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Biomedical subjects

M C Pike

Publications and source records attributed to M C Pike.

At least 163 records · Page 9Linked to original sources
PubMed1989

LHRH agonists and the prevention of breast and ovarian cancer.

Early age at natural menopause or bilateral ovariectomy substantially reduce a woman's lifetime risk of breast cancer. Reversible 'bilateral ovariectomy' can now in effect be achieved by 'high-dose' luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by 'low-dose' oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a 'low-dose' progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer.

Breast Neoplasms↗
PubMed1989

Geographical variation in mortality from leukaemia and other cancers in England and Wales in relation to proximity to nuclear installations, 1969-78.

The distribution of mortality from 11 causes of death (lymphoid leukaemia, other leukaemia, leukaemia of all types, Hodgkin's disease, other lymphomas, all lymphomas, multiple myeloma, lung cancer, other malignancies, all malignancies and all other causes) has been examined in three age groups throughout England and Wales over the period 1969-78. The reorganisation of local authority administration in 1974 meant that the smallest areas that could be examined were 400 county districts or (in some cases) approximate county districts formed by aggregating pre-1974 local authority areas. The variation in the numbers of deaths observed about the numbers expected was assessed using log-linear models to estimate the effect on the relative risk in each district associated with social class, rural status, population size, health authority region and proximity to one of 15 nuclear installations. Trends in risk with increasing proximity to an installation (as judged by the proportion of the population resident within 10 miles) were examined after adjustment for the other four variables. The results showed that in districts near to an installation there were significant excess mortalities in persons under 25 years of age from leukaemia (RR = 1.15, P = 0.01) and especially from lymphoid leukaemia (RR 1.21, P = 0.01) and from Hodgkin's disease (RR 1.24, P = 0.05) and a significant deficiency of mortality from lymphoid leukaemia in persons aged 25-64 years. No significant trends were observed with an increasing proportion of the population near to the installations and the greatest excess mortality from lymphoid leukaemia in young persons was observed in the districts with the intermediate proportion of the population (10.0-65.9%) near an installation.

Adolescent↗
PubMed1989

Increased phosphatidylinositol kinase activity in psoriatic epidermis.

Phosphatidylinositol (PI) kinase is activated by growth factors, such as epidermal growth factor (EGF), and is thought to be involved in cellular proliferation. Psoriasis is a hyperproliferative epidermal disease in which EGF receptor expression is altered and phospholipase C activity is increased. Considering the potential importance of growth factor stimulated phosphoinositide metabolism in the genesis of abnormal growth, we measured PI kinase activity in epidermal keratome biopsies from normal skin and the lesional and nonlesional skin of psoriatic patients. The PI kinase activity in 10 psoriatic involved plaques was increased 6.7-fold (Vmax = 67.1 +/- 23.9 pmol formed/min/mg protein +/- SE) when compared with 11 normal epidermal biopsies (Vmax = 10.0 +/- 1.3 pmol/min/mg protein, p less than 0.025). Similar results were noted when enzyme activity was standardized using DNA content. The apparent Km of PI kinase for ATP in involved psoriatic biopsies (0.45 +/- 0.14 mM) was also significantly (p less than 0.025) increased compared with normals (0.11 +/- 0.02 mM). The PI kinase activity in 11 biopsies of nonlesional psoriatic epidermis was not statistically different from normal epidermis. Both psoriatic and normal PI kinases required Mg++ and were inhibited by Ca++. The polyamine, spermine, a known activator of PI kinase in other tissues, stimulated normal but not psoriatic epidermal PI kinase. Both normal and psoriatic PI kinase activities had an apparent mol wt of 85,000. Increased synthesis of phosphoinositides by PI kinase in psoriatic tissue may provide more substrate for phospholipase C; a key enzyme in growth factor-mediated signal transduction.

1-Phosphatidylinositol 4-Kinase↗
PubMed1989

Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels.

We have examined serum levels of oestradiol (E2), sex-hormone binding globulin (SHBG) and human chorionic gonadotrophin (hCG) during early pregnancy in relation to smoking status at the time of sampling in a series of 147 women. Smoking was associated with significantly depressed serum levels of E2, SHBG and hCG: in smokers, E2 levels were on average 17.6% lower (P = 0.037), SHBG levels were 12.4% lower (P = 0.15), and hCG levels were 21.5% lower (P = 0.044). There appeared to be a steady decline in these values with increasing cigarette consumption. These lower hormone levels in smokers may explain certain adverse effects of smoking in pregnancy.

Adult↗
PubMed1988

Personal and family history of lung disease as risk factors for adenocarcinoma of the lung.

To identify risk factors for adenocarcinoma of the lung, a population-based case-control study of 336 female cancers of this cell type and an equal number of neighborhood controls was conducted between 1983 and 1986. After adjusting for personal smoking, personal and family histories of lung disease emerged as additional risk factors. A personal history of any lung disease was associated with a 40% increase in risk [smoking adjusted relative risk (SARR) = 1.4, 95% confidence interval (CI) = 1.0, 2.0] with a more marked increase in risk for lung diseases occurring during childhood (SARR = 1.9, 95% CI = 1.2, 3.2) and for tuberculosis (SARR = 10.0, 95% CI = 1.1, 90.1). Family histories of tuberculosis (SARR = 2.0, 95% CI = 1.1, 3.6) and of lung cancer (SARR = 3.9, 95% CI = 2.0, 7.6) were also risk factors for adenocarcinoma of the lung. Increasing risk was observed with decreasing intake of dietary beta-carotene. After adjusting for personal smoking, women in the lowest quartile of intake showed a two-fold increased risk relative to those in the highest quartile of intake (P = 0.003). There were also some suggestive differences between cases and controls in their reproductive history and hormone use.

Adenocarcinoma↗
PubMed1988

Inhibition of phosphoinositide metabolism in human polymorphonuclear leukocytes by S-adenosylhomocysteine.

Transmembrane signaling by chemoattractants in leukocytes appears to require activation of phosphoinositide metabolism with subsequent generation of the second messenger substances, inositol(1,4,5)trisphosphate and diacylglycerol. In addition, previous studies have shown that conditions which lead to an intracellular increase in S-adenosylhomocysteine (AdoHcy), a by-product and competitive inhibitor of S-adenosylmethionine-mediated methylation reactions, inhibit all chemoattractant-mediated functions of leukocytes, suggesting that AdoHcy also interferes with chemoattractant transmembrane signaling. In the present study, we determined whether AdoHcy altered the metabolism of phosphoinositides in human polymorphonuclear leukocytes. Treatment of 32P-labeled polymorphonuclear leukocytes with the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, plus exogenous adenosine and L-homocysteine thiolactone, conditions which cause an increase in AdoHcy, produced as much as a 37% decrease in the amount of [32P]phosphatidylinositol 4-monophosphate associated with the cells. The formation of inositol bisphosphate was inhibited by as much as 45% by erythro-9-(2-hydroxy-3-nonyl)adenine, adenosine, and L-homocysteine thiolactone suggesting decreased availability of phosphatidylinositol 4-monophosphate. In support of this, AdoHcy, in concentrations ranging from 0.01 to 0.1 mM, inhibited the transfer of gamma-32P from gamma-[32P] ATP to phosphatidylinositol (PtdIns). The inhibition of PtdIns kinase was competitive with an apparent Ki for AdoHcy of 43 microM. Increased intracellular AdoHcy reduced chemoattractant-mediated increases in inositol(1,4,5)trisphosphate formation suggesting abrogation of transmembrane signaling. These findings for the first time demonstrate that AdoHcy is a competitive inhibitor of PtdIns kinase and thus a regulator of the phosphoinositide pathway.

Adenine↗
PubMed1988

Characterization of phosphatidylinositol and phosphatidylinositol-4-phosphate kinases in human neutrophils.

Phosphodiesteric cleavage of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) is required for transmembrane signaling by chemoattractants in human polymorphonuclear leukocytes (PMN). Considering the importance of PtdIns-4,5-P2 as a reservoir for second messenger substances, we have characterized the enzyme system that synthesizes this phospholipid in human PMN, consisting of kinases for phosphatidylinositol (PtdIns) and phosphatidylinositol-4-phosphate (PtdIns-4-P). The preferred phosphate donor for both enzymes was ATP as compared with GTP. The respective Km for ATP for PtdIns kinase and PtdIns-P kinase were 0.049 +/- 0.013 and 0.062 +/- 0.005 mM and for GTP were 0.242 +/- 0.016 and 0.186 +/- 0.037 mM. PtdIns stimulated the activity of PtdIns kinase to a greater extent than PtdIns-4-P kinase. PtdIns-4-P inhibited the activity of detergent-solubilized PtdIns kinase and stimulated particulate PtdIns-4-P kinase, whereas both enzymes exhibited substrate inhibition to PtdIns-4,5-P2. Mg2+ was the preferred cation for both enzymes, but the apparent Km values (4.1 +/- 0.9 mM for PtdIns kinase and 1.0 +/- 0.7 mM for PtdIns-4-P kinase) were significantly different (p less than 0.005). Mn2+ partially substituted for Mg2+, and both enzymes were inhibited by Ca2+. The polyamine spermine stimulated PtdIns-4-P kinase activity to a greater extent and at lower concentrations than PtdIns kinase. PtdIns kinase was easily solubilized in both Triton X-100 and Nonidet P-40, whereas PtdIns-4-P kinase remained in a detergent-nonextractable membrane fraction. These findings demonstrate that the enzyme system in human PMN that forms PtdIns-4,5-P2 is composed of two distinct enzymes with similar characteristics.

1-Phosphatidylinositol 4-Kinase↗
PubMed1988

A case-control study of male breast cancer.

A case-control study was conducted in Los Angeles County, CA, of 75 male breast cancer cases aged 20-74 yr at diagnosis to investigate the role of a number of suspected risk factors. The study involved both interviews and laboratory measurements. Factors under study included fertility and marital history, obesity, alcohol and cigarette consumption, use of drugs known or suspected of causing gynecomastia, family history of breast cancer, history of radiation exposure to the upper body, sex chromatin analysis, serum levels of prolactin, testosterone, estrone, estradiol and sex-hormone-binding globulin, as well as urinary levels of estrone, estradiol, and estriol. Two patients versus no controls tested positive for sex chromatin and were excluded from further analyses. The only statistically significant risk factor identified was greater weight of the cases at age 30; a man who weighed 80 or more kg at age 30 had twice the risk of breast cancer of a man weighing less than 60 kg at that age. Serum estrone levels were positively, and sex-hormone-binding globulin levels were negatively, related to body weight, and we interpret the greater weight of the cases as suggesting that the underlying risk factor is an increased exposure to bioavailable estrogen. None of the differences observed between cases and controls for either the serum or urinary hormone levels was, however, statistically significant and there did not appear to be any large absolute excess of estrogens or deficit of testosterone in the cases. This apparent contradiction may be explained by the fact that there was little difference in weight between the cases and controls at the time of sampling.

Adult↗
PubMed1988

The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer.

The protective effect of early menopause shows that ovarian hormones increase the risk of breast cancer: it is likely that this is because they stimulate breast cell division. The mitotic rate of breast cells is higher during the luteal phase of the menstrual cycle than during the follicular phase, suggesting either that progesterone and oestrogen together induce more mitoses than oestrogen alone (the 'oestrogen plus progestagen hypothesis') or that oestrogen alone induces breast cell mitoses in a dose-dependent manner and that progesterone has no effect (the 'oestrogen alone hypothesis'). Both hypotheses are consistent with the known effects of reproductive history, obesity, combined oral contraceptives and oestrogen replacement therapy (ERT) on breast cancer risk, but while the oestrogen alone hypothesis predicts that hormone replacement therapy with oestrogen and a progestagen (HRT) will cause the same increase in risk as ERT, the oestrogen plus progestagen hypothesis predicts that HRT will cause a greater increase in risk than ERT. Both hypotheses suggest that the risk of breast cancer could be reduced by delaying the onset of regular ovulatory menstrual cycles and by minimizing the therapeutic use of oestrogens, and possibly of progestagens, in postmenopausal women. It may be possible to design hormonal contraceptives that will decrease breast cancer risk.

Adult↗
PubMed1988

Maternal hormone levels in early gestation of cryptorchid males: a case-control study.

A case-control study was conducted to assess maternal hormonal factors associated with increased risk of bearing a cryptorchid son. Serum samples were collected during the first trimester of pregnancy from participants in the US Collaborative Perinatal Study. Twenty-five mothers of normal offspring (controls) were individually matched on medical center, age, parity, weight and length of gestation at the time of sampling to women bearing sons who had a diagnosis of cryptorchidism at one year of age or older. Compared with controls, mothers of cryptorchid sons (cases) had significantly greater percentages of non-protein bound (P = 0.010) and albumin-bound (P = 0.014) estradiol during the first trimester of the index pregnancy. On average, cases had 16% more bioavailable oestradiol than controls. Levels of human chorionic gonadotropin, testosterone, non-protein bound testosterone and sex-hormone binding globulin did not differ between the two groups. The data presented support the hypothesis that cryptorchidism results from elevated maternal oestrogen levels early in pregnancy.

Adult↗
PubMed1988

Lung cancer and passive smoking: predicted effects from a mathematical model for cigarette smoking and lung cancer.

Epidemiological studies of active smokers have shown that the duration of smoking has a much greater effect on lung cancer risk than the amount smoked. This observation suggests that passive smoking might be much more harmful than would be predicted from measures of the level of exposure alone, as it is often of very long duration frequently beginning in early childhood. In this paper we have investigated this using a multistage model with five stages. The model is shown to provide an excellent fit to data on the incidence of lung cancer among smokers, ex-smokers and non-smokers in a cohort of male British doctors. Contrary to our expectation the model predicted only a slight increase in relative risk with increasing duration of passive exposure. Allowing for exposures early in life does not therefore explain the discrepancy between the relative risk of about 1.5 calculated from epidemiological studies of lung cancer and the low levels of exposure indicated by cotinine measurements in those passively exposed.

Aged↗
PubMed1988

The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.

The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%.

Adult↗
PubMed1988

Role of the fetal pituitary in cryptorchidism induced by exogenous maternal oestrogen during pregnancy in mice.

A single subcutaneous injection of 5 or 1 mg oestradiol given to pregnant female mice on Day 14 of pregnancy resulted in all male offspring being cryptorchid. Pituitary LH content, testicular weights and structure, seminal vesicle weights and the structure of the reproductive tract as a whole were monitored on the day of birth and at 2, 4, 8 and 14 weeks of age. Apart from an initial significant reduction in pituitary LH at the time of birth, no other marked differences were seen between control and treated animals except that all oestrogen-treated males lacked a gubernaculum and the testes were freely mobile within the abdomen. Hypogonadal (hpg) male mice lacking GnRH are cryptorchid but have a normal gubernaculum and their testes develop and descend normally if treated with gonadotrophins. When the mothers of hpg mice were treated with oestradiol the male offspring lacked a gubernaculum. These results indicate that perturbations of the fetal hypothalamic/pituitary axis play no significant part in oestrogen-induced cryptorchidism in mice.

Animals↗