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M C Pike

Publications and source records attributed to M C Pike.

At least 217 records · Page 12Linked to original sources
PubMed1984

Transductional mechanisms of chemoattractant receptors on leukocytes.

Phagocytic leukocytes contain receptors for chemoattractants on their cell surface. Binding of chemotactic factors to these receptors initiates a number of coordinated cellular responses in a strict dose-dependent manner. Motility-related functions such as shape change, cytoskeletal rearrangement, and chemotaxis are stimulated by relatively low doses of chemoattractants, while microbiocidal or cytotoxic functions (i.e., secretion of lysosomal enzymes or stimulation of the respiratory burst), require approximately 10- to 50-fold higher concentrations of these agents. The receptor for oligopeptide chemotactic factors on leukocytes has provided an important model for the study of stimulus-response coupling in phagocytic cells. This receptor on human polymorphonuclear leukocytes exists in two affinity states that are partially interconvertible. Guanine nucleotides regulate the convertibility between a portion of the high- and low-affinity states, thereby suggesting that a nucleotide regulatory protein allosterically modifies receptor affinity and participates in its transduction mechanisms. A fraction of the high-affinity receptors in PMN membranes is not subject to guanine nucleotide regulation and appears to be formed by prior exposure of the receptors to specific agonists. This high-affinity form of the oligopeptide chemoattractant receptor is rapidly internalized at 37 degrees C, and its formation may be dependent on aggregation or covalent modification of the receptor. The chemotaxis and microbiocidal functions of PMNs can be divergently manipulated by pharmacological agents indicating that the transduction mechanisms for these two types of processes are independently regulated. Aliphatic alcohols at doses that induce mild fluidization of PMN membranes increase the average affinity of the chemoattractant receptor and enhance chemotactic functions but markedly depress lysosomal enzyme secretion and the respiratory burst. In contrast, polyene antibiotics that bind to membrane cholesterol lower the receptor's affinity and depress chemotactic functions but enhance secretion of specific granule enzymes. In addition, transmethylation reactions mediated by S-adenosyl-methionine appear to regulate receptor affinity. When such reactions are blocked pharmacologically, the oligopeptide receptor on macrophages reverts to a lower average affinity form and is ineffective in transducing chemotactic as well as microbicidal functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphotericin B↗
PubMed1984

A chemoattractant receptor on macrophages exists in two affinity states regulated by guanine nucleotides.

The binding characteristics of the oligopeptide chemoattractant receptor on guinea pig macrophages and macrophage membrane preparations were characterized using detailed binding studies and computer analysis. Viable macrophages bound the radiolabeled chemoattractant N-formyl-methionyl-leucyl-[3H]phenylalanine with single dissociation constant (KD) of 18.4 +/- 4.6 nM with 15,300 +/- 1,800 sites per cell. Binding data from membrane preparations indicated the presence of two classes of binding sites with KD of 1.5 +/- 0.4 nM and 25.5 +/- 11.0 nM. Approximately 23% of the receptors were in the high affinity state. In the presence of added guanine nucleotide di- or triphosphates, the high affinity receptors in the membrane preparations were converted to low affinity states with no change in the total receptor number. Nonhydrolyzable derivatives of GTP were most potent in converting the receptor from its high to low affinity state. These data suggest that the affinity state of the oligopeptide chemoattractant receptor in macrophages is regulated by guanine nucleotides and GTPase, implying that the transduction mechanisms of this receptor may be controlled by a guanine nucleotide regulatory unit.

Animals↗
PubMed1984

Age at natural menopause and breast cancer risk: the effect of errors in recall.

Many case-control studies of breast cancer have reported estimates of relative risk of approximately 1.9 for menopause after 54 years of age when compared with menopause before 45 years of age. These estimates may be biased towards unity because of errors in recall of a woman's age at menopause. This paper investigates the magnitude of error associated with self-classification of women into categories of age at menopause by using personal interview and medical record data of 67 control women from a case-control study of breast cancer conducted in two retirement communities near Los Angeles in 1977-1978. These estimates of "misclassification" error are combined with various sets of "true" relative risks to yield "observable" relative risks. It is demonstrated that the relative risks associated with various age at menopause groups are likely to range from 1-3.4 rather than 1-1.9 as has been reported in the literature.

Adult↗
PubMed1984

Breast cancer.

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Adolescent↗
PubMed1984

Chemoattractant receptors on phagocytic cells.

Chemoattractant receptors on leukocytes can trigger a number of cellular responses, including the cytoskeletal reorganization, changes in cell shape, directed motility, lysosomal enzyme secretion, and activation of the respiratory burst. The dose of chemoattractants required to induce motility-related functions is generally at least ten-fold smaller than the dose required to initiate secretory and respiratory burst activities. This finding and other pharmacological evidence clearly indicate that the two types of functions (i.e. motility and secretion) are regulated differently and can be divergently modified by drugs. The affinity of the oligopeptide chemoattractant receptor on polymorphonuclear leukocytes and macrophages is heterogeneous and dynamically regulated by guanine nucleotides and prior agonist exposure. High- and low-affinity forms of the oligopeptide receptor have been identified by direct binding studies. Our data suggest that low doses of agonists can initiate interconversion of low- and high-affinity states of that portion of chemoattractant receptors regulated by guanine nucleotides. On the other hand, high doses of agonists sufficient to induce chemotactic desensitization, lysosomal enzyme secretion, and the respiratory burst lead to the formation of a new population of high-affinity receptors. These binding sites are insensitive to the effects of guanine nucleotides and appear to be rapidly internalized. Transmethylation reactions mediated by S-adenosyl methionine are required for the activation of a phospholipase and release of arachidonate from leukocytes by chemotactic factors. We suggest that release of arachidonate from membrane phospholipid activates and translocates a cytosolic but loosely membrane-associated protein kinase C into the membrane and that this kinase participates in stimulus-response coupling of chemoattractant receptors.

Animals↗
PubMed1984

The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments.

A generally accepted format for the numerical description of the carcinogenic potency of a particular chemical in a particular strain of animals is desirable so that statements from different sources about potency and attempts by different authors to correlate potency with particular laboratory measurements will be comparable. The choice of an appropriate standard format is to a certain extent arbitrary. In this paper we recommend that the TD50 (tumorigenic dose rate 50) be used. TD50 can be calculated for a single target site or combination of sites. The TD50, in analogy with the LD50, is defined as that chronic dose rate (in mg/kg body weight/day) which would halve the actuarially adjusted percentage of tumor-free animals at the end of a standard experiment time--the "standard lifespan" for the species. This paper consists of a brief discussion of the TD50, sufficient to make the general reader familiar with the properties of such an index, an appendix discussing methods for its estimation and certain conventions we have adopted for use in analyzing "nonstandard" experiments. A major problem in calculating any index of carcinogenic potency is that much published material gives only the final crude percentage of tumor-bearing animals at each dose, instead of percentages adjusted for the effects of intercurrent mortality or data from which these adjusted percentages can be derived. If the dose level administered to the animals is toxic, then premature death from nonneoplastic causes may prevent some dosed animals that would have developed tumors from actually doing so. This will particularly affect the high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effects of reserpine on prolactin levels and incidence of breast cancer in postmenopausal women.

Epidemiological studies of reserpine use and breast cancer have generally found only small increases in breast cancer risk, even after long-term use. Prolactin levels in short-term reserpine users have been reported to be in the range of those of lactating women, levels which rodent experiments suggest should greatly increase breast cancer incidence. We measured prolactin levels in 15 women who had been taking reserpine-containing drugs for at least 5 years and compared them to levels in 15 women taking non-reserpine-containing antihypertensives and 15 women taking no antihypertensive medicines. Although reserpine users had significantly elevated levels of prolactin, their mean level was only approximately 50% greater than the mean level of the combined results from the two control groups. Based on a statistical model of breast cancer incidence, we calculate that such increases in prolactin in the postmenopausal period would be likely to cause only small increases in breast cancer risk, as have been observed in epidemiological studies.

Aged↗
PubMed1984

Calculation of carcinogenic potency from long-term animal carcinogenesis experiments.

An index of carcinogenic potency for chemicals tested in chronic animal experiments is described. By analogy with the well-known 'lethal dose 50' (LD50) of quantal bioassay, a 'tumorigenic dose 50' (TD50) may be defined (in the absence both of tumors in the control group and of intercurrent deaths) as that (daily) dose of chemical which gives 50% of the test animals tumors by some fixed age. Tumors in the control (zero-dose) group are handled exactly as for the LD50, and intercurrent deaths are handled by life-table methods. Nonparametric procedures are developed for estimating the TD50 and for constructing confidence intervals. These are based on likelihoods which assume that the tumor hazard is linear in dose.

Aniline Compounds↗
PubMed1983

Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use.

A case-control study of 314 breast cancer patients aged less than 37 at diagnosis and 314 individually matched controls was done to assess the influence of oral-contraceptive (OC) use on the risk of the disease. Long-term use before age 25 of combination-type OCs with a "high" content of the progestogen component was associated with increased risk of breast cancer: the relative risk was approximately 4 after 5 years of such use, and 9 cases and no controls had used such combination-type OCs for more than 6 years before age 25. Use of combination-type OCs with a "low" progestogen component appears to increase breast-cancer risk little or not at all.

Adult↗
PubMed1983

Practical guide for estimating risk for familial breast cancer.

Life-table analysis was used to estimate the cumulative risk of breast cancer to various ages for mothers and sisters of breast cancer patients in a population-based series. These cumulative risk estimates were then used to derive a probability of breast cancer diagnosis within each decade between ages 20 and 70 for mothers and sisters, according to age of diagnosis in the patient and whether the disease was unilateral or bilateral. Risks for relatives of premenopausal patients with unilateral disease were no higher than those for relatives of postmenopausal patients. Relatives of premenopausal patients with bilateral disease had higher risk than relatives of patients with unilateral disease, irrespective of age at diagnosis in those with unilateral disease. Sisters were at higher risk than were mothers.

Actuarial Analysis↗
PubMed1983

'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer.

For most cancer sites there is a linear log-log relationship between incidence and age. This relationship does not hold for breast cancer, and certain 'key' breast cancer risk factors suggest that breast tissue does not 'age' in step with calendar time. A quantitative description of 'breast tissue age' is suggested which brings the age-incidence curve of breast cancer into line with the common log-log cancers and explains quantitatively the known key risk factors. The model also explains the 'anomalous' finding that although early first birth is protective, late first birth carries a higher risk than nulliparity. US breast cancer rates are some four to six times the rates in Japan--the model suggests that the key risk factors, when considered jointly with weight, can explain about 85% of the difference.

Adolescent↗
PubMed1983

Physical fitness and subsequent myocardial infarction in healthy workers.

Physical work capacity (PWC), a measure of physical fitness, was assessed by bicycle ergometry on 2,779 healthy men younger than 55 years who were subsequently followed up for an average of 4.8 years for symptomatic myocardial infarction (MI). There were 36 MIs. The relative risk (RR) of MI for below median PWC, adjusted for conventional risk factors for heart disease, was 2.2 (95% confidence limits, 1.1 and 4.7). This increased risk appeared to be limited to men with certain other risk factors present simultaneously: above-median cholesterol level, smoking, above-median systolic BP, or a combination of these. Among men with at least two of these factors, the adjusted RR for below-median PWC was 6.6 (95% confidence limits, 2.3 and 27.8). Poor physical fitness may be an important risk factor for heart disease, especially when conventional risk factors are also present.

Adult↗
PubMed1983

Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: differential changes in high-density lipoprotein subclasses.

Oral contraceptives containing DL-norgestrel or norethindrone with ethinyl estradiol were administered by random assignment to 21 menstruating women, matched for anthropometric measurements, age, diet, alcohol consumption, smoking, and exercise habits. Pretreatment and 7-week treatment blood samples were obtained and assayed for serum cholesterol, triglyceride high-density lipoprotein cholesterol (HDL-C), and total high-density lipoprotein (HDL), HDL2a, HDL2b, and HDL3 subclasses by analytic ultracentrifugation. Subjects using the norethindrone oral contraceptive had a significant increase in HDL-C: baseline, 46 mg/dl; 7 weeks, 51 mg/dl. Values for the subjects using the norgestrel oral contraceptive were not significantly changed: 46 and 44 mg/dl, respectively. Users of the norethindrone oral contraceptive had significant elevations of total HDL and HDL3, while norgestrel oral contraceptive users demonstrated no significant changes. HDL2b increased with the norethindrone oral contraceptive and declined with the norgestrel oral contraceptive. The changes in HDL2b from baseline to treatment were not significant (p greater than 0.05), but the change with the norethindrone oral contraceptive did differ significantly from that with the norgestrel oral contraceptive (p less than 0.02). These changes may indicate oral contraceptive-induced alterations in HDL structure and metabolism that could be related to the risk of development of atherosclerosis.

Adult↗
PubMed1983

The epidemiology of endometrial cancer in young women.

A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.

Adenocarcinoma↗