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The economics of a pharmacy-based central intravenous additive service for paediatric patients.

This study was designed to compare the costs of a pharmacy-based Central Intravenous Additive Service (CIVAS) with those of traditional ward-based preparation of intravenous doses for a paediatric population. Labour costs were derived from timings of preparation of individual doses in both the pharmacy and ward by an independent observer. The use of disposables and diluents was recorded and their acquisition costs apportioned to the cost of each dose prepared. Data were collected from 20 CIVAS sessions (501 doses) and 26 ward-based sessions (30 doses). In addition, the costs avoided by the use of part vials in CIVAS was calculated. This was derived from a total of 50 CIVAS sessions. Labour, disposable and diluent costs were significantly lower for CIVAS compared with ward-based preparation (p < 0.001). The ratio of costs per dose [in 1994 pounds sterling] between ward and pharmacy was 2.35:1 (2.51 pounds:1.07 pounds). Sensitivity analysis of the best and worst staff mixes in both locations ranged from 2.3:1 to 4.0:1, always in favour of CIVAS. There were considerable costs avoided in CIVAS from the multiple use of vials; the estimated annual sum derived from the study was 44,000 pounds. In addition, CIVAS was less vulnerable to unanticipated interruptions in work flow than ward-based preparation. CIVAS for children was more economical than traditional ward-based preparation, because of a cost-minimisation effect. Sensitivity analysis showed that these advantages were maintained over a full range of skill mixes. Additionally, significant savings accrued from the multiple use of vials in CIVAS.

Catheterization, Central Venous↗

Variability of consecutive in vivo MR flow measurements in the main portal vein.

OBJECTIVE: The variability of consecutive cine phase-contrast MR flow measurements could significantly affect their use for clinical decisions, especially during provocative testing. The purposes of this study were to determine the normal variability of flow and consecutive flow measurements in the main portal vein on MR images and to determine how intraobserver variability, interobserver variability, and MR imager variability affect these measurements. SUBJECTS AND METHODS: MR flow measurements were acquired four consecutive times at the same location in the main portal vein of 12 subjects and three consecutive times at the same location in a nonpulsatile vessel model. All acquisitions were completed within 10 min. All main portal vein MR data sets were evaluated manually in a blinded review by two independent observers during three separate sessions spaced a mean of 4.5 weeks apart. Flow model data sets were evaluated during a single session by one observer. Variabilities were subsequently calculated by a components-of-variance analysis and by the coefficient of variation (SD/mean x 100). RESULTS: Of the total variance, 90% was due to flow variability among subjects (intersubject), 6% to flow variability within one subject (intrasubject), 2% to intraobserver variability, and 2% to interobserver variability. The coefficient of variation of consecutive MR portal vein flow measurements within a single subject was 11% +/- 5% (range, 3-23%). Intra- and interobserver variabilities were 5% +/- 2% (range, 1-11%) and 4% +/- 4% (range, 0-17%), respectively. MR imager variability was 1% +/- 1% (range, 0-2%). CONCLUSION: The mean variability of consecutive cine phase-contrast MR flow measurements in the main portal vein is 11% +/- 5% and could affect research and clinical protocols that employ this technique.

Adult↗

MR angiography of renal artery stenosis: value of the combination of three-dimensional time-of-flight and three-dimensional phase-contrast MR angiography sequences.

OBJECTIVE: It has been reported and also has been our preliminary experience that many false ostial stenoses are attributable to a loss of signal intensity at the origin of the renal arteries when three-dimensional (3D) phase-contrast MR angiography is used. Our objective was to add a 3D time-of-flight MR angiography sequence to the 3D phase-contrast MR angiography sequence to better analyze the origin of the main renal arteries. We assessed the value of the combination of these two MR angiography sequences for the depiction of renal artery stenosis. SUBJECTS AND METHODS: Forty-six patients suspected of having renal artery stenosis on the basis of clinical history, physical examination, and laboratory data were prospectively enrolled. Intraarterial digital subtraction angiography findings were available for all patients. Using intraarterial digital subtraction angiography, we considered stenosis to be significant when the vessel was narrowed more than 50%. During MR angiography, half of the data were reconstructed by interpolation to avoid long acquisition times. Total acquisition times were less than 15 min. MR angiography findings were interpreted independently by two radiologists who were unaware of the findings of intraarterial digital subtraction angiography. With 3D phase-contrast MR angiography, any cutoff in signal intensity or any narrowing of the vessel diameter of more than 50% from the renal ostium to the renal hilum was considered to represent significant stenosis. With 3D time-of-flight MR angiography, our image analysis was focused on the origin of the arteries. Any cutoff in signal intensity in the first centimeter of the renal artery was considered to represent significant stenosis. RESULTS: Intraarterial digital subtraction angiography showed 105 renal arteries, including 15 supernumerary renal arteries. Eleven stenoses were localized to the main hilar renal arteries. Using time-of-flight MR angiography, we found that polar supernumerary renal arteries of small caliber and intrarenal branches of renal arteries were not adequately displayed. Using phase-contrast MR angiography to evaluate only whether the main hilar renal arteries were stenotic, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to be 100%, 65%, 28%, 100%, and 69%, respectively. Using a combination of the two imaging sequences, we found that the specificity, positive predictive value, and accuracy were increased to 90%, 58%, and 92%, respectively. CONCLUSION: For detecting stenoses of the main renal arteries but not for visualizing small accessory renal arteries or distal branches, our results support the use of a combination of the two MR angiography sequences. For now, this combination of sequences should be viewed primarily as a technique for screening patients.

Adult↗

Reliability of gait parameters in children under two years of age.

The walking movement of children of school age and adults can be regarded as very consistent. However, few studies have reported reliability of gait parameters in very young children that may be used as normative data for the clinical assessment of gait. In the present study, nine normal children of ages 10 to 21 mo. were assessed cross-sectionally using three-dimensional video analysis and digitization to assess within-day reliability of gait kinematics. Between-subject differences in gait kinematics were also examined. In addition, one child was assessed at the onset of independent walking and at monthly intervals thereafter to assess changes in gait kinematics during the first 8 mo. of autonomous walking. The case study allowed the acquisition of pilot data for longitudinal studies of this age group. 10 kinematics variables regarded as indicators of efficient walking were measured, and reliability was assessed using one-way analysis of variance and coefficient of variation. The study showed that all children produced reliable within-day results; however, the gait of each child was unique. In the case study, the between-month differences in gait kinematics were significant. The findings may be of clinical interest for pediatricians and child neurologists given the lack of normative data for this age group.

Cross-Sectional Studies↗

Ciprofloxacin resistance in Campylobacter jejuni: case-case analysis as a tool for elucidating risks at home and abroad.

OBJECTIVE: To determine factors independently associated with the acquisition of a ciprofloxacin-resistant Campylobacter jejuni infection. METHODS: Self-completion questionnaires were used to collect clinical, demographic and exposure data from cases of campylobacter infection reported to a sentinel surveillance scheme in England and Wales. Isolates from those cases were referred to the Public Health Laboratory Service Campylobacter Reference Unit for speciation, subtyping and antimicrobial resistance testing. Cases infected with a ciprofloxacin-resistant C. jejuni were compared with cases infected with a sensitive strain using case-case analysis. Single risk variable analysis and logistic regression analysis were employed. The analysis was restricted by travel status to control for the confounding effect of foreign travel. RESULTS AND CONCLUSION: Over half (55%) of the campylobacter infections acquired abroad were resistant to ciprofloxacin, compared with 10% of UK-acquired strains [relative risk 5.23; 95% confidence interval (CI) 4.58-5.96]. For travel-associated cases, ciprofloxacin-resistant infections were independently associated with travel to Spain [odds ratio (OR) 6.87; 95% CI 3.52-13.38], Portugal (OR 22.40; 95% CI 4.36-114.99) or Cyprus (OR 11.74; 95% CI 1.28-108.02), and the consumption of chicken (OR 4.95; 95% CI 2.12-11.56) or bottled water (OR 3.70; 95% CI 1.69-8.10). Indigenous cases infected with a ciprofloxacin-resistant strain were more likely to report the consumption of pre-cooked cold meats (OR 2.13; 95% CI 1.44-3.13). The risk of acquiring a ciprofloxacin-resistant campylobacter infection was strongly associated with foreign travel. Restricting the analyses by travel status revealed different sets of risk exposures for acquiring a resistant C. jejuni strain, suggesting that different intervention strategies will be required.

Adult↗

Acquisition of upper body stability during walking in toddlers.

This study examines the development of head and trunk movements in toddlers as they begin to walk independently. The data are from a longitudinal study of 7 infants observed from the onset of walking over a period of 46-80 weeks. Head and trunk rotations were measured in the frontal and sagittal planes together with global gait parameters (progression velocity, step cadence, length and width, duration of double support phase). The results showed that during the first weeks of walking head and trunk oscillations significantly decreased, indicating that considerable progress is made in upper body stabilization. Dramatic changes in global gait parameters also occurred at this time. After this first period of rapid changes, gait parameters continued the same developmental trend but with slower changes. The close relation between gain in head and trunk stability and improvement in walking efficacy is discussed on the basis of the individual developmental trends.

Child Development↗

Critical examination of the uniformity requirements for single-photon emission computed tomography.

It is generally recognized that single-photon emission computed tomography (SPECT) imposes very stringent requirements on gamma camera uniformity to prevent the occurrence of ring artifacts. The purpose of this study was to examine the relationship between nonuniformities in the planar data and the magnitude of the consequential ring artifacts in the transaxial data, and how the perception of these artifacts is influenced by factors such as reconstruction matrix size, reconstruction filter, and image noise. The study indicates that the relationship between ring artifact magnitude and image noise is essentially independent of the acquisition or reconstruction matrix sizes, but is strongly dependent upon the type of smoothing filter applied during the reconstruction process. Furthermore, the degree to which a ring artifact can be perceived above image noise is dependent on the size and location of the nonuniformity in the planar data, with small nonuniformities (1-2 pixels wide) close to the center of rotation being less perceptible than those further out (8-20 pixels). Small defects or nonuniformities close to the center of rotation are thought to cause the greatest potential corruption to tomographic data. The study indicates that such may not be the case. Hence the uniformity requirements for SPECT may be less demanding than was previously thought.

Gamma Cameras↗

Salicylate triggers heat shock factor differently than heat.

Sodium salicylate has the unusual property of partially inducing the human heat shock response (Jurivich, D. A., Sistonen, L., Kroes, R., and Morimoto, R. I. (1992) Science 255, 1243-1245). Salicylate induces the DNA binding state of the human heat shock transcription factor (HSF), but this is insufficient to elevate heat shock gene expression. Because it is not known how HSF enhances heat shock gene expression, further analysis of the transcriptionally inert, salicylate-induced HSF was undertaken to potentially identify components of the heat shock response that are necessary for full transcriptional induction. Like thermal stress, exposure of HeLa cells to salicylate led to the induction of HSF1 into a DNA-bound state. Despite continued exposure of cells to salicylate, HSF1.DNA binding attenuated much more rapidly than a continuous heat shock. Western blot analysis revealed that the salicylate-induced form of HSF1 was not hyperphosphorylated like the heat-induced form. Furthermore, supershifts of the HSF1 bound to an heat shock element (HSE) oligonucleotide by monoclonal antibodies to phosphoamino acids revealed that salicylate induced threonine phosphorylation of HSF1, whereas heat led to a predominance of HSF1 serine phosphorylation. These data suggest that salicylate-independent signals are necessary to convert HSF1 into a transactivator of heat shock gene expression and that brief acquisition of DNA binding by this factor is insufficient to maximally enhance transcription.

Blotting, Western↗

An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression.

The cDNA microarray is one technological approach that has the potential to accurately measure changes in global mRNA expression levels. We report an assessment of an optimized cDNA microarray platform to generate accurate, precise and reliable data consistent with the objective of using microarrays as an acquisition platform to populate gene expression databases. The study design consisted of two independent evaluations with 70 arrays from two different manufactured lots and used three human tissue sources as samples: placenta, brain and heart. Overall signal response was linear over three orders of magnitude and the sensitivity for any element was estimated to be 2 pg mRNA. The calculated coefficient of variation for differential expression for all non-differentiated elements was 12-14% across the entire signal range and did not vary with array batch or tissue source. The minimum detectable fold change for differential expression was 1.4. Accuracy, in terms of bias (observed minus expected differential expression ratio), was less than 1 part in 10 000 for all non-differentiated elements. The results presented in this report demonstrate the reproducible performance of the cDNA microarray technology platform and the methods provide a useful framework for evaluating other technologies that monitor changes in global mRNA expression.

Analysis of Variance↗

MEA-Tools: an open source toolbox for the analysis of multi-electrode data with MATLAB.

Recent advances in electrophysiological techniques have created new tools for the acquisition and storage of neuronal activity recorded simultaneously with numerous electrodes. These techniques support the analysis of the function as well as the structure of individual electrogenic cells in the context of surrounding neuronal or cardiac network. Commercially available tools for the analysis of such data, however, cannot be easily adapted to newly emerging requirements for data analysis and visualization, and cross compatibility between them is limited. In this report we introduce a free open source toolbox called microelectrode array tools (MEA-Tools) for the analysis of multi-electrode data based on the common data analysis environment MATLAB (version 5.3-6.1, The Mathworks, Natick, MA). The toolbox itself is platform independent. The file interface currently supports files recorded with MCRack (Multi Channel Systems, Reutlingen, Germany) under Microsoft Windows 95, 98, NT, and 2000, but can be adapted to other data acquisition systems. Functions are controlled via command line input and graphical user interfaces, and support common requirements for the analysis of local field potentials, extracellular spike activity, and continuous recordings, in addition to supplementary data acquired by additional instruments, e.g. intracellular amplifiers. Data may be processed as continuous recordings or time windows triggered to some event.

Action Potentials↗

Association of sexual activity with colonization and vaginal acquisition of group B Streptococcus in nonpregnant women.

In a longitudinal cohort study of 1,248 nonpregnant young women recruited from three Pittsburgh, Pennsylvania, health clinics in 1998-2000, the authors investigated risk factors associated with vaginal acquisition of group B Streptococcus (GBS). Rectal and vaginal swabs for GBS culture and demographic and behavioral interview data were obtained from the women at enrollment and at three 4-month intervals. Cox proportional hazards models were used to evaluate risk factors for GBS acquisition among the 1,089 women with follow-up data. At enrollment, 365 (29.2%) of the 1,248 study participants were vaginally colonized with GBS. Of 767 women who were GBS-negative at enrollment, 344 (44.9%) acquired vaginal GBS colonization during follow-up. The following factors were independently associated with vaginal acquisition of GBS at the 0.05 significance level: African-American race (hazard ratio (HR) = 1.5, 95% confidence interval (CI): 1.2, 1.9), having multiple sex partners during the past 4 months (HR = 1.7, 95% CI: 1.1, 2.5), having frequent sexual intercourse during the past 4 months (HR = 1.5, 95% CI: 1.1, 2.2), and having sexual intercourse within the 5 days prior to the follow-up visit (HR = 1.6, 95% CI: 1.3, 2.0). These results show that sexual activity is an important risk factor for vaginal acquisition of GBS.

Adolescent↗

Accelerated time-resolved 3D contrast-enhanced MR angiography at 3T: clinical experience in 31 patients.

PURPOSE: To evaluate whether time-resolved 3D MR-angiography at 3T with a net acceleration factor of eight is applicable in clinical routine and to evaluate whether good image quality and a low artifact level can be achieved with a temporal update rate that allows for additional information on pathologies. MATERIALS AND METHODS: Thirty-one consecutive patients underwent time-resolved 3D contrast-enhanced MR-angiography on a 3T system. Imaging consisted of accelerated 3D gradient echo sequences combining parallel imaging with an acceleration factor of four, partial Fourier acquisition along phase and slice encoding direction, and twofold temporal acceleration using view sharing. Data volumes representing the arterial and venous contrast phases were independently evaluated by two experienced radiologists by grading of image quality and artifact level on a 0-3 scale. RESULTS: Time-resolved MR-angiography was successfully performed in all subjects without the need for contrast agent bolus timing. Excellent arterial (average score = 2.65 +/- 0.32) and good venous (average score = 2.56 +/- 0.28) diagnostic image quality and little image degrading due to artifacts (average score = 2.20 +/- 0.16) were confirmed by both independent readers (agreement in 65.2% of all evaluations). In 14 patients vascular pathologies were identified in the arterial phases. In eight examinations temporal resolution and depiction of contrast agent dynamics provided additional information about pathology. DISCUSSION: Without the necessity for additional bolus timing, time-resolved 3D contrast-enhanced MR-angiography with imaging acceleration along both the spatial encoding direction and temporal domain revealed excellent diagnostic image quality in neurovascular and thoracic imaging. Despite the limited spatial resolution as compared to high-resolution imaging of the carotid artery bifurcation, the results demonstrate the applicability of contrast-enhanced MR-angiography in thoracic and abdominal MRA as well as cervical imaging with a temporal update rate allowing for additional information on pathologies. Future studies may include an evaluation of optimal trade-offs between spatial and temporal resolution, different acceleration factors and a comparison to the gold-standard for accuracy.

Adolescent↗

Surface integration of velocity vectors from 3D digital colour Doppler: an angle independent method for laminar flow measurements.

BACKGROUND: The study was designed to test the angle independence of a dynamic three-dimensional digital colour Doppler method for laminar flow measurement. The technique acquired three-dimensional data by rotational acquisition and used surface integration of Doppler vector velocities and flow areas in time and space for flow computation. METHOD: A series of pulsatile flows (peak flow 55-180 ml/s) through a curved tube were studied with reference flow rates obtained using an ultrasonic flow meter. Colour Doppler imaging was performed at three angles to the direction of flow (20 degrees, 30 degrees, 40 degrees), using a multiplane transoesophageal probe controlled by an ATL HDI5000 system. Integration of digital velocity vectors over a curved three-dimensional surface across the tube for each of the 11 flow rates at each angle was performed off-line to compute peak flow. RESULTS: Peak flow rates correlated closely (r=0.99) with the flow meter with the mean difference from the reference being -0.8+/-2 x 4 ml/s, 0.9+/-2.6 ml/s, 1.0+/-2 x 3 ml/s for 20 degrees, 30 degrees and 40 degrees respectively. Comparison of the three angle groups showed no significant differences (P=0.15, ANOVA). When sampled obliquely, the flow area on the curved surface increased while the velocities measured decreased. CONCLUSION: Surface integration of velocity vectors to compute three-dimensional Doppler flow data is less angle dependent than conventional Doppler methods.

Blood Flow Velocity↗

[Three-dimensional thickness and volume measurements of the knee joint cartilage by MR tomography: reproducibility in volunteers].

OBJECTIVE: To determine the reproducibility of three-dimensional volume and thickness measurements of the knee joint cartilage with MRI in volunteers. METHODS: The knees of 7 healthy individuals (ages 23 to 58 yrs.) were sagittally imaged with a resolution of 2 x 0.31 x 0.31 mm3, using a fat-suppressed FLASH-3 D sequence. The knee was repositioned in between replicate acquisitions, 6 data sets being obtained in each case. After semiautomatic segmentation and three-dimensional reconstruction of the cartilage, the thickness was determined independent of the original section orientation. The coefficient of variation for repeated volume measurements and the deviations of the maximal cartilage thickness values were calculated subsequently. RESULTS: The mean variation of the cartilage volumes of the replicate measurements was 1.4% (+/- 0.8%) in the patella, 1.7% (+/- 1.5%) in the femur, 3.0% (+/- 1.2%) in the medial tibial plateau and 3.5% (+/- 2.0%) in the lateral tibial plateau. The comparison of the distribution patterns of cartilage thickness yielded a high degree of agreement. Only in rare cases deviations of more than 0.5 mm were observed. CONCLUSIONS: The results show that the presented method for determining the quantitative distribution of articular cartilage yields a high degree of precision. It offers new possibilities in screening risk groups, monitoring the course of degenerative joint disease and the investigation of functional adaptation of the cartilage to mechanical loading.

Adult↗

Ablation of Go alpha-subunit results in a transformed phenotype and constitutively active phosphatidylcholine-specific phospholipase C.

Modulation of the components involved in mitogenic signaling cascades is critical to the regulation of cell growth. GTP-binding proteins and the stimulation of phosphatidylcholine (PC) hydrolysis have been shown to play major roles in these cascades. One of the enzymes involved in PC hydrolysis, a PC-specific phospholipase C (PC-PLC) has received relatively little attention. In this paper we examined the role of a particular heterotrimeric GTP-binding protein, Go, in the regulation of cell growth and PC-PLC-mediated hydrolysis of PC in IIC9 fibroblasts. The Go alpha-subunit was ablated in IIC9 cells by stable expression of antisense RNA. These stably transfected cells acquired a transformed phenotype as indicated by: (a) the formation of multiple foci in monolayer cultures, (b) the acquisition of anchorage-independent growth in soft agar; and (c) an increased level of thymidine incorporation in the absence of added mitogens. These data implicate Goalpha as a novel tumor suppressor. Interestingly, PC-PLC activity was constitutively active in the Goalpha-ablated cells as evidenced by the chronically elevated levels of diacylglycerol and phosphorylcholine in the absence of growth factors. In contrast, basal activities of PC-phospholipase D, phospholipase A2, or phosphoinositol-PLC were not affected. These data demonstrate, for the first time, a role for Go in regulating cell growth and provide definitive evidence for the existence of a PC-PLC in eukaryotic cells. The data further indicate that a subunit of Go, is involved in regulating this enzyme.

Animals↗

PC-based system for retrospective cardiac and respiratory gating of NMR data.

A method and a means for retrospectively clustering NMR k-space measurement profiles with respect to both cardiac and respiratory phases were developed to explore strategies for (1) reducing cardiovascular and respiratory flow/motion image artifacts and (2) improving T1 and T2 characterization of the heart. The image data are collected at a uniform rate so that echo (TE) and repetition (TR) times are independent of the varying cardiac cycle R-R interval and/or respiratory motions. Cardiac (C) time, respiratory (R) time or diaphragm position, and NMR data acquisition (A) cycle time are collected by microcomputer in parallel with free running (untriggered) image collection on a standard magnetic resonance imager. After the raw data equivalent of multiple images are collected, the C-A-R phase timing data are uploaded from the microcomputer to the scanner's minicomputer for use in a normalized C-R phase plane clustering of the image raw data. Each profile's position in the C-R phase plane is determined and then clustered into a new set of data, one image being equivalent for each desired C-R phase combination. These raw data are then zero-filled and (optionally) filtered to compensate for the nonuniform k-space sampling and, finally, reconstructed. Cardiac "cines" made from these retrospectively gated images are comparable to similarly phased triggered images. When high time resolution is required, retrospective gating can be expected to show improvements over triggering, especially toward the critical latter part of the cardiac cycle, where coronary artery filling occurs. The system described can readily be assembled from generally available components.

Electrocardiography↗

Development, validation, and applications of a new laboratory-scale indirect impedancemeter for rapid microbial control.

We introduce a new laboratory-scale impedance-meter which is specially intended for indirect technique. It consists of a software system enabling data acquisition via a connected bus which is wired to the measuring cells. These measuring cells are individual impedance-meters that can be activated independently of one another. In the current configuration, the device is slightly affected by temperature, but it can register as little as 10.9 micromol of CO(2). With Bacillus subtilis, Escherichia coli, and Saccharomyces cerevisiae cultures, the conductance responses were highly replicable and repeatable for inocula concentrations of 1-10(8) colony-forming units (CFU) ml(-1). The main use for such devices could be the detection of contamination in foodstuffs. Several of these foodstuffs, when incubated at 37 degrees C, spontaneously release quite large amounts of CO(2). Our impedance meter, however, was able to detect an E. coli presence in canned French beans at 2.35 x 10(-2) CFU ml(-1) and a S. cerevisiae contamination of apple purée in glass jars at 6.1 x 10(-3) CFU ml(-1). The conductance response and the detection time (the time needed for a significant change in conductance) were correlated to the concentration of ampicillin (an antibiotic added to E. coli cultures). The device is thus able to detect the presence of inhibitory compounds in milk or other foodstuffs. Some industrial assays are in process to complement these laboratory tests. Compared with other available techniques for CO(2) measurement (manometry, infrared, radioactive labeling), the technique put forward here appears to be the best compromise between sensitivity, technical constraints, and cost. A commercial version of the impedance meter would enable routine measurements in the quality control of foodstuffs, pharmaceuticals, cosmetics and in R&D laboratories.

Bacillus subtilis↗

High progesterone receptor concentration in a variant of the ZR-75-1 human breast cancer cell line adapted to growth in oestrogen free conditions.

Culture of ZR-75-1 human breast cancer cells for 5 days in the absence of oestrogens (phenol red-free medium supplemented with dextran coated charcoal stripped 5% fetal calf serum) resulted in a slowing of growth rate and loss of progesterone receptors. Oestradiol at 10(-9) M markedly stimulated growth and progesterone receptor synthesis over a 5-day period. While medroxyprogesterone acetate (10(-10) to 10(-6) M) inhibited growth of ZR-75-1 cells growing in complete medium, in the short-term absence of oestrogens low concentrations were growth stimulatory. Cells deprived of oestrogens for 5 days retained sensitivity to growth inhibition by 4-hydroxy tamoxifen. ZR-75-1 cells were also adapted to growth in the absence of oestrogens over a 5-month period. These cells (ZR-PR-LT) failed to express binding sites characteristic of the type 1 oestrogen receptor but progesterone receptor expression was at a level normally associated with oestrogen induction. Adapted cells were growth inhibited by oestradiol, 4-hydroxy tamoxifen and medroxyprogesterone acetate, but despite elevated progesterone receptor expression the progestin was only marginally more inhibitory than in the parent line. Our data indicate a poor quantitative relationship between response to progestins in vitro and progesterone receptor concentration and support previous findings that acquisition of an oestrogen independent phenotype does not necessarily result in resistance to anti-oestrogens.

Antineoplastic Agents↗