Although hepatic ischemia-reperfusion (IR) injury is partially mediated by tumor necrosis factor-␣ (TNF), we recently found that low-dose TNF before IR is hepatoprotective. We examined the seemingly conflicting roles of TNF in mediating liver injury in a partial hepatic IR model using TNF gene knockout (TNF ko) mice to allow TNF replacement at specified times. Compared with wild-type mice, TNF ko mice exhibit minimal alanine aminotransferase release and few hepatonecrotic lesions during the early (time, 2 hours) and late (time, 24 hours) phases of IR. TNF ko mice differed from wild-type mice in that TNF ko mice exhibited no activation or induction of nuclear factor-B, p38, cyclin D1, or proliferating cell nuclear antigen after IR. A single low-dose TNF injection 1 minute before the onset of hepatic ischemia restored hepatic IR injury in TNF ko mice. To clarify the importance of TNF for hepatoprotection, preconditioning (10 minutes of ischemia and 10 minutes of reperfusion) was performed before the onset of IR for TNF ko mice whose capacity to undergo IR injury had been restored by TNF replacement. Ischemic preconditioning failed to protect these mice from TNF-augmented IR injury; however, following the administration of intravenous TNF (1 g per kg body weight, which mimics the early increase in hepatic and plasma TNF levels that is mobilized by ischemic preconditioning), significant hepatoprotection against both the early and late phases of TNF-augmented IR injury was observed. In conclusion, TNF appears to mediate both the early and late phases of liver injury in hepatic IR, but it also is an essential mediator of hepatoprotective effects brought about by ischemic preconditioning. ( H epatic ischemia-reperfusion (IR) is a significant complication of hepatic resection, liver transplantation, and circulatory shock, and it contributes to the mechanisms of certain types of toxic liver injury. IR-related liver injury results from an intense inflammatory response initiated by oxidative stress in the liver parenchyma during reperfusion. This response involves Kupffer cells, which release cytokines such as tumor necrosis factor-␣ (TNF); these cytokines amplify inflammation by inducing the expression of neutrophilattracting chemokines and by up-regulating vascular adhesion molecules. 1,2 TNF levels have been found to increase during hepatic ischemia and remain detectable in plasma and liver tissue until the late reperfusion phase. Nonetheless, to date, all evidence implicating TNF as a mediator of hepatic IR injury is indirect. Colletti et al. 3 found that pretreatment with anti-TNF antibody before the onset of hepatic IR significantly reduced pulmonary and hepatic injury in a rodent model. Rudiger et al. 4 subsequently demonstrated that pentoxifylline, a methylxanthine inhibitor of TNF production in vivo, dramatically reduced hepatic IR injury as assessed by serum aminotransferase release and animal survival.TNF exerts protean and often conflicting biologic effects, depending on cell type and context. In the liver, t...
Background: There is currently no national screening programme for prostate cancer in England, but eligible men can request a prostate-specific antigen (PSA) test from their general practitioner (GP). There are no routinely available data to monitor the extent of PSA testing and referral. Aim: The aim of this study was to investigate the rate of PSA testing in general practice and subsequent patterns of referral. person-years were tested at least once in 2010, and 9.45 (95% CI 9.37-9.53) in 2011. Rates increased with age and decreased with increasing level of deprivation. Of the 53,069 men tested in 2010, 11,289 (21.3%) had a previous PSA test within the past 12 months. Of men with raised PSA according to age specific guidelines, 22.4% (2113/9425) were referred to secondary care within 14 days, with 36% of the remainder retested within 6 months. Conclusions: Rates of PSA testing have increased compared with earlier studies; the data suggest that many GPs are retesting men with raised PSA rather than referring immediately. More routine data on PSA testing, including reasons for testing, and subsequent management and outcomes, are required. What's knownRates of prostate-specific antigen (PSA) testing in England have been found to be low compared with those in some other European countries. The Prostate Cancer Risk Management Programme aims to ensure that men requesting a PSA test are fully informed of the advantages and disadvantages of PSA testing and prostate cancer risk factors, and recommends agespecific cut-off levels for referral for further investigation. What's newOverall rates of PSA testing in England were higher than previous estimates (9.45 per 100 person years in 2011), but rates of referral according to age specific PSA guidelines were low. The data suggest that many GPs are retesting men with a raised PSA before referral. There is a need for more routinely available data to monitor rates of and reasons for testing, and subsequent management and outcomes.
Background: There is currently no national prostate cancer screening programme in the UK. However, patients 50 years and older are entitled to a prostate specific antigen (PSA) test, if informed on the advantages and disadvantages of testing and their risk of cancer. The Prostate Cancer Risk Management Programme (PCRMP) provides this guidance. Aim: The aim of this study was to access GPs' views and understanding of PSA testing, prostate cancer screening and early detection. Method: A total of 708 questionnaires were returned by GPs across two English regions in 2013 and the GP questionnaire responses were quantitatively analysed. Results: In the 699 completed questionnaires, the majority of GPs were well informed about PSA testing, screening and early detection. Only 32% used guidelines for referral, 14% knew all age-specific PSA referral levels, 71% that Black men have a higher prostate cancer risk than White men (22% correctly answered threefold increase) and 82% that family history is a risk factor. A further 78% thought electronic prompts during consultation would encourage PCRMP guideline usage and 75% had never been offered a PSA test and prostate cancer educational course, of which 73% would like to attend a course. Only 23% were aware of the latest PSA screening evidence (1) and 94% would like an update. Conclusions: Participating GPs seem to be well informed but need more information and tools to help follow recommended guidance. In particular, increased awareness of PCRMP guidelines especially by automated methods, further educational courses and evidence updates would be beneficial. What's known• To our knowledge, there are no similar large published surveys on GPs views and understanding of PSA testing, screening and early detection within England and the PCRMP guidelines.
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