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Biomedical subjects

C J Smith

Publications and source records attributed to C J Smith.

At least 55 records · Page 3Linked to original sources
PubMed2000

Urinary mutagenicity in nonsmokers following exposure to fresh diluted sidestream cigarette smoke.

Ten healthy male and 10 healthy female 'never-smoking' subjects (ages 21-50) participated in a 5-day environmental room study to determine if an acute exposure to a high level of fresh diluted sidestream smoke (FDSS) would alter urinary mutagenicity. On Monday, Tuesday, Thursday and Friday, the 20 subjects sat in environmental rooms for 7.33h and were exposed to filtered and humidified air. On Wednesday, the 20 subjects were exposed in the environmental rooms for 7.33h to an average respirable suspended particle (RSP) concentration of 179 microg/m(3) of FDSS generated by machine smoking 1R4F Kentucky reference cigarettes. This level of FDSS is approximately three times the ETS level seen in the top 5% of US workplaces which allow smoking. A cumulative 7.33h air sample from each environmental room was collected and determined to be mutagenic by Ames Salmonella assay. Subjects' urinary mutagenicity was measured on Wednesday as compared with Tuesday or Thursday by assaying concentrates of 24h urine samples in Ames Salmonella bacterial strains TA98 and YG1024. Diet was strictly controlled on all study days, with broiled and pan-fried meat not served to minimize ingestion of mutagenic protein pyrolysis products. Although all the urinary mutagenicity values were within the range reported for minor changes in diet, the subjects experienced a small but statistically significant increase (p<0.05) in urinary mutagenicity in strain YG1024, but not in the less sensitive strain TA98 on the day of FDSS exposure.

Adult↗
PubMed2000

Comparative QSAR evidence for a free-radical mechanism of phenol-induced toxicity.

Phenol and 14 substituted-phenols were tested for their ability to impair epithelial cell membrane integrity in WB rat liver cells as determined by an increase in lactate dehydrogenase release. Two quantitative structure-activity relationship (QSAR) regression equations were developed which showed that separate mechanisms of phenolic cytotoxicity are important - nonspecific toxicity due to hydrophobicity and formation of phenoxyl radicals. The equations most predictive of phenol toxicity are denoted as log1/C=-0. 98sigma(+)+0.77logP+0.23 or log1/C=-0.11BDE+0.76logP+0.21, respectively, where C is the minimum concentration of substituted-phenol required for a toxic response. P is the octanol-water partition coefficient, sigma(+) is the electronic Hammett parameter and BDE is the OH homolytic bond dissociation energy. In the literature, phenol toxicity correlated to sigma(+) is rare, but there is strong evidence that phenols possessing electron-releasing groups may be converted to toxic phenoxyl radicals. A common feature in a variety of cells is generation of elevated amounts of reactive oxygen species (ROS) associated with a rapid growth rate. The slightly elevated cancer risk associated with the use of Premarin may be due to phenoxyl-type radicals derived from one or more of its components.

Animals↗
PubMed2000

Inhaled corticosteroid use and bone-mineral density in patients with asthma.

BACKGROUND: Inhaled corticosteroids are absorbed into the systemic circulation, but the extent to which they have adverse effects on bone is uncertain. The question is important since 3% of the European population take an inhaled corticosteroid regularly and may do so for many years. METHODS: We studied the dose-response relation between cumulative inhaled corticosteroid dose and bone-mineral density at the lumbar spine and proximal femur in 196 adults (119 women) with asthma aged 20-40 years. Patients had taken an inhaled corticosteroid regularly for at least 6 months, and had had limited exposure to systemic steroids. Cumulative dose of inhaled corticosteroid was calculated from questionnaires and computerised and written general-practice records, and its effect on bone-mineral density was estimated by multiple regression analysis. FINDINGS: Median duration of inhaled corticosteroid treatment was 6 years (range 0.5-24), and median cumulative dose was 876 mg (87-4380). There was a negative association between cumulative dose of inhaled corticosteroid and bone-mineral density at the lumbar spine (L2-L4), femoral neck, Ward's triangle, and trochanter, both before and after adjustment for the effects of age and sex. A doubling in dose of inhaled corticosteroid was associated with a decrease in bone-mineral density at the lumbar spine of 0.16 SD (95% CI 0.04-0.28). Similar decreases were found at the femoral neck, Ward's triangle, and trochanter. Adjustment for potential confounding factors including physical activity and past oral, nasal, dermal, and parenteral corticosteroids did not weaken the associations. INTERPRETATION: This study provides evidence of a negative relation between total cumulative dose of inhaled corticosteroid and bone-mineral density in patients with asthma.

Absorptiometry, Photon↗
PubMed2000

A novel covalent modification of nitrogenase in a cyanobacterium.

In extracts of the unicellular cyanobacterium Gloeothece, the Fe-protein of nitrogenase can be separated by SDS-PAGE into two antigenically identifiable components. Unlike the situation in photosynthetic bacteria such as Rhodospirillum rubrum, these two forms do not arise from covalent modification of the protein by ADP-ribosylation. Rather, the Fe-protein of Gloeothece nitrogenase is subjected to modification by palmitoylation.

Cyanobacteria↗
PubMed2000

Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart.

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.

Animals↗
PubMed2000

The relative toxicity of compounds in mainstream cigarette smoke condensate.

Many different in vivo and in vitro tests are currently used to assess the toxicity of chemicals and complex mixtures such as cigarette smoke condensate. In vivo tests include assays in rodents to determine carcinogenicity, tumorigenicity and reproductive effects In vitro tests of mutagenicity are conducted with both bacterial and mammalian cell systems. A first step towards lowering the toxicity of cigarette smoke condensate is the identification of the relevant compound However, changing the concentration of a given smoke component may not linearly alter the biological activity of the complex mixture due to interactive effects. The "effective toxicity" of a chemical constituent is a function of the concentration, the metabolic fate, the potency in in vivo and in vitro assays, and the ability to reach the target tissues. The logarithm of the octanol-water partition coefficient (log P) is an important parameter since it affects metabolism, biological transport properties and intrinsic toxicity. Using concentration data from the International Agency for Cancer Research (IARC), biological activity data from the Registry of Toxic Effects of Chemical Substances (RTECS) database and measured and calculated log P values, we have rank ordered some of the important compounds in cigarette smoke condensate by their measured or potential toxicity. Condensates from different cigarette brands, tar categories and styles vary in their concentrations of these compounds. Chemicals of greater commercial or scientific interest may be toxicity tested more extensively, thereby increasing the probability of positive test results and highlighting the need for consideration of structure-activity relationships.

Acetaldehyde↗
PubMed2000

"IARC group 2B Carcinogens" reported in cigarette mainstream smoke.

In the third and final part of a series surveying the international literature on the "IARC carcinogens" in cigarette mainstream smoke, the "IARC Group 2B carcinogens" are reviewed. A search of the published literature shows that of 227 chemical components classified as Group 2B, that is, "possible carcinogens," by the International Agency for Research on Cancer (IARC), 48 have previously been reported in cigarette mainstream smoke. Owing to its highly interactive molecular nature, removal from or inhibition of a given mutagenic or carcinogenic chemical within the complex aerosol mixture cannot reliably be predicted to reduce either the overall mutagenicity or carcinogenicity. However, in the absence of experimental data demonstrating an increase in adverse biological activity resulting from removal or inhibition of a potentially carcinogenic constituent, negation of the activity of the potential carcinogen may be considered as a desirable circumstance.

Carcinogens↗
PubMed2000

"IARC group 2A Carcinogens" reported in cigarette mainstream smoke.

As a follow-up to an earlier study on IARC Group I compounds, further efforts have been made to evaluate the international literature on cigarette mainstream smoke for reports on constituents classified as IARC "Group 2A: probably carcinogenic to humans" and IARC "Group 2B: possibly carcinogenic to humans." IARC classifies 59 agents, mixtures and exposures as Group 2A. Of the overall list of 59, 50 represent chemical entities or complex mixtures ( [IARC,] ). When only chemical entities which have their origin from cigarette components (tobacco and paper) are considered, further searching of the international literature has revealed that nine chemical compounds of the 50 Group 2A listings have been reported in cigarette mainstream smoke ( Table 1 ). In micrograms/cigarette (mug/cig), the ranges reported for each of the nine compounds are as follows: formaldehyde (3.4-283); benzo[a]pyrene (B[a]P) (0.004-0. 108); dibenz[a,h]anthracene (DB[a,h]A) (0.004-0.076); N-nitrosodiethylamine (DEN) (non-detectable-0.0076); benz[a]anthracene (B[a]A) (trace-0.08); N-nitrosodimethylamine (DMN) (non-detectable-0.7-1.62); acrylamide (1.1-2.34); 1,3-butadiene (16-77); and 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) (0. 00026-0.00049).

Animals↗
PubMed2000

Clathrin coat construction in endocytosis.

Electron cryomicroscopy of the clathrin coat and X-ray crystallography of parts of the clathrin heavy chain combine to give a detailed picture of the clathrin molecule, assembled as a cage. Recently determined domain structures of other components of the endocytic machinery, particularly the mu2 subunit and the alpha-appendage domain of the AP2 adaptor complex, provide important information on the sequence of recognition events involved in the dynamic process of clathrin coat assembly.

Adaptor Protein Complex 1↗
PubMed2000

Novel polyketide metabolites from a species of marine fungi.

Fermentation of a marine fungal species obtained from a tissue sample of a marine sponge collected in Indonesia in October 1996, yielded the novel hexaketide compounds iso-cladospolide B (1); seco-patulolide C (2); the 12-membered macrolides, pandangolide 1 (3) and pandangolide 2 (4); and the known terrestrial fungal metabolite, cladospolide B (5).

Fungi↗
PubMed2000

Current and potential therapeutic uses of lanthanide radioisotopes.

In the last 25 years, diagnostic nuclear medicine has come to depend on the versatile chemistry of a single radioisotope, technetium-99m (Tc-99m). Different chelating molecules can be used to guide Tc-99m through various physiological pathways in the body to gain information about disease states. No single radioisotope similarly dominates therapeutic applications. In the field of radioisotope therapy, much discussion and debate have focused on what radioisotope might be "ideal" for treatment of malignant tumors. The ideal may not be a single radioisotope, but rather the class of very closely related radiolanthanides and lanthanide-like radioisotopes. These radioisotopes possess strikingly similar chemistries and thus all may be conjugated to biomolecules using a single chelate, the DOTA moiety (and its chemical analogs). They also provide a wide range of physical characteristics, such as half-lives and beta energies, that can be chosen to match the biological properties of the conjugated biomolecule and the malignant tumor. Thus, the radiolanthanide-DOTA bioconjugate model provides a set of physically diverse, but chemically very similar, therapeutic radiopharmaceutical agents, the individual members of which can be tailored to treat specific types of cancers.

Alpha Particles↗
PubMed2000

Vanillin (3-methoxy-4-hydroxybenzaldehyde) inhibits mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C but not (137)Cs gamma-radiation at the CD59 locus in human-hamster hybrid A(L) cells.

We have investigated the ability of the naturally occurring plant essence vanillin (3-methoxy-4-hydroxybenzaldehyde) to inhibit mutation at the CD59 locus on human chromosome 11 by hydrogen peroxide, N-methyl-N-nitrosoguanidine, mitomycin C and (137)Cs gamma-radiation in human-hamster hybrid A(L) cells. Previous studies using vanillin have suggested that it can inhibit chromosome aberrations induced by hydrogen peroxide and mitomycin C, as well as inhibiting X-ray- and UV-induced mutations at the hprt locus. Other studies with vanillin have shown that it can increase both the toxicity and mutagenicity of ethyl methane sulfonate and increase the induction of sister chromatid exchange by mitomycin C and a variety of other mutagens. The increased sensitivity of the A(L) assay, which is due in part to its ability to detect both small (single locus) and large (multilocus) genetic damage, allows us to measure the effect of vanillin at low doses of mutagen. Vanillin is shown, in these studies, to inhibit mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C, as well as to enhance the toxicity of these agents. Vanillin had no effect on either toxicity or mutation induced by (137)Cs gamma-radiation. The vanillin-induced potentiation of H(2)O(2) toxicity is shown not to involve inhibition of catalase or glutathione peroxidase. These results show that vanillin is able to inhibit mutation at the CD59 locus and modify toxicity in a mutagen-specific manner. Possible mechanisms to explain the action of vanillin include inhibition of a DNA repair process that leads to the death of potential mutants or enhancement of DNA repair pathways that protect from mutation but create lethal DNA lesions during the repair process.

Animals↗
PubMed2000

Schizotypal symptoms in the relatives of schizophrenia patients: an empirical analysis of the factor structure.

This study examined the nature of schizotypal symptoms in the relatives of schizophrenia patients and investigated phenomenological differences in symptomatology manifested by a familial sample and a clinical sample of personality disorder patients. Confirmatory factor analyses were used to test models of DSM-III-R schizotypal symptoms in the first degree relatives (n = 172) of schizophrenia patients. A multisample analysis was conducted to determine whether the same model adequately described the schizotypal symptoms rated in the relatives of schizophrenia patients and in clinically selected personality disorder patients. The results indicated that a three-factor model consisting of cognitive/perceptual, interpersonal, and disorganization factors yielded the best fit to the data from the relatives of schizophrenia patients, but that this model did not adequately describe both the relatives of schizophrenia patients and personality disorder patients. These findings indicate that the structure of schizotypal symptoms in the relatives of schizophrenia patients is similar to the three-factor model of schizophrenia symptoms often reported, but not the same as the structure of schizotypal symptoms in clinically selected personality disorder patients.

Adolescent↗
PubMed2000

Environmental tobacco smoke, cardiovascular disease, and the nonlinear dose-response hypothesis.

Two recent government reports have focused attention on the hypothesis that environmental tobacco smoke (ETS) exposure increases the risk of cardiovascular disease (CVD) in nonsmokers. The first report was published by the California Environmental Protection Agency (CAEPA) in 1997. The second report was issued in 1998 by the Scientific Committee on Tobacco and Health (SCOTH) in the United Kingdom. A meta-analysis of five large prospective epidemiology studies reports that the relative risk for actively smoking 20 cigarettes per day is 1.78. Active smoking exposes the smoker to approximately 16 times the ETS concentration, and 100- to 300-fold the total smoke dose experienced by a nonsmoker (Smith and Ogden, 1998, JAMA 280, 32-33.). Despite the much lower smoke exposure, these government reports estimate the relative risk for ischemic heart disease in ETS-exposed nonsmokers at 1.30 (CAEPA) and 1.23 (SCOTH). As an explanation for this nonlinear dose-response anomaly, platelet aggregation is proposed to be a plausible and quantitatively consistent mechanism. Herein, evidence is presented suggesting that this low-dose hypothesis is inconsistent with the biochemistry and physiology of platelets and with the literature on the cardiovascular pathology of active smoking. In addition, several important biases and confounders are ignored. These epidemiologic biases and confounders include the following: misclassification of smokers as nonsmokers; improper use of death certificates as surrogates for mortality statistics; underreporting of diabetes and hypertension in the relatives of smokers; and additional atherogenic risk factors in smoking households. Future field studies on ETS and CVD should emphasize proximal markers of risk for thrombosis in exposed nonsmokers. Proximal thrombogenic risk markers identified in field studies should be mechanistically examined under controlled exposure conditions.

Bias↗
PubMed2000

A prospective randomized placebo-controlled double-blinded pilot study of misoprostol rectal suppositories in the prevention of acute and chronic radiation proctitis symptoms in prostate cancer patients.

OBJECTIVE: Radiation proctitis is a known complication of radiation therapy for prostate cancer. Available medical treatment is usually ineffective and has focused on relieving symptoms after damage has occurred. Our study aimed at evaluating the use of misoprostol rectal suppositories in the prevention of acute as well as chronic radiation proctitis symptoms. METHODS: A prospective, randomized, placebo-controlled, double-blinded trial was conducted in patients with recently diagnosed stages B and C prostate cancer who underwent external beam irradiation. Patients received either a misoprostol or a placebo suppository 1 h before each radiation session. Misoprostol suppositories were made from two 200-microg tablets (Cytotec, Searle Pharmaceuticals, Skokie, IL), whereas the placebo was made from cocoa butter. A 12-point radiation proctitis symptom score was obtained from each patient at 4, 8, 12, and 36 wk after radiation therapy. RESULTS: A total of 16 patients were enrolled. Seven patients received placebo, and nine patients received misoprostol. Mean radiation proctitis symptom scores in the placebo group were 4.86, 5.86, 5.71, and 3.83 at 4, 8, 12, and 36 wk, respectively. The mean scores in the misoprostol group were 0.78, 0.67, 0.33, and 0.37 at 4, 8, 12, and 36 wk, respectively. The difference between the two groups was statistically significant (p < 0.05) at 4, 8, 12, and 36 wk. CONCLUSION: Misoprostol rectal suppositories significantly reduce acute and chronic radiation proctitis symptoms in patients receiving radiation therapy for prostate cancer.

Acute Disease↗
PubMed2000

The redox-sensitive transcriptional activator OxyR regulates the peroxide response regulon in the obligate anaerobe Bacteroides fragilis.

The peroxide response-inducible genes ahpCF, dps, and katB in the obligate anaerobe Bacteroides fragilis are controlled by the redox-sensitive transcriptional activator OxyR. This is the first functional oxidative stress regulator identified and characterized in anaerobic bacteria. oxyR and dps were found to be divergently transcribed, with an overlap in their respective promoter regulatory regions. B. fragilis OxyR and Dps proteins showed high identity to homologues from a closely related anaerobe, Porphyromonas gingivalis. Northern blot analysis revealed that oxyR was expressed as a monocistronic 1-kb mRNA and that dps mRNA was approximately 500 bases in length. dps mRNA was induced over 500-fold by oxidative stress in the parent strain and was constitutively induced in the peroxide-resistant mutant IB263. The constitutive peroxide response in strain IB263 was shown to have resulted from a missense mutation at codon 202 (GAT to GGT) of the oxyR gene [oxyR(Con)] with a predicted D202G substitution in the OxyR protein. Transcriptional fusion analysis revealed that deletion of oxyR abolished the induction of ahpC and katB following treatment with hydrogen peroxide or oxygen exposure. However, dps expression was induced approximately fourfold by oxygen exposure in DeltaoxyR strains but not by hydrogen peroxide. This indicates that dps expression is also under the control of an oxygen-dependent OxyR-independent mechanism. Complementation of DeltaoxyR mutant strains with wild-type oxyR and oxyR(Con) restored the inducible peroxide response and the constitutive response of the ahpCF, katB, and dps genes, respectively. However, overexpression of OxyR abolished the catalase activity but not katB expression, suggesting that higher levels of intracellular OxyR may be involved in other physiological processes. Analysis of oxyR expression in the parents and in DeltaoxyR and overexpressing oxyR strains by Northern blotting and oxyR'::xylB fusions revealed that B. fragilis OxyR does not control its own expression.

Amino Acid Sequence↗
PubMed2000

In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF.

The mechanisms that account for acetylcholine (ACh)-induced responses of skeletal muscle arterioles of mice lacking endothelial nitric oxide (NO) synthase (eNOS-KO) were investigated. Isolated, cannulated, and pressurized arterioles of gracilis muscle from male eNOS-KO (74.1 +/- 2.3 microm) and wild-type (WT, 87.2 +/- 2.1 microm) mice developed spontaneous tone accounting for 63 and 61% of their passive diameter (116.8 +/- 3.4 vs. 143.2 +/- 2.8 microm, respectively) and dilated dose-dependently to ACh (10(-9)-10(-7) M). These dilations were significantly smaller in vessels of eNOS-KO compared with WT mice (29.2 +/- 2.0 microm vs. 46.3 +/- 2.1 microm, at maximum concentration) but responses to the NO donor, sodium nitrite (NaNO(2), 10(-6)-3 x 10(-5) M), were comparable in the vessels of the two strains. N(G)-nitro-L-arginine (L-NNA, 10(-4) M), an inhibitor of eNOS, inhibited ACh-induced dilations by 60-90% in arterioles of WT mice but did not affect responses in those of eNOS-KO mice. In arterioles of eNOS-KO mice, dilations to ACh were not affected by indomethacin but were essentially abolished by inhibitors of cytochrome P-450, clotrimazole (CTZ, 2 x 10(-6) M) or miconazole (MCZ, 2 x 10(-6) M), as well as by either high K(+) (40 mM) or iberiotoxin [10(-7) M, a blocker of Ca(2+)-dependent K(+) channels (K(Ca) channels)]. On the other hand, in WT arterioles CTZ or MCZ inhibited ACh-induced dilations only by approximately 10% and only in the presence of L-NNA. These results indicate that in arterioles of eNOS-KO mice, endothelium-derived hyperpolarizing factor (EDHF), synthesized via cytochrome P-450, accounts entirely for the mediation of ACh-induced dilation via an increase in K(Ca)-channel activity. In contrast, in arterioles of WT mice, endothelium-derived NO predominantly mediates ACh-induced dilation in which participation of EDHF becomes apparent only after inhibition of NO synthesis.

Acetylcholine↗