Search PubMed⌕ Search

Biomedical subjects

L Webster

Publications and source records attributed to L Webster.

At least 55 records · Page 3Linked to original sources
PubMed1993

Measurement of cremophor EL following taxol: plasma levels sufficient to reverse drug exclusion mediated by the multidrug-resistant phenotype.

BACKGROUND: Paclitaxel (Taxol) is the first of a new class of cytotoxic agents with activity against tumors resistant to other drugs. For clinical use, paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant Cremophor EL (Cremophor). We have previously shown that Cremophor will block the P-glycoprotein drug efflux pump responsible for the multidrug-resistant phenotype. Overexpression of P-glycoprotein is one mechanism of in vitro resistance to a number of currently used cytotoxic agents including paclitaxel. PURPOSE: Our aim was to develop a bioassay to measure plasma levels of Cremophor and to determine whether or not plasma levels of Cremophor achieved during paclitaxel therapy are sufficient to inhibit the activity of the P-glycoprotein. METHODS: All patients studied had histologically proven, advanced ovarian carcinoma with measurable or evaluable disease and had received at least one prior platinum-containing regimen. The bioassay used flow cytometry to measure the increase in equilibrium intracellular daunorubicin levels in multidrug-resistant human T-cell leukemia cells (CEM/VLB100) in the presence of a series of concentrations of Cremophor. Levels of Cremophor were measured in plasma from 21 patients after a 3-hour infusion of 135 or 175 mg/m2 paclitaxel. Both dose levels were given following premedication with oral dexamethasone, intravenous promethazine hydrochloride, and intravenous cimetidine. The Cremophor bioassay involved incubation of CEM/VLB100 cells (5 x 10(5)) for 1 hour with 2 micrograms/mL daunorubicin in 0.5 mL HL-1 medium plus 0.5 mL plasma prior to flow cytometric analysis. Pretreatment plasma was used to derive a standard curve for the effect of Cremophor on equilibrium daunorubicin levels. All measurements were done in triplicate. RESULTS: In vitro experiments indicated that, for maximal inhibition of P-glycoprotein activity, concentrations of Cremophor of 0.1% (vol/vol) were required. At the end of a 3-hour infusion of paclitaxel, plasma levels of Cremophor in 19 of 21 patients were 0.1% or higher and 0.09% in the remaining two. Concentrations of 5-20 microM paclitaxel dissolved in ethanol without Cremophor did not inhibit P-glycoprotein in this assay. CONCLUSION: The concentrations of Cremophor measured in plasma drawn from patients after a 3-hour infusion of paclitaxel at 135 or 175 mg/m2 were found to be sufficient to inhibit P-glycoprotein activity in vitro. IMPLICATIONS: The efficacy of paclitaxel against some tumors may be aided by its administration in a vehicle solution containing Cremophor in quantities that reach concentrations in the plasma sufficient to reverse multidrug resistance of neoplastic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Estrogen inhibits the growth of estrogen receptor-negative, but not estrogen receptor-positive, human mammary epithelial cells expressing a recombinant estrogen receptor.

Estrogen is essential for the growth of the normal mammary gland and most estrogen receptor (ER)-positive mammary carcinomas. To better understand the differences between the estrogen response pathways in normal and tumor cells, we have stably transfected ER-negative immortal, nontumorigenic human mammary epithelial cells and ER-negative breast cancer cells with an ER-encoding expression vector. Unexpectedly, estrogen treatment (1.0 nM) inhibited the proliferation of ER-transfected nontumorigenic and tumor-derived cells. The control transfectants and parental cells exhibited no response to estrogen concentrations as high as 1.0 microM. This inhibitory effect was attributed to a decreased growth rate and a perturbation of the cell cycle distribution by estrogen treatment of the ER transfectants. The inhibitory response was blocked by cotreatment with the antiestrogen ICI 164,384 as predicted for a pure antagonist of estrogen action. However, treatment with the antiestrogen hydroxytamoxifen caused growth inhibition, implying that hydroxytamoxifen acts as an agonist of estrogen action in ER-transfected cells. Since estrogen is a mitogenic and not a growth-inhibitory stimulus for ER-positive breast cancers and cell lines, we tested the effect of constitutive, high level expression of the ER in ER-positive tumor cells. Stable transfection of ER-positive MCF-7 and T47D cells with the ER expression vector yielded cells with varying amounts of ER. At ER levels comparable to those found in the ER-negative transfected cells, the MCF-7 and T47D ER transfectants were not inhibited by estrogen. These data suggest that ER-positive breast cancer cells can tolerate higher constitutive levels of ER expression than ER-negative cells. The mechanism by which this is accomplished may be an essential step in the process which yields ER-positive tumors.

Animals↗
PubMed1993

Exercise countermeasure protocol management expert system.

Exercise will be used primarily to countermeasure against deconditioning on extended space flight. In this paper we describe the development and evaluation of an expert system for exercise countermeasure protocol management. Currently, the system includes two major subsystems: baseline prescription and prescription adjustment. The baseline prescription subsystem is designed to provide initial exercise prescriptions while prescription adjustment subsystem is designed to modify the initial prescription based on the exercised progress. The system runs under three different environments: PC, SUN workstation, and Symbolic machine. The inference engine, baseline prescription module, prescription adjustment module and explanation module are developed under the Symbolic environment by using the ART (Automated Reasoning Tool) software. The Sun environment handles database management features and interfaces with PC environment to obtain physical and physiological data from exercise units on-board during the flight. Eight subjects' data have been used to evaluate the system performance by comparing the prescription of nine experienced exercise physiologists and the one prescribed by the expert system. The results of the validation test indicated that the performance of the expert system was acceptable.

Analysis of Variance↗
PubMed1992

Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer.

Toremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites, N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1-3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.

Adult↗
PubMed1992

A survey of Minnesota home care agencies' perceptions of physician behaviors.

A survey of Minnesota home care agencies assessed perceptions of and satisfaction with the home care practices, knowledge, and skills of Minnesota family physicians and other primary care physicians. We found that physicians did not make many home visits and that agencies were moderately dissatisfied with that practice. Family physicians visited significantly more frequently than other primary care physicians and, in rural areas, received significantly higher satisfaction ratings from agencies. The areas most frequently noted that could benefit from improvement of physician skills/knowledge regarding home care were: better home care clinical skills (38.5% of respondents), knowledge of home care technology and capabilities (37%), and knowledge of reimbursement policies and practice (29%).

Clinical Competence↗
PubMed1991

The home care practice and attitudes of Minnesota family physicians.

OBJECTIVE: Assess home care practice and attitudes of Minnesota family physicians (FPs). DESIGN: Mailed survey. SETTING: State of Minnesota. PARTICIPANTS: Members of the Minnesota Academy of Family Physicians, 80% of the FPs practicing in the state. INTERVENTION: A 55-item mailed, self-complete questionnaire regarding general practice and personal physician characteristics (18 questions), specific questions regarding geriatric and home care practice and related attitudes (37 questions); up to four reminder or follow-up surveys were sent. MAIN OUTCOME MEASURES: Descriptive summary of FP home care practice and attitudes. RESULTS: Eighty percent of surveys were completed, 76% of responding physicians made at least one home visit in the previous year, and 92% of home visits were to geriatric patients. Discriminant function analysis identified six significant (P less than 0.001) variables that explained 52% of the variance (r2 = 0.52, Wilks Lambda = 0.48) in home visiting behavior between frequent home visiting FPs (greater than 24 visits/year) and non-visiting FPs. FPs most likely to do home visiting were older and tended to have small group or solo practices in rural settings. CONCLUSION: The survey documented continued decline (from previously published surveys) of physician home visiting behavior and widespread dissatisfaction with reimbursement. However, attitudes regarding home care provided by other professionals were highly positive.

Attitude of Health Personnel↗
PubMed1991

A comparison between computer-controlled and set work rate exercise based on target heart rate.

Good exercise prescriptions provide work rates (WRs) that maintain heart rates (HR) in a target zone and at a percent of maximum metabolic equivalent (%METmax). HR and MET were evaluated from computer-controlled and set WR (constant speed) sessions (20 min at 65% METmax). Computer-controlled WR used a control algorithm to adjust speed and grade to maintain the target HR. The set WR (mean +/- S.D.) HR (139 +/- 8 bpm) was lower (p less than 0.05) than the target (147 +/- 3 bpm) and computer-controlled HRs (153 +/- 5 bpm). The set WR MET (8.6 +/- 2.2) was not different than the target (8.6 +/- 2.2), but both were lower than computer-controlled exercise (9.7 +/- 2.2). Computer-control time in target HR zone (16 +/- 5 min) was significantly (p less than 0.004) greater than set WR exercise (6 +/- 5 min). Computer-controlled WR was significantly better in maintaining target HR and the MET values were not physiologically different than target WRs.

Adult↗
PubMed1987

Effect of the 1983 Mental Health Act on the management of psychiatric patients.

Two principal objectives of the 1983 Mental Health Act were to decrease the use of emergency orders and to give patients on observation orders the right of appeal. Statistics were collected from the 13 hospitals that admit acute psychiatric patients in the Greater Manchester area, and the figures for 1980-1 were compared with those for 1984-5. Changes in use of the different sections were examined in university units, large psychiatric hospitals, and district general hospital units. The use of emergency orders decreased and the use of treatment orders increased; the use of observation orders remained unchanged. Many more patients exercised their right of appeal in 1984-5, but the number discharged by tribunals remained small. The nurses' holding power was used infrequently. The different types of hospital are now more concordant in their use of these orders than before the 1983 act.

Commitment of Persons with Psychiatric Disorders↗
PubMed1983

Subtypes of Legionella pneumophila serogroup 1 associated with different attack rates.

From January, 1982, through February, 1983, 20 cases of nosocomial legionnaires' disease caused by Legionella pneumophila serogroup 1 were identified in two adjoining hospital buildings, UH and RH. Although the buildings housed similar patient populations and the hot water systems in each were colonised with similar numbers of L pneumophila serogroup 1, 19 cases (1.03/1000 discharges) occurred in UH and only 1 case (0.08/1000 discharges) occurred in RH. Three subtypes of L pneumophila serogroup 1 were defined by plasmid content and monoclonal antibody binding patterns; two were unique to the environmental and patient isolates from UH and one was unique to RH. The marked differences in the attack rates suggest that the UH subtypes may be more pathogenic than the RH subtype and that the subtyping of L pneumophila might be a useful tool for studying the epidemiology of legionnaires' disease.

Cross Infection↗
PubMed1977

Cystic fibrosis screening by sweat analysis: a critical review of techniques.

Currently employed methods for the assay of electrolytes in sweat, relevant to the diagnosis of cystic fibrosis, are critically evaluated with particular reference to the measurement of electrical conductivity. Attention is drawn to the factors responsible for potentially large errors. On the basis of experimentation, supported by laboratory practice, recommendations are made for the reduction of these errors to clinically acceptable levels. Data concerning sodium and potassium content, electrical conductivity and osmolality of undiluted sweat collections are compared. The feasibility and comparative advantages of measuring sweat osmolality with a vapour pressure osmometer are discussed.

Child↗
PubMedDate not supplied

Implications from a field study regarding the relationship between polycyclic aromatic hydrocarbons and glutathione S-transferase activity in mussels.

An aluminium smelter on the west coast of Scotland discharges an aqueous effluent containing polycyclic aromatic hydrocarbons (PAHs) at the head of Loch Leven. The loch also supports two mussel (Mytilus edulis) farms. Data are presented on burdens of PAHs in the soft tissues of mussels and the effect of these contaminants on glutathione S-transferase (GST) activity in mussel hepatopancreas. GST activity is shown to be correlated with total PAH burden and also with the concentrations of certain individual PAHs. These field data show that high molecular weight PAHs are closely correlated to GST activity, whereas low molecular weight PAHs are not. This suggests that 5- and 6-ring PAHs have a more pronounced role than 2- to 4-ring compounds in inducing GST activity in mussels from Loch Leven. It is proposed that it may be more appropriate to link GST activity with 5- and 6-ring compounds only, rather than with the total PAH burden.

Animals↗
PubMedDate not supplied

Different levels of mussel (Mytilus edulis) DNA strand breaks following chronic field and acute laboratory exposure to polycyclic aromatic hydrocarbons.

Levels of polycyclic aromatic hydrocarbons (PAHs) including benzo[a]pyrene (B[a]P) were at least seven-fold higher in mussels sampled from a polluted site (Loch Leven, in Scotland, UK) compared to a nearby clean reference site (Loch Etive) throughout the year 2000. Levels of DNA strand breaks (alkaline COMET assay) using both gill and digestive gland nuclei were similar at both sites despite the difference in contaminant load (total PAH). In contrast, mussels collected from a reference site (Port Quin, Cornwall, UK) had an increase in DNA strand breaks in digestive gland cells following laboratory exposure to B[a]P-dosed Isochrysis galbana. However, after 14 days high dose (20 ppb-exposed diet) animals had returned to levels similar to the controls. There was no evidence of increased necrosis or apoptosis after treatments. The results from these two studies suggest that an adaptive response may prevent ongoing DNA damage in mussels exposed to high levels of B[a]P and PAH contamination.

Adaptation, Physiological↗