General practitioner perception of prostate-specific antigen testing has improved, but more awareness of prostate cancer risk in younger patients is still awaited.

BACKGROUND: In 2006, a county-wide survey of general practitioners (GPs) in the United Kingdom (UK) identified a reluctance to refer younger men with abnormal prostate specific antigen (PSA) levels. Younger men have the most to gain from early-detection of prostate cancer (PCa), which remains a national government priority in the UK and around the world. We sought to assess changes in perception of abnormal PSA-values amongst UK GPs over the past 10 years. MATERIALS AND METHODS: A total of 500 self-administered paper questionnaires were distributed to individually named GPs. One hundred and forty two responded (28.4%), representing a patient population of ∼600,000. A series of visual analogue questions assessed referral thresholds and understanding of risk factors related to the development of PCa. RESULTS: GPs with a median of 23-years experience responded. Although mean PSA threshold for referral to urology did fall between 2006 and 2016 in both the 45-year (5.42 ng/mL vs. 4.61 ng/mL P = 0.0003) and 55-year (5.81 ng/mL vs. 5.30 ng/mL P = 0.0164) age groups, the median referral values were unchanged. Significantly, referral thresholds quoted for younger men (<65 years) were considerably higher than recommended UK maximum PSA-levels. Using case-based scenarios, practitioners appeared more likely to refer older men with abnormal PSA values, with GPs reporting an average 56.2% likelihood of referring an asymptomatic 55-year-old with elevated age-adjusted PSA of 4.6 ng/mL. A total of 95.1% recognised a family history of PCa to be a potential risk factor but other at-risk categories were not so clearly understood. CONCLUSION: Awareness of abnormal PSA values in UK primary care is improving, but continues to lag behind the evidence. Strategies to disseminate knowledge of maximum PSA-values to GPs should focus especially on those for younger patients.

In vitro evaluation of the potential role of sulfite radical in morphine-associated histamine release.

BACKGROUND: Intravenous morphine use is associated with elevated histamine release leading to bronchoconstriction, edema and hemodynamic instability in some patients. This study evaluated the possibility that sulfite, which is present as a preservative in many morphine preparations, might contribute to histamine release in vitro. RESULTS: The human mast cell line, HMC-1, was exposed to various morphine concentrations, in the absence of sulfite, under cell culture conditions. Clinically attained concentrations of morphine (0.018microg/ml and 0.45microg/ml) did not cause increased histamine release from mast cells. There was a significant increase in histamine release when the morphine concentration was increased by 1184-fold (668microg/ml morphine). Histamine release from mast cells exposed to morphine and/or sulfite required the presence of prostaglandin H synthetase. Histamine release in experiments using sulfite-containing morphine solutions was not statistically different from that observed in morphine-only solutions. CONCLUSION: Sulfite in sulfite-containing morphine solutions, at concentrations seen clinically, is not responsible for histamine release in in vitro experiments of the human mast cell line, HMC-1. This does not preclude the fact that sulfite may lead to elevation of histamine levels in vivo.

Rationale for single and high dose treatment regimens with azithromycin.

The rationale for the use of single dose and shorter course azithromycin treatment regimens is based on the pharmacokinetic properties of azithromycin. The drug has a long elimination half-life (>50 h), which enables short course 1- or 3-day dose regimens to be clinically effective. Azithromycin is concentrated within phagocytic cells and tissues and it achieves targeted delivery by these cells to sites of infection. In vitro and in vivo models have demonstrated that azithromycin is taken up, transported and released at the sites of infection by phagocytic cells such as polymorphonuclear neutrophils and macrophages. Uptake is not saturable; therefore delivery of the total dose of azithromycin as a 1- or 3-day regimen should lead to increased uptake and delivery of the drug to sites of infection.

Caspase-mediated cleavage of adenovirus early region 1A proteins.

Adenovirus 2 and 12 early region 1A (Ad2 and Ad12 E1A) proteins were cleaved during cisplatin-induced apoptosis of Ad-transformed rat and human cells. Cleavage was inhibited in the presence of caspase inhibitors such as Z-VAD-FMK. In Ad12 transformants both 13S and 12S E1A proteins were cleaved at a similar rate. In Ad2 transformants the E1A 13S component was appreciably less stable than the 12S component. In in vitro studies Ad2 and Ad12 E1A 13S and Ad2 12S proteins were rapidly cleaved by caspase 3 whereas Ad12 12S E1A and Ad12 13S E1A were rapidly degraded by caspase 7. Cleavage sites in Ad12 13S proteins for caspase 3 have been determined. Initial cleavage occurred at D24 and D150; this was followed by cleavage at D204 and D242. Caspase-3-mediated cleavage of Ad12 13S E1A destroyed its ability to bind to CBP and TBP but interaction between C terminal E1A polypeptides and CtBP was observed. During viral infection Ad5 and Ad12 E1A 12S proteins were markedly more stable than 13S proteins but no difference was observed in Ad E1A levels in the absence or presence of the caspase inhibitors Z-VAD-FMK or Z-D(OMe)-E(OMe)-V-D(OMe)-CH(2)F. Limited caspase 3 and 10 activation occurred during infection with the E1B 19K(-) virus Ad2 pm1722 but little or no activation of caspase 3 was observed during wt virus infection. Examination of protein cleavage during viral infection of A549 cells showed proteolysis of lamin B and PARP in response to Ad5 wt and Ad2 pm1722. Protein degradation in response to both viruses was partially inhibited by Z-VAD-FMK. Following infection of human skin fibroblasts lamin B was degraded, although only limited changes in PARP levels were observed. We have concluded that Ad E1A is cleaved by caspases during apoptosis but not during viral infection. However, some of the processes commonly associated with apoptosis occur during viral infection, particularly with E1B 19K(-) mutants, although apoptosis per se is not evident.