Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.     

Deep-freezing versus 4 degrees preservation of avascular osteocartilaginous shell allografts in rats

Osteocartilaginous allografts (distal femurs of rats) were stored at 4 degrees for six, 12, 24, and 48 hours and at -80 degrees for five days and then evaluated for viability of the bone and cartilage. Storage at 4 degrees for 12 or 24 hours had little effect on cartilage viability but decreased bone viability to 40% and 10% of controls, respectively. Storage at -80 degrees for five days resulted in nonviable bone in all cases but showed an either/or response of cartilage, with high viability in two cases and nonviability in the other eight cases. In a second set of experiments, femurs from rats were stored in situ at 4 degrees for 12 or 24 hours or were harvested and stored at -80 degrees for five days, after which they were transplanted into rats of a different strain. The antibody response to each set of femurs was measured at two, six, and 12 weeks after operation. The 4 degrees storage resulted in a moderately decreased immunogenicity, whereas the storage at -80 degrees resulted in significantly reduced immunogenicity.     

Measurement of oxygen uptake in the non-steady-state

The purpose of these experiments was to develop and validate an open-circuit technique for measurement of gas exchange during the transition from rest to constant load steady-state exercise. The design of the open-circuit system employed to measure gas exchange in these experiments used a mixing chamber to collect the subject's expired ventilation where fractions of O2 and CO2 were determined via electronic gas analyzers. A gasometer was used to measure inspired ventilation and the analog signals from the two gas analyzers and the gasometer were sent to a microcomputer for computation of VO2. In calculating VO2, the mixed expired gas concentrations were matched with ventilatory volume using a previously determined time delay. To determine the validity of the open-circuit system, four subjects performed a series of 16 rest-to-work transitions on a cycle ergometer. In eight of the experiments, serial measurements of VO2 were obtained every 20 s for 3 min using the open-circuit mixing chamber system while the additional eight experiments used the Douglas bag technique. No significant difference (p greater than 0.05) existed between VO2 values calculated by the two techniques. Mean differences in VO2 between the two techniques during the first three 20-s measurement periods were 6, 53, and 63 ml, respectively. Using the Douglas bag technique as the standard, this represents a relative measurement error of 0.1%, 4.5%, and 3.6%, respectively, at the above time intervals. These data demonstrate that an open-circuit system employing a mixing chamber and the appropriate time delay to match expired gas fractions and ventilation is a sensitive means of measurement of VO2 in the non-steady-state.     

Administration to humans of ORG 21465, a water soluble steroid i.v. anaesthetic agent

Ten male volunteers received a 1-min i.v. infusion of a new water soluble steroid anaesthetic agent, ORG 21465. Individuals received doses ranging from 0.8 to 1.8 mg kg-1. All subjects experienced venous pain at the site of injection; those receiving 1.0 mg kg-1 or more became anaesthetized. There was no evidence of histamine release and apnoea did not occur. Excitatory phenomena were observed in all subjects and were dose related; no spikes were seen on the EEG. Pharmacokinetic analysis supported a three-compartment (non-weight- related) model with compartmental volumes V1, V2 and V3 of 4.31, 14.2 and 89.4 litre, respectively. Clearance from the central compartment V1 was 1.55 litre min-1. Inter-compartmental clearances Q1 and Q2 were 2.54 and 1.79 litre min-1. We found that ORG 21465 was an effective anaesthetic in humans. The relationship between sedation, anaesthesia and excitation requires further exploration.      

RETROPERITONEAL SCHWANNOMA: A CASE SERIES AND REVIEW

Schwannomas account for only a small percentage of retroperitoneal tumours. Presentation is typically varied and non-specific and pre-operative diagnosis is difficult. Herein are described five cases of retroperitoneal schwannoma. Presentation was varied, ranging from abdominal pain, abdominal mass, obstructed labour or an incidental finding. All patients had either an abdominal computed tomography scan and/or ultrasound performed. Pre-operative biopsy either by fine needle aspiration (in one patient) or core biopsy in two patients was unhelpful. In four patients with smaller tumours, complete excision was possible with no apparent long-term morbidity and no clinical evidence of recurrent tumour with follow up from 3.5 months to 11 years. For the largest tumour, complete surgical excision was not attempted as it would have entailed significant morbidity.     

Circadian variation in the frequency of onset of chest pain in elderly patients with acute myocardial infarction.

This study reports the time of onset of chest pain in 792 consecutive elderly patients admitted to a coronary care unit with myocardial infarction during a 10-year period. Statistical analysis demonstrated a bimodal frequency distribution with peaks in the time of onset of chest pain between 23 h 30 and 00 h 30 and between 06 h 30 and 08 h 30.     

Symptoms and health status before and six weeks after open cholecystectomy: a European cohort study.ECHSS Group. European Collaborative Health Services Study Group.

The impact of open cholecystectomy on patients' symptoms and health status and their level of satisfaction has been examined to provide a basis for comparison with newer rival treatments. A prospective cohort study using patient and surgeon completed questionnaires before and six weeks after surgery was carried out in 14 general hospitals in eight European countries. Five hundred and eighty three patients were recruited consecutively in 1990 to 1991. Information on their symptoms, general health status, activities of daily living, and satisfaction with their care were collected. After surgery 42.8% of patients reported that they were free of symptoms. Symptoms varied in their responsiveness to surgery--six weeks after surgery 89% of those who had complained of vomiting had improved, 81% of nausea, 69% of loss of appetite, 65% of abdominal pain, and 51% of flatulence. In contrast 28.1% of patients still suffered from flatulence and 23.5% continued to complain of abdominal pain. Most patients' (62.7%) general health improved, 28% were unchanged, and 9.3% were worse. After surgery most patients reported no restrictions in their normal social activities (75-90% depending on the activity) and most (89.5%) felt the results of their operation had been as expected or better than expected. Most patients undergoing open cholecystectomy reported an improvement in their symptoms, health status, and social functioning. This was reflected in their high level of satisfaction. Some patients, however, gained no benefit and a small proportion were worse than before surgery.     

Keratan sulphate in rheumatoid arthritis, osteoarthritis, and inflammatory diseases.

Serum concentrations of antigenic keratan sulphate determined by an enzyme linked immunosorbent assay (ELISA) with a monoclonal antibody were studied in patients with rheumatoid arthritis (RA), osteoarthritis, ankylosing spondylitis, other inflammatory diseases, and a large control group of women without arthritis. Mean keratan sulphate concentrations were low in 117 women with RA compared with 227 female control subjects matched for age drawn from a community survey. There were significant correlations between serum keratan sulphate concentrations in patients with RA and serum C reactive protein and the erythrocyte sedimentation rate. Serum keratan sulphate concentrations were also low in 29 men and women with ankylosing spondylitis and 29 patients with arthritis and high concentrations of C reactive protein. In 98 women undergoing an operation for benign breast disease there were decreases in serum keratan sulphate concentrations after the operation which correlated with doses in serum C reactive protein. No differences were found in keratan sulphate concentrations in 137 women with osteoarthritis compared with controls. Within the group with osteoarthritis there were no differences for the various joint groups and there was no obvious correlation with radiographic severity or progression. These findings suggest serum keratan sulphate is unlikely to be useful as a diagnostic marker in osteoarthritis or RA but indicate a role for inflammation in the regulation of cartilage loss.