A unifying mechanism for the role of microtubules in the regulation of [Ca2+]i and contraction in the cardiac myocyte.
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Animals↗
Biomedical subjects
E White
Publications and source records attributed to E White.
Modulation of Ca(2+) signaling by microtubule disruption in rat ventricular myocytes and its dependence on the ruptured patch-clamp configuration.
In the absence of hypertrophic proliferation of microtubules, microtubule disruption by colchicine does not modulate contraction of adult cardiac myocytes. However, Gomez et al (Circ Res. 2000;86:30-36) recently reported that disruption of microtubules by colchicine in ruptured patch-clamped myocytes increased I(Ca,L) density and [Ca(2+)](i) transient amplitude and depressed the response of these parameters to the beta-adrenoceptor agonist isoproterenol. These effects were ascribed to stimulation of adenylyl cyclase by increased intracellular free tubulin. In the present study, we show that in intact rat ventricular myocytes, 2 to 4 hours of exposure to 10 micromol/L colchicine had no effect on shortening or [Ca(2+)](i) transient amplitude or on the amplitude of I(Ca,L) in perforated patch-clamped cells, under basal conditions and after stimulation with 1 micromol/L isoproterenol. However, in ruptured patch-clamped myocytes, basal I(Ca,L) was 2-fold higher after treatment with colchicine compared with vehicle and, in contrast to vehicle-treated cells, I(Ca,L) did not increase in response to isoproterenol. Cell width decreased during ruptured patch-clamp experiments in colchicine-treated but not vehicle-treated myocytes. We conclude that in cells with intact sarcolemma, colchicine does not modulate Ca(2+) signaling or the response to beta stimulation. However, the combination of microtubule disruption by colchicine and the ruptured patch configuration activates I(Ca,L) and attenuates the response to beta stimulation. We propose that these effects may be due to loss of free tubulin by intracellular dialysis or to increased sensitivity to mechanical stimulation as a result of microtubule disruption. These findings have important implications for cardiomyopathies associated with decreased free tubulin or a diminished microtubular network. The full text of this article is available at http://www.circresaha.org.
Amphotericin B↗
Effects of antibiotics on the contractility and Ca2+ transients of rat cardiac myocytes.
We have compared the effects of streptomycin sulphate, gentamicin sulphate and neomycin sulphate on cell shortening (our index of contractility) and intracellular Ca2+ ([Ca2+](i)) transients of rat ventricular myocytes. All three agents abolished shortening and [Ca2+](i), transients but streptomycin was significantly less potent than the other agents. The IC(50) of streptomycin was 0.37 mM for shortening and 0.78 mM for [Ca2+](i), approximately an order of magnitude greater than equivalent values for gentamicin and neomycin. Gentamicin and streptomycin shortened the action potential duration of most cells but prolonged the action potential duration of others. We therefore conclude that multiple ionic mechanisms affecting action potential duration are modulated by these antibiotics. Our observations are consistent with the negative inotropic effect of antibiotics being caused by a decrease in Ca2+ influx causing a reduction in the [Ca2+](i) transient.
Action Potentials↗
Contribution of angiotensin II, endothelin 1 and the endothelium to the slow inotropic response to stretch in ferret papillary muscle.
We investigated the contribution of angiotensin II and endothelin I to the slow positive inotropic response observed following stretch of isolated ferret papillary muscle from 88% to 98% of the length at which maximum force is generated. Angiotensin antagonists losartan and saralasin did not affect the magnitude of the slow response in ferret papillary muscle. The ETA-selective antagonist BQ123 slightly reduced the magnitude of the slow response (P > 0.05). In the presence of PD145065 (an ETA and ETB antagonist), the magnitude of the slow response was reduced significantly by 50%. Removal of the endothelium with 1% Triton X-100 reversed the slow response to stretch. We conclude that, in the ferret, endothelin I acting through ETA and ETB receptors, contributes to the slow response although it is not the sole mediator. Angiotensin II is not a prerequisite for the slow response to stretch. We have shown for the first time that the endocardial endothelium plays a pivotal role in this phenomenon in cardiac papillary muscle.
Angiotensin II↗
The Fourth Quinquennial National Community Mental Health Nursing Census of England and Wales.
Within an increasingly articulate policy framework, changes to the United Kingdom National Health Service have taken place and these have impacted on mental health service provision. They have particular implications for the work of community mental health nurses (CMHNs). Since 1980, a five-yearly national census of CMHNs has been conducted. Selected findings from the latest census, commissioned by the Department of Health, are set within the context of data derived from the three previous studies. Substantive implications which flow from the changes detected in the practice, organisation and management, and education of community mental health nurses in England and Wales, are discussed.
Adult↗
p53-dependent apoptosis pathways.
The p53 tumor suppressor limits cellular proliferation by inducing cell cycle arrest and apoptosis in response to cellular stresses such as DNA damage, hypoxia, and oncogene activation. Many apoptosis-related genes that are transcriptionally regulated by p53 have been identified. These are candidates for implementing p53 effector functions. In response to oncogene activation, p53 mediates apoptosis through a linear pathway involving bax transactivation, Bax translocation from the cytosol to membranes, cytochrome c release from mitochondria, and caspase-9 activation, followed by the activation of caspase-3, -6, and -7. p53-mediated apoptosis can be blocked at multiple death checkpoints, by inhibiting p53 activity directly, by Bcl-2 family members regulating mitochondrial function, by E1B 19K blocking caspase-9 activation, and by caspase inhibitors. Understanding the mechanisms by which p53 induces apoptosis, and the reasons why cell death is bypassed in transformed cells, is of fundamental importance in cancer research, and has great implications in the design of anticancer therapeutics.
Apoptosis↗
Bone mineral density and breast cancer risk in postmenopausal women.
Two recent studies have shown a woman's bone mineral density (BMD) (a composite measure of exposure to many different factors throughout one's lifetime) predicts breast cancer. In a prospective cohort study, we examined whether hip BMD was associated with breast cancer risk among 8203 postmenopausal women. During an average follow-up of 3.7 years, 131 incident breast cancer cases (102 invasive) were identified. Cox proportional hazards models were used to obtain estimates of the relative risk of breast cancer. Our results demonstrate an increase in breast cancer risk among women with higher BMD. Independent of age, geographic area, and body mass index, relative to the lowest BMD quartile the risk of breast cancer (95% confidence interval) by increasing quartile was 1.9 (1.1, 3.2), 1.5 (0.8, 2.6), and 1.5 (0.8, 2.7), respectively. An examination of other factors important in determining BMD may help explain the positive association between BMD and breast cancer.
Aged↗
Correlates of serum alpha- and gamma-tocopherol in the Women's Health Initiative.
PURPOSE: There is increasing evidence that vitamin E (primarily alpha- and gamma-tocopherol) may reduce the risk of cardiovascular disease and some cancers, therefore it is important to understand factors that influence blood levels. METHODS: The correlates of serum alpha- and gamma-tocopherol were investigated among participants in the Women's Health Initiative (WHI), a 40-site disease prevention trial. Subjects were 1047 postmenopausal women aged 50-79 years, who provided fasting blood specimens and detailed information on diet, supplement use, and other factors at entry to the study (1994-96). RESULTS: Total serum cholesterol and triglycerides were highly correlated with serum alpha- and gamma-tocopherol concentrations and were controlled for in all analyses along with age, ethnicity and body mass index (BMI). Alpha and gamma-tocopherol were strongly negatively correlated (partial r = -0.69). The strongest predictor of serum tocopherols was average daily intake of vitamin E from supplements (partial r = 0.60 for alpha, r = -0.54 for gamma). Other factors associated with increased alpha- and/or decreased gamma-tocopherol concentrations were serum retinol and carotenoids, supplemental vitamin C, alpha-tocopherol intake from food, dietary fiber, and Hispanic ethnicity. Factors associated with lower alpha- and/or higher gamma-tocopherol concentrations included gamma-tocopherol intake from food, total fat intake, and BMI. Age, income, hormone use, and geographic location were "spuriously" associated with serum tocopherol levels through their association with supplement use, i.e., there was no such association among the subset of women not taking supplements. CONCLUSIONS: Vitamin E intake from supplements and BMI are the major independent predictors of serum tocopherol levels in women, whereas dietary factors only play a small role.
Aged↗
Variation in mammographic breast density by race.
PURPOSE: Because of the observed racial differences in risk of developing breast cancer, the authors conducted a study to determine the variation in breast density, a strong predictor of breast cancer risk, by race and age. METHODS: Study subjects were women enrolled in Group Health Cooperative of Puget Sound, Seattle, WA, aged 20-79 years, who had a screening mammogram between 6/1/96 and 8/1/97. Women with increased breast density (BI-RADS "heterogeneously dense" and "extremely dense") (n = 14,178) were compared to those with fatty breasts (BI-RADS "almost entirely fat" and "scattered fibroglandular tissue") (n = 14,323). Logistic regression was used with adjustment for age, parity, age at first birth, menopausal status, current use of hormone replacement therapy, and body mass index. RESULTS: The odds ratio (OR) for having dense breasts versus fatty breasts, comparing Asian to White women, increased from 1.2 [95% confidence interval (CI) 0.9-1.6] for women age <45 to 1.6 (95% CI 1.3-2.2) for women over 65. Conversely, the OR for Black compared to White women was highest for the women age 65 and younger (OR 1.7 (1.2-2.3), 1.3(1.0-1.7), and 1.7 (1.2-2.3) for women age <45, 46-55, and 56-65, respectively), whereas Black women over 65 had similar density as Whites. Hispanic women had similar density compared to Whites for all ages. CONCLUSIONS: These racial differences in breast density generally do not conform to differences in race and age-specific breast cancer incidence rates.
Adult↗
A study of some characteristics of individual clones of Schistosoma mansoni with emphasis on the biological and metabolic activities.
The variability within schistosome populations was explored using mixed populations of cercariae from multimiracidial snail infections and individual clones of Schistosoma mansoni cercariae obtained from monomiracidial snail infections. We investigated the heterogeneity between different clones of S. mansoni with respect to infectivity and metabolism. One difference between clones of cercariae was found in the recovery of adult worms from Balb/C mice. Recovery of adult worms was greater after infections with a mixed population than with a clonal population. To investigate some biochemical features of individuals in clones or mixed populations, the uptake of [35S]methionine into individual parasites and their membrane proteins was measured. Isoelectric focusing of a soluble membrane fraction: the frozen-thawed supernatant extracted from individual clones, showed the presence of proteins of isoelectric point between 7.2 and 8.2 in all clones. These proteins were less labelled with [35S]methionine in the clones than in the mixed population. It was concluded that basic proteins are synthesized by all clones and in the mixed population but at different rates. Differences in the rate of incorporation of [35S]methionine into the surface membranes of schistosomula and adult worms derived from individual clones are reported. In addition, a direct correlation between the percentage of recovery of adult worms from mice infected with individual clones of S. mansoni and the rate of incorporation of [35S]methionine into schistosomula of these particular clones was observed. It is suggested that the high rate of metabolism shown by an individual clone may account for the enhanced survival of the cercariae derived from that clone during penetration of the skin and migration through the vertebrate host. In order to examine individuals in a population of schistosomula, from a clone or mixed population, the lysosome-specific fluorescent probe LysoTracker DND-99 was used to label the parasites and quantitative fluorescent measurements were made on individual parasites. There were significant differences between clones and a mixed population. Furthermore, the variation between individuals from a mixed population was greater than from that in any clone, just as was found in the infectivity studies. Freshly transformed schistosomula of individual clones labelled with the LysoTracker DND-99 showed less variations in the quantitative uptake of the dye within a single clone when compared to the mixed population. We conclude that for any biochemical and biological parameter, a population of cercariae consists of individuals showing a wide range of values, with a much greater range in a mixed population. This variability is likely to have great relevance for infectivity of the final host and the efficacy of drugs and the immune system.
Animals↗
Melanoma risk in relation to height, weight, and exercise (United States).
Height and weight and derivations thereof are positively associated with a number of cancers. While several authors have reported an increased risk of melanoma among people at the higher extremes of these measures, the association has not been fully explored. New cases of primary cutaneous melanoma in 1997 in western Washington State (n = 386) were compared to controls selected by random-digit dialing (n = 727). Each study participant completed a telephone survey, and data were collected on height, weight, sun-related melanoma risk factors, demographic characteristics, as well as habits such as diet and exercise. Risk of melanoma was analyzed by logistic regression with adjustment for age, hair color, lifetime sun exposure, and fruit and vegetable intake. An excess risk of melanoma was identified in men in the upper quartiles of height (OR = 2.4, 95% confidence interval (CI) = 1.3-4.5), weight (OR = 2.8, CI = 1.5-5.2), and body surface area (OR = 2.8, CI = 1.5-5.1) vs. the lowest quartiles. In women, no association was present for any anthropometric measure. In addition, we found that men and women exercising five to seven days per week were at a decreased risk of melanoma (OR = 0.7, CI = 0.5-1.0). The anthropometric findings are largely consistent with previous studies, while this is the first report of an association of exercise with melanoma risk. The mechanisms for the effect of exercise and for the difference between men and women in the effect of anthropometric factors are unknown. Future research in basic and epidemiologic science should focus on biochemical or behavioral explanations for these observations.
Adult↗
Colorectal cancer following tamoxifen therapy for breast cancer (United States).
BACKGROUND: An analysis combining data from several clinical trials has raised concern that tamoxifen therapy may increase the risk of a subsequent colorectal malignancy. We conducted a nested case-control study to test this hypothesis. METHODS: A cohort of women diagnosed with breast cancer in 1978-1992 was identified from the western Washington population-based cancer registry. Cases included women who subsequently developed colorectal cancer prior to 1995. Controls were a random sample of the cohort who did not develop a second primary malignancy, matched to cases on age, stage, and year of initial cancer diagnosis. Tamoxifen use was ascertained by medical record abstraction and physician questionnaires. RESULTS: Thirty-six percent of the 122 cases for whom information could be obtained received tamoxifen versus 38% of 194 controls. Relative to non-users and adjusted for receipt of other therapies, there was no increased risk of colorectal cancer associated with tamoxifen use in general (matched odds ratio [mOR] = 0.9, 95% CI 0.6-1.6), longer durations of use (for > or =37 months, mOR = 0.8, 95% CI 0.4-1.9), higher cumulative doses of therapy (for > or =15 g, mOR = 0.8, 95% CI 0.4-1.6), or use that started at least 5 years prior to the end of study follow-up (mOR = 1.1, 95% CI 0.3-3.7). CONCLUSIONS: We found no overall increased risk for colorectal cancer among tamoxifen users.
Adult↗
Bone mineral density and endogenous hormones and risk of breast cancer in postmenopausal women (United States).
OBJECTIVE: This case-cohort study was designed to examine whether total hip bone mineral density (BMD) is independently associated with breast cancer over and above its association with other determinants, including levels of total and bioavailable estradiol and testosterone and sex-hormone binding globulin. METHODS: Our study population was selected from a cohort of 8,203 postmenopausal women who were screened for the Fracture Intervention Trial in 1992, at which time BMD was assessed, and blood samples were obtained. A total of 109 women developed breast cancer during four years of follow-up; 173 other randomly selected women from the larger cohort were also selected. Cox proportional hazards with robust variance adjustment was used for these analyses. RESULTS: Relative to women in the lower fourth of the BMD distribution, the risk associated with being in the upper fourth was 2.6 (95% confidence interval (CI) 1.1-5.8). After adjusting for serum hormone levels, the corresponding relative risk was 2.5 (95% CI 0.9-5.2). With body mass index and number of years since menopause added to the multivariate analysis, the relative risk decreased to 1.4 (95% CI 0.5-4.0). CONCLUSIONS: BMD may not influence breast cancer risk independent of its relationship with endogenous hormones and measured covariates.
Aged↗
The association of dietary fat and plant foods with endometrial cancer (United States).
OBJECTIVES: To examine the associations of dietary fat and selected plant foods with endometrial cancer in a population-based case-control study. METHODS: Six hundred and seventy-nine incident cases of endometrial cancer diagnosed between 1985 and 1991, and 944 population-based controls completed a 98-item semi-quantitative food-frequency questionnaire and a detailed in-person interview which collected information on endometrial cancer risk factors. Logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) of endometrial cancer, adjusted for age, county, energy intake, hormone use, smoking and, in separate models, for body mass index (BMI: kg/m2). RESULTS: Percent energy from fat was associated with an increased risk of endometrial cancer (highest quintile cf. lowest: OR = 1.8, 95% CI 1.3-2.6), with saturated and monounsaturated fats being the main contributors of risk. There was a stronger association between dietary fat and endometrial cancer among groups with higher circulating estrogen levels (i.e. women with higher BMI, users of unopposed estrogens, non-smokers, and younger age at menarche). Consumption of fruits or vegetables was inversely associated with endometrial cancer risk (highest quintile cf. lowest: OR = 0.65, 95% CI 0.46-0.93 and OR = 0.61, 95% CI 0.43-0.88, respectively). Further adjustment for BMI resulted in little or no attenuation of the ORs and associated CIs. CONCLUSIONS: These results provide support for the theory that a low-fat, high-fruit and high-vegetable diet may reduce the risk of endometrial cancer, and that these dietary factors may act independently of the effect of BMI.
Aged↗
The scientific study of unusual rapid wound healing: a case report.
This paper examines in a Western medical setting the claim made by a Middle Eastern school of Sufism that its members can attain unusually rapid wound healing from deliberately caused bodily damage. The demonstration involved a Sufi practitioner inserting an unsterilized metal skewer through one side of the cheek area of the face (lateral buccal) and out through the other side. The insertion was observed by Western scientists. The left facial puncture healed within 2 minutes; the right facial puncture was three-quarters healed after 8 hours. According to the practitioner, the piercing was not associated with subjective pain. Radiological, immunological, and electroencephalograph (EEG) recordings were taken before and after the insertion. A random event generator (REG) was also run during the demonstration. Radiological and axial CT images documented the presence of the metal skewer through the cheeks. EEG findings were inconclusive. Immunological recordings showed no alterations. There was a trend toward REG non-randomness and, therefore, negentropy or increased complexity and order, which may be associated with the re-establishment of tissue integrity. Such rapid wound healing has therapeutic implications for new treatments of serious medical and pain-related problems as well as implications for the study of "paranormal" healing phenomena.
Adult↗
Usual interstitial pneumonia.
Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF), but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high resolution thin section computed tomographic scans (provided the radiographic features are classical). Historically, patients labeled as "IPF'' encompassed a group of disorders including UIP as well as other idiopathic interstitial pneumonias, which differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Single-lung transplantation is a viable option for patients failing medical therapy. Novel therapeutic strategies based upon inhibiting fibroproliferation or enhancing alveolar reepithelialization are desperately needed. In this article, we discuss diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).
Journal Article↗
Asian breast cancer survival in the US: a comparison between Asian immigrants, US-born Asian Americans and Caucasians.
BACKGROUND: This study examines whether acculturation of Asian American women, assessed by place of birth, is associated with survival after diagnosis of breast cancer. We hypothesized that environmental factors associated with acculturation, such as a high-fat diet, would result in a pattern of better survival for first-generation Asians compared with subsequent-generation Asian Americans. METHODS: Analyses compare survival among women of four ethnic groups (Chinese [n = 1842], Japanese [n = 3319], Filipino [n = 1598] and a random sample of Caucasians [n = 10,000]) who were diagnosed with primary invasive breast carcinoma in three Surveillance, Epidemiology, and End Results Program (SEER) regions (San Francisco/Oakland, Hawaii, Seattle/Puget Sound) between 1973 and 1994. Analyses by birthplace compare first-generation Asian immigrants with subsequent-generation Asian Americans of the same ethnicity. Analyses were based on the Cox proportional hazards model and adjusted for age at diagnosis, stage of disease, year of diagnosis, type of treatment, marital status, and SEER region. RESULTS: Japanese women had significantly better survival than all other races, but there were no significant differences in survival between Chinese, Filipino, and Caucasian women. There were no significant differences in survival by place of birth within each Asian ethnic group, after adjustment for demographic characteristics, stage of disease, and treatment. CONCLUSION: The findings do not support the hypothesis that acculturation of Asian American women is associated with decreased breast cancer survival.
Acculturation↗
Corticosteroids in idiopathic pulmonary fibrosis.
Corticosteroids were the mainstay of therapy for idiopathic pulmonary fibrosis (IPF) for more than four decades, but their efficacy is unproven and toxicities are substantial. The course of IPF is characterized by progressive respiratory insufficiency, leading to death within 3 to 8 years from the onset of symptoms. Although a subset (10-20%) of patients survives more than 10 years, there is no evidence that any form of therapy alters the natural history of the disease. Nonetheless, given the poor prognosis, a trial of corticosteroids is often given. Because of the rarity of IPF, randomized, placebo-controlled therapeutic trials have not been done. Further, no studies have compared differing dosages or duration of corticosteroid in matched patients. Interpretation of therapy efficacy is obscured by several factors including heterogeneous patient populations, inclusion of patients with histologic entities other than usual interstitial pneumonia, lack of objective, validated endpoints, different criteria for "response." We review published data regarding corticosteroid therapy for IPF and present a rationale for stratifying therapy based on host, demographic, and clinical factors that influence prognosis as well as risk for corticosteroid complications.
Adrenal Cortex Hormones↗