Response from lieberman and colleagues

Respond on comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165     

Mortality and morbidity related to injuries from falls in British Columbia

Falls are a major health problem for persons aged 65 years and over. This study examined differences in patterns of fall-related injuries and deaths between age groups, sexes, and among Health Regions of BC. For those under the age of 65 years, fall-related injuries are highest among males, whereas for those 65 and over, falls among females exceed those among males by 2:1. For persons aged 65 and over, 84% of hospital days for unintentional injuries involve falls, with transportation and "other" unintentional injuries contributing 16%. While older women are hospitalized more often for fall-related injuries, more older men die from fall-related injuries. Hospitalization rates due to injuries from falls are highest in the Northern Regions of BC. Policy implications of the findings are discussed.     

Treatment planning for brachytherapy: an integer programming model, two computational approaches and experiments with permanent prostate implant planning

An integer linear programming model is proposed as a framework for optimizing seed placement and dose distribution in brachytherapy treatment planning. The basic model involves using 0/1 indicator variables to describe the placement or non-placement of seeds in a prespecified three-dimensional grid of potential locations. The dose delivered to each point in a discretized representation of the diseased organ and neighbouring healthy tissue can then be modelled as a linear combination of the indicator variables. A system of linear constraints is imposed to attempt to keep the dose level at each point to within specified target bounds. Since it is physically impossible to satisfy all constraints simultaneously, each constraint uses a variable to either record when the target dose level is achieved, or to record the deviation from the desired level. These additional variables are embedded into an objective function to be optimized. Variations on this model are discussed and two computational approaches--a branch-and-bound algorithm and a genetic algorithm--for finding 'optimal' seed placements are described. Results of computational experiments on a collection of prostate cancer cases are reported. The results indicate that both optimization algorithms are capable of producing good solutions within 5 to 15 min, and that small variations in model parameters can have a measurable effect on the dose distribution of the resulting plans.     

Antitumour prodrug development using cytochrome P450 (CYP) mediated activation

An ideal cancer chemotherapeutic prodrug is completely inactive until metabolized by a tumour-specific enzyme, or by an enzyme that is only metabolically competent towards the prodrug under physiological conditions unique to the tumour. Human cancers, including colon, breast, lung, liver, kidney and prostate, are known to express cytochrome P450 (CYP) isoforms including 3A and 1A subfamily members. This raises the possibility that tumour CYP isoforms could be a focus for tumour-specific prodrug activation. Several approaches are reviewed, including identification of prodrugs activated by tumour-specific polymorphic CYPs, use of CYP-gene directed enzyme prodrug therapy and CYPs acting as reductases in hypoxic tumour regions. The last approach is best exemplified by AQ4N, a chemotherapeutic prodrug that is bioreductively activated by CYP3A. This study shows that freshly isolated murine T50/80 mammary carcinoma and RIF-1 fibrosarcoma 4-electron reduces AQ4N to its cytotoxic metabolite, AQ4 (T50/80 Km = 26.7 microM, Vmax = 0.43 microM/mg protein/min; RIF-1 Km = 33.5 microM, Vmax = 0.42 microM/mg protein/min) via AQM, a mono-N-oxide intermediate (T50/80 Km = 37.5 microM; Vmax = 1.4 microM/mg protein/min; RIF-1 Km = 37.5 microM; Vmax = 1.2 microM/mg protein/ min). The prodrug conversion was dependent on NADPH and inhibited by air or carbon monoxide. Cyp3A mRNA and protein were both present in T50/80 carcinoma grown in vivo (RIF-1 not measured). Exposure of isolated tumour cells to anoxia (2 h) immediately after tumour excision increased cyp3A protein 2-3-fold over a 12 h period, after which time the cyp protein levels returned to the level found under aerobic conditions. Conversely, cyp3A mRNA expression showed an initial 3-fold decrease under both oxic and anoxic conditions; this returned to near basal levels after 8-24 h. These results suggest that cyp3A protein is stabilized in the absence of air, despite a decrease in cyp3A mRNA. Such a 'stabilization factor' may decrease cyp3A protein turnover without affecting the translation efficiency of cyp3A mRNA. Confirmation of the CYP activation of AQ4N bioreduction was shown with human lymphoblastoid cell microsomes transfected with CYP3A4, but not those transfected with CYP2B6 or cytochrome P450 reductase. AQ4N is also reduced to AQ4 in NADPH-fortified human renal cell carcinoma (Km = 4 microM, Vmax = 3.5 pmol/mg protein/min) and normal kidney (Km = 4 microM, Vmax = 4.0 pmol/mg protein/min), both previously shown to express CYP3A. Germane to the clinical potential of AQ4N is that although both normal and tumour cells are capable of reducing AQ4N to its cytotoxic species, the process requires low oxygen conditions. Hence, AQ4N metabolism should be restricted to hypoxic tumour cells. The isoform selectivity of AQ4N reduction, in addition to its air sensitivity, indicates that AQ4N haem coordination and subsequent oxygen atom transfer from the active-site-bound AQ4N is the likely mechanism of N-oxide reduction. The apparent increase in CYP3A expression under hypoxia makes this a particularly interesting application of CYPs for tumour-specific prodrug activation.     

Diabetes care: who are the experts?

OBJECTIVES--To identify issues that patients and professionals consider important in diabetes care and differences in their priorities for care and to determine patients' and professionals' judgements of the relative importance of their chosen priorities. DESIGN--Structured group interviews using the nominal group technique. SETTING--Five district health authorities on Tyneside. SUBJECTS--Five nominal groups: expert (seven), non-expert (seven) health care professionals; insulin dependent (four), non-insulin dependent patients (eight); and carers of diabetic patients (eight). MAIN MEASURES--Items important in diabetes care to each nominal group (themes of care), ranked into a series of "top 10" items for each group, and allocated a score according to relative importance to individual members; scores were standardised by individual weighting and group weighting for comparison within and between groups. RESULTS--Patients and professionals agreed that information given to patients, interaction between professionals and patients, patient autonomy, and access were important for good diabetes care, but the importance assigned to each differed. Thus the professionals emphasised empathy and aspects of good communication and patients the desire to know enough to live a "normal" life. Differences were also found within the patient groups; these related to changes in patients' needs at specific points in the development of their illness and in their orientations to care. CONCLUSION--Patients differ from professionals in their orientation to diabetes care, and they can, and should, be involved in setting priorities for care. Since these priorities are dynamic further work is needed to explore the nature of patient satisfaction with diabetes care.