Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach.

Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging approach to search for low-penetrance susceptibility alleles in a study of up to 4,647 cases and 4,564 controls, in a two-stage study design. We identified seven tagging SNPs using genotype data from the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project and typed these, and an additional three SNPs, in 2,345 breast cancer cases and 2,284 controls (set 1). Three SNPs showed no evidence for association and were not studied further, whereas seven SNPs (rs11571171, rs7116336, rs660149, rs10895068, rs500760, rs566351, and rs1042838) exhibited significant associations at P < 0.1 using either a heterogeneity or trend test and progressed to be genotyped in set 2. After both stages, only one SNP was significantly associated with an increased risk of breast cancer - the PGR-12 (rs1042638) V660L valine to leucine polymorphism [VL heterozygotes (odds ratio, 1.13; 95% confidence interval, 1.03-1.24) and the LL homozygotes (odds ratio, 1.30; 95% confidence interval, 0.98-1.73), P(het) = 0.008, P(trend) = 0.002]. Similar estimates were obtained in a combined analysis of our data with those from three other published studies. We conclude that the 660L allele may be associated with a moderately increased risk of breast cancer, but that other common SNPs in the PGR gene are unlikely to be associated with a substantial risk of breast cancer.     

Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose.     

Photochemical inactivation of duck hepatitis B virus in human platelet concentrates: a model of surrogate human hepatitis B virus infectivity

BACKGROUND: Photochemical decontamination of platelet concentrates (PCs) has been demonstrated by the use of 8-methoxypsoralen and ultraviolet A light. Systems for studying the inactivation of blood- borne viruses facilitate the evaluation of photochemical decontamination protocols. STUDY DESIGN AND METHODS: Duck hepatitis B virus (HBV), a model for human HBV, was adapted for the study of hepadnavirus inactivation. A highly specific in vitro infectivity assay used primary duck hepatocyte cultures and was followed by the detection of replicated duck HBV sequences. RESULTS: Duck HBV-infected primary duck hepatocyte cultures produced authentic infectious virus. High- titer (> 10(9) virus genome equivalents/mL) duck HBV-infected sera were completely inactivated in serum or PCs by the use of 100 micrograms per mL of 8-methoxypsoralen and 70 J per cm2 of ultraviolet A light. Intracellular duck HBV (> 4.2 log10) in PCs was also inactivated. Culture results were confirmed by a sensitive duckling infectivity assay that indicated that 6.3 log10 of infectious duck HBV had been inactivated by photochemical decontamination. CONCLUSION: The sensitivity of the culture assay was comparable to that of the duckling assay using polymerase chain reaction gene amplification to detect duck HBV. Duck HBV inactivation in PCs was dependent on the dose of ultraviolet A light and independent of 8-methoxypsoralen concentrations of 100 to 300 micrograms per mL: 100 micrograms per mL 8- methoxypsoralen inactivated 4 to 5 log10 of virus in conjunction with 20 to 40 J per cm2 of ultraviolet A light. The polymerase chain reaction-enhanced duck HBV culture system has utility in optimizing photochemical decontamination protocols.     

Can ventilation while on cardiopulmonary bypass improve post-operative lung function for patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether ventilation during cardiopulmonary bypass (CPB) improves post-operative lung function. Altogether 187 relevant papers were identified using the below mentioned search, 9 papers represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that a wide range of ventilatory strategies, while on cardiopulmonary bypass, have been attempted including CPAP with positive airway pressures of 5-15 cm H(2)O, high frequency low volume ventilation (with 100 breaths per min), inspired oxygen concentrations from 21% to 100% and bilateral extra-corporeal circulation using the lungs to oxygenate the blood while on bypass. While some small and transient benefits for CPAP with 10 cm H(2)O have been demonstrated, no convincing clinical benefits for any of these strategies have been shown and thus ventilation while on cardiopulmonary bypass cannot be supported as a strategy to improve post-operative lung function.     

Is the Allen's test adequate to safely confirm that a radial artery may be harvested for coronary arterial bypass grafting?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether the Allen's test, plethysmography, Doppler ultrasound or MRI imaging was the best method of assessing the presence of adequate collateral blood flow in the arm preoperatively prior to radial artery harvest for conduits during CABG surgery. Altogether 176 papers were identified using the reported search of which 15 represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that whilst there are theoretical limitations with the Allen's test, for most patients it is an adequate method of assessing collateral arm flow prior to radial artery harvest and several large studies have confirmed the absence of neurological and vascular adverse outcome with a modified Allen's test cut-off point of up to 12 s. However, if there are concerns about collateral flow then a second confirmatory test such as dynamic Doppler ultrasound or measurement of digital pressure changes with radial artery occlusion can also be used prior to harvest. Newer techniques such as Gadolinium-enhanced magnetic resonance angiography have also been described to confirm adequate collateral circulation prior to radial artery harvest for CABG conduit and whilst in time they might come to represent an ultimate 'gold standard' they are clearly too expensive and impracticable for everyday use.