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PubMed1984

Alkaline elution of rat testicular DNA: detection of DNA strand breaks after in vivo treatment with chemical mutagens.

The alkaline elution technique was used to measure DNA strand breaks in rat testes after intraperitoneal injection of several chemicals known to cause heritable mutations in rodents. Methyl methanesulfonate (MMS), ethyl methanesulfonate, methylnitrosourea, and ethylnitrosourea all produced single strand breaks in rat testicular DNA. For both of these pairs of homologous alkylating agents the relative potency was methyl analog greater than ethyl analog. Strand breaks produced by MMS appeared rapidly (within 2 h) in rat testicular DNA and were partially repaired within 24 h. Studies with low doses of MMS indicate that the assay has the sensitivity to detect DNA strand breaks in the testis after a dose of only 5 mg/kg. Variability in DNA elution profiles for individual control animals and for individual animals given identical doses of MMS was small. In contrast to the results with known mutagens, intraperitoneal injection of nonmutagens such as dimethyl sulfoxide, phenol, and Triton X-15, did not produce strand breaks in testicular DNA. These data indicate that this assay detects DNA strand breaks in the rat testis. The results for several heritable mutagens and nonmutagens are qualitatively predictive of mutagenic activity in the testis.

Animals↗

PubMed1993

Variability in response to D-penicillamine: pharmacokinetic insights.

D-Penicillamine (D-Pen) is one of a group of chemically similar drugs which are efficacious in rheumatoid arthritis and which have similar patterns of biotransformation and similar toxicity. These similarities suggest associations between the transformations of D-Pen and it's toxicity and efficacy. Oxidation, methylation, formation of stable adducts with protein, interaction with metals and reduction of oxygen species have been shown in-vivo or in-vitro. Metabolism to a sulphoxide may occur and may be relevant to toxicity. Intracellular concentrations of D-Pen and metabolites are largely unknown.

Biotransformation↗

PubMed1985

Assessment of chemically induced DNA repair in primary cultures of human bronchial epithelial cells.

A procedure has been developed to assess chemically induced DNA repair in freshly isolated, primary cultures of human bronchial epithelial (HBE) cells. HBE cells were isolated from eight samples of autopsy material or surgical specimens and incubated with test chemicals and [3H]thymidine. Viability as measured by trypan blue exclusion averaged 90%. Chemically induced DNA repair was assessed as unscheduled DNA synthesis (UDS) by quantitative autoradiography. The direct-acting agent methyl methanesulfonate induced DNA repair in HBE cells in all eight cases studied, indicating that the cultures were viable and capable of DNA repair in response to DNA damage. Benzo(a)pyrene induced DNA repair in all cultures whereas dimethylnitrosamine failed to induce UDS in any culture, suggesting an organ-specific pattern of metabolic activation. 1,6-Dinitropyrene was positive in cultures prepared from autopsy material but negative in cultures prepared from surgical specimens. Formaldehyde did not induce UDS in any sample examined. This system may be useful in assessing the genotoxic potential of environmental chemicals in human bronchial epithelial cells, give an indication of interindividual variability, and provide valuable information for comparison to proposed animal models for the human bronchus.

Aged↗

PubMed2006

Bladder tumor contains higher N7-methylguanine levels in DNA than adjacent normal bladder epithelium.

Schistosoma haematobium-infected patients are more likely to develop bladder cancer and be more exposed to carcinogenic N-nitroso compounds than uninfected patients. As N7-methylguanine is a marker of exposure to methylating agents of this type, we have measured N7-methyldeoxyguanosine 3'-monophosphate (N7-MedGp) by (32)P postlabeling. DNA was isolated from 42 paired normal and tumor tissue of Egyptians with bladder cancer. N7-MedGp was detected in DNA from 93% of the tumors and 74% of the normal bladder tissue samples. Adduct levels were highly variable and ranged from 0.04 to 6.4 and from 0.02 to 0.72 micromol/mol deoxyguanosine 3'-monophosphate (dGp) in tumor and normal DNA, respectively. N7-MedGp levels in normal and tumor DNA were highly correlated with one another (P = 0.007). The mean difference (95% confidence interval) in adduct levels between tumor and normal DNA was 0.21 (0.13-0.32) micromol/mol dGp and this was statistically significant (P < 0.001). The adduct ratio (tumor DNA/normal DNA) varied between 0.2 and 136 (median, 4.6). N7-MedGp levels were not associated with gender, age, or the presence of schistosomiasis. However, lower N7-MedGp levels were found in normal DNA from individuals lacking the GSTM1 gene (P = 0.03) but not the GSTT1 gene or in subjects with the Ile105Val GSTP1 polymorphism. These results show that exposure to methylating agents is widespread and suggest that such exposure may play a role both in tumor initiation and progression.

Bacterial Infections↗

PubMed1990

Glutamate- and aspartate-induced extracellular potassium and calcium shifts and their relation to those of kainate, quisqualate and N-methyl-D-aspartate in the isolated turtle cerebellum.

Ion-selective microelectrodes can be used to evaluate the characteristics and laminar distribution of excitatory amino acid agonist-induced K+ and Ca2+ shifts in the extracellular environment of brain cells. This report describes the pattern of K+ increases and Ca2+ decreases elicited by glutamate and aspartate at 100 microns intervals in the isolated turtle cerebellum. These responses were compared to ion shifts evoked by kainate, quisqualate and N-methyl-D-aspartate. Glutamate and aspartate produced indistinguishable laminar patterns of ion shifts, with the greatest [K+]o and [Ca2+]o shifts in the granular layer. The average maximum granular and molecular layer increases in [K+]o were, respectively, 130% and 24% larger than the increase in the Purkinje cell layer. Kainate-induced increases in [K+]o also followed this granular greater than molecular greater than Purkinje cell layer pattern; however, the corresponding [Ca2+]o decreases were smaller and more variable. Quisqualate-evoked ion shifts in the molecular layer closely mimicked the shape of glutamate- and aspartate-induced responses. In the granular layer, however, quisqualate caused little ion change during iontophoresis followed by large [K+]o and [Ca+]o shifts after the end of the pulse. The minimal ion shifts induced during quisqualate application in the granular layer gave this agonist the distinction of being the only agent tested to have its greatest direct effect in the molecular layer. N-Methyl-D-aspartate caused large, two-phase [K+]o and [Ca2+]o shifts in the granular layer, only small [K+]o rises in the Purkinje cell and ventral molecular layers, and no response in the dorsal molecular layer. The lack of similarity between glutamate- and aspartate-induced ion shifts in the granular layer and those of any one agonist demonstrate the mixed agonist action of glutamate and aspartate in the cerebellum. These studies provide new information about the dynamics of excitatory amino acid receptor activation that is complementary to autoradiographic receptor mapping data and to single cell electrophysiological studies.

Amino Acids↗

PubMed2000

Responses of the tropical bont tick, Amblyomma variegatum (Fabricius), to its aggregation-attachment pheromone presented in an air stream on a servosphere.

Male Amblyomma variegatum ticks feeding on a host release a mixture of o-nitrophenol and methyl salicylate which serves to attract conspecifics. The behavioural responses of A. variegatum on a servosphere to these volatiles presented in an air stream are detailed here. In still air, ticks walked on all eight legs, but with long halts. In contrast, the air stream caused continuous walking and induced a reaching response where the forelegs actively sampled the air. Such reaching increased the angular velocity and reduced walking speed, effects that were amplified in the presence of vapours from o-nitrophenol and methyl salicylate in the air flowing over the ticks. Vapour from a 1:1 mixture of o-nitrophenol and methyl salicylate was attractive over a 10(4)-fold concentration range providing an increase in upwind displacement of 20-40%, significantly higher than the natural ratio where o-nitrophenol vapour predominates. Although the responses to o-nitrophenol vapour were variable when presented alone, this chemical was consistently attractive when delivered with steer hair odour unattractive on its own. Moreover, the upwind walk to this combination did not cause a change in speed or angular velocity. This supports the hypothesis that the response to the pheromone is enhanced by host odour.

Air Movements↗

PubMed1984

Cimetidine-methylprednisolone-theophylline metabolic interaction.

The pharmacokinetics of theophylline and methylprednisolone were examined before and during cimetidine treatment in an asthmatic woman who required long-term administration of these drugs. Cimetidine reduced theophylline plasma clearance by 30 percent, and measurement of urinary metabolites showed that 3-methylxanthine formation was inhibited more strongly than that of the methylated uric acid metabolites. Assessment of methylprednisolone disposition following oral and intravenous doses revealed no effect of cimetidine on the bioavailability (74 to 81 percent absorption) or plasma clearance (22 to 24 liters per hour) of the steroid. Thus, cimetidine exhibits variable and selective effects on the biotransformation pathways of drugs important in asthma therapy.

Adult↗

PubMed1975

Light-induced de-epoxidation of violaxanthin in lettuce chloroplasts. IV. The effects of electron-transport conditions on violaxanthin availability.

1. In isolated chloroplasts of Lactuca sativa var. Manoa, the size of the violaxanthin fraction which is available for de-epoxidation is not directly dependent on electron transport but rather related to the reduced level of some electron carrier between the photosystems. This is concluded from the effects of various electron-transport conditions on violaxanthin availability: Under conditions of electron transport through both photosystems, availability was saturated at a lower electron-transport rate with actinic light at 670 than at 700 nm. Under conditions of electron transport through Photosystem I, availability was smaller for linear electron flow from reduced N-methylphenazonium methosulfate via methylviologen to oxygen than from cyclic electron flow mediated by either N-methylphenazonium methosulfate or 2,6-dichlorophenolindophenol; in addition for linear flow from reduced N-methyphenazonium methosulfate via methylviologen to oxygen, availability increased with decreasing light intensity. 2. The postulated carrier whose reduced level is related to availability seems to be some carrier between plastoquinone and the primary acceptor of Photosystem II or plastoquinone itself. This conclusion follows from the fact that availability increased with increasing light intensity under conditions of electron flow through both photosystems and that 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (greater than or equal to 1 mu M) had no effect on availability, whereas low levels of 3, 3-(3',4'-dichlorophenyl)-1,1-dimethylurea resulted in decreased availability (50 percent decrease at 1 mu M). Furthermore, availability in 3,3-(3',4'-dichlorophenyl)-1,1-dimethylurea-poisoned chloroplasts was fully restored by 2-methyl-1,4-naphtoquinone (menadione) which mediates cyclic electron flow through plastoquinone. 3. Violaxanthin availability was zero in the dark and increased in the light to maximum of 67 percent of the total violazanthin in chloroplasts. It is proposed that this variable violaxanthin availability reflects conformational changes on the internal surface of the thylakoid membrane which result in variable exposure of violaxanthin to the de-epoxidase. The fact that not all of the violaxanthin was available for de-epoxidation may indicate a heterogenous distribution of violaxanthin in the membrane.

Aerobiosis↗

PubMed1977

The effects of tiadenol, clofibrate and clofibride on bile composition in the rat.

Biliary secretion was studied in normolipidemic rats after a 7 day treatment with the hypolipidemic drugs, tiadenol (bis-(hydroxyethylthio)-1,10-decane), clofibrate and clofibride (chloro-4-phenoxy-2-methyl-2-propionate of dimethylcarbamoyl-3-propyl). All three drugs decreased blood cholesterol and total lipids, increased liver weight and liver catalase content, and decreased biliary excretion of cholesterol. The biliary concentrations of bile salts, phospholipids and cholesterol decreased to a variable extent, in such a way that the ratio of bile salts + phospholipids to cholesterol was increased by the drugs. The bile salt independent fraction was increased. The effects were qualitatively similar for all three drugs tested, but quanitative differences appeared for some of the parameters.

Amides↗

PubMed2006

Multinuclear NMR spectroscopic and theoretical study on the interactions between diperoxovanadate complex and picoline-like ligands.

To understand the substituting effects of organic ligands on the reaction equilibrium, the interactions between diperoxovanadate complex [OV(O(2))(2)(H(2)O)](-) and a series of picoline-like ligands in solution were explored using 1D multinuclear ((1)H, (13)C, and (51)V) magnetic resonance, 2D diffusion ordered spectroscopy (DOSY), and variable temperature NMR in 0.15 mol/l NaCl ionic medium for mimicking the physiological conditions. The order of reactive capability of the picoline-like ligands with [OV(O(2))(2)(H(2)O)](-) is found to be picolinamide>N-methylpicolinamide>methyl picolinate>ethyl picolinate approximately propyl picoliniate>isopropyl picolinate. The substituting group influences the reactivity by either steric effect or electron-donating effect. Competitive coordination interactions result in a series of new seven-coordinated peroxovanadate species [OV(O(2))(2)L](-) (L=picoline-like ligands). Their coordination ways were confirmed by density functional calculations.

Carbon↗

PubMed2000

An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette's syndrome.

Several lines of evidence suggest that a genetic component underlies Tourette's syndrome (TS). We investigated both the role of the insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and that of the Val-158-Met substitution in the catechol-O-methyl-transferase (COMT) gene in conferring susceptibility to TS. Fifty-two TS patients were recruited and compared with a control group of 63 healthy subjects. Neither a genotypic nor an allelic association was found; subdividing TS patients according to clinical variables, such as a co-diagnosis of obsessive-compulsive disorder (OCD) and a positive family history for obsessive compulsive disorder or tics, also failed to reveal a significant association. The lack of significance for 5-HTTLPR and COMT polymorphisms in conferring liability to TS does not exclude a role of different functional polymorphisms in genes coding for serotonergic or dopaminergic structures in the etiology of TS. In fact, TS is a complex disorder and these genes most likely have only a minor genetic effect in its etiology.

Adult↗

PubMed2004

Landscape-level approach to assess aquatic exposure via spray drift for pesticides: a case study in a Mediterranean area.

The development of methods to extract information from landscape analysis to refine risk assessment is becoming increasingly important. This paper presents results from a pesticide surface water exposure assessment at the watershed scale, based on a combination of edge of field studies, large-scale monitoring studies, and modeling activities with GIS-based landscape analysis methodologies covering an area of approximately 3200 ha surrounding the Simeto River in Sicily (Italy). The dynamic behavior of the pesticide chlorpyrifos-methyl was modeled in two different steps: calculation of the fraction of the application rate that is deposited beyond the field edge and simulation of the fate and persistence of the pesticide in the aquatic environment. Drift loads showed high spatial variability. Considering spray drift deposition as a fraction of the pesticide application rate, 60% of the results were < or = 0.02 (equal to 0.04 mg/m2). Only 8.5% of the results were above 0.5. The highly variability of the landscape factors was reflected in the results. More than 60% of the predicted pesticide concentrations were less than the limit of quantification (0.05 microg/L), affecting about 75% of the total length of the river tract analyzed. Predicted pesticide concentrations were higher than 0.1 microg/L in 23% of cases, but this corresponded to an insignificant portion of the river (1.2% of the total length). These results suggest that management options, such as increased no-spray zones, could provide further protection for surface water. These could be modeled to illustrate their overall impact. As an alternative, the introduction of a 20-m no-spray zone clearly reduced potential exposure, and 92% of the water body was protected. Estimated data are in agreement with data collected during a field monitoring study.

Air Movements↗

PubMed2006

Sorption-desorption of imidacloprid and its metabolites in soil and vadose zone materials.

Sorption-desorption is one of the most important processes affecting the leaching of pesticides through soil because it controls the amount of pesticide available for transport. Subsurface soil properties can significantly affect pesticide transport and the potential for groundwater contamination. This research characterized the sorption-desorption of imidacloprid (1-[(6-chloro-3-pyridinyl)-methyl]-N-nitro-2-imidazolidinimine) and three of its metabolites, 1-[(6-chloro-3-pyridinyl)methyl]-2-imidazolidinone (imidacloprid-urea), 1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-1H-imidazol-2-amine (imidacloprid-guanidine), and 1-[(6-chloro-3-pyridinyl)methyl]-1H-imidazol-2-amine (imidacloprid-guanidine-olefin), as a function of changing soil properties with depth in two profiles extending from the surface to a depth of 1.8 or 8 m. Sorption of each compound was highly variable and hysteretic in all cases. Normalizing the sorption coefficients (K(f)) to the organic carbon or the clay content of the soil did not reduce the variability in sorption coefficients for any compound. These results illustrate the importance of evaluation of the sorption data used to predict potential mobility. Understanding the variability of soil properties and processes as a function of depth is necessary for accurate prediction of pesticide dissipation.

Adsorption↗

PubMed1999

An open trial comparing isradipine with hydralazine and methyl dopa in the treatment of patients with severe pre-eclampsia.

Placental blood flow is decreased in pre-eclampsia and is worsened by decreasing blood pressure. Hydralazine, which causes vasodilatation, does not affect placental bed vessels. Calcium channel blockers (like isradipine) are vasodilators that do affect placental bed vessels and should improve blood flow even while decreasing blood pressure. The aim of the study was to determine if isradipine (parenteral and oral) was better than parenteral hydralazine and oral methyl dopa in severe pre-eclampsia in achieving better control of blood pressure. The study was a prospective randomised trial performed at The University Hospital of the West Indies. The sample consisted of 39 women with severe pre-eclampsia. Variables examined consisted of blood pressure before and after treatment, the increment in gestational age at delivery related to treatment, fetal Apgar score and birth weight. There were no significant differences in any of these variables between the two groups. Isradipine was as effective as hydralazine in reducing maternal blood pressure and in prolonging pregnancy.

Clinical Trial↗

PubMed1976

Phosphatidylcholine synthesis in castor bean endosperm.

Three pathways for phosphatidylcholine synthesis were assayed in castor bean (Ricinus communis var. Hale) endosperm. Phosphatidylethanolamine: S-adenosylmethionine methyl transferase occurred predominantly in the endoplasmic reticulum fraction, but some activity appeared in the mitochondria. Phosphorylcholine glyceride transferase occurred exclusively in the endoplasmic reticulum. The phosphorylcholine glyceride transferase activity was approximately 20-fold greater than the methylation pathway in the endoplasmic reticulum. No exchange activity was found. The Michaelis constant for the methylation was 31 mum for S-adenosylmethionine; phosphatidylethanolamine promoted the reaction slightly while other intermediates stimulated it by about 50%. The pH optimum was 9. Phosphorylcholine glyceride transferase had a Michaelis constant of 9.7 mum for cytidine diphosphate choline but variable results were obtained from diglycerides. The pH optimum was 7.5 and a divalent cation was required, Mg(2+) giving the greatest stimulation.

Journal Article↗

PubMed2006

Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis.

PURPOSE: Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. EXPERIMENTAL DESIGN: Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed. RESULTS: Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival. CONCLUSIONS: Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.

Alkenes↗

PubMed2004

COX-2, MMP-9, and Noguchi classification provide additional prognostic information about adenocarcinoma of the lung. A study of 117 patients from Brazil.

We report immunohistochemical staining results for cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 in primary tumors of 117 patients with resected adenocarcinoma of the lung (median follow-up, 20 months). For COX-2, we graded the degree of tumor staining according to the sum of staining intensity and the proportion of cells staining. For MMP-9, we used morphometry to quantify cytoplasmic staining. We used the Cox proportional hazards model to analyze overall survival. With only 29 patients censored at last follow-up, after controlling for the effect of pathologic stage, staining for COX-2 and MMP-9 and subtype of tumor were related significantly to survival (P < 6 x 10(-5)). The effects of COX-2 and MMP-9 were opposite. Whereas any staining for COX-2 decreased the hazard and increased survival time, increased staining for MMP-9 increased the hazard and decreased survival time. The results also suggested that staining for COX-2 decreases with dedifferentiation. Our results suggest that staining for the combination of COX-2 and MMP-9 and categorizing tumors into papillary and nonpapillary types may provide important prognostic information for patients with resected adenocarcinoma of the lung; it is possible that these 3 variables could aid decisions about postoperative adjuvant treatment.

Adenocarcinoma↗

PubMed1988

In vivo behavior of murine epidermal cell lines derived from initiated and noninitiated skin.

The in vivo behavior of cell cultures derived from normal and carcinogen-treated mouse epidermis was studied by implanting the cultures in a s.c. vascularized bed protected by a silicone chamber. Cells derived from normal adult mouse epidermis as well as cells derived from tumor-promoter-treated skin were unable to grow in these systems. Conversely, cell lines derived from skin initiated with single doses of N-methyl-N'-nitro-N-nitrosoguanidine or 9,10-dimethyl-1,2-benzanthracene proliferated in these chambers, reforming an epithelial structure. The type of structure in the chambers varied, ranging from formation of almost normal epithelia to atypical invasive behavior. The variable in vivo behavior among the different cell lines may be attributed to the initiation agent, the number of passages of the cultures, random genetic events, the strain of mouse, or a combination of these factors. Most of the cell types used in this study and all the cell lines that were able to grow in these chambers were selected for resistance to Ca-induced terminal differentiation. However, resistance to terminal differentiation according to the Ca2+ switch does not always correlate with the ability to grow in the chambers, since cell lines derived from spontaneous foci of resistance failed to grow in this system. These studies showed some of the possibilities of the SC silicone chambers to study the histogenic potential of cell lines derived from carcinogen-treated epidermis. This system also appears suitable to study the complex relationship between epidermal cells and specialized (dermal) stroma.

9,10-Dimethyl-1,2-benzanthracene↗