Silicone gel and animal models of autoimmune disease.
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Animals↗
Biomedical subjects
K L White
Publications and source records attributed to K L White.
Toxicology and humoral immunity assessment of decamethylcyclopentasiloxane (D5) following a 1-month whole body inhalation exposure in Fischer 344 rats.
D5 is a low-molecular-weight cyclic siloxane used for industrial and consumer product applications. The objective of the present study was to assess potential toxic and immunomodulatory consequences of inhalation exposure to D5. Male and female Fischer 344 rats (25/group) were exposed by whole body inhalation to 0, 10, 25, 75, or 160 ppm D5 6 h/day, 7 days/week for 28 days. Clinical signs, body weights, and food consumption were recorded. On the day following the final exposure, 10 rats/group/sex were euthanized and a complete necropsy performed. Following a 14-day nonexposure recovery period, the remaining 5 rats/sex/group were necropsied. Body and organ weights were obtained and a complete set of tissues was taken for histopathology. Samples were also collected for serum chemistry, hematology, and urinalysis. Immunotoxicology-designated rats (10/sex/group) were immunized with sheep erythrocytes (sRBC) 4 days prior to euthanasia and cyclophosphamide (CYP) was administered i.p. to positive controls on days 24 through 28. The anti-sRBC antibody-forming cell (AFC) response was evaluated in a standard plaque assay. Blood was also collected for examination in the anti-sRBC enzyme-linked immunosorbant assay (ELISA). D5 exposure did not modulate humoral immunity, while the internal control, CYP, produced the expected suppression of the AFC response. D5 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. Serum alkaline phosphatase (SAP) was significantly decreased in females at terminal (12%, 160 ppm) and recovery sacrifice. A significant increase in the liver-to-body weight ratio was observed in female animals at the end of exposures (13%, 160 ppm), but was not noted in recovery animals from the same exposure group. In males, significant increases in liver-to-body weight (5%) and thymus-to-body weight (14%) ratios were also noted at the high dose at terminal sacrifice and were not present at recovery. At recovery only, a significant increase in spleen-to-body weight ratios (14 and 17%; 25 and 160 ppm, respectively) was noted. At the end of exposure, histopathological analysis indicated an increased incidence and severity of nasal (Level 1) goblet cell proliferation. Focal macrophage accumulation in the lung was also observed to be increased in incidence in both sexes at 160 ppm. At the end of the recovery period, the effects in both of these organs appeared to be reversible. In summary, D5 inhalation exposure did not alter humoral immunity and caused only minor, transient changes in hematological, serum chemistry, and organ weight values. Histopathological changes were confined to the respiratory tract and appeared to be reversible. The no observed effect level for systemic toxicity, based primarily on the liver weight changes, was 75 ppm.
Animals↗
Localization and regulation of ryanodine receptor in bovine oocytes.
We have previously reported that injection of ryanodine receptor agonists into mature bovine oocytes induces intracellular calcium release, indicative of the existence of ryanodine receptors. In this experiment, further evidence of the ryanodine receptor localization, and developmental regulation in bovine oocytes is presented. The possible physiological significance is also suggested. Using a rabbit antibody against the rabbit cardiac muscle ryanodine receptor, the ryanodine receptor was observed uniformly localized in the periphery of mature bovine oocytes, while a weak and discontinuous signal was observed in the germinal vesicle intact stage of bovine oocytes. As oocytes progress to the metaphase I stage, the ryanodine receptor localization became more intense and continuous, yet not comparable to that observed in the metaphase II oocytes. These modifications correlate with the intracellular calcium responsiveness to ryanodine. A 200-microM injection of ryanodine induces a low intracellular calcium transient in germinal vesicle-stage bovine oocytes, while peaked intracellular calcium transients are subsequently observed in the metaphase II-stage oocytes. However, no significant changes in the amplitude of intracellular calcium transients induced by 250 nM inositol 1,4,5-trisphosphate and 10 microM ionomycin were observed in oocytes at a comparable stage. Fertilization induced a significant decrease in ryanodine receptor signal; similar changes were also observed in oocytes injected with 200 microM ryanodine or incubated with 10 microM ionomycin. However, no changes in ryanodine signal were observed in oocytes injected with vehicle medium. Furthermore, injection of either ryanodine or inositol 1,4,5-trisphosphate induced subsequent pronuclear formation and cleavage. These data indicate that the ryanodine receptor is closely regulated and associated with early cellular changes following fertilization; stimulation of this receptor results in the activation of bovine oocytes, and it is likely that this receptor may play a role at fertilization.
Animals↗
Reactive oxygen species activity and lipid peroxidation in Helicobacter pylori associated gastritis: relation to gastric mucosal ascorbic acid concentrations and effect of H pylori eradication.
BACKGROUND: Helicobacter pylori is an independent risk factor for gastric cancer, and this association may be due to the bacterium causing reactive oxygen species mediated damage to DNA in the gastric epithelium. High dietary ascorbic acid intake may protect against gastric cancer by scavenging reactive oxygen species. AIMS: To assess reactive oxygen species activity and damage in gastric mucosa in relation to gastric pathology and mucosal ascorbic acid level, and to determine the effect of H pylori eradication on these parameters. PATIENTS: Gastric biopsy specimens were obtained for analysis from 161 patients undergoing endoscopy for dyspepsia. METHODS: Reactive oxygen species activity and damage was assessed by luminol enhanced chemiluminescence and malondialdehyde equivalent estimation respectively. Ascorbic acid concentrations were measured using HPLC. RESULTS: Chemiluminescence and malondialdehyde levels in gastric mucosa were higher in patients with H pylori gastritis than in those with normal histology. Successful eradication of the bacterium led to decreases in both parameters four weeks after treatment was completed. Gastric mucosal ascorbic acid and total vitamin C concentrations were not related to mucosal histology, but correlated weakly with reactive oxygen species activity (chemiluminescence and malodialdehyde levels). CONCLUSIONS: Data suggest that reactive oxygen species play a pathological role in H pylori gastritis, but mucosal ascorbic acid is not depleted in this condition.
Adult↗
Interleukin 2 promoter/enhancer controlled expression of a synthetic cecropin-class lytic peptide in transgenic mice and subsequent resistance to Brucella abortus.
The addition of an antimicrobial that can be synthesized by the mammalian immune system at the point of challenge may enhance disease resistance. A possible group of agents are cecropins, broad-spectrum antimicrobial peptides, which have been described and characterized. They are relatively non-toxic to normal cells from multicellular organisms but are toxic to a wide range of bacteria, protozoa and fungi, as well as infected and abnormal cells. Twenty-six lines of transgenic mice were produced by pronuclear injection of DNA consisting of the 5'-flanking region from -593 to +110 of the mouse interleukin 2 (IL-2) gene, Shiva 1a (a synthetic cecropinclass lytic peptide), and the SV40 polyadenylation/splice signal. A reverse-transcription PCR assay determined that two lines of transgenic mice were produced whose spleen-derived lymphocytes could be induced to transcribe and mature mRNA for Shiva 1a by exposure to 3.25 mg ml-1 of Con A. Two lines were challenged with an inoculation of 5 x 10(4) Brucella abortus strain 2308. After four weeks, there were significantly fewer B. abortus organisms in the spleens of transgenic mice than in non-transgenic control mice of the same strain (p < 0.05). Since the controlling regions of the IL-2 enhancer and the amino acid sequence of the signal peptide are highly conserved among several species, it is likely that this recombinant gene will function in other mammals.
Animals↗
Vitamin E and carotenoids in gastric biopsies: the relation to plasma concentrations in patients with and without Helicobacter pylori gastritis.
The carotenoids--lycopene and alpha- and beta-carotene-- and alpha-tocopherol were measured in plasma and in mucosal biopsies in normal subjects and in those infected with Helicobacter pylori. Two indexes of the presence of the reactive oxygen species malondialdehyde and chemiluminescence were measured in biopsies taken from adjacent sites in the same patient. In general, plasma and mucosal concentrations of all antioxidants correlated well and were of a similar order or magnitude in plasma and mucosa. There was no significant difference between the slope of the regression lines nor an overall difference in the concentrations of these antioxidants between the H. pylori-positive and control groups, indicating an absence of effect of H. pylori infection. However, a marked difference was seen in chemiluminescence and malondialdehyde concentrations in biopsies. For chemiluminescence this was highly significant. These findings confirm the presence of free radicals in the mucosa of H. pylori-infected patients and suggest therefore that the lipid-soluble antioxidants have either no role in protecting mucosal cells from free radical damage or, if they are able to scavenge these species, they are then rapidly regenerated to their original forms by redox and other processes.
Adult↗
Hospital restructuring in North America and Europe.
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Europe↗
Prolactin-induced termination of obligate diapause of mink (Mustela vison) blastocysts in vitro and subsequent establishment of embryonic stem-like cells.
The mink reproductive cycle includes an obligatory period of embryonic diapause and delayed implantation, which continues in vitro and reduces the efficiency of embryonic stem (ES) cell establishment. Blastocysts recovered on day 7 and on days 13-16 after final mating were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with various concentrations of prolactin to determine optimal conditions for embryo attachment and subsequent establishment of embryonic stem cells. Five treatments were applied to both ages of blastocyst: A, DMEM control (n = 16); B, DMEM + 5 micrograms prolactin ml-1 after 10 days initial culture in DMEM alone (n = 17); after 1 day of initial culture: C, DMEM + 10 ng prolactin ml-1 (n = 17); D, DMEM + 1 microgram prolactin ml-1 (n = 19); and E, DMEM + 5 micrograms prolactin ml-1 (n = 17). Prolactin terminated diapause of day 13-16 blastocysts at all concentrations tested. The maximum attachment of embryos in vitro and subsequent production of ES-like cells occurred in medium supplemented with 5 micrograms prolactin ml-1. Prolactin did not affect attachment rates for day 7 blastocysts when 5 micrograms prolactin ml-1 was added, but prolactin at concentrations of 1 microgram ml-1 and 5 micrograms ml-1 when added on day 1 of culture enhanced ES-like cell line establishment. Two principal cell types were observed in the colonies: small stem cells and trophoblast-like cells with large areas of cytoplasm. The morphological evaluation of mink ES-like cell colonies was confirmed by cytochemical staining for alkaline phosphatase. Mink embryonic stem-like cells were found to stain positive for alkaline phosphatase. Alkaline phosphatase activity was lost upon cellular differentiation.
Alkaline Phosphatase↗
Immunotoxicity of 2',3'-dideoxyinosine in female B6C3F1 mice.
2',3'-dideoxyinosine (ddI) is one of several purine analogues used for the treatment of HIV and the acquired immunodeficiency syndrome (AIDS). These nucleoside analogues are promising in their inhibition of viral reverse transcriptase and termination of DNA synthesis. However, each of these drugs has toxicity associated with its use. A previous immunotoxicological evaluation of 2',3'-dideoxyadenosine (ddA), the parent compound of ddI, showed that ddA suppresses humoral immunity. These studies were undertaken to determine the potential for immunotoxicity due to treatment with ddI. This evaluation included an assessment of innate and acquired immunity after exposure to ddI (100, 250, 500, and 1000 mg/kg/day) for 14, 28 or 180 days. There were no overt signs of toxicity related to treatment with ddI except for a decrease in body weight in the group treated with the highest dose of ddI for 180 days. Overall, 6 months of treatment with ddI showed minimal effects on specific organs with the exception of the spleen and thymus. ddI selectively targets the immune system, with assays that challenge humoral immunity being more affected than those testing cell-mediated immunity. Innate immunity was unaffected by ddI treatment. Cell-mediated immunity, as measured by proliferative response to allogeneic cells (MLR) and the T cell mitogen (Concanavalin A), was moderately suppressed. There were no ddI associated effects on NK function or macrophage function as measured by the vascular clearance rate and phagocytic uptake of the tissue macrophages. The most sensitive indicator of ddI-induced immunotoxicity is suppression of the response to the T-dependent antigen, sheep red blood cells (sRBC). The No Observable Adverse Effect Level (NOAEL) for toxicity to the immune system following 14 days of exposure to ddI is 250 mg/kg. A suppression of the humoral immune response was seen at the lowest dose tested after treatment for 28 and 180 days. Thus, the NOAEL for both of these treatment periods is below 100 mg/kg/day.
Animals↗
The ecology of medical care: origins and implications for population-based healthcare research.
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Adult↗
The measurement of caring.
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Clinical Trials as Topic↗
MHC class I-dependent presentation of exoerythrocytic antigens to CD8+ T lymphocytes is required for protective immunity against Plasmodium berghei.
T lymphocytes are believed to play a major role in protection against malaria. Previous experiments using in vivo depletion of CD8+ T cells, reconstitution with CD8+ T splenic cells, and adoptive transfer of CD8+ CTL clones demonstrated that protection against the exoerythrocytic stage of the murine strain, Plasmodium berghei malaria, was CD8+ T cell-dependent. Despite evidence for the critical role of CD8+ CTL, neither the cellular nor the molecular requirements for CD8+ T cell induction or for recognition of malaria Ags are known. In this study, we wished to define the role of CD8+ T cells and MHC class I molecules by using the P. berghei malaria attenuated sporozoites (SPZ) protection model in beta 2-microglobulin (beta 2m) knockout (-/-) mice. In contrast to observations that beta 2m-/- mice are resistant to many infectious diseases by compensatory mechanisms involving non-class I-restricted T cells, we found that beta 2m-/- mice failed to be protected against P. berghei SPZ, although immunization with attenuated SPZ induced production of IL-2, INF-gamma, anti-circumsporozoite protein IgG, and proliferative T cells. The lack of compensatory mechanisms involving non-CD8+ T cells was particularly evident in the failure to adoptively transfer protective immunity with wild-type SPZ-immune splenic T cells. From our data it can be concluded that CD8+ T cells induced during immunization with attenuated SPZ must recognize liver-expressed Ags presented by class I molecules to engage effectively in a response leading to destruction of the malaria parasites.
Animals↗
The adjuvancy of silicones: dependency on compartmentalization.
Studies have been conducted in mice (B6C3F1) and rats (Sprague Dawley, Fischer 344) to investigate the adjuvancy potential of silicone mammary gel and the low molecular weight silicone fluid, octamethylcyclotetrasiloxane (D4). Dependent on the experimental conditions employed, a divergent data profile emerges. If the antigen (bovine serum albumin, BSA) is emulsified with either the gel or the D4 prior to intramuscular immunization, an amplified anti-BSA IgG antibody response, as measured by multipoint ELISA methodology, is noted over the 8 week measurement period. In parallel studies, a variety of non-silicone personal care ingredients (lanolin, white mineral oil, isopropyl palmitate) were also capable of amplifying this humoral response relative to the non-adjuvant phosphate buffered saline control. These observations are consistent with the empirical knowledge that hydrophobic substances tend to augment immune responses. However, under conditions in which the antigen is not blended with the silicone prior to immunization, normal immune responses are noted. In short (10 day) and long (180 day) term gel implant studies, the optimal IgM and IgG antibody responses, as determined in the antibody forming cell assay, were equivalent between the gel implanted and control animals. Moreover, under similar exposure conditions, no adjuvancy was noted in the three Host Resistance models (B16F10 Melanoma, Listeria monocytogenes, and Streptococcus pneumoniae) tested. Antibody forming cell studies conducted after 28 days of oral or inhalation exposure to D4 have also yielded responses similar to the non-silicone exposed vehicle controls. Collectively, these data suggest that in the absence of premixing the antigen with the silicone test material, there does not appear to be any silicone induced adjuvant response.
Adjuvants, Immunologic↗
Two-stage designs for the logistic regression model in single-agent bioassays.
In this paper we focus on the use of a two-stage procedure for logistic regression that emphasizes predicting response through the use of the Q-optimality criterion. The use of D-optimality in the first stage is primarily to allow best possible parameter estimates as one enters the second stage. However, it is important to understand that there are many ways to formulate the two-stage procedure. It may involve any optimality criterion in either stage. In fact, theoretically, one need not stop at two stages. It was our intention in this paper to demonstrate the potential in the two-stage procedure in cases in which good initial parameter estimates are not available. Those investigators who are interested in the software for the two-stage procedure described here should contact Dr. William R. Myers.
Animals↗
Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals.
High dietary ascorbic acid intake appears to protect against gastric cancer. This may be due to its action as a scavenger of reactive radical species formed in the gastric mucosa, resulting in a reduced level of radical-mediated DNA damage. We have studied 82 patients, of whom 37 had Helicobacter pylori-associated gastritis, a condition which predisposes to gastric cancer. Using electron paramagnetic resonance (EPR) spectroscopy we have demonstrated, for the first time, that ascorbyl radicals are generated in human gastric mucosa, presumably as a result of scavenging of free radicals by ascorbic acid. Quantification of ascorbyl radicals demonstrates that there is a higher concentration in those patients with H.pylori gastritis compared with subjects with normal histology (P < 0.01). We also found gastric mucosal luminol-enhanced chemiluminescence and malondialdehyde concentrations (which are believed to be markers of radical generation and tissue damage) to be higher in patients with H.pylori gastritis compared with those with normal histology (P < 0.001 and P < 0.01 respectively). The observed concentrations of the ascorbyl radical correlate with the level of luminol-enhanced chemiluminescence (r = 0.41, P < 0.001), but not with malondialdehyde concentrations (r = 0.08, P = 0.47). Mucosal ascorbic acid and total vitamin C concentrations did not vary between histological groups, nor did they correlate with mucosal levels of the ascorbyl radical, chemiluminescence or malondialdehyde. These data suggest that ascorbic acid is acting as a scavenger of free radicals generated in human gastric mucosa. The experiments therefore provide direct supportive evidence for the hypothesis that ascorbic acid protects against gastric cancer by scavenging reactive radical species which would otherwise react with DNA, with resultant genetic damage.
Adult↗
Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: effects of gastritis and oral supplementation.
Epidemiological evidence suggests that high dietary ascorbic acid reduces gastric cancer risk. It may do this by either reducing N-nitroso compound formation in gastric juice, or by scavenging reactive oxygen species in gastric mucosa. The aim of this study was to discover if potential ascorbic acid protection might be increased by supplementation. Thirty two patients were supplemented with ascorbic acid, 500 mg twice daily for two weeks. Gastric juice, plasma, and upper gastrointestinal biopsy ascorbate concentrations were measured and compared with values in 48 unsupplemented patients. It was found that ascorbic acid and total vitamin C concentrations were considerably higher in biopsy specimens from oesophagus, body, antrum, duodenum, and rectum, compared with values in plasma or gastric juice. Plasma and mucosal concentrations were unaffected by the presence of chronic gastritis but gastric juice concentrations were substantially lower in patients with chronic gastritis than in patients with normal histological assessment (p < 0.01). Patients receiving ascorbic acid supplements had higher ascorbic acid concentrations in plasma (p < 0.001), gastric juice (p < 0.001), and at all biopsy sites in the upper gastrointestinal tract (p < 0.05). Gastric juice ascorbic acid and total vitamin C concentrations in gastritic patients, however, were still less after supplementation than in normal subjects (p < 0.01). These data suggest that high ascorbic acid intake could reduce gastric cancer risk, but its protective effect might be greater if gastritis is treated (for example, by Helicobacter pylori eradication).
Adult↗
Treatment of obsessive-compulsive disorder with fluvoxamine: a multicentre, double-blind, placebo-controlled trial.
One hundred and sixty patients with a primary diagnosis of obsessive-compulsive disorder were enrolled in a multicentre, randomized, double-blind, placebo-controlled study of fluvoxamine. After a placebo washout phase, patients were randomized to treatment with placebo or fluvoxamine (100-300 mg/day) for 10 weeks. Seventy-eight patients in each group were evaluable for efficacy. Fluvoxamine was significantly more effective than placebo as assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the National Institute of Mental Health Obsessive-Compulsive (NIMH-OC) scale and the Global Improvement item of the Clinical Global Impression (CGI) scale. The percentage of patients classified as "responders" (much or very much improved according to the Global Improvement item) was also significantly higher in the fluvoxamine group from Week 6 onwards, with 33.3% of fluvoxamine-treated patients and 9.0% of those given placebo classified as "responders" at endpoint. The "responders" to fluvoxamine experienced a substantial clinical benefit as reflected in decreases in their Y-BOCS and NIMH-OC scores. Fluvoxamine was well tolerated with the majority of adverse events considered mild or moderate.
Adult↗
The ecology of medical care. 1961.
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Disease↗