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Biomedical subjects

E S Marshall

Publications and source records attributed to E S Marshall.

At least 19 recordsLinked to original sources
PubMed2004

In vitro modelling of human tumour behaviour in drug discovery programmes.

Human tumour cell lines have played an important part in our understanding of cancer and have been used extensively in the discovery and characterisation of new chemotherapeutic drugs. A potential weakness of such cell lines is that they may have lost important properties originally possessed in vivo, including potential targets for therapy. This review discusses how possible differences between tumour cells in cancer patients and cell lines might be identified by the use of short-term cultures of human tumour cells taken directly from cancer tissue, termed here primary cultures. Cell-cycle time is one important difference between tumours and cell lines and it is known that the cell-cycle times of primary cultures cover the same wide range as estimated in vivo cell-cycle times. Because tumour cells have at least two pathways to cell death, one from interphase and one from mitosis, changes in cell-cycle length can modify the balance of such pathways. Responses of primary cultures to DNA-damaging drugs and inhibitors of growth factor receptors also differ from those of cell lines, suggesting that the process of developing a cell line can result in the loss of important cellular responses. Without an appreciation of these changes our ability to discover new targets for the development of improved cancer therapy may be jeopardised. The identification of cell lines that preserve potential targets is an important goal in cancer biology and research using primary cultures will help in this identification.

Antineoplastic Agents↗
PubMed2001

Induction of ependymal, glial, and neuronal transactivation by intraventricular administration of the SGLT1 Na+-D-glucose cotransporter inhibitor phlorizin.

Reports that food intake is stimulated by intracerebroventricular (i.c.v.) administration of the SGLT1 Na+-D-glucose cotransport inhibitor, phlorizin, suggest that decreased central glucose uptake is a stimulus for compensatory motor activity underlying restoration of energy imbalance. In order to identify central cell populations that are functionally responsive to decreased SGLT1 function in the brain, the present study utilized immunocytochemical techniques to demonstrate cellular expression of the inducible activator protein-1 transcription factor, Fos, following i.c.v. delivery of phlorizin. Groups of adult male rats were treated with phlorizin at a dose of 10, 50, or 250 microg/animal, then sacrificed 2 hr later by transcardial perfusion. Ependymal expression of Fos-immunoreactivity (-ir) was observed throughout most of the cerebroventricular system, except the medullary fourth ventricle, at each dose examined. Higher doses of the transport inhibitor elicited immunostaining of periventricular glia, characterized by cytoplasmic glial fibrillary acidic protein-ir, underlying the lateral, third, and rostral fourth ventricles and cerebral aqueduct. These doses also resulted in the transcriptional activation of neurons in discrete brain sites, including the rostral medial preoptic area, median preoptic n., preoptic and hypothalamic periventricular n., subfornical organ, thalamic medial habenular and paraventricular n., hypothalamic paraventricular, ventromedial, and arcuate n., and n. of the solitary tract. These results show that nonexcitable cells located throughout much of the central neuroaxis and discrete populations of neurons in the brain are genomically responsive to pharmacological inhibition of central SGLT1 function. Evidence for the functional responsiveness of these cell types to manipulation of energy-dependent glucose transport suggests that cellular uptake of this metabolic fuel may serve as an indicator of central energy substrate availability, and that alterations in glucose uptake via this specific mechanism may be the source of regulatory signals involved in the maintenance of energy homeostasis.

Animals↗
PubMed2001

Nursing work force in practice and education: what can we learn from the current crisis?

A major factor in the growing crisis in health care is the serious shortage of nurses in practice and education. The current work force shortage is different and more critical than previous cyclical deficits. Because it is projected to be of unprecedented severity and to endure long into the future, it demands significant attention and innovation. Nurses in clinical practice and in faculty roles are growing older, and the nursing work force in general is becoming relatively less educated. A strong nursing work force of the future will require new approaches to recruitment, preparation, and retention of nurses, interdisciplinary partnerships, and infusion of support from a variety of sources.

Education, Nursing↗
PubMed2001

Effects of estradiol on glucoprivic transactivation of catecholaminergic neurons in the female rat caudal brainstem.

Hyperphagic and hypothalamic neuroendocrine responses to acute glucose deprivation are modified by the ovarian steroid estradiol (E). Observations of genomic activation of catecholaminergic (CA) neurons in the hindbrain lateral reticular nucleus, nucleus of the solitary tract, and area postrema (AP) by glucopenia support their potential function in pathways mediating regulatory effects of this metabolic challenge within the brain. Expression of E receptors by these cells suggests that their activity may be sensitive to steroid modulation during glucopenia. The present studies investigated the role of E on transcriptional activation of caudal brainstem CA neurons by the glucose antimetabolite, 2-deoxy-D-glucose (2DG). Ovariectomized rats were implanted with s.c. Silastic capsules containing E (30 or 250 microg/ml) or sesame oil, and injected i.p. 7 days later with 400 mg 2DG/kg or saline. Tyrosine hydroxylase (TH)-immunoreactive (-ir) neurons in the C(1)/A1, C2, C3, A2, A5, and A6 cell groups and AP were colabeled for Fos following antimetabolite administration, whereas vehicle injection resulted in negligible nuclear staining of these cells. With the exception of A2, A6, and AP cells, mean numbers of Fos- and TH-/Fos-ir-positive neurons in these brain sites did not differ between E- and sesame oil-implanted groups. Numbers of TH-positive A2 and A6 neurons that expressed Fos in response to 2DG were significantly greater in rats implanted with the high E dose vs. either the low steroid dose or sesame oil. These results show that the magnitude of cellular Fos labeling within discrete hindbrain CA neuron populations varies in accordance with circulating E levels. These findings suggest that E may exert potential modulatory effects on glucoprivic activation of the Fos stimulus/transcription cascade and consequent compensatory genomic responses within specific areas of the female rat caudal brainstem.

Animals↗
PubMed2000

Caudal brainstem Fos expression is restricted to periventricular catecholamine neuron-containing loci following intraventricular administration of 2-deoxy-D-glucose.

Reports that food intake is stimulated by fourth ventricular administration of glucose antimetabolites or uptake inhibitors suggest that glucose deprivation within the periventricular caudal brainstem activates compensatory neural mechanisms that restore global metabolic stasis. In the present study, Fos immunocytochemistry was employed to characterize the distribution of neurons within this region of the male rat brain that undergo genomic activation in response to intraventricular delivery of the antiglycolytic agent, 2-deoxy-D-glucose (2DG). Fos immunoreactivity (-ir) was only detected in the locus coeruleus (LC), nucleus of the solitary tract (NTS), and area postrema (AP) following drug treatment, whereas immunostaining for Fos was absent from these structures in the vehicle-treated control group. Dual-label immunocytochemical processing of sections of these loci for Fos- and tyrosine hydroxylase (TH)-ir revealed that, in each site, a majority of TH-ir-positive neurons were co-labeled for this nuclear protein in response to this treatment paradigm. These results provide evidence for the transcriptional activation of catecholaminergic neurons in discrete periventricular caudal brainstem structures during central glucopenia. Taken together with pharmacological evidence for the initiation of glucoprivic regulatory signaling within neural tissue accessible from the fourth ventricle, the present findings suggest that LC A6, NTS precommissural C2 and commissural A2, and AP TH-ir-positive neurons may function to monitor and/or signal alterations in periventricular glucose metabolism as a means of defending central substrate balance.

Animals↗
PubMed2000

Radiation-induced cell cycle delays and p53 status of early passage melanoma cell lines.

Cell cultures exposed to DNA-damaging agents such as gamma radiation respond by arresting at cell cycle checkpoints, and the p53 tumor suppressor protein is strongly implicated in this behavior. We have investigated the TP53 status and cell cycle response to ionizing radiation of a series of early passage cell lines (designated NZM1 to NZM15) previously developed from patients with metastatic melanoma. The TP53 status of each of the cell lines was determined by single-strand conformation polymorphism and DNA sequence analysis. The majority of the lines appeared to have a wild-type TP53 gene sequence, consistent with published studies. Two lines (NZM4 and NZM7.2) were found to have an identical T-->C transition mutation in nucleotide 721 (exon 7) of the coding region. NZM7.2 (mutant) and NZM7.4 (wild-type) were clonally derived from the same line (NZM7). The existence of radiation-induced cell cycle arrest in G and/or G2M phase was determined 16 h after irradiation (6.3 Gy) by DNA staining and flow cytometric analysis. The mitotic inhibitor paclitaxel was used as a reference compound, with or without irradiation, to assess the efficiency of radiation-induced cell cycle arrest. G1 phase arrest was associated only with the presence of the wild-type TP53 gene, but the efficiency of induced arrest varied among the cell lines and the period of G phase arrest appeared to be short. A significant difference (P < 0.002) was also found between the efficiency of induction of G2 phase arrest and the presence of wild-type TP53 gene. The results provide evidence that although the melanoma cell lines generally had an intact TP53 gene, the efficiency of p53-mediated cycle arrest might be deficient and contribute to the resistance of this tumor to treatment.

Adult↗
PubMed1999

Stimulation of tumors to synthesize tumor necrosis factor-alpha in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy.

The selective induction of tumor vascular collapse represents an exciting approach to cancer treatment. However, clinical evaluation of tumor necrosis factor-alpha (TNF), an agent that accomplishes this goal, has been limited by systemic toxicity, and clinical approaches using bacterial components to induce TNF production have also been disappointing. Our laboratory has developed synthetic low molecular weight inducers of TNF, including 5,6-dimethylxanthenone-4-acetic acid (DMXAA), as an alternative strategy. DMXAA induces rapid vascular collapse in transplantable murine tumors and induces TNF synthesis in vitro in both murine and human systems. We show here that the extent of DMXAA-induced TNF synthesis is greater in tumors than that in the spleen, liver, or serum. As shown by in situ hybridization studies of the murine Colon 38 tumor, DMXAA induced tumor as well as host cells to express TNF mRNA. The distribution of cells containing TNF mRNA in tumor tissues after DMXAA administration contrasted significantly with that obtained after lipopolysaccharide (LPS) treatment, although splenic and hepatic tissues showed a similar distribution of TNF mRNA-positive cells. In the Colon 38 tumor, the action of LPS was limited to host cells in the periphery of the vessels. DMXAA treatment induced 7-fold higher peak TNF levels in tumor than in serum. In contrast, LPS treatment induced 9-fold higher TNF levels in serum than in tumor. DMXAA induced 35-fold higher TNF activity in the Colon 38 tissue than did LPS. One ovarian, one squamous, and three melanoma human tumor xenografts implanted in athymic nude mice expressed TNF mRNA of human and murine origin in response to DMXAA, confirming that DMXAA can activate both host and tumor cells. The use of low molecular weight agents to induce TNF synthesis in situ in the tumor represents a novel approach to TNF-mediated therapy of cancers.

Animals↗
PubMed1999

Elderly patients' perceptions of care in the emergency department.

OBJECTIVE: Patients' perceptions and satisfaction are areas of growing concern in health care research, but little has been reported from the perspective of elderly persons. The purpose of this study was to describe elderly patients' perceptions of care in the emergency department. METHODS: A qualitative, descriptive study design was used. Twelve elderly people were interviewed following a treatment episode in 1 of 3 emergency departments in the western United States and data were submitted to content analysis according to qualitative, interpretive methodology. FINDINGS: The following 5 themes emerged from the analysis: "needs for information," "observations of waiting time," "perceptions of professional competency and caring service," "concerns about process and facility design," and "personal tolerance." DISCUSSION: Findings support some aspects of existing literature and offer additional information regarding care of elderly persons in the emergency department. Results also support the need for more research in the area of the actual experience of elderly patients in the emergency department.

Aged↗
PubMed1999

Mom empowerment, too! (ME2): a program for young mothers involved in substance abuse.

Substance abuse among young people is of critical concern to public health nurses. When substance abusers are young mothers without the skills, experience, guidance, or resources to become adequate parents, this problem is compounded This study examined a community-based intervention program for young mothers from the perspective of 42 participants. A qualitative, descriptive design was used within a process of participatory action research. Two major domains emerged from the data: risk perceptions and behaviors, and health promoting perceptions and behaviors. The study demonstrated the value of obtaining data from the participants and offers implications for practice and research.

Adolescent↗
PubMed1999

Religion, gender, and autonomy: a comparison of two religious women's groups in nursing and hospitals in the late nineteenth and early twentieth centuries.

Modern historical research of women and nursing has largely neglected the role of religious groups, particularly in the American frontier. The image of women at the end of the 19th century was one of submission to male authority and confinement to the domestic sphere. However, in the pluralistic West, a variety of organized religious women built and administered hospitals, initiated professional nursing, and provided effective health care services. This article compares cases of Catholic nuns and Mormon women as exemplars in a conceptual context of religious devotion, gender roles, and autonomy among women's religious organizations at the dawn of the 20th century.

Catholicism↗
PubMed1999

Adherent and nonadherent medication-taking in elderly hypertensive patients.

Nonadherence to medications is a significant reason why patients fail to control their blood pressure. Little work has been attempted to conceptualize medication-taking behaviors from the patient's perspective. This study examined factors that influence elderly hypertensive patients' adherence or nonadherence to prescribed medications. Using a qualitative descriptive research design, 21 hypertensive elderly people were interviewed. Two domains of adherence were identified: purposeful use of the medication for the control of patient's blood pressure and establishing and maintaining patterns of medication-taking. Two similar domains also emerged for nonadherence: purposeful and incidental. Adherence behaviors were dependent on the person's decision to take hypertension medication, access to medications, and ability to initiate treatment and maintain a medication-taking pattern. The timing and location of pills were integral parts of establishing patterns of taking medications. Inadequate access to medications or interruption of a person's pattern were associated with the incidental missing of medications.

Aged↗
PubMed1999

Short-term cultures of clinical tumor material: potential contributions to oncology research.

The culture of surgical tumor specimens has long been considered as a potential approach to the tailoring of chemotherapy and radiotherapy to the individual patient, and to the development of improved therapy. Recent work highlighting the importance of cell-cell interactions in the growth and survival of cancer tissue, as well the demonstrated importance of drug- or radiation-induced loss of tumor cells (for instance by apoptosis), points to a need to reexamine the question of what information might be derived from such cultures. In this commentary, we consider whether the short-term culture of human tumor tissue as small cellular aggregates, preserving to some extent the three-dimensional organization of tumors in vivo, can be used to obtain information on the behavior of cancer cells before and after therapy. Using [3H]thymidine incorporation as an end-point, we show how the shapes of dose-response curves might be used to estimate two key cytokinetic properties of the cultured cells, proliferation rate, and susceptibility to drug- or radiation-induced cell death. We have illustrated this discussion with our studies of melanoma, ovarian cancer, and lung cancer samples. We consider how application of culture methods may lead not only to the discovery of new antitumor drugs, but also to improved choice of patients' treatment.

Antineoplastic Agents↗
PubMed1998

Inhibition of growth of primary human tumour cell cultures by a 4-anilinoquinazoline inhibitor of the epidermal growth factor receptor family of tyrosine kinases.

The epidermal growth factor receptor (EGFR) is thought to mediate the action of the mitogens EGF and tumour growth factor-alpha (TGF-alpha) in a variety of cancers, including those of the lung, breast and ovary. A number of new selective inhibitors of EGFR tyrosine kinase have now been developed as potential new antitumour agents. We used a potent inhibitor of this tyrosine kinase, 6-amino-4-[(3-bromophenyl)amino]-7-(methylamino)quinazoline (SN 25531; PD 156273), to determine the responses of primary cultures derived from patients with cancer of the lung, ovary, breast, cervix and endometrium. Cells were cultured in 96-well plates and proliferation assessed by incorporation of 3H-thymidine. Measured growth inhibitory concentrations IC50 values) varied from 1 nM to 14 microM with a 1000-fold differential between sensitive and resistant cultures. Results were compared with rates of proliferation, estimated using a paclitaxel-based method. We also measured the IC50 values for the tyrosine kinase inhibitor using a number of established human cell lines, and compared them with EGFR content using fluorescent antibody staining and flow cytometry. The presence of EGFR was found to be necessary, but not sufficient, for in vitro response. Only a small number of cell lines (3 of 7 for lung, 1 of 7 for ovarian, 2 of 3 squamous cell and 0 of 12 for melanoma) were sensitive to the tyrosine kinase inhibitor. In contrast, 40 of the 50 primary cultures (including 14 of 15 lung cancer samples and 14 of 19 ovarian cancer samples) were sensitive.

Adult↗
PubMed1998

Recreating life: toward a theory of relationship development in acute home care.

The aim of this research was to explain some processes used by family caregivers and care recipients with acute conditions to develop and maintain satisfying care relationships in home settings. Grounded theory method was used to develop a beginning theory of individual and relationship growth and development. From a sample obtained through two home health agencies, 9 dyads (e.g., care recipient and family caregiver) were interviewed once, 4 dyads twice, and 1 dyad three times. The substantive theory that emerged--recreating life--suggests that caregivers and care recipients respond to disrupted realities caused by illness through redefining self and redefining the relationship. Four mitigating factors affecting the developmental process were identified: (a) prognosis, (b) progress, (c) social support, and (d) professional support.

Acute Disease↗
PubMed1995

Adenosine radionuclide perfusion imaging in the preoperative evaluation of patients undergoing peripheral vascular surgery.

To define the clinical and adenosine test variables that predicted perioperative cardiac events, 122 patients who received adenosine radionuclide perfusion imaging before peripheral vascular surgery were reviewed. Events included pulmonary edema, an ischemic end point of acute myocardial infarction (AMI) or cardiac death. Five patients underwent coronary revascularization before the surgical procedure. Of the 117 remaining patients, 19 had pulmonary edema, 10 had an AMI, and 2 died after peripheral vascular surgery. Most of the patients (78%) were in an intermediate-risk group as indicated by the presence of > or = 1 clinical risk factor as defined by the Eagle criteria. The only predictor of perioperative pulmonary edema was a history of congestive heart failure (33% vs 4%; p = 0.002). No clinical variables predicted AMI or death. The adenosine variables that were univariate predictors of AMI and death were the number of reversible perfusion defects (1.75 +/- 1.84 vs 0.75 +/- 0.90; p = 0.001) and the number of coronary artery distributions with a radionuclide perfusion defect (1.33 +/- 0.64 vs 0.85 +/- 0.67; p = 0.022). The number of reversible perfusion defects was the only multivariate predictor of ischemic events (p = 0.017). The presence of > 1 reversible defect was associated with an increased frequency of ischemic events (68% vs 28%; p = 0.045). The sensitivity and specificity of > 1 reversible defect was 58% and 73%, respectively, with a positive and negative predictive value of 19% and 94%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Prognostic significance of ST-segment depression during adenosine perfusion imaging.

To determine the significance of ST-segment depression during adenosine perfusion imaging for predicting future cardiac events, 188 patients with interpretable electrocardiograms were assessed 1 to 3 years (mean 21.5 +/- 6.6 months) after adenosine testing. At least 1 mm of ST-segment depression was observed in 32 (17%) patients, with > or = 2 mm of ST-segment depression in 10 (5.3%). Thirty-seven cardiac events occurred during the study period: 2 cardiac deaths, 5 nonfatal myocardial infarctions, 6 admissions for unstable angina, and 24 revascularizations. Univariate predictors of events were a history of congestive heart failure, previous non-Q-wave myocardial infarction, previous coronary angioplasty, use of antianginal medication, ST-segment depression during adenosine infusion (particularly > or = 2 mm), any reversible perfusion defect, transient left ventricular cavity dilation, and the severity of perfusion defects. Multivariate analysis identified > or = 2 mm ST-segment depression as the most significant predictor of cardiac events (relative risk [RR] = 6.5; p = 0.0001). Other independent predictors of events were left ventricular dilation (RR = 3.8; p = 0.002), previous coronary angioplasty (RR = 3.3; p = 0.001), a history of non-Q-wave myocardial infarction (RR = 2.3; p = 0.01), and the presence of any reversible defect (RR = 2.0; p = 0.05). We conclude that ST-segment depression occurs uncommonly during adenosine infusion, but the presence of > or = 2 mm of ST-segment depression is an independent predictor of future cardiac events and provides information in addition to that obtained from clinical variables and the results of adenosine perfusion imaging.

Adenosine↗