Mortality and cancer incidence in a cohort of meatworkers

Methods: In a retrospective cohort study, a list of members of a meatworkers union in Australia was matched with the national death and cancer registries. Standardised mortality ratios (SMR) and standardised incidence ratios (SIR) were calculated using Australian population rates. Exposure to animal viruses, animal blood, animal faeces, and plastic pyrolysis products was assigned according to job title. A nested case control analysis examined the risk of mortality and cancer incidence by each exposure.

Results: There were approximately 20 000 subjects available for analysis. Male workers had increased risk of mortality from all causes (SMR 116, 95% CI 105 to 128) and from injury (SMR 131, 95% CI 108 to 157). Risk of incident lung cancer in males was non-significantly increased (SIR 164, 95% CI 97 to 259) and males had a raised risk of head and neck cancer (SIR 188, 95% CI 103 to 315). There were no significant associations with specific exposures.

Conclusions: Compared to the general Australian population, meatworkers have increased risk of death from all causes, death from injury, and incident lung and head and neck cancer. Analysis by occupational exposures did not disclose any strong evidence of specific occupational risk factors, although this analysis was limited by small numbers of some outcomes and exposure assessment which was based on job titles only.

     

Impact of dose-distribution uncertainties on rectal ntcp modeling. II: Uncertainty implications

A trial of nonescalated conformal versus conventional radiotherapy treatment of prostate cancer has been carried out at the Royal Marsden NHS Trust (RMH) and Institute of Cancer Research (ICR), demonstrating a significant reduction in the rate of rectal bleeding reported for patients treated using the conformal technique. The rate of bleeding has been shown to fall significantly as the extent of rectal wall receiving a planned dose-level in excess of 57 Gy is reduced. Dose-distributions delivered to the rectal wall over the course of radiotherapy treatment inevitably differ from planned distributions. In a previous paper estimates were obtained of the uncertainties in some planned rectal dose-distribution parameters generated by patient setup error, rectal wall movement and the variable degree of rectal wall distension. Here these uncertainties are combined to obtain estimates of the total planning uncertainties in rectal dose-distribution parameters thought likely, on the basis of mechanistic biological modeling, to correlate strongly with the complication rate. Working from these totaled uncertainty values, together with values of patient-to-patient and technique-to-technique differences in planned dose-distribution parameters, it can be inferred that the rectal dose-distribution uncertainties: (i) Have only a marginal impact on fits of a normal tissue complication probability (ntcp) model to RMH/ICR dose-distribution and grade 1, 2, 3 bleeding data (slightly flattening observed volume-response curves); (ii) only slightly reduce the power of a 2 x 100 patient trial of conformal versus conventional prostate radiotherapy to detect a significantly lower rate of grade 1,2,3 rectal bleeding amongst conformally treated patients; (iii) do not diminish the information content of individual planned patient dose-distribution data to the point where the fitting of technique-averaged data would provide as sensitive a test of the existence of a volume effect as the fitting of individual patient data.     

Anticardiolipin antibody associated arterial thrombosis following fibula fracture

A case is described of a 20-year-old college student in whom open reduction and internal fixation of a Weber B fibula fracture was complicated by arterial thrombosis and gangrene of the foot. The patient subsequently required a below-knee amputation. A hypercoagulability workup revealed the presence of an anticardiolipin antibody. Although this is an extremely unusual complication, young female patients with a positive personal or family history of early thrombotic events, such as DVT, multiple pregnancy loss, or early myocardial infarction, should be viewed as being at increased risk. Additional risk factors such as oral contraceptive use, should be sought during the initial history.     

Cyclic ketone inhibitors of the cysteine protease cathepsin K

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.     

'They've forgotten that I'm the mum': constructing and practising motherhood in special care nurseries

Little sociological research has sought to investigate the ways in which women with hospitalized newborn infants construct and practice motherhood. This article seeks to address this lacuna, using data from a qualitative research project based in two Australian neonatal nurseries. Thirty-one mothers of hospitalized newborns and 20 neonatal nurses were interviewed, and other data were obtained via observations of the nurseries, tape-recorded verbal interactions between parents and nursery staff and casual conversations with mothers and nurses. The data revealed that while the mothers' and nurses' discourses on what makes a 'good mother' in the context of the neonatal nursery converged to some extent, there were important differences. The mothers particularly emphasized the importance of physical contact with their infants and breastfeeding, while the nurses privileged presence in the nursery and willingness to learn about the infant's condition and treatment. There was evidence of power struggles between the mothers and nurses over the handling and treatment of the infants, which had implications for how the mothers constructed and practised motherhood. The mothers attempted to construct themselves as 'real mothers', which involved establishing connection with their infants and normalizing them. In time, many of the mothers sought to position themselves as the 'experts' on their infants. For their part, the nurses attempted to position themselves as 'teachers and monitors of the parents', 'protectors of the infants' and 'experts' by virtue of their medical training and experience. Differences in defining the situation resulted in frustration, resentment and anger on the part of the mothers and disciplinary and surveillance actions on the part of many of the nurses, both covert and overt. The nurses' attitude to and treatment of the mothers was integral in the development of the mothers' relationship with their infants in the nurseries, and this influence extended beyond discharge of the infants.     

Correlations between dose-surface histograms and the incidence of long-term rectal bleeding following conformal or conventional radiotherapy treatment of prostate cancer

BACKGROUND AND PURPOSE: In a randomized trial, the incidence of rectal bleeding among patients treated for prostate cancer using conformal radiotherapy was significantly lower (p = 0.002) than that among those treated conventionally. Here the relationship between rectal dose distributions and incidences of bleeding is assessed. METHODS AND MATERIALS: Rectal dose-surface histograms (DSHs) have been calculated for 79 trial patients. The relationship between the DSHs and incidences of Grade 1-3 bleeding has been explored using both semiempiric and biologic (parallel) model-based approaches. RESULTS: Semiempiric analysis of the trial data suggests that it is more useful to work with DSH fractional surface areas multiplied by outlined rectal lengths than with either raw DSH fractional areas or fractional areas multiplied by absolute total outlined rectal surface area. Fitting the parallel model to length-multiplied rectal DSHs and complication data reveals the existence of a significant volume effect, the rate of Grade 1-3 bleeding falling by 1.1% (95% confidence interval [0.04, 2.2]%) for each 1% decrease in the fraction of rectal wall (outlined over an 11-cm length) receiving a dose of more than 57 Gy. CONCLUSION: The existence of this volume effect suggests that dose escalation can be achieved using conformal techniques, although the extent to which doses may be safely escalated cannot be reliably estimated from the trial data.     

Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.     

An outbreak of food poisoning in a military establishment

Background: An outbreak of food poisoning in a military establishment mess was investigated and remedial measures suggested.