WHITE COATS AND NO TROUSERS: NARRATING THE EXPERIENCES OF WOMEN TECHNICIANS IN MEDICAL LABORATORIES, 1930-90.

Laboratory technicians are a vital part of any working lab. Not only is their knowledge and expertise important for the success of research, but they also often maintain the lab's intellectual and social life. Despite the importance of their work, they are rarely acknowledged in publications, and leave only a few traces within the historical recordthe voices of women laboratory technicians are even harder to uncover. This paper attempts to correct this imbalance by presenting the narratives of women who worked as laboratory technicians at places such as the National Institute for Medical Research (NIMR), the Wellcome Research Laboratories, and established hospital and university labs in Cambridge, Oxford and London. The data were collected though narrative interviews. Specifically, the paper looks at the roles of these women within the lab, their experiences of the social and gender dynamics of the lab, and the development of expertise in regard to the work they carried out and the extent to which they received credit for their contributions to science.

Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay.

The single cell gel electrophoresis comet assay has become established as a sensitive technique for measuring DNA strand breaks. The technique has been modified to allow the sensitive detection and quantitation of DNA interstrand cross-linking at the single cell level. Cells are irradiated immediately before analysis to deliver a fixed level of random strand breakage. After embedding of cells in agarose and lysis, the presence of cross-links retards the electrophoretic mobility of the alkaline denatured cellular DNA. Cross-links are, therefore, quantitated as the decrease in the comet tail moment compared with irradiated controls. Using this method, a linear response of cross-linking versus dose of chlorambucil over a wide dose range was demonstrated in human lymphocytes after drug treatment ex vivo. The method was also sensitive enough to determine cross-linking in clinical samples after chemotherapy. For example, crosslinking was observed in the lymphocytes of patients receiving ifosfamide (3 g/m2/day) as a continuous infusion for 3-5 days or as a 3-h infusion daily for 3 days. Cross-links were detected in all patients within 3 h, with no evidence of DNA single strand break formation. In patients receiving continuous infusion, a plateau of cross-linking was reached by 24 h. In the patients receiving ifosfamide over 3 h, a clear decrease in the peak level of cross-linking was observed before subsequent infusions.

Measurement of drug-induced DNA interstrand crosslinking using the single-cell gel electrophoresis (comet) assay.

DNA damaging agents have been widely used in cancer chemotherapy for many years and have proved successful in the treatment of both solid tissue and haematological malignancies. Many commonly used clinical agents, such as members of the nitrogen mustard, chloroethylnitrosourea, dimethane-sulphonate and platinum classes, are bifunctional. DNA interstrand crosslinks (ISC) formed in cells are clearly critical cytotoxic lesions and the formation of DNA ISC has been shown to correlate with cytotoxicity in vitro (1-5). Acquired resistance in vitro to such agents can occur by a number of mechanisms, for example altered drug transport (6), intracellular detoxification via enhanced glutathione and glutathione-S-transferase activity (7), but enhanced DNA repair capacity can also play an important role (3). Clinically the mechanisms of acquired resistance to DNA damaging agents are less clear but enhanced repair of ISC has been suggested to play a role in the acquired resistance of some cancers, e.g., chronic lymphocytic leukaemia to nitrogen mustards (8). In addition, the inherent sensitivity (and curability) of some tumors, e.g., testicular cancer, to DNA damaging agents may result in part from their inability to repair critical DNA lesions (9).

The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study.

In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.

Urinary proton magnetic resonance studies of early ifosfamide-induced nephrotoxicity and encephalopathy.

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.

Metabolism of ifosfamide during a 3 day infusion.

Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3-DC and CX. The proportion in the form of IPM, however, remained unchanged. With successive cycles the amount of 2-DC and IPM increased by about 10% per course. A very wide variation in the amount of each metabolite was reproducibly seen between patients, but no evidence for a genetic polymorphism was found. Urinary dechloroethyl metabolites correlated positively with each other and negatively with CX. Although autoinduction increases 'activation' of ifosfamide when given over 3 days, our evidence suggests that competing metabolic pathways prevent an increase in the amount of active metabolite formed.

Pharmacokinetics of 10-ethyl-10-deaza-aminopterin, edatrexate, given weekly for non-small-cell lung cancer.

We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m2 was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10 +/- 0.07, 0.8 +/- 0.3 and 7 +/- 7 h, respectively. The mean plasma clearance was 25 +/- 14 l/h, with 18% +/- 11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with r2 = 0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.

Transoesophageal cardiac pacing.

An elderly patient, whilst undergoing anaesthesia for a total hip replacement, developed a marked bradydysrhythmia suggestive of sick sinus syndrome. The heart rate was unaffected by atropine 1.2 mg administered intravenously. Cardiac pacing was achieved by means of a non-invasive transoesophageal pacemaking catheter. The simplicity of this technique although temporary, is ideal for emergencies.

Rapid intubation with fazadinium. A comparison of fazadinium with suxamethonium and alcuronium.

The speed of onset and intubation conditions have been compared for suxamethonium 1 mg/kg, alcuronium 0-32 mg/kg and fazadinium 1 mg/kg and 1-25 mg/kg. Fazadinium 1 mg/kg was not significantly different in times to intubation from suxamethonium although the latter gave a highly significant greater number of patients with excellent conditions. The higher dose of 1-25 mg/kg fazadinium did not give significantly better intubating conditions than the lower dose. Although the times to intubation for the two dose levels of fazadinium did not differ statistically, the higher dose was significantly slower in onset than suxamethonium. Alcuronium was slower than either suxamethonium or fazadinium 1 mg/kg in producing satisfactory conditions. The nondepolarizing drug, fazadinium, may be a useful neuromuscular blocking agent in emergency cases where rapid intubation is required and when it is wished to avoid possible or probable adverse effects from the depolarising drug suxamethonium.