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S McClean

Publications and source records attributed to S McClean.

35 records · Page 2Linked to original sources
PubMed1994

Differential cytotoxic effects of docetaxel in a range of mammalian tumor cell lines and certain drug resistant sublines in vitro.

The in vitro cytotoxic effects of docetaxel (Taxotere; RP56976, NSC688503) proved both time and concentration dependent. Amongst thirteen human cell lines from various tumor types, exposure to increasing concentrations of docetaxel over 24 hrs resulted in a plateau-shaped dose response curve, suggesting that increased cell kill becomes more dependent on increased exposure duration than on concentration. IC50 concentrations (reducing survival by 50%) ranged from 0.13-3.3 ng/ml, with three neuroblastoma lines proving most sensitive and three breast and two colon carcinoma lines showing least sensitivity. There was significant cross-resistance to docetaxel in the classic multidrug resistant (MDR) Chinese hamster ovarian (CHO) CHRC5 line and the human lymphoblastoid CCRF-CEMVLB1000 line, as well as in two vincristine (VCR)-selected MDR MCF-7 sublines. All four of these MDR sublines overexpress P-glycoprotein (Pgp), as did a 6-fold docetaxel-selected resistant CHO subline. As an apparent corollary, in two human teratoma lines selected for etoposide resistance and showing some cross-resistance to VCR and in two CHO sublines expressing low levels of VCR resistance, yet all proving Pgp positive, no docetaxel cross-resistance was identified. Verapamil modulated docetaxel resistance only in sublines expressing resistance to the drug and overexpressing Pgp. Four other human tumor sublines selected for resistance to 5-fluorouracil, cisplatin or teniposide, showed a lack of cross-resistance to docetaxel. Furthermore, cross-resistance to docetaxel was not apparant in four epipodophyllotoxin-selected resistant sublines with alterations in topoisomerase II, indicating its effectiveness against tumor cells expressing the topoisomerase II-related MDR phenotype. Our observation that docetaxel cross-resistance was not automatically expressed by classic MDR tumour cells appears of interest and of potential clinical relevance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Modified multiple drug resistance phenotype of Chinese hamster ovary cells selected with X-rays and vincristine versus X-rays only.

Exposure of Chinese hamster ovary (CHO) cells to fractionated X-irradiation [ten fractions of 9 Gray (Gy)] resulted in the expression of a multiple drug resistance phenotype which was distinct from that of drug-selected cells in two features: (i) resistance to vinca alkaloids and epipodophyllotoxins but sensitivity to anthracyclines was retained; (ii) overexpression of P-glycoprotein (Pgp) but regulated by post-translational stability rather than by any elevation in Pgp mRNA (Hill et al., 1990). It was also reported that when these cells (designated DXR-10) were subsequently exposed to another ten fractions of 9 Gy (20 x 9 Gy in total), no further increases in drug resistance or in the extent of Pgp expression were observed. To examine this apparent plateauing of the drug resistance phenotype following X-ray pretreatment, DXR-10 cells were instead treated with ten pulsed vincristine exposures. The resultant cell line, designated DXR-10/VCR-10, proved to be more resistant to vincristine, implying that the effect of further drug selection was additive to that of X-ray pretreatment. In addition, these cells showed resistance to doxorubicin and increased Pgp expression which was matched by a concomitant elevation in Pgp mRNA. These findings appear to confirm that Pgp expression is differentially regulated in tumour cells showing drug resistance after drug as opposed to X-ray selection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Stochastic models for geriatric in-patient behaviour.

Departments of geriatric medicine engage in two distinct forms of clinical activity: acute/rehabilitative and long-stay care. These are organizationally distinct and have very different resource needs. Current hospital planning models, however, assume that patients all move through the system at the same rate, thereby ignoring this effect of inherent heterogeneity in patient behaviour. The present paper describes the movement of patients through geriatric hospitals by a two-stage continuous-time Markov model, where the stages represent acute/rehabilitative and long-stay patients respectively. Patients are initially admitted to the first stage, from which they may depart from the system, by death or discharge, or move into the second stage, from which they eventually depart by death or discharge (unlikely). Admissions are modelled in two ways: either as replacements for departures or as a Poisson stream. Expressions for the distribution and movement of numbers of patients are derived and evaluated for data from a number of hospitals. Such an approach has the advantage, over previous crude models, of taking into account different types of patients and introducing variability, thus making it possible to extract variances as well as means of numbers of geriatric patients requiring hospital care.

Aged↗
PubMed1993

Characterization of the P-glycoprotein over-expressing drug resistance phenotype exhibited by Chinese hamster ovary cells following their in-vitro exposure to fractionated X-irradiation.

Exposure of the Chinese hamster ovarian AuxB1 cell line in vitro to fractionated X-irradiation generated sublines designated DXR-10, which proved resistant to multiple drugs and overexpressed P-glycoprotein (Pgp), as judged by Western blotting using the C219 monoclonal antibody. Further characterization of these irradiated DXR-10 sublines has provided evidence for: (i) the expression of cross-resistance to gramacidin D, taxol, puromycin and Navelbine, but not to daunomycin or mitoxantrone; (ii) overexpression of the class I Pgp, as judged by Western blotting using the C494 monoclonal antibody; (iii) decreased accumulation of 3H-vincristine, which could be enhanced by verapamil addition; (iv) unaltered accumulation and subcellular distribution of adriamycin; (v) significantly increased rhodamine 123 accumulation in the presence of verapamil; (vi) plasma-membrane ultrastructural modifications resulting in a significantly increased surface area; (vii) numerous clonal karyotypic alterations, with abnormalities involving the long arm of chromosome 1 being consistently identified; (viii) a lack of overexpression of sorcin; (ix) increased total glutathione levels and overexpression of glutathione S-transferase pi. The fact that only certain of these features are considered characteristic of the 'classic' multidrug-resistant CHRC5 cell line supports our earlier proposal that exposure to fractionated X-irradiation results in the expression of a unique drug-resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Dominant expression of multiple drug resistance after in vitro X-irradiation exposure in intraspecific Chinese hamster ovary hybrid cells.

BACKGROUND: Exposure of Chinese hamster ovary (CHO) cells to fractionated x irradiation in vitro has led to expression of a distinctive multiple-drug-resistant phenotype. This phenotype is characterized by overexpression of P-glycoprotein without an increase in P-glycoprotein messenger RNA or gene amplification; increased glutathione S-transferase (GST) activity; and resistance to vincristine, colchicine, and etoposide but not to doxorubicin. PURPOSE: To investigate whether this phenotype is dominant or recessive, we established intraspecific hybrids by fusion of x-ray-treated, drug-resistant CHO cells (DXR-10I or DXR-10II) with drug-sensitive CHO cells (E29). METHODS: Drug resistance levels were determined in the wild-type CHO cell line AuxB1, the drug-sensitive E29 line, the x-ray-pretreated lines, and the hybrid lines by colony-forming assay of cells grown in increasing concentrations of colchicine, vincristine, or doxorubicin. The hybrids were characterized by analysis of DNA content, P-glycoprotein expression by Western blotting, GST activity by use of 1-chloro-2,4-dinitrobenzene as substrate, and sensitivity to reversal of resistance to vincristine by exposure to verapamil. RESULTS: These hybrids proved resistant to colchicine (two-fold) and vincristine (five- to seven-fold) but not to doxorubicin. After the hybrids were exposed to verapamil, vincristine cytotoxicity was increased 10- to 12-fold. The hybrid lines exhibited levels of P-glycoprotein comparable to those of the unfused x-ray-treated parent cell line, suggesting that P-glycoprotein overexpression is a dominant trait in these hybrid lines. Interpretation of the role of increased GST activity in these hybrids was inconclusive because of the very high levels of GST in the drug-sensitive cell-fusion partner. CONCLUSIONS: The multiple-drug-resistant phenotype following x-ray treatment of CHO cells in vitro was dominantly expressed. Overall, these data are consistent with the hypothesis that this phenotype is a consequence of the dominant genetic alteration resulting from exposure to x irradiation. IMPLICATIONS: This work adds weight to our hypothesis that there is a biological basis for the expression of clinical drug resistance in certain patients whose tumors have been previously irradiated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Evidence of post-translational regulation of P-glycoprotein associated with the expression of a distinctive multiple drug-resistant phenotype in Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells following exposure to fractionated X-irradiation in vitro dominantly expressed a distinctive multiple drug-resistant phenotype, characterised by resistance to vinca alkaloids, epipodophyllotoxins and colchicine, but not to anthracyclines, together with overexpression of P-glycoprotein (Pgp), but without any concomitant elevation in Pgp mRNA (J Natl Cancer Inst 1990, 82, 607-612; 1992, 85, 48-53). To investigate the mechanism of this Pgp overexpression, Pgp stability ws examined in an X-irradiation pretreated subline and compared with that of two colchicine-selected drug-resistant CHO sublines. These studies revealed a slower turnover of Pgp in the X-irradiated cells (T1/2 > or = 40 h) relative to the drug-selected sublines (T1/2 = 17 h), indicating that Pgp overexpression appears to be differently regulated in these independently-derived resistant sublines. These data add support to our proposal that the development of drug resistance following X-irradiation may arise by a mechanism distinct from that operating after drug selection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Nurse manpower demand: a review of United Kingdom methodologies.

Forecasting the demand for nurses is a complex and difficult problem. However, in a climate of economic cutbacks and disadvantageous demographic trends, it is essential that adequate methods are developed to predict both the supply and demand for nurse manpower. To this end a number of methods have been constructed, particularly in the last decade. In this paper we survey the work that has been done to provide an effective way of forecasting nurse manpower demand. The two most common approaches are from the 'top-down' or 'bottom-up'. However, an evolutionary method which allows for modification and detailed refinement is more likely to provide a means of taking into account the complexities of the system. Finally, we focus on the nursing hours per patient (NHPP) ratio as a possible tool for demand forecasting. This index is easily calculated and is readily adaptable to the bottom-up approach.

Bed Occupancy↗
PubMed1993

Expression of P-glycoprotein-mediated drug resistance in CHO cells surviving a single X-ray dose of 30 Gy.

We reported previously that Chinese hamster ovary (CHO) cells surviving exposure to repeated doses of 9 Gy of X-irradiation in vitro expressed a multiple drug resistance phenotype characterized by cross-resistance to epipodophyllotoxins and to Vinca alkaloids, and by P-glycoprotein (Pgp) overexpression (Hill et al. 1990). We have now shown that exposure of these CHO cells to a single 30-Gy X-ray dose similarly resulted in the survivors expressing resistance to vincristine and to etoposide and overexpressing Pgp. In agreement with data obtained on cells which received repeated X-ray exposures, this Pgp overexpression occurred in the absence of any significant elevation of Pgp mRNA. However, the reduced ability to accumulate rhodamine 123 identified in these sublines, and the ability of verapamil to reverse this accumulation defect, implies that the Pgp which was overexpressed was functional. These findings indicate that a series of X-ray exposures is not necessary for expression of this distinctive multiple drug resistance phenotype, suggesting that this results not from a general 'stress-type' response but rather more specifically from the radiation exposure itself, with both single-dose and repeated X-irradiation selecting for similar genetic mutants.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Modelling in-patient bed usage behaviour in a department of geriatric medicine.

The flow of patients through geriatric hospitals has been previously described in terms of acute and long-stay states where the bed occupancy at a census point is modelled by a mixed exponential model. Using data for sixteen years the model was fitted to successive annual census points, in order to provide a description of temporal trends. While the number of acute patients has remained fairly stable during the period, the model shows that there has been a decrease in the number of long-stay patients. Mean lengths of stay in our geriatric hospital before death or discharge have decreased during the study period for both acute and long-stay patients. Using these fits of the mixed exponential model to census data, a method is provided for predicting future turnover of patients. These predictions are reasonably good, except when the turnover patterns go through a period of flux in which assumption of stability no longer holds. Overall, a methodology is presented which relates census analysis to the behaviour of admission cohorts, thus producing a means of predicting future behaviour of patients and identifying where there is a change in patterns.

Aged↗
PubMed1992

Using a manpower database to analyse the nurse limbo stock.

A manpower database for nurses employed by the Department of Health and Social Services (DHSS) in Northern Ireland is used to identify the qualified nurses not currently employed by the DHSS, i.e. the limbo stock, and describe this stock in terms of age, sex, length of previous service, grade and location. This information is invaluable for manpower planners who must decide on how many vacancies can be filled by recruitment from the limbo stock, as opposed to training new nurses. Such a methodology provides a valuable tool for the nurse manpower planner.

Adult↗
PubMed1991

Using a manpower database to model nurse turnaround and return to service.

A manpower database for nurses employed by the Department of Health and Social Services in Northern Ireland has been developed. This database contains information on all nurses employed between March 1977 and July 1988 and consists of data on all posts held in this period, including breaks in service. The authors show how these data may be used to analyse the durations of spells in post and spells out of service prior to departure to a number of destinations for the sister and staff nurse grades. The results are presented in a graphical format which enables us to evaluate the relative proportion of departures to each destination and at what stage in service these departures are likely to occur. Such a methodology provides a valuable tool for the nurse manpower planner, and utilizes personnel data which are routinely collected by most health authorities.

Career Mobility↗
PubMedDate not supplied

A decision support system for bed-occupancy management and planning hospitals.

The planning of services within a hospital is a complex task which relies on the availability of accurate data. Such data on patterns of bed occupancy enable us to develop tools which assess performance measures based on activity within a hospital and its beds, and hence they improve the efficiency of bed management and they facilitate the more effective use of resources. We report the development of a bed-occupancy-modelling package that uses a mathematical model to separate the pattern of bed occupancy in hospitals into acute, rehabilitative, and long-stay components. The bed-occupancy management and planning system analyses data downloaded from the patient administrative system. A query-by-example function is then used to separate the data into meaningful subgroups, such as age groups, or the various specialties. The underlying model is a mixed exponential where the number of terms in the mixture corresponds to the number of stages in the hospital spell, typically, acute, rehabilitative, and long stay. The software has been used to analyse data from a number of different specialties and services. A 'what-if' capability [correction of capacility] allows the planner to assess the effect of changes prior to their introduction.

Bed Occupancy↗