or kidney. Be metal instillation caused no deaths and minimal pulmonary changes over the time studied, indicating that the pulmonary lesions were due to Cu rather than Be. Cu cleared the lung with a half-time of 0. 5-2 days. Be cleared with a half-time of several weeks or longer. Results of this study suggest that exposure to BeCu alloy is more acutely toxic to lung than Be metal. The results of tissue analyses also indicate that, while the Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure.

Acute Disease↗
PubMed2000

T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen.

The fate of antigen-specific T cells was characterized in myelin basic protein (MBP) T-cell receptor (TCR) transgenic (Tg) mice after oral administration of MBP. Peripheral Th cells are immediately activated in vivo, as indicated by upregulation of CD69 and increased cytokine responses (Th1 and Th2). Concurrently, surface TCR expression diminishes and internal TCR levels increase. When challenged for experimental autoimmune encephalomyelitis during TCR downmodulation, Tg mice are protected from disease. To characterize Th cells at later times after antigen feeding, it was necessary to prevent thymic release of naive Tg cells. Therefore, adult Tg mice were thymectomized before treatment. TCR expression returns in thymectomized Tg mice 3 days after MBP feeding and then ultimately declines in conjunction with MBP-specific proliferation and cytokine responses (Th1-type and Th2-type). The decline correlates with an increase in apoptosis. Collectively, these results demonstrate that a high dose of fed antigen induces early T-cell activation and TCR downmodulation, followed by an intermediate stage of anergy and subsequent deletion.

Administration, Oral↗
PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part I: Carcinogenicity of 1,2,3,4-diepoxybutane.

Reports in the literature suggest that one reason for the greater sensitivity of mice to the carcinogenicity of 1,3-butadiene (BD) is that exposed mice metabolize much more of the BD to 1,2,3,4-diepoxybutane (BDO2) than do exposed rats. The purpose of this study was to determine the tumorigenicity of BDO2 in rats and in mice exposed to the same concentration of the agent. Female B6C3F1 mice and Sprague-Dawley rats, 10 to 11 weeks old, 56 per group, were exposed by inhalation to 0, 2.5, or 5.0 ppm BDO2, 6 hours/day, 5 days/week for 6 weeks. Preliminary dosimetry studies in rodents exposed for 6 hours to 12 ppm BDO2 indicated that blood levels would be expected to be approximately 100 and 200 pmol/g at the two exposure concentrations in the rat and twice those levels in the mouse. During the 6-week exposure, the mice at the high exposure level showed signs of labored breathing during the last week, and four mice died. In the others, however, the respiratory symptoms disappeared after exposure ended. Rats showed no clinical signs of toxicity during exposure but developed labored breathing after the end of the exposure leading to the death of 13 rats within 3 months. At the end of the exposure, some animals (8 per group) were evaluated for the acute toxicity resulting from the BDO2 exposure. The remaining exposed rats and mice were held for 18 months for observation of tumor development. At the end of the exposure, rats had no biologically significant alteration in standard hematological parameters, but mice had a dose-dependent increase in neutrophils and decrease in lymphocytes. In both species the significant histopathologic lesions were in the nose, concentrated around the main airflow pathway. Necrosis, inflammation, and squamous metaplasia of the nasal mucosa, as well as atrophy of the turbinates, were all present at the end of exposure to 5.0 ppm. Within 6 months, necrosis and inflammation subsided, but squamous metaplasia remained in the mice. In rats that died after exposure, squamous metaplasia was seen in areas of earlier inflammation and, in other rats, extended beyond those areas with time. The metaplasia was severe enough to restrict and occlude the nasopharyngeal duct. Later, keratinizing squamous cell carcinomas developed from the metaplastic foci in rats but not mice. At the end of 18 months, the only significant increase in neoplasia in the exposed rats was a dose-dependent increase in neoplasms of the nasal mucosa (0/47, 12/48, and 21/48 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). Neoplasia of the nasal mucosa did not increase significantly in the mice; neoplastic lesions in the mice were observed in reproductive organs, lymph nodes, bone, liver, Harderian gland, pancreas, and lung. The only significant increase in neoplasms in a single organ in the mice was in the Harderian gland (0/40, 2/42, and 5/36 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). This tumor accounts for the apparent trend toward an increase in total neoplastic lesions in mice as a function of dose (10/40, 7/42, and 16/36 for control, 2.5 ppm, and 5.0 ppm exposures, respectively). These findings indicate that the metabolite of BD, BDO2, is carcinogenic in the respiratory tract of rats. An increase in respiratory tract tumors was not observed in similarly exposed mice despite the fact that preliminary studies indicated mice should have received twice the dose to tissue compared with the rats. High cytosolic activity of detoxication enzymes in the mouse may account, in part, for the differences in response.

Administration, Inhalation↗
PubMed1999

Multiplex analysis of mutations in four genes using fluorescence scanning technology.

Multiplex analysis of genetic mutations using fluorescence scanning methodology is an accurate, efficient, and cost-effective approach to genotypic characterization. Fluorescence labeling during the synthesis of polymerase chain reaction primers allows the application of this technology to well-established protocols. We have simultaneously analyzed the four polymorphisms of factor V Leiden (G1691A), prothrombin G20210A, 5,10-methylenetetrahydrofolate reductase C677T, and cystathionine beta-synthase 844ins68. Three of these mutations have been associated with an increased risk of thrombosis. Following polymerase chain reaction with fluorescence-labeled primers, the polymerase chain reaction products were digested with an appropriate restriction enzyme (if necessary for detection of the mutation), diluted into one tube per sample for co-loading (multiplex loading), and analyzed with GeneScan software for fragment analysis following capillary electrophoresis on an ABI PRISM 310 Genetic Analyzer (Foster City, CA, USA). Multiplex loading increased throughput without compromising precision.

Cystathionine beta-Synthase↗
PubMed1999

Uptake, tissue distribution, and excretion of brevetoxin 3 administered to rats by intratracheal instillation.

Brevetoxins are cyclic polyether neurotoxins produced by the marine dinoflagellate Ptychodiscus brevis. Blooms of P. brevis (red tides) are toxic to fish, marine mammals, and humans. Humans exposed to seaspray aerosols containing brevetoxins may experience respiratory tract irritation. Because a major route of human exposure to brevetoxins is via the respiratory tract, the objective of this study was to examine the toxicokinetics of brevetoxin 3 (PbTx-3) administered to the lung by intratracheal instillation. Twenty-one male F344/Crl BR rats, 12 wk of age, were administered 3H-PbTx-3 (1 microCi, 6.6 microg PbTx-3/kg) by intratracheal instillation. Groups of 3 rats were sacrificed at 0.5, 3, 6, 24, 48, and 96 h after exposure, and tissues were collected. Three additional rats were placed in glass metabolism cages for collection of urine and feces over a 7-d period. PbTx-3-associated activity was cleared rapidly from the lung and distributed throughout the body, chiefly to the carcass, intestines, and liver. Blood, brain, and fat contained the lowest percentages of the administered dose. Although a majority of the PbTx-3 was cleared rapidly from lung, liver, and kidneys, approximately 20% of the initial concentration present in each organ was retained for 7 d. Concentrations of PbTx-3 in brain and fat were low, but remained relatively constant over time. Approximately twice as much PbTx-3-associated activity was excreted in feces than in urine, with the majority of excretion occurring within 48 h after instillation. The results of this study indicate that over 80% of the PbTx-3 is rapidly absorbed from the lung to the blood and distributed to all tissues. The tissues containing the greatest amount of PbTx-3-associated activity reflect the compound's site of deposition, storage compartment, and major route of metabolism and excretion. These results illustrate that brevetoxin exposure by the respiratory route results in systemic distribution of brevetoxin and suggest that the initial respiratory irritation and bronchoconstriction may only be a part of the overall toxicological consequences associated with brevetoxin inhalation.

Adipose Tissue↗
PubMed1999

Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis.

Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unresponsiveness to CNS Ags and ameliorates murine relapsing experimental autoimmune encephalomyelitis (REAE). However, a recent clinical trial in which multiple sclerosis patients were treated with repeated doses of oral myelin was unsuccessful in reducing disease exacerbations. Therefore, we directly compared the tolerizing capacity of myelin vs MBP during REAE in B10.PL mice. Oral administration of high doses of myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T cell responses. In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T cell proliferation and cytokine responses. The frequency of IL-2-, IFN-gamma-, and IL-5-secreting MBP-specific T cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of oral tolerance after high Ag doses. We have previously shown that the dosage and timing of Ag administration are critical parameters in oral tolerance induction. Studies presented here demonstrate that Ag homogeneity is also important, i.e., homogeneous Ag (MBP) is more effective at inducing oral tolerance than heterogeneous Ag (myelin).

Administration, Oral↗