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D Siegel

Publications and source records attributed to D Siegel.

At least 19 recordsLinked to original sources
PubMed1992

Prevalence and correlates of herpes simplex infections. The population-based AIDS in Multiethnic Neighborhoods Study.

OBJECTIVE: To examine the extent and correlates of infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in an inner-city community, we studied the prevalence of antibodies to these viruses and their association with risk behaviors in a representative sample of unmarried white, black, and Hispanic adults living in San Francisco, Calif. DESIGN: Cross-sectional, community-based, random household survey. PARTICIPANTS: In 1988 and 1989, we surveyed 1770 unmarried men and women aged 20 to 44 years from three San Francisco neighborhoods of varying geographic and cultural characteristics. MAIN OUTCOME MEASURES: HSV-1 and HSV-2 antibodies based on an immunodot assay using type-specific glycoproteins gG-1 and gG-2. RESULTS: Of blood samples from 1212 participants available for testing, 750 (62%) had HSV-1 antibodies and 400 (33%) had HSV-2 antibodies. After controlling for other variables, HSV-1 antibody was significantly correlated (P less than .05) with older age (in heterosexual men, women, and homosexually active men), less education (in heterosexual men and women), and Hispanic (especially those not born in the United States) or black race. HSV-2 antibody was significantly correlated (P less than .05) with female gender, number of lifetime sexual partners and older age (in heterosexual men and women), and low levels of education and black or Hispanic race (in women). Among those with antibody to HSV-2, only 28 (19%) of 149 men and 32 (13%) of 251 women reported a history of genital herpes. However, most men (62%) and women (84%) who reported a history of genital herpes had HSV-2 antibodies. We observed a similar pattern (low sensitivity and moderate specificity) for a history of facial herpes and the presence of HSV-1 antibodies. After controlling for other variables, HSV-2 antibodies were associated with a lower frequency of HSV-1 antibodies among homosexual men infected with the human immunodeficiency virus. CONCLUSIONS: HSV-1 antibodies were found in nearly two thirds of single urban adults and were most common among Hispanics not born in the United States. HSV-2 antibodies were found in one third of this population and were associated with risk behaviors for sexually transmitted diseases. For both facial and genital herpes infections, self-reporting of infection was very insensitive and moderately specific.

Adult↗
PubMed1992

Bioreductive activation of mitomycin C by DT-diaphorase.

The role of DT-diaphorase (DTD, EC 1.6.99.2) in the bioreductive activation of mitomycin C was examined using purified rat hepatic DTD. The formation of adducts with reduced glutathione (GSH), binding of [3H]mitomycin C to DNA, and mitomycin C-induced DNA interstrand cross-linking were used as indicators of bioactivation. Mitomycin C was metabolized by DTD in a pH-dependent manner with increasing amounts of metabolism observed as the pH was decreased from 7.8 to 5.8. The major metabolite observed during DTD-mediated reduction of mitomycin C was 2,7-diaminomitosene. GSH adduct formation, binding of [3H]mitomycin C and mitomycin C-induced DNA interstrand cross-linking were observed during DTD-mediated metabolism. In agreement with the pH dependence of metabolism, increased bioactivation was observed at lower pH values. Temporal studies and experiments using authentic material showed that 2,7-diaminomitosene could be further metabolized by DTD resulting in the formation of mitosene adducts with GSH. DNA cross-linking during either chemical (sodium borohydride) or enzymatic (DTD) mediated reduction of mitomycin C could be observed at pH 7.4, but it increased as the pH was decreased to 5.8, showing the critical role of pH in the cross-linking process. These data provide unequivocal evidence that the obligate two-electron reductase DTD can bioactivate mitomycin C to reactive species which can form adducts with GSH and DNA and induce DNA cross-linking. The use of mitomycin C may be a viable approach to the therapy of tumors high in DTD activity, particularly when combined with strategies to lower tumor pH.

Animals↗
PubMed1992

Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cł.

The enzyme DT-diaphorase (DTD; NAD(P)H:quinone oxidoreductase, EC 1.6.99.2), is an obligate two electron reductase which catalyzes reduction of a broad range of substrates, including quinones. We report here variations in DTD concentrations among different classes of lung tumors known also to vary in their responsiveness to cytotoxic agents. Small cell lung carcinomas (SCLCs) and cell lines derived from them have the low DTD activities and mRNA content characteristic of normal human lung, whereas non-small cell lung carcinomas (NSCLCs) have greatly elevated levels. DTD activity was increased up to 80-fold in NSCLC tumors relative to normal lung and 20-35-fold in NSCLC relative to SCLC cell lines. Increased DTD activity appeared to be a function of the NSCLC phenotype rather than a result of derivation from a cell type rich in DTD, since all histological classes of NSCLC showed this phenotype. In addition, where transfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to a NSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC, carcinoids, and a few NSCLC lines) typically had far lower DTD activities than did cell lines which lacked neuroendocrine markers (most NSCLC cells and mesotheliomas). High DTD activity may be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenografts derived from NSCLC cell lines with high DTD that were grown in athymic nude mice were more susceptible to the antitumor quinone, mitomycin C, than were xenografts derived from SCLC cells containing low DTD. These data provide a mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC.

Animals↗
PubMed1992

Silent myocardial ischemia in men with systemic hypertension and without clinical evidence of coronary artery disease.

The prevalence, characteristics and circadian pattern of silent myocardial ischemia, and its association with ventricular arrhythmias was studied in hypertensive men aged 35 to 70 years (mean 61) without clinical cardiac disease. Participants were withdrawn from diuretic treatment and received 1 month of oral electrolyte repletion with 40 mmol of potassium chloride, and 400 mg of magnesium oxide daily. Twenty-four-hour Holter monitoring was then performed. Episodes of silent myocardial ischemia occurred in 50 of 186 men (27%) and lasted from 2 to 289 minutes (mean 30 and median 18). Statistical analysis comparing the interval from midnight to 6 A.M. with each of the other three 6-hour time intervals revealed that participants were less likely to have silent myocardial ischemia in this period (p less than 0.01 for each comparison) than at other times of the day. There was little difference in the proportion of men with a frequent or complex ventricular arrhythmia during the entire day or within 1 hour of the silent myocardial ischemic episode (or during a comparable time period) comparing those with to those without silent myocardial ischemia. These findings indicate that silent myocardial ischemia occurs in approximately 25% of an older population of hypertensive men without history of symptomatic cardiac disease. The circadian pattern of frequency of silent ischemic events in men free of clinical cardiac disease is similar to that reported for patients with cardiac disease and coincides with that reported for sudden death. There was no significant association between silent myocardial ischemia and ventricular arrhythmias.

Adult↗
PubMed1992

Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.

DT-diaphorase (DTD) mediated reduction of a series of 2,5-bis-substituted-3,6-diaziridinyl-1,4-benzoquinones was found to increase the level of DNA interstrand cross-linking (ISC) formed at neutral pH with an enhancement observed as the pH was decreased to 5.8. The analogues used were symmetrically alkyl-substituted carbamoyl ester analogues of AZQ (D1-D7), 3,6-diaziridinyl-1,4-benzoquinone (DZQ), the 2,5-dimethyl derivative (MeDZQ), and a 2,5-bis[(2-hydroxyethyl)amino] analogue (BZQ). At pH 5.8, the level of DNA ISC induced by enzymatic reduction was as follows: DZQ greater than MeDZQ much greater than D1 (methyl) greater than D3 (n-propyl) greater than D2 (AZQ; ethyl) greater than D5 (n-butyl) greater than D7 (sec-butyl) greater than D4 (isopropyl) D6 greater than (isobutyl). A similar trend was observed at pH 7.2. The level of DNA ISC induced by BZQ, which is not a substrate for DTD, was not increased by enzymatic reduction. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the DNA ISC induced by these quinones upon enzymatic reduction. MeDZQ and DZQ reacted with guanines, as measured by Maxam and Gilbert sequencing, with a sequence selectivity similar to that of the nitrogen mustard class of antitumor agents. Enzymatic reduction of DZQ and MeDZQ by DTD was found to alter their sequence-selective alkylation. Reduced DZQ showed enhanced guanine alkylation in 5'-GC-3' sequences and new sites of adenine alkylation in 5'-(A/T)AA-3' sequences. Reduced MeDZQ only showed new sites of adenine alkylation at 5'-(A/T)AA-3' sequences but no enhancement of guanine alkylation. The new sites of adenine alkylation were found to be inhibited in the presence of magnesium and rapidly converted into apurinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1992

Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men.

OBJECTIVE: To investigate the patterns of electrolyte abnormalities resulting from thiazide administration and whether they cause ventricular arrhythmias, and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides. DESIGN: Double-blind, randomized controlled trial. PARTICIPANTS: A total of 233 hypertensive men aged 35 to 70 years. INTERVENTIONS: Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide. They were then randomized to 2 months of treatment with (1) hydrochlorothiazide; (2) hydrochlorothiazide with oral potassium; (3) hydrochlorothiazide with oral potassium and magnesium; (4) hydrochlorothiazide and triamterene; (5) chlorthalidone; or (6) placebo. MAIN OUTCOME MEASURES: Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels. RESULTS: Of the 233 participants, 212 (91%) completed the study. Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group (P less than 0.01), and this mean difference was not affected by supplementation with potassium, with potassium and magnesium, or with triamterene. However, the supplements did prevent the occasional occurrence of marked hypokalemia; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation (P less than 0.01). Similarly, the overall proportion of men with ventricular arrhythmias was not affected by randomized treatment, but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less (P = .02). Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide, nor were they related to ventricular arrhythmias. CONCLUSIONS: In the majority of hypertensive patients, treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias. However, because some individuals will develop hypokalemia after starting diuretic therapy, serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated.

Adult↗
PubMed1992

Circadian variation in ventricular arrhythmias in hypertensive men.

Circadian patterns have been observed for various cardiovascular functions and events including sudden cardiac death. This study examined whether ventricular arrhythmias could be a pathophysiologic explanation for the increase in prevalence of sudden cardiac death observed between 6 A.M. and noon. Hypertensive men 35 to 70 years of age and without a history of symptomatic cardiac disease were withdrawn from diuretic treatment and received 1 month of oral electrolyte repletion with both 40 mmol of potassium chloride and 400 mg of magnesium oxide daily. Then continuous 24-hour Holter monitoring was performed and ventricular arrhythmias were classified by 6-hour time intervals. The interval from 6 A.M. to noon revealed a higher prevalence of complex or frequent ventricular arrhythmias than the interval from midnight to 6 A.M., as well as a higher mean number of ventricular premature complexes per hour. The differences were statistically significant (p less than 0.01) and amounted to increases of about one third. Ventricular arrhythmias during the other two 6-hour periods were intermediary in frequency. It is concluded that the increase in sudden cardiac death noted in the morning might be related, at least in part, to an increase in frequency of ventricular arrhythmias; the implications of this observation for preventive cardiology deserve further investigation.

Aged↗
PubMed1992

Condom use in multi-ethnic neighborhoods of San Francisco: the population-based AMEN (AIDS in Multi-Ethnic Neighborhoods) Study.

We examined the prevalence and correlates of condom use in a community-based sample of unmarried heterosexual and gay/bisexual Whites, Blacks, and Hispanics (aged 20 to 44 years) in San Francisco (n = 1229). Only 9% of heterosexual males reported always using condoms, and fewer of those with multiple sexual partners (6%) reported always using condoms compared with those in monogamous relationships (12%). Much higher proportions of gay/bisexual men reported always using condoms (48%). Racial differences in condom use were observed only among women. Sexual communication and the sexual enjoyment value of condoms were consistent correlates of condom use across gender and sexual orientation, while other condom-related beliefs were significant predictors of condom use only for men. In general, condom promotion programs should build sexual communication skills, teach people how to enhance enjoyment with condoms, and reduce psychological barriers to condom acquisition and use.

Adult↗
PubMed1992

Smokeless tobacco, cardiovascular risk factors, and nicotine and cotinine levels in professional baseball players.

BACKGROUND: The use of smokeless tobacco (ST), which has increased in popularity over the past 2 decades, results in considerable systemic exposure to nicotine. Nicotine might contribute to atherosclerosis by an effect on cardiovascular risk factors. METHODS: The effects of ST use on cardiovascular risk factors and cotinine and nicotine levels were studied in 1061 professional baseball players during spring training in 1988 and 1989. RESULTS: Of the study participants 477 (45%) were users. ST use was more common among Whites (55%) than among Blacks (29%) or Hispanics (21%), and users reported heavier consumption of alcohol (p less than .001) and had higher mean serum caffeine levels (p less than .001) than nonusers. ST users did not differ from nonusers in adjusted levels of systolic and diastolic blood pressure, pulse, and total or HDL-cholesterol. Among ST users, participants using snuff had higher mean serum cotinine levels than those who used chewing tobacco (p less than .001). There was no association between serum cotinine levels and adjusted levels of any cardiovascular risk factor studied. However, higher diastolic blood pressures were associated with higher mean serum nicotine levels (p = .02). CONCLUSIONS: Smokeless tobacco use has at most a modest effect on cardiovascular risk factors in young physically fit men.

Adult↗
PubMed1992

Is perception of exertion a unique characteristic?

This study assessed the extent to which perception of exertion (RPE), as measured by Borg's 1971 scale using bicycle ergometry, is a unique perceptual trait. Correlations run for 35 subjects between RPE and a battery of seven perceptually oriented tasks were not significant, implying that RPE may be a unique perceptual ability.

Humans↗
PubMed1992

Mitomycin C.

Explore the source record for details and available documents.

Animals↗
PubMed1992

Relationship between DT-diaphorase-mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity.

A series of 2,5-bis-substituted 3,6-diaziridinyl-1,4-benzoquinones have been tested for their ability to be reduced by the two-electron NAD(P)H:(quinone acceptor) oxidoreductase [DT-diaphorase (DTD); EC 1.6.99.2]. Symmetrically alkyl-substituted carbamoyl ester analogs of 2,5-ethyl(carboethoxyamino)3,6-diaziridinyl-1,4- benzoquinone [AZQ], 3,6-diaziridinyl-1,4-benzoquinone (DZQ), and its 2,5-dimethyl derivative (MeDZQ) were tested. The rate of reduction by DTD was DZQ greater than MeDZQ greater than n-butyl- (D5) greater than sec-butyl- (D7) greater than n-propyl- (D3) greater than methyl- (D1) greater than ethyl- (AZQ) greater than i-butyl- (D6) greater than i-propyl- (D4) substituted derivatives. The hydroxyethylamino analog (BZQ) was not a substrate for DTD. The order of toxicity to HT-29 human colon carcinoma cells (at 1-log cell kill) was MeDZQ greater than DZQ greater than BZQ greater than D1 greater than D5 greater than AZQ greater than D7 greater than D3 greater than D6 greater than D4. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the cytotoxicity of DZQ, MeDZQ, AZQ, D3, D4, D5, D6, and D7, with little inhibition of D1 cytotoxicity. Alkaline elution assays suggested that DZQ induced DNA strand breaks, whereas MeDZQ induced DNA interstrand crosslinks in HT-29 cells. The formation of both classes of lesions was inhibited by dicumarol. DZQ and MeDZQ were 5-6-fold less cytotoxic to the DTD-deficient BE cell line, whereas BZQ was more cytotoxic to this cell line than the HT-29 cell line. BZQ was capable of inducing dicumarol-insensitive DNA interstrand crosslinks in both cell lines. In summary, these data show a trend between the rate of reduction by DTD of an analog and its ability to induce cytotoxicity in HT-29 cells, and they support a role for DTD in the bioreductive activation of AZQ and its analogs.

Animals↗
PubMed1992

Risk for AIDS in multiethnic neighborhoods in San Francisco, California. The population-based AMEN Study.

To examine the actual and potential spread of human immunodeficiency virus (HIV) from an acquired immunodeficiency syndrome (AIDS) epicenter to surrounding neighborhoods, we studied the prevalence of the viral infection and AIDS risk behaviors from 1988 to 1989 in a representative sample of unmarried whites, African Americans, and Hispanics living in San Francisco. We surveyed 1,770 single men and women aged 20 to 44 years (a 64% response rate) in a random household sample drawn from 3 neighborhoods of varying geographic and cultural proximity to the Castro District where the San Francisco epidemic began. Of 1,369 with blood tests, 69 (5%) had HIV antibodies; all but 5 of these reported either homosexual activity (32% HIV-positive; 95% confidence interval [CI] = 23%, 41%), injection drug use (5% HIV-positive; CI = 1%, 14%), or both (59% HIV-positive; CI 42%, 74%). Homosexual activity was more common among white men than among African-American or Hispanic men, but the proportion of those infected was similar in the 3 races. Both the prevalence of homosexually active men and the proportion infected were much lower in the 2 more outlying neighborhoods. Risk behaviors in the past year for acquiring HIV heterosexually--sex with an HIV-infected person or homosexually active man or injection drug user, unprotected sexual intercourse with more than 4 partners, and (as a proxy) having a sexually transmitted disease--were assessed in 1,573 neighborhood residents who were themselves neither homosexually active men nor injection drug users. The prevalence of reporting at least 1 of these risk behaviors was 12% overall, and race-gender estimates ranged from 5% among Hispanic women to 21% among white women. We conclude that in San Francisco, infection with HIV is rare among people who are neither homosexually active nor injection drug users, but the potential for the use spread of infection is substantial, as 12% of this group reported important risk behaviors for acquiring the virus heterosexually.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Determinants of condom use among junior high school students in a minority, inner-city school district.

Condoms reduce the risk of human immunodeficiency virus (HIV) transmission; however, their use among adolescents has been inconsistent. Little is known about factors which motivate consistent condom use, particularly among younger adolescents. In a study designed to identify such factors, 1899 inner-city junior high school students were surveyed. In June 1988, students completed an anonymous self-report questionnaire assessing HIV-related knowledge, attitudes, and behaviors. Among sexually active students (N = 403), logistic regression analysis evaluated the influence of demographic, psychosocial, and behavioral factors on frequency of condom use. Respondents who believe condoms are effective in preventing HIV transmission were 2.2 times more likely to report using condoms consistently during sexual intercourse; those with low perceived costs associated with condom use were 1.9 times more likely to be consistent users. Number of lifetime sexual partners was inversely related to frequency of condom use. Respondents with a history of three or more sex partners were half as likely to use condoms consistently. Factors not associated with consistent condom use include age, age at sexual debut, ethnicity, HIV knowledge, perceived efficacy to avoid HIV infection, and alcohol and drug use. School- and community-based HIV prevention programs will have to go beyond the didactic transfer of factual information and include more interactive teaching strategies to improve adolescents' attitudes toward condoms are self-efficacy to increase condom use and to counter negative peer influences and adolescents' perceptions of invulnerability. Physicians are an underutilized source of HIV prevention information. They have an important role in counseling adolescents about effective HIV-prevention methods and dispelling misperceptions which hinder consistent condom use.

Acquired Immunodeficiency Syndrome↗
PubMed1991

NAD(P)H:quinone oxidoreductase (DT-diaphorase) activity and mRNA content in normal and neoplastic mouse lung epithelia.

DT-diaphorase (DTD) is a flavoprotein which catalyzes obligate two-electron reduction of a diverse group of substrates. We have reported previously that non-tumorigenic mouse lung alveolar type-II pneumocytes have high DTD activity, while cell lines derived from lung tumors do not. In contrast, other investigators, using human lung tissue, reported increased DTD activity in tumors compared with normal tissue. We therefore investigated DTD associated with mouse lung neoplasia in vivo as well as in vitro. Pulmonary tumors had far less DTD activity compared with normal mouse lung. Correspondingly, a tumorigenic mouse lung cell line which arose as a spontaneous transformant of a normal cell line had very low DTD activity compared with non-tumorigenic lung cells. DTD-specific mRNA levels were also much higher in normal cell lines than in neoplastic ones. DTD was localized histochemically in type-II pneumocytes in situ, but was not observed by this technique in normal bronchiolar epithelia or in tumor cells. These data show that, unlike what has been observed in human lung cancer, a marked decrease in DTD content and activity accompanied mouse lung tumorigenesis in vivo and neoplastic transformation in vitro.

Animals↗
PubMed1991

A note on the inhibition of DT-diaphorase by dicoumarol.

The participation of DT-diaphorase or NAD(P)H:(quinone acceptor) oxidoreductase (E.C. 1.6.99.2) in metabolism or in events leading to toxicity is often implied on the basis of the inhibitory effects of dicoumarol. DT-diaphorase functions via a ping pong bi-bi kinetic mechanism involving oxidized and reduced flavin forms of the free enzyme. Dicoumarol, a potent (Ki = 10 nM) inhibitor, binds to the oxidized form of the enzyme, competitively versus reduced pyridine nucleotide. Inhibition is effectively complete at 1 microM dicoumarol in typical studies using DCPIP, one of the best known substrates for the enzyme, as electron acceptor. The antitumor quinone Diaziquone (AZQ) is a poor substrate for DT-diaphorase relative to DCPIP, but effective inhibition of its reduction requires ten-fold higher concentrations of dicoumarol than for inhibition of DCPIP reduction under otherwise similar conditions. The variable inhibition of DT-diaphorase by dicoumarol dependent on the efficiency of the electron acceptor can be explained on the basis of the complete rate equation describing its ping pong type kinetic mechanism. Thus, the concentration of dicoumarol used to inhibit DT-diaphorase must be chosen carefully and consideration should be given to the efficiency of the electron acceptor. The absence of an inhibitory effect using low doses of dicoumarol cannot rule out a reaction mediated by DT-diaphorase. Although higher doses of dicoumarol may be required to inhibit DT-diaphorase mediated metabolism of less efficient electron acceptors, the use of such doses in cells may also affect biochemical processes other than DT-diaphorase and should be approached with caution.

Animals↗
PubMed1991

Fibronectin in healing flexor tendons subjected to immobilization or early controlled passive motion.

The medial and lateral forepaw flexor tendons of 20-adult mongrel dogs (n = 40) were transected and repaired with a modified Kessler suture. Post-operatively the dogs were subjected either to immobilization or early controlled passive digital motion. Sacrifices were at 3, 7, 10 and 17 days. The tendons of the contralateral limbs were left intact and used as controls. Urea-heparin-extracted fibronectin was quantitated by competitive ELISA in the tendons and sheaths at the four post-injury/repair time periods. In both groups (controlled passive motion and immobilization), fibronectin concentrations were higher in the injured tissues than in control tissues. However, peak fibronectin concentration (7-days post-injury/repair) was approximately twice as high in the controlled passive motion tissues as in the immobilized tissues. It was concluded, therefore, that, relative to early controlled passive motion, early immobilization depresses the accumulation of tissue fibronectin during the early stages of healing following injury.

Animals↗