Biomedical subjects
J Parker
Publications and source records attributed to J Parker.
Animal rights: reaching the public.
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Glutathione conjugation of perchloroethene in subcellular fractions from rodent and human liver and kidney.
Perchloroethene (Per) is a widely used industrial solvent and common environmental contaminant. In rats, long-term inhalation of Per is known to cause a small increase in the incidence of renal tubule cell tumors in males only; renal toxicity is seen in female rats and in both sexes of mice after prolonged Per exposure. The renal toxicity of Per is likely mediated by a glutathione-dependent bioactivation reaction. Glutathione S-transferase mediated formation of S-(1,2,2-trichlorovinyl)glutathione is the first step in a sequence of reactions finally resulting in the formation of reactive intermediates in the kidney. In this study, we compared the enzymatic rates of formation of S-(1,2,2-trichlorovinyl)glutathione in liver and kidney subcellular fractions from rats, mice, and from both sexes of humans (n = 11). In microsomal fractions from the liver and kidney of all three species, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione from Per could not be observed. S-(1,2,2-Trichlorovinyl)glutathione formation (the structure was confirmed by electrospray mass spectrometry) was observed in liver cytosol from both male and female rats and mice. However, the rates of S-(1,2,2-trichlorovinyl)glutathione formation in liver cytosol from male rats (84.5+/-12 pmol/mg per min) were approximately four times higher than from female rats (19.5+/-8 pmol/mg per min) and from both sexes of mice (27.9+/-6 and 26.0+/-4 pmol/mg per min). Low rates of S-(1,2,2-trichlorovinyl)glutathione formation were also seen in kidney cytosol from mice (12+/-6 pmol/mg per min), but not from rats. In human liver subcellular fractions, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione could not be detected. The human liver cytosolic fractions, however, exhibited glutathione S-transferase activity (as determined using 1-chloro-2,4-dinitrobenzene and hexachlorobutadiene as marker substrates) in the same order of magnitude as rat and mouse liver cytosol. In contrast to other marker activities for glutathione S-transferases, the ability of all human liver cytosol samples to catalyze the glutathione conjugation of 1,2-dichloro-4-nitrobenzene was three orders of magnitude lower compared to rat and mouse liver cytosol. 1,2-Dichloro-4-nitrobenzene conjugation was also four times higher in liver cytosol from male rats compared to female rats. The results suggest that the ability of the human liver to catalyze the formation of S-(1,2,2-trichlorovinyl)glutathione from Per is at least two orders of magnitude lower than that of rat liver, and that sex-specific differences in the extent of hepatic conjugation of Per with glutathione, which may be relevant for nephrotoxicity, occur in rats.
Expression of MUC1 mucin on activated human T cells: implications for a role of MUC1 in normal immune regulation.
MUC1 mucin is expressed by normal and malignant epithelial cells and is thought to function through cell-cell interactions and transmembrane signal transduction events. Secreted cancer-associated MUC1 is immunosuppressive and inhibits human T-cell proliferation. We report here that newly synthesized MUC1 is expressed on the surface of mitogen-activated human T cells and is also found in soluble form in the supernatants from cultures of mitogen-activated human T cells. After removal of the mitogenic stimulus from the T-cell cultures, MUC1 expression is downregulated. The addition of anti-MUC1 monoclonal antibody to mitogen-activated cultures partially inhibits the T-cell proliferative response. These data suggest that MUC1 serves an immunodulatory function for human T lymphocytes.
Gene-for-gene disease resistance without the hypersensitive response in Arabidopsis dnd1 mutant.
The cell death response known as the hypersensitive response (HR) is a central feature of gene-for-gene plant disease resistance. A mutant line of Arabidopsis thaliana was identified in which effective gene-for-gene resistance occurs despite the virtual absence of HR cell death. Plants mutated at the DND1 locus are defective in HR cell death but retain characteristic responses to avirulent Pseudomonas syringae such as induction of pathogenesis-related gene expression and strong restriction of pathogen growth. Mutant dnd1 plants also exhibit enhanced resistance against a broad spectrum of virulent fungal, bacterial, and viral pathogens. The resistance against virulent pathogens in dnd1 plants is quantitatively less strong and is differentiable from the gene-for-gene resistance mediated by resistance genes RPS2 and RPM1. Levels of salicylic acid compounds and mRNAs for pathogenesis-related genes are elevated constitutively in dnd1 plants. This constitutive induction of systemic acquired resistance may substitute for HR cell death in potentiating the stronger gene-for-gene defense response. Although cell death may contribute to defense signal transduction in wild-type plants, the dnd1 mutant demonstrates that strong restriction of pathogen growth can occur in the absence of extensive HR cell death in the gene-for-gene resistance response of Arabidopsis against P. syringae.
Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial.
OBJECTIVE: To compare the effectiveness of biofeedback/relaxation, exercise, and a combined program for the treatment of fibromyalgia. METHODS: Subjects (n = 119) were randomly assigned to one of 4 groups: 1) biofeedback/relaxation training, 2) exercise training, 3) a combination treatment, or 4) an educational/attention control program. RESULTS: All 3 treatment groups produced improvements in self-efficacy for function relative to the control condition. In addition, all treatment groups were significantly different from the control group on tender point index scores, reflecting a modest deterioration by the attention control group rather than improvements by the treatment groups. The exercise and combination groups also resulted in modest improvements on a physical activity measure. The combination group best maintained benefits across the 2-year period. CONCLUSION: This study demonstrates that these 3 treatment interventions result in improved self-efficacy for physical function which was best maintained by the combination group.
Nitrate reductase alters 3-nitrotyrosine accumulation and cell cycle progression in LPS + IFN-gamma-stimulated RAW 264.7 cells.
Nitrite (NO2-), an end product of nitrogen radical metabolism, has recently been shown to increase tyrosine nitration by activated leukocytes indicating that nitrite modulates the immune response. We investigated the hypothesis that nitrite may increase nitration of molecular targets within activated cells leading to altered cell cycle progression. Intracellular nitrite was increased by transfection of murine macrophage-like RAW 264.7 cells with the nitrate reductase gene obtained from barley. Nitrate reductase facilitates the conversion of nitrate to nitrite; thus when extracellular nitrate is present, intracellular nitrite will be increased. Results show that addition of KNO3 increases NO2- production and intracellular nitrotyrosine accumulation in the transfectant but not the parent. Inhibition of nitric oxide synthesis with L-NAME during activation with IFN-gamma + LPS reduced NO2- production to the same extent in both cell lines; however, cellular accumulation of nitrotyrosine was reduced by only 25% in the transfectant (P = 0.21) and 49% in the parent cell line (P = 0.007), suggesting that intracellular nitrite increased nitrotyrosine accumulation through a pathway not requiring NO synthesis, i.e., myeloperoxidase system. Approximately 15% of the transfected cells had 4n DNA content 24 h postactivation compared to < 1% of the parent cells. Increased DNA copy number was correlated to nitrotyrosine accumulation. These findings show that intracellular nitrite can increase accumulation of nitrotyrosine and that nitration is linked to cell cycle perturbation.
Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic.
The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.
Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-L-cysteine in rats and humans after inhalation.
Chronic exposure of rodents to perchloroethene (PER) increased the incidence of liver tumors in male mice and resulted in a small but significant increase in the incidence of renal tumors in male rats. The tumorigenicity of PER is mediated by metabolic activation reactions. PER is metabolized by cytochrome P450 and by conjugation with glutathione. Cytochrome P450 oxidation of PER results in trichloroacetyl chloride which reacts with water to trichloroacetic acid (TCA) which is excreted. The formation of S-(trichlorovinyl)glutathione (TCVG) from PER results in nephrotoxic metabolites. TCVG is cleaved to S-(trichlorovinyl)-L-cysteine (TCVC) and acetylated to N-acetyl-S-(trichlorovinyl)-L-cysteine (N-ac-TCVC), which is excreted with urine. TCVC is also cleaved in the kidney by cysteine conjugate beta-lyase to dichlorothioketene which may react with water to dichloroacetic acid (DCA) or with cellular macromolecules. The object of this study was to comparatively quantify the dose-dependent excretion of PER metabolites in urine of humans and rats after inhalation exposure. Three female and three male human volunteers and three female and three male rats were exposed to 10, 20, and 40 ppm PER for 6 h, and three female and three male rats to 400 ppm. A dose-dependent increase in the excretion of TCA and N-ac-TCVC after exposure to PER was found both in humans and in rats. A total of 20.4 +/- 7.77 mumol of TCA and 0.21 +/- 0.05 mumol of N-ac-TCVC were excreted in urine of human over 78 h after the start of exposure to 40 ppm PER; only traces of DCA were present. After identical exposure conditions, rats excreted 1.64 +/- 0.42 mumol of TCA, 0.006 +/- 0.002 mumol of N-ac-TCVC and 0.18 +/- 0.04 mumol of DCA. Excretion of N-ac-TCVC in male rats exposed to 400 ppm PER (103.7 nmol) was significantly higher, compared to female rats (31.5 nmol) exposed under identical conditions. N-ac-TCVC was rapidly eliminated with urine both in humans (t1/2 = 14.1 h) and in rats (t1/2 = 7.5 h). When comparing the urinary excretion of N-ac-TCVC, a potential marker for the formation of reactive intermediates in the kidney, humans received a significantly lower dose (3 nmol/kg at 40 ppm) compared to rats (23.0 nmol/kg) after identical exposure conditions. In addition, rats excreted large amounts of DCA which likely is a product of the beta-lyase-dependent metabolism of TCVC in the kidney. The obtained data suggest that glutathione conjugate formation and beta-lyase-dependent bioactivation of TCVC in PER metabolism is significantly higher in rats than in humans. Thus, using rat tumorigenicity data for human risk assessment of PER exposure may overestimate human tumor risks.
Sex determination in plants.
The majority of flowering plants produce flowers that are "perfect." These flowers are both staminate (with stamens) and pistillate (with one or more carpels). In a small number of species, there is spatial separation of the sexual organs either as monoecy, where the male and female organs are carried on separate flowers on the same plant, or dioecy, where male and female flowers are carried on separate male (staminate) or female (pistillate) individuals. Sex determination systems in plants, leading to unisexuality as monoecy or dioecy, have evolved independently many times. In dioecious plant species, the point of divergence from the hermaphrodite pattern shows wide variation between species, implying that the genetic bases are very different. This review considers monoecious and dioecious flowering plants and focuses on the underlying genetic and molecular mechanisms. We propose that dioecy arises either from monoecy as an environmentally unstable system controlled by plant growth substances or from hermaphroditism where the underlying mechanisms are highly stable and control does not involve plant growth substances.
Mammography screening among California Medicare beneficiaries: 1993-1994.
BACKGROUND: Over half of all breast cancer deaths occur among women 65 years of age or older. However, mammography screening decreases with increasing age, despite better survival rates for tumors detected early. METHODS: Health Care Financing Administration data from 1993 and 1994, and 1990 United States Census data were used to assess the impact of race, age, Medicaid coverage, and community-level socioeconomic indices on mammography screening for over 800,000 California Medicare beneficiaries. RESULTS: Women who were African American, older, or had Medicaid coverage were significantly less likely to have a biennial mammogram than their counterparts. Women living in areas with fewer college educated residents, with a higher proportion of Mexican or Asian residents had lower use of mammography. However, African-American and Caucasian women with Medicaid coverage had equally low mammography rates (AOR = 1.01, 95% CI .97-1.04), while African-American women with and without Medicaid had similarly low mammography rates (AOR = .96, 95% CI .92-1.01). CONCLUSIONS: Despite dual coverage, Medicare beneficiaries enrolled in Medicaid had few mammograms. African-American Medicare beneficiaries, with and without Medicaid, had low mammography rates. Intervention efforts should be targeted toward these women.
Generation of antibodies to Di- and trichloroacetylated proteins and immunochemical detection of protein adducts in rats treated with perchloroethene.
Antibodies directed against chemical specific protein modifications are valuable tools to detect and comparatively quantify protein modifications. Both Nepsilon-(dichloroacetyl)-L-lysine and Nepsilon-(trichloroacety)l-L-lysine have been detected as modified amino acids in liver and kidneys of rats treated with perchloroethene (PER) after proteolysis. These protein modifications are formed by the interaction of reactive metabolites formed from PER with proteins. In this study we developed monospecific antibodies to dichloroacetylated and to trichloroacetylated amino acids to detect modified proteins in the target organs of PER toxicity. These antibodies were prepared by immunization of rabbits with modified keyhole limpet hemocyanin (KLH) coupled with either the dichloroacetyl or trichloroacetyl moiety. Enzyme-linked immunosorbent assays (ELISA) indicated that the polyclonal rabbit sera recognized dichloroacetylated or trichloroacetylated rabbit serum albumin (RSA), but not unmodified protein. Therefore, we further purified rabbit antisera on either Nepsilon-(dichloroacetyl)-L-lysine or Nepsilon-(trichloroacetyl)-L-lysine immobilized to immunoaffinity columns to obtain monospecific antibodies. The potential of these antibodies in the detection of di- and trichloroacetylated proteins and their selectivity for the desired dichloroacetyl or trichloroacetyl group was demonstrated in competitive enzme-linked immunosorbent assays with several structurally related compounds. Anti-dichloroacetyl (anti-DCA) antibody binding to dichloroacetylated RSA was inhibited by Nepsilon-(dichloroacetyl)-L-lysine with an IC50 value of 150 microM whereas inhibition by Nepsilon-(monochloroacetyl)-L-lysine and Nepsilon-(trichloroacetyl)-L-lysine showed an IC50 value of 100 mM. The binding of the anti-trichloroacetyl (anti-TCA) antibody to trichloroacetylated RSA was inhibited by Nepsilon-(dichloroacetyl)-L-lysine with an IC50 value of 80 mM. The inhibition by Nepsilon-(trichloroacetyl)-L-lysine was again 3 orders of magnitude stronger resulting in an IC50 value of 90 microM. Nepsilon-(acetyl)-L-lysine and unmodified RSA did not effect antibody binding to the chemically modified antigen. The antibodies were also successfully applied to detect modified proteins in subcellular fractions of liver and kidney from PER treated rats demonstrated in immunoblot. Protein adduct formation from different PER metabolism pathways was confirmed by the observation that the majority of dichloroacetylated proteins were located in kidney mitochondria and trichloroacetylated proteins were located in liver microsomes.
Clear-cell carcinoma of the ovary in a 19-year-old woman.
The risk of inadvertently treating an ovarian malignancy is always present regardless of the patient's age, clinical history, ultrasound features, serum tumour markers, menopausal status and intraoperative findings. This risk can be minimized by paying particular attention to high-risk characteristics in any of the above assessment criteria and by obtaining an intraoperative frozen section if there is any suspicion of malignancy. The same approach should be used whether the initial treatment is by laparotomy or laparoscopy. We present a case of clear-cell carcinoma of the ovary in a 19-year-old woman where there was delay in diagnosis and treatment as a result of an incorrect initial histopathology assessment. This appears to be the youngest patient reported in the literature with a clear-cell carcinoma of the ovary.
A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy.
The use of single-dose intramuscular methotrexate for the primary treatment of ectopic pregnancy is increasing in frequency in many countries. We performed a systematic review of all available studies and case reports of intramuscular methotrexate to examine the therapeutic efficacy, side-effects and complication rates of this new treatment approach. The pooled data show a successful resolution rate of 71% (95% confidence interval 58% to 81%) after a single dose of intramuscular methotrexate and 84% (95% confidence interval 77% to 90%) after 1 or 2 doses. Side-effects were experienced by 24% (95% confidence interval 9% to 47%) of patients and 10% (95% confidence interval 7% to 14%) had a ruptured ectopic pregnancy. The pooled data show that single-dose intramuscular methotrexate is associated with a high failure rate. Follow-up is prolonged and there is a significant incidence of minor side-effects. Serious complications and side-effects have occurred. The use of intramuscular methotrexate should be confined to clinical trials until more evidence is obtained to support its more widespread use.
Comparison of progenitor cell content in sequential peripheral blood progenitor collections after mobilization with chemotherapy and granulocyte macrophage colony-stimulating factor.
Optimal timing of peripheral blood progenitor cell (PBPC) harvest to collect maximal stem cell numbers is unknown. We assessed the progenitor cell content in 128 PBPC harvests from 21 patients primed with chemotherapy and granulocyte macrophage-colony stimulating factor (GM-CSF) in relation to absolute neutrophil count (ANC) at collection time. Samples were obtained by leukapheresis during rebound from chemotherapy-induced neutropenia while receiving GM-CSF, and assayed by flow cytometry for CD34+ and by colony assays for CFU-GM and BFU-E. The CD34+ cell concentrations per sample tended to be greater at an ANC < 1,000 mm3 and decreased with rising ANC (p = 0.001). The CFU-GM and BFU-E concentrations per sample remained relatively constant with rising ANC (p = 0.72, p = 0.90, respectively). Total CD34+ cell number per harvest per kg slightly increased with ANC levels (p = 0.044) whereas the total CFU-GM and the total BFU-E per kilogram increased more modestly with rising ANC (p < 0.001, p < 0.001, respectively). We conclude that after priming with chemotherapy and GM-CSF, PBPC could be collected at different absolute neutrophil counts without greatly affecting total CD34+ cell numbers. The greater concentration of CD34+ progenitor cells at a lower ANC together with the CFU-GM and BFU-E peaking with higher ANC suggest a less mature progenitor cell population at lower ANC levels.
A comparison of HIV risk behaviors among women drug users from two cities in a rural state: recommendations for targeted prevention.
Most HIV prevention programs for women target individual risk behaviors while the influence of larger contextual factors, such as city of residence, are often neglected. This preliminary study compares women drug users from two different cities in the largely rural state of Kentucky on HIV risk behaviors. The women are from Lexington, a medium sized metropolitan area, and from Louisville, a large metropolitan area. Comparisons between the women from the two cities indicate that there are many similarities in their risk behaviors, but also some important differences. The women from Lexington (the smaller city), are more likely to be at risk for becoming infected with HIV due to their drug use, while the women from Louisville (the larger city) are more likely to be at risk because of their sex exchange practices and economic situation. The implications for prevention are discussed.
An American tragedy.
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