Cholesterol, apolipoproteins, and the risk of myocardial infarction.
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Aspirin↗
Biomedical subjects
J A Simon
Publications and source records attributed to J A Simon.
Predictors of smoking relapse after noncardiac surgery. Study of Perioperative Ischemia (SPI) Research Group.
OBJECTIVES: We studied 235 smokers who were admitted for major noncardiac surgery and who survived hospitalization to determine the frequency and predictors of smoking relapse 1 year after hospitalization. METHODS: We analyzed data collected prospectively from the Study of Perioperative Ischemia. We determined smoking status by self-report. RESULTS: At 12 months posthospitalization, 142 (76%) of the 186 surviving patients had resumed smoking. Significant independent predictors of relapse at 12 months were a history of alcohol abuse and a history of heavy cigarette smoking (P less than 0.01 and P less than 0.05, respectively). CONCLUSIONS: Since smokers commonly undergo surgery, the perioperative period provides a valuable window of opportunity for smoking cessation interventions designed to decrease the high rate of smoking relapse after surgery.
Analysis of Variance↗
Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines.
Dominant-negative and/or loss-of-function mutations of the p53 tumor suppressor gene are frequently found in squamous cell carcinomas of the skin and of the head-and-neck region. In order to identify the precise mechanisms of inactivation of p53 in tumors of this class, we examined the status of p53 RNA, protein and DNA in a panel of eight human squamous carcinoma cell lines (head-and-neck, 3; esophagus, 1; lung, 1; uterine cervix, 2; vulva, 1). Three lines (A253, CaLu-1, SqCC/Y1) failed to express any p53 mRNA. A253 cells contained a single p53 allele without mutations in exons 2-9, suggesting that the lack of transcription was the result of mutations in the regulatory region of the gene. Both p53 alleles were deleted in CaLu-1 cells, whereas the single allele present in SqCC/Y1 cells was rearranged and carried two missense mutations in exon 5. Two cell lines (A431, FaDu) expressed only 50% of the normal level of p53 mRNA, either because only one allele was present (A431), or because only one of the two alleles was transcribed (FaDu). The two cervical carcinoma lines (CaSki, C4-1) expressed normal levels of p53 mRNA, but no wild type protein, presumably as a result of accelerated degradation by the human papillomavirus 16 or -18 E6 oncoprotein present in these cells as previously described (Scheffner et al., Proc. Natl. Acad. Sci. USA 88:5523-5527; 1991). Three of the lines expressed only mutant p53 protein (A431, FaDu, CE-48) resulting from missense mutations in codons 248 and 273.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Vitamin C and cardiovascular disease: a review.
Vitamin C functions as a regulator of the catabolism of cholesterol to bile acids in the guinea pig and has been demonstrated to be an important factor in lipid regulation of the guinea pig, rabbit and rat. Correlation studies in humans have shown an inverse relationship between vitamin C intake and cardiovascular disease mortality. Observational and experimental studies in humans have yielded inconsistent results, but taken together indicate that for individuals with high total cholesterol concentrations, greater than or equal to 5.20 mmol/L (200 mg/dl) and less than full tissue saturation, increasing the concentration of vitamin C may have a salutary effect on total cholesterol. Vitamin C's effect on promoting the production and inhibiting the degradation of prostacyclin is reviewed, as are implications of these findings regarding thrombosis and atherogenesis. Evidence indicative of a protective effect on lipid peroxidation by vitamin C is examined. Analysis of the literature regarding groups at high risk for coronary heart disease reveals that men, the elderly, smokers, diabetics, hypertensives and perhaps oral estrogen-containing contraceptive users have lowered plasma vitamin C levels. Evidence linking vitamin C to human cardiovascular disease is largely circumstantial, but taken in total, is suggestive of an association. Further examination of the relationship between vitamin C and cardiovascular disease is warranted.
Animals↗
A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.
Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC----TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C----T substitutions. p53 mutations in internal malignancies do not show these UV-specific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogen-related step in a gene involved in the subsequent human cancer.
Aged↗
Caffeine, prostacyclin, and exercise-induced bronchoconstriction.
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Bronchoconstriction↗
Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system.
OBJECTIVE: To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch. DESIGN: Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period. SETTING: Normal human volunteers were studied in an academic research environment. PATIENTS, PARTICIPANTS: The subject pool included eight healthy postmenopausal women between 32 and 60 years of age. INTERVENTIONS: In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use. MAIN OUTCOME MEASURES: Serum E2 levels were measured in both groups. RESULTS: Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours. CONCLUSION: The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.
Absorption↗
Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea.
OBJECTIVE: To compare two dosages of oral micronized progesterone (P) and placebo for withdrawal bleeding and side effects. DESIGN: Prospective, randomized, double-blind. SETTING: Academic institution. PARTICIPANTS: Out of 190 screened with oligomenorrhea/amenorrhea, 60 who qualified completed the study. INTERVENTIONS: A 10-day course of (1) oral micronized P 300 mg, (2) oral micronized P 200 mg, or (3) placebo. MAIN OUTCOME MEASURES: Withdrawal bleeding, side effects, and changes in lipids. Endogenous estradiol (E2) concentrations at baseline and P concentrations during treatment were correlated with bleeding response. RESULTS: Withdrawal bleeding occurred in 90% of women taking 300 mg, 58% of women taking 200 mg, and 29% of women taking placebo (P less than 0.0002 for 300 mg versus placebo). Side effects occurred similarly among the groups (P = not significant). Lipid concentrations were unchanged. Endogenous E2 and treatment P concentrations were of limited predictive value for withdrawal bleeding. CONCLUSIONS: Progesterone 300 mg induced significantly more withdrawal bleeding than placebo, with similar side effects. Bleeding response cannot be predicted reliably from E2 and P concentrations.
Administration, Oral↗
Detection of the ovulatory-luteinizing hormone surge with an enzyme-linked immunospecific human urinary luteinizing hormone assay: applicability to nonhuman primates.
Heterologous antibodies have frequently been used to develop assays in other species. Human urinary LH kits, widely available for predicting the LH surge, offer a unique opportunity to determine the timing of ovulation and mating in nonhuman primates. We tested three commercially available ovulation predictor kits for utility in two macaque species. Midfollicular, midcycle, and castrate urines and their corresponding serum samples were assessed for LH activity using established RIAs as well as urinary ovulation kits. Macaque LH did not sufficiently cross-react with the human urinary anti-LH antibodies in any of the predictor test kits. Although these kits offer excellent results in predicting ovulation by measurement of urinary LH in humans, they appear not to be applicable for urinary LH detection in rhesus nor cynomolgus macaques.
Animals↗
Percutaneous absorption of 17 beta-estradiol in ovariectomized rhesus monkeys: skin and serum pharmacokinetics.
The skin and serum kinetics of percutaneous estradiol (E2) gel (Oestrogel; Besins-Iscovesco Laboratories, Paris, France) absorption in 11 ovariectomized rhesus monkeys (3 pretreated with diethylstilbestrol [DES]) was studied. The gel (1.5 mg E2) mixed with 7.5 x 10(5) cpm tritiated E2 (3H-E2) was applied to abdominal skin. Serial skin biopsies were taken from the application area and at 1 and 3 cm beyond, as well as from perineum and dorsal skin; and radioactivity measured to estimate tissue levels of E2 derived from percutaneous delivery. Simultaneous femoral serum samples were taken for RIA of E2. Skin 3H-E2 reached a peak at approximately 60 minutes, which was sustained for about 10 hours. Lateral diffusion of the radiolabeled E2 was limited to about 1 cm. Serum E2 levels reached a peak at 60 minutes and remained elevated for 20 hours after a single application. A strong correlation existed between skin and serum E2 levels: r = 0.828. DES did not modify the E2 skin absorption kinetics, but in 2 of 3 monkeys DES reduced the E2 serum levels, suggesting an effect after skin absorption. We conclude that percutaneously delivered E2 manifests a sustained entry into serum. The steady state of continuous release of E2 into circulation derives from a postabsorption skin reservoir of estrogen product.
Administration, Cutaneous↗
Calcium metabolism in postpartum lactation: the effect of estrogen status.
Postpartum lactation represents a unique state of increased calcium demand in which women are also hyperprolactinemic and hypoestrogenic. This is associated with increased calcium mobilization from bone and bone loss. To better understand the effect of estrogen (E) status on calcium metabolism during lactation, we studied 10 long-term lactating women at 12 weeks postpartum when they were hypoestrogenic and again at 37.4 +/- 3.4 (+/- SD) weeks during the midfollicular phase of their second ovulatory cycle. Urinary and serum markers of calcium metabolism were measured at these intervals. The results revealed that when E was low, osteocalcin and hydroxyproline were increased with a lower circulating parathyroid hormone (PTH) level, whereas reciprocal changes were noted when E was increased. The findings suggest that E status can modulate PTH's ability to mobilize one's stores of calcium.
Adult↗
Predictive value of a single serum pregnancy associated plasma protein-A or progesterone in the diagnosis of abnormal pregnancy.
The value of a single measurement of serum levels of pregnancy associated plasma protein-A (PAPP-A) or progesterone (P4) in predicting abnormal gestations was assessed in 65 patients. P4 was greater than 20 ng/ml (mean +/- SEM 61.2 +/- 6.6 ng/ml, range 22.4-100.0 ng/ml) in all patients with normal intrauterine pregnancies (n = 21), and greater than 20 ng/ml (mean +/- SEM 8.5 +/- 3.9 ng/ml, range 0.1-68.8 ng/ml) in 16 out of 17 patients destined to abort spontaneously. Patients with ectopic gestations (n = 27) exhibited P4 values less than 20 ng/ml (mean +/- SEM 6.4 +/- 1.2 ng/ml, range 0.1-17.2 ng/ml). P4 levels in normal pregnancies were significantly higher (P = 0.001) than those of abnormal gestations. PAPP-A levels ranged from undetectable to 6448 mIU/ml in normal gestations. In 42 out of 44 abnormal pregnancies levels of PAPP-A were less than 100 mIU/ml, as were 7 out of 14 normal intrauterine pregnancies of less than 7 weeks gestational age. No ectopic demonstrated a value of PAPP-A greater than 50 mIU/ml and in 23 out of 27 ectopics, levels were undetectable. However, PAPP-A was less specific than P4 in correctly discriminating normal from abnormal gestations and exhibited lower positive and negative predictive values. It can be concluded therefore that a single PAPP-A measurement is of limited value in discerning normal from abnormal pregnancy prior to 8 weeks gestation. However, a single serum P4 is highly accurate and specific in detecting abnormal pregnancy, regardless of gestational age.
Female↗
Luteal phase hyperprolactinemia during ovulation induction with human menopausal gonadotropins: incidence, recurrence, and effect on pregnancy rates.
Hyperprolactinemia may develop during ovulation induction with human menopausal gonadotropins and hCG (hMG/hCG). Because elevated serum prolactin (PRL) has several adverse effects on female reproductive function, this event has been implicated as a factor to explain the difference between ovulation and pregnancy rates in hMG/hCG treatment cycles. The incidence and severity of hyperprolactinemia in the luteal phase of hMG/hCG-stimulated cycles was investigated in a large series of patients. We analyzed 240 consecutive, ovulatory hMG/hCG cycles in 96 women from July 1984 to January 1986. All women had failed to conceive with clomiphene citrate, and had normal luteal phase PRL levels during unstimulated cycles. Daily serum total estrogens were determined during hMG administration. Serum progesterone and PRL were determined in the mid-luteal phase (7 days post-hCG administration). In 7.5% of the cycles, luteal phase PRL elevations were greater than 25 ng/mL. Only 2.5% of cycles had levels of PRL greater than 35 ng/mL. Hyperprolactinemia infrequently recurred in different cycles of the same patient (two of 16 patients, 12.5%). Cycles with hyperprolactinemia were found to have significantly higher preovulatory estrogen levels. Serum progesterone levels were not significantly decreased in cycles with elevated PRL. Pregnancy rates in cycles with and without hyperprolactinemia were similar (7.7 versus 11.1%, respectively; P greater than .05). We conclude that the development of luteal phase hyperprolactinemia during ovulation induction with hMG/hCG is an isolated event. High preovulatory estrogen levels may predispose to its development. Because hyperprolactinemia is uncommon and is usually mild, other factors must be responsible for the difference between ovulation and pregnancy rates using hMG/hCG.
Chorionic Gonadotropin↗
Gonadotropin-releasing hormone infusion interval: importance in pharmacodynamics.
Circulating gonadotropin-releasing hormone (GnRH) levels were measured during and after intravenous infusion intervals ranging from 0.08 minutes to 5 minutes and doses ranging from 1 to 25 micrograms per pulse. In all dose groups (1 vs. 5 vs. 25 micrograms), the peak levels of GnRH decreased from the 0.08 minute to the 5 minute infusion interval. Our results suggest that the infusion interval over which GnRH is administered has profound effects on the amount, duration, and pattern of GnRH measured in the peripheral circulation.
Animals↗
Characterization of recombinant DNA derived-human luteinizing hormone in vitro and in vivo. Efficacy in ovulation induction and corpus luteum support.
The present data are the first, to our knowledge, to demonstrate the production feasibility of a commercially available medication of pure human luteinizing hormone from recombinant DNA technology (rechLH). The rechLH preparation achieved ovulation induction and corpus luteum support in the primate menstrual cycle. The observations described herein indicate the opportunity for significant improvement in the treatment of infertile women and men who require gonadal stimulation. Recombinant DNA-derived gonadotropin products, rechLH in this case, will have several therapeutic advantages compared with current medications extracted from urine. These advantages include (1) better reliability of an available supply of hormone and (2) improved treatment flexibility in determining the optimal dose ratio of follicle-stimulating hormone and luteinizing hormone or avoidance of the long-acting effects of human chorionic gonadotropin, as the needs of individual patients may dictate.
Animals↗
Structure and expression of ubiquitin genes of Drosophila melanogaster.
We isolated and characterized two related ubiquitin genes from Drosophila melanogaster, polyubiquitin and UB3-D. The polyubiquitin gene contained 18 repeats of the 228-base-pair monomeric ubiquitin-encoding unit arranged in tandem. This gene was localized to a minor heat shock puff site, 63F, and it encoded a constitutively expressed 4.4-kilobase polyubiquitin-encoding mRNA, whose level was induced threefold by heat shock. To investigate the pattern of expression of the polyubiquitin gene in developing animals, a polyubiquitin-lacZ fusion gene was introduced into the Drosophila genome by germ line transformation. The fusion gene was expressed at high levels in a tissue-general manner at all life stages assayed. The ubiquitin-encoding gene, UB3-D, consisted of one ubiquitin-encoding unit directly fused, in frame, to a nonhomologous tail sequence. The amino acid sequence of the tail portion of the protein had 65% positional identity with that of yeast UBI3 protein, including a region that contained a potential nucleic acid-binding motif. The Drosophila UB3-D gene hybridized to a 0.9-kilobase mRNA that was constitutively expressed, and in contrast to the polyubiquitin gene, it was not inducible by heat shock.
Amino Acid Sequence↗
Clomiphene citrate attenuates hyperprolactinemia associated with ovarian hyperstimulation in the primate menstrual cycle.
Exogenous human menopausal gonadotropin (hMG) therapy produces transient hyperprolactinemia during ovulation induction or ovarian hyperstimulation for in vitro fertilization, and hyperprolactinemia has been linked to decreased fertility. Coadministration of clomiphene citrate (CC) with hMG is often used to decrease the total amount of hMG used in such patients, but whether this results in less hyperprolactinemia is not known. As the hyperprolactinemia in this setting is a threshold phenomenon dependent on the strength and duration of estrogen exposure, we investigated whether CC acted as an estrogen to enhance PRL secretion or as an antiestrogen deterring estradiol (E2)- and progesterone (P4)-induced hyperprolactinemia in nonhuman primates. Normally cycling (control) monkeys (n = 4) received E2 benzoate (12.5 micrograms/kg, im, daily) on menstrual cycle days 6-33 and continuous crystalline P4 via Silastic implants on days 20-33, a regimen known to initiate hyperprolactinemia. Treated monkeys (n = 5) received the same regimen, except that oral CC (15 mg daily) was given on days 6-33. Daily serum samples were assayed for E2, P4, and PRL. Both treatments caused significant (P less than 0.05) increases in serum PRL concentrations during P4 administration. The CC-treated monkeys had significantly smaller increases in mean PRL [21 +/- 1.5 (+/- SEM) vs. 44 +/- 6.3 ng/mL (micrograms/L); P less than 0.05] and smaller mean area under the PRL response curve [288 +/- 35 (+/- SEM) vs. 588 +/- 121 ng/day.mL (micrograms/day.L); P less than 0.05] than the control monkeys. We conclude that CC attenuates the hyperprolactinemia response to E2/P4 synergy in monkeys by acting as an antiestrogen. If coadministered with hMG for ovulation induction or ovarian hyperstimulation for in vitro fertilization, CC should attenuate hMG-induced hyperprolactinemia, thereby reducing its potentially adverse effects on fertility.
Animals↗
A germline transformation analysis reveals flexibility in the organization of heat shock consensus elements.
Maximal expression of the Drosophila heat shock gene hsp70 can be activated by a pair of heat shock consensus elements (HSE's) positioned close to the transcription start site. In contrast, required HSE's of other heat shock genes (i.e., hsp26, 27, 23) are located several hundred base pairs (bp) farther upstream of their start sites. Using germline transformation, we analyzed the requirements for HSE organization in the hsp70 and hsp26 regulatory regions. A 51 bp fragment containing the two proximal hsp70 HSE's was sufficient to rescue the heat shock response of an hsp26-lacZ gene devoid of its HSE's. Heat inducibility was restored with either orientation of the fragment relative to the hsp26 transcription start. In hsp70 gene constructions, relocation of hsp70 HSE's to more remote positions by inserting 127 or 331 bp into the regulatory region failed to substantially reduce expression. Thus, in contrast to their native configurations, the hsp26 promoter can be activated by HSE's solely in a proximal position and the hsp70 promoter can be activated by remote HSE's. In addition, a simple and sensitive assay for quantitative measurement of beta-galactosidase activity in crude fly extracts is described.
Animals↗