Uterine leiomyomas: mechanisms of tumorigenesis.

Uterine leiomyomas, also called fibroids, are the most common reproductive tract neoplasm and the leading indication for hysterectomy in premenopausal women. The discovery and development of medicinal therapies for uterine leiomyoma have been hampered by a lack of understanding regarding the etiology and molecular mechanisms underlying the development of these lesions. Although the estrogen responsiveness of uterine leiomyoma is well established, the impact of environmental estrogens and their contribution to the development of these tumors is currently unknown. The Eker rat model of uterine leiomyoma has proven useful for addressing these issues and understanding the pathophysiology of this disease. The Eker rat is the only animal model that develops spontaneous uterine leiomyomas, and these tumors share many characteristics with those found in humans. The availability of tumor-derived cell lines from these rats has made this a valuable in vitro/in vivo model system for experimental studies to investigate molecular mechanisms of disease and to design interventional and preventative strategies for this clinically relevant tumor.

A collaborative model for employee health and nursing education. Successful program.

Combining the talents and skills of CON faculty and students with those of the CAVHS health professionals has demonstrated the synergy that can be obtained through collaboration. The health care needs of CAVHS employees continue to provide a fertile ground for the education, service, and research missions of the CON. The Program outcomes and employee satisfaction ratings, combined with the positive educational outcomes in the CON, have led to strengthened relationships between nursing education and the veterans health care system. The results of this partnership are illustrated by the recent signing of an additional 3 year contract for the CAVHS.

An in vivo/in vitro model to assess endocrine disrupting activity of xenoestrogens in uterine leiomyoma.

Xenoestrogens with endocrine disrupting activity have been associated with the dysregulation of reproductive function and promotion of malignancies in experimental animals and human populations. The high incidence of uterine leiomyomas, a benign estrogen-responsive neoplasm of the uterine myometrium, calls into question the potential influence of xenoestrogens in the pathogenesis of these tumors. An in vivo/in vitro animal model, the Eker rat, that can be used to assess the estrogen-like agonist activity of potential endocrine disruptors in the uterine myometrium is discussed. Using this model, several in vitro assays are developed that demonstrate that compounds from three major classes of xenoestrogens can mimic the effect of estrogen on leiomyoma cells and act as estrogen receptor (ER) agonists: phytoestrogens, organochlorine pesticides and pharmacologic agents. These compounds can stimulate transcription via the ER and upregulate the expression of an estrogen-responsive gene in uterine leiomyoma cells. The use of these in vitro assays has also advanced our ability to predict the agonist activity of potential therapeutic agents in the uterine myometrium. Selective estrogen receptor modulators (SERMs), while able to act as agonists in some tissues such as the bone and uterine endometrium, act as antagonists in vivo in the uterine myometrium and in our in vitro assays. This antagonist activity in the uterine myometrium suggests that SERMs may be useful in the treatment of uterine leiomyoma.

Influence of exogenous estrogen receptor ligands on uterine leiomyoma: evidence from an in vitro/in vivo animal model for uterine fibroids.

The remarkable frequency of uterine leiomyoma in the human population calls into question the potential for the participation of environmental factors in tumor etiology. Having been implicated in the dramatic rise in hormone-related cancers in recent years, endocrine disruptors are salient suspects in this pathogenesis, although the mechanism by which they might participate is unclear. Investigations using the Eker rat model show that uterine leiomyoma may have an enhanced sensitivity to modulation via the estrogen receptor. This sensitivity could make these tumors a target for disruption by exogenous estrogen receptor ligands. Direct evidence for a pathogenic role of exogenous compounds in leiomyomas is lacking; however, it can be demonstrated that such diverse agents as organochlorine pesticides, dietary flavonoids, botanical extracts, and therapeutic antiestrogens have either estrogen agonist or antagonist function in myometrial tissues. The use of this model will help define the impact of exogenous estrogen receptor modulators on uterine leiomyoma and will permit the evaluation of strategies for therapeutic intervention.

Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro.

Although benign, uterine leiomyomas occur with high frequency and significant morbidity in reproductive-age women, and they present a significant health problem. Leiomyomas develop in the uterine myometrium and are sensitive to ovarian hormones, making them potential target sites for endocrine disruptors. Here we utilize cell lines derived from rat uterine leiomyomas to determine if a panel of 7 organochlorine pesticides have potential agonist activity in myometrial cells using cellular and molecular in vitro assays. The organochlorine pesticides investigated have been previously characterized as having agonist activity in other hormonally responsive tissues, but their effects have not been studied in uterine myometrial cells. In Eker rat leiomyoma-derived cells, HPTE, kepone, and the alpha isomer of endosulfan stimulated proliferation, an effect dampened by the antiestrogen ICI 182,780. In addition, these compounds stimulated transcription of the vitellogenin estrogen-response element via the ER in a transcriptional reporter gene assay and induced the expression of an endogenous estrogen-responsive gene, the progesterone receptor (PR). This contrasted with the agonist profile of methoxychlor, dieldrin, toxaphene, and endosulfan-beta. These compounds, unable to stimulate proliferation of uterine leiomyoma cells, did exhibit agonistic activity in these cells at the transcriptional level in the estrogen-sensitive reporter gene assay, and they were also able to upregulate PR message. These data demonstrate that organochlorine pesticides act as estrogen receptor agonists in Eker rat uterine myometrial cells, and they indicate a need for further investigation of the potential tissue-specific agonist activity of these pesticides and their role in the pathogenesis of uterine leiomyoma.

Definitive functional evidence for a tumor suppressor gene on human chromosome 7q31.1 neighboring the Fra7G site.

We have previously shown that loss of heterozygosity (LOH) on human chromosome (hchr) 7 at q31.1 is common in a variety of tumors of epithelial origin. Frequent LOH of a specific chromosomal marker is indicative of a closely linked tumor suppressor gene (TSG). However, recent reports have also indicated that such a high frequency of LOH could be due to the presence in this region of the second most common aphidicolin-inducible fragile site in the human genome (Fra7G). To address this controversy, we introduced single copies of hchr7 or hchr12 into a highly aggressive human prostate carcinoma cell line (PC3) by microcell-mediated transfer. The tumorigenicity of six clones of PC3/hchr7 hybrids and three clones of PCRhchr12 hybrids, obtained in four separate fusion experiments, were studied in BALB/c nude mice. All but one of the PC3/hchr7 hybrids increased tumor latency by at least twofold, whereas none of the PC3/hchr12 hybrids delayed tumor onset. No differences in the in vitro growth rate were observed among any of the cell lines assayed (parental and hybrids) suggesting that the observed tumor suppression was due to factors other than cell cycle regulation. Deletion mapping of the PC3/hchr7 tumors obtained after reversion to the malignant phenotype revealed a common region of loss centred around 7q31.1, supporting the TSG hypothesis. The smallest commonly deleted region was approximately 1.5 Mb in size and flanked by the markers D7S486 and D7S655.

Intraocular pressure-lowering activity of phenolic antioxidants in normotensive rabbits.

PURPOSE: The purpose of this study was to determine the intraocular pressure (IOP)-lowering activity of phenolic antioxidants injected intravenously into normotensive rabbits. Antioxidants belonging to the following classes were tested: cinnamic acids; flavonols; flavanols; anthocyanidins; isoflavones; and tannic acid. METHODS: Test compounds were dissolved in either water or oil/saline as vehicle and injected intravenously into normotensive rabbits. IOP was monitored hourly after injection and expressed as a percent relative to preinjection values. Controls were conducted using vehicle alone. IOP from each eye was averaged to provide one value per rabbit. Dose-response data beginning at 0.01 mg-2 mg doses were collected for compounds shown to be active at 1 mg. RESULTS: Epigallocatechin, epigallocatechin gallate and myricetin lowered IOP below control levels at doses of 1 mg. Tannic acid was the most active, lowering IOP more than 30% at doses of 200 microg. CONCLUSION: Only phenolic antioxidants containing a pyrogallol B-ring system and nonaromatic C-ring (epigallocatechin, epigallocatechin gallate and myricetin) or possible galloyl glucosides as found in tannic acid were active in lowering IOP, with tannic acid being the most active. Other antioxidants were not active in this system suggesting a more specific structural requirement for interacting with appropriate ocular systems. The protein or proteoglycan-binding properties of these molecules may also be important in this activity.

Estrogen receptor activation via activation function 2 predicts agonism of xenoestrogens in normal and neoplastic cells of the uterine myometrium.

The possible contribution of endocrine disrupters to human disease, particularly those compounds that modulate the estrogen receptor (ER), has recently drawn considerable attention. The tissue specificity of effects mediated by the ER is well recognized, although the mechanism of this specificity is not understood sufficiently to predict the effects of a particular ligand in different target tissues. Although the divergence of ER-mediated effects in the breast, bone, and uterine endometrium has been described, a frequently overlooked site of estrogen action is the smooth muscle of the uterus. The uterine myometrium is the tissue of origin of an extremely common hormone-responsive tumor, uterine leiomyoma, a tumor with a significant impact on women's health and a possible environmental influence. This report describes an in vitro/in vivo system for identifying the effects of ER ligands in the myometrium and elucidating their mechanism of action. Several natural and synthetic xenoestrogens were evaluated at the cellular and molecular level for their ability to mimic estrogen action in uterine myometrial tissues. Diethylstilbestrol, coumestrol, genistein, naringenin, and endosulfan were able to activate the AF2 function of the ER in vitro and demonstrated agonist activity in estrogen-responsive myometrial cells, as determined by induction of proliferation and increased message levels of progesterone receptor. Compounds that could not activate AF2 function (4-hydroxy-tamoxifen, LY117018, and LY317783) did not act as estrogen agonists. For agonists, rank order of potency was predicted by receptor affinity; however, endosulfan displayed a surprising degree of activity, despite negligible receptor binding. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypical agonist and antagonist effects, respectively, in the intact myometrium of sexually mature rats. The results presented here suggest that some exogenous ER ligands may mimic the effects of endogenous estrogens on uterine leiomyoma and may contribute to a complex hormonal milieu that impacts both normal and neoplastic myometrium.

Career opportunities for doctoral-prepared nurses.

As we face the 21st century, transitions fare occurring in all of society's major institutions. Nowhere is this transition more evident than in education and the health care industry. There is an explosion of information and the use of educational technology is now opening doors never entered before. In health care, greater influence by third-party players and consumers can be seen as major factors in a new and more highly competitive health care system. With the advent of managed health care, clearly more money must be spent in nursing research since in mos instances, nursing is a big ticket item in any health care agency's budget. Determining best practice models and testing them, participating in outcomes research that looks in multidisciplinary practice, and developing new knowledge to serve the needs of our rapidly changing and diverse population requires more and better prepared nurse researchers. The 21st century will also bring unprecedented numbers of nursing faculty who are part of the baby boomer generation face-to face with retirement. The retirement of these doctoral-prepared faculty will create a huge vacuum that will demand to be filled. Clearly, given the demographics in our country, as these doctoral-prepared nurses reach retirement age, they and their peers will begin to experience the chronic illnesses that are characteristic of our older citizens. More, not less, professional nurses will be needed to meet the demand for health promotion, disease prevention, and care of the acute and chronically ill. More, not less, nursing faculty will be needed to produce the require number of professional nurses and to replace their retiring colleagues. A doctoral degree in nursing will be the key to many opportunities and will bring greater rewards than those who hold the same degree today. For the next generation of graduates, the doctor degree in nursing will truly be a "hot ticket item".

Managing patients with carotid stenosis.

Patients with carotid stenosis present multiple challenges to the medical-surgical nurse case manager. Implementing a defined critical pathway for the patient undergoing a carotid endarterectomy can result in quality cost-effective care, fewer complications, and less possibility of future stroke.

Investing in a master's degree.

One of the most important decisions you will ever make is the decision to invest your time and money in a master's degree. It is a big investment and often requires real sacrifice for you and your family. Since this decision is of paramount importance over the life of your career, it should be approached as a major topic to research. The first step in the process is a thorough review of your own goals and career expectations. Once you decide returning to graduate school is right for you, then you must turn your attention to finding the school that meets your goals for specialized study, as well as the location that best suits your lifestyle. A good place to start the search is in the library among a number of up-to-date references on master's nursing programs. A second source is the Internet. To find out more about the school locations, two good sources are the city's chamber of commerce and the Internet. Acquiring a master's degree in nursing will be a challenge, but one that will pay big dividends in your future nursing career.

Loss of heterozygosity on murine chromosome 6 in two-stage carcinogenesis: evidence for a conserved tumor suppressor gene.

We have recently demonstrated that loss of heterozygosity (LOH) at 7q31 is frequent in many kinds of human primary tumors and that introducing a single human chromosome (hchr) 7 into a murine squamous cell carcinoma (SCC)-derived cell line suppresses the malignant phenotype. To investigate whether the putative tumor suppressor gene on hchr 7 is conserved in mice, we studied LOH on mouse chromosome (mchr) 6 in chemically induced SCCs in (C57BL x DBA2) F1 (B6D2F1) females. LOH analysis was performed by polymerase chain reaction amplification of 17 (CA)n microsatellite repeats in mchr 6 A1-C3. As expected, all the B6D2F1-derived tumors were informative for all the locus assayed. The highest percentage of LOH in the hchr 7q-homologous segment was found at D6Mit50 (60.0%) and the other markers in this segment had LOH incidences normally distributed around the peak. The high incidence of LOH in the tumors studied suggests that a tumor suppressor gene relevant to the development of epithelial cancers is present on mchr 6 A2. As this segment is homologous with hchr 7q31, these data suggest that the putative tumor suppressor gene is conserved in the two species and explains the suppression of tumorigenicity when a single hchr 7 is introduced to a murine SCC cell line.

Evidence against cannabinoid receptor involvement in intraocular pressure effects of cannabinoids in rabbits.

Cannabinoid receptor involvement in the intraocular-pressure (IOP)-lowering effect of the cannabinoids has not been determined. These receptors bind four structural classes of agonists: the classical and the nonclassical cannabinoids, the aminoalkylindoles and the arachidonylethanolamides (the endogenous ligands). We examined the IOP effect in normotensive rabbits after systemic administration of an aminoalkylindole, WIN-55,212-2, and of (R)-(+)-methanandamine, a hydrolysis-resistant endogenous ligand derivative. The decrease in IOP for 6 animals treated with WIN-55,212-2 was marginal and for 6 animals treated with (R)-(+)-methanandamide was negligible compared to animals treated with vehicle alone. These studies suggest that the IOP-lowering effects of cannabinoids are not mediated by a cannabinoid receptor in rabbits.

Case management of the patient with pituitary tumor.

Many medical-surgical nurse case managers will care for patients with pituitary tumors at some point in their careers. These patients present multiple challenges throughout their courses of treatment. Using astute assessment and intervention skills, the nurse case manager can positively influence the outcomes of therapy for these patients, whether they are in the diagnostic, treatment, or follow-up phase of care. Nursing management can indeed make a difference in the costs of money, time, and functional disabilities experienced by patients with pituitary tumors.

Prevalence of glioblastoma multiforme subjects with prior herbicide exposure.

The charts of 100 patients with established diagnoses of glioblastoma multiforme (GBM) provided the data base for a descriptive study of patients' exposure to herbicides. The study focused on place of residence and occupation during the year prior to diagnosis of GBM. Although subjects reported residences in 33 of the 75 counties in Arkansas, more than one-third of the sample came from just 3 counties in which rice, cotton or wood products are produced. These industries were reported as the occupations of almost one-third of the sample for whom occupations involved a risk of herbicide exposure. The findings of this study add to the epidemiological profile of those at risk for GBM and underscore the need for assessment of residence and occupation on a consistent basis when counseling patients and providing health education.

The first 5 years after the dissertation.

To succeed in academia, nursing faculty members must devote the first 5 years following the dissertation to achieving a standard to tenure characteristic of the profession. Most institutions in the country adhere to the American Association of University Professors' guidelines for tenure. These guidelines mandate excellence in teaching, scholarship, and service. A fourth characteristic, leadership, is increasingly considered in tenure decisions. The expectations of an academic career in nursing serve as the foundation for a framework to evaluate the likelihood of success in a particular setting. A detailed 5-year plan for achieving tenure is proposed.

Prevalence of glioblastoma multiforme in subjects with prior therapeutic radiation.

This retrospective study profiled subjects with glioblastoma multiforme (GBM) who had previously received therapeutic radiation. A chart review was conducted of 100 adult patients diagnosed with GBM and referred to a major medical center in the southwestern United States. Seventeen patients received previous radiation therapy with an average dose of 48.5 Grey (Gy) and an average latency period of 15 years between initial therapy and GBM diagnosis. Of these 17, four white females fit all four attribution criteria for radiation-induced GBM. Two had been treated with radiation for prolactinomas, one for pinealoma and one for squamous cell cancer of the ethmoid sinus. The addition of these four case studies to the previously published descriptions of 80 cases of gliomas, 36 of which were GBM, subsequent to radiation therapy provides additional support for considering therapeutic radiation as a risk factor for GBM development.

Financial responsibility and budget decision making.

The nursing budget constitutes one of the largest department budgets in most hospitals and in many cases involves managing millions of dollars. The degree to which the nurse executive has freedom to control financial resources has a major impact on the hospital's ability to compete in a rapidly changing marketplace characterized by a severe nursing shortage. Findings indicate a continuing problem with authority in matters germane to resource allocation.