Stephen McNally

Early stress protein gene expression in a human model of ischemic preconditioning.

Intermittent clamping of the porta hepatis (PHC) is commonly performed during liver surgery to reduce blood loss and has been reported to precondition livers resulting in improved outcome after liver surgery (humans) and transplantation (animals). This study investigated the early expression of cytoprotective stress proteins during ischemia-reperfusion induced by PHC. Liver samples were taken before and after each event in a two-cycle ischemia-reperfusion protocol using 15 minutes of PHC followed by 5 minutes of reperfusion. Liver tissue was analyzed by real-time polymerase chain reaction for heme oxygenase (HO)-1 and heat shock protein (HSP)-70 mRNA expression. Extracted protein was analyzed by Western blot for HO-1, and HSP-70 and nuclear extracts were analyzed by DNA mobility shift assay for hypoxia inducible factor (HIF)-1&agr; and heat shock factor (HSF)-1. Within minutes of PHC, significant increases in HO-1 mRNA expression were detected, and these were maintained throughout the protocol (P<0.01). Protein expression of HO-1 (P<0.03) and HO-1 activity (P<0.05) were similarly increased between the start and end of ischemia- reperfusion (40 minutes). Binding of active HIF-1&agr; to its consensus sequence was increased within 15 minutes of the start of the ischemia-reperfusion cycle. Although evidence of the transcriptionally active form of HSF-1 was detected at the same time point, this was not reflected in measurable changes in HSP-70 mRNA or protein. In conclusion, expression of the cytoprotective protein HO-1 is significantly up-regulated in the liver within minutes of PHC. It is likely that HO-1 contributes to the early protective effects of ischemic preconditioning.

Enhanced recovery following liver surgery: a systematic review and meta-analysis

BACKGROUND Enhanced recovery after surgery (ERAS) programmes aim to improve postoperative outcomes. They are being utilized increasingly in hepatic surgery. This review aims to evaluate the impact of ERAS programmes on outcomes following liver surgery. METHODS EMBASE, MEDLINE, PubMed and the Cochrane Database were searched for trials comparing outcomes in patients undergoing liver surgery utilizing ERAS principles with those in patients receiving conventional care. The primary outcome was occurrence of postoperative complications within 30 days. Secondary outcomes included length of stay (LoS), functional recovery and adherence to ERAS protocols. RESULTS Nine articles were included in the review, of which two were randomized controlled trials (RCTs). Overall complication rates were 25.0% (range: 11.5-46.4%) in ERAS patients, and 31.0% (range: 11.8-46.2%) in conventional care patients. Significantly reduced overall complication rates following ERAS care were demonstrated by a meta-analysis of the data reported in the two RCTs (odds ratio: 0.49, 95% confidence interval 0.28-0.84; P = 0.01) The median LoS reported by the studies was 5.0 days (range: 2.5-7.0 days) in ERAS patients, and 7.5 days (range: 3.0-11.0 days) in non-ERAS patients. Recovery milestones, when reported, were improved following ERAS care. CONCLUSIONS The adoption of ERAS protocols improves morbidity and LoS following liver surgery. Future ERAS programmes should accommodate the unique requirements of liver surgery in order to optimize postoperative outcomes.

Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.

Preconditioning treatments hold significant potential for improving outcomes in solid organ transplantation. Protective phenotypes can be induced using certain drugs. Curcumin is a biologically active component of turmeric and has been reported to induce stress proteins in certain cell lines, leading to cell protection. This study investigates in detail the effect of curcumin on the stress-response in human hepatocytes, in particular its effect on heme oxygenase 1 (HO-1) and its cytoprotective effect. Pretreatment with curcumin protected hepatocytes in a model of oxidative injury and this protection was mediated through HO-1. In a model of cold preservation injury, curcumin pretreatment resulted in elevation of HO-1 throughout the cold storage and rewarming period, and was cytoprotective against oxidative injury. This is the first study to demonstrate that curcumin induces HO-1 in human hepatocytes, and that the protective effects of curcumin pretreatment may have clinical potential in hepatic transplantation.

Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury.

Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.

Analgesia after open abdominal surgery in the setting of enhanced recovery surgery: a systematic review and meta-analysis.

IMPORTANCE The optimal analgesic technique following open abdominal surgery within an enhanced recovery protocol remains controversial. Thoracic epidural is often recommended; however, its role is increasingly being challenged and alternative techniques are being suggested as suitable replacements. OBJECTIVE To determine by meta-analysis whether epidurals are superior to alternative analgesic techniques following open abdominal surgery within an enhanced recovery setting in terms of postoperative morbidity and other markers of recovery. DATA SOURCES A literature search was performed of EMBASE, Medline, PubMed, and the Cochrane databases from 1966 through May 2013. STUDY SELECTION All randomized clinical trials comparing epidurals with an alternative analgesic technique following open abdominal surgery within an enhanced recovery protocol were included. DATA EXTRACTION AND SYNTHESIS All studies were assessed by 2 independent reviewers. Study quality was assessed using the Cochrane bias assessment tool and the Jadad and Chalmers modified bias risk assessment tools. Dichotomous data were analyzed by random or fixed-effects odds ratios. Qualitative analysis was performed where appropriate. RESULTS Seven trials with a total of 378 patients were identified. No significant difference in complication rate was detected between epidurals and alternative analgesic methods (odds ratio, 1.14; 95% CI, 0.49-2.64; P = .76). Subgroup analysis showed fewer complications in the patient-controlled analgesia group compared with epidural analgesia (odds ratio, 1.97; 95% CI, 1.10-3.53; P = .02). Following qualitative assessment, epidural analgesia was associated with faster return of gut function and reduced pain scores; however, no difference was observed in length of stay. CONCLUSIONS AND RELEVANCE Epidurals may be associated with superior pain control but this does not translate into improved recovery or reduced morbidity when compared with alternative analgesic techniques when used within an enhanced recovery protocol.

Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells.

Heme oxygenase‐1 catalyzes the breakdown of heme and is protective in models of kidney transplantation. In this study we describe the induction of heme oxygenase‐1 mRNA and protein by insulin. Following treatment with insulin, a five‐fold increase in heme oxygenase‐1 mRNA and a four‐fold increase in protein expression were observed in renal adenocarcinoma cells; insulin‐induced heme oxygenase‐1 expression was also demonstrated in mouse primary tubular epithelial cells. The induction of heme oxygenase‐1 in renal adenocarcinoma cells was blocked by actinomycin D and cycloheximide and was abolished by the phosphatidylinositol 3‐kinase inhibitor, LY294002, but not by the inactive analog LY303511. Overexpressing a dominant‐negative form of Akt abrogated the heme oxygenase‐1‐inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase‐1 promoter activity and protein expression. The transcription factor NF‐E2‐related factor‐2 was found to translocate to the nucleus following insulin treatment in a phosphatidylinositol 3‐kinase‐dependent manner. Pretreatment with NF‐E2‐related factor‐2 small‐interfering RNA abolished insulin‐induced heme oxygenase‐1 induction. Insulin was also found to activate the mitogen‐activated protein kinase cascades p38 and extracellular signal‐related kinase; however, inhibition of these pathways with SB202190 and PD98059 did not alter insulin‐induced heme oxygenase‐1 expression. Thus, insulin induces heme oxygenase‐1 mRNA and protein expression in renal cells in a phosphatidylinositol 3‐kinase/Akt and NF‐E2‐related factor‐2‐dependent manner.

Factors in perioperative care that determine blood loss in liver surgery

OBJECTIVES Excessive blood loss during liver surgery contributes to postoperative morbidity and mortality and the minimizing of blood loss improves outcomes. This study examines pre- and intraoperative factors contributing to blood loss and identifies areas for improvement. METHODS All patients who underwent elective hepatic resection between June 2007 and June 2009 were identified. Detailed information on the pre- and perioperative clinical course was analysed. Univariate and multivariate analyses were used to identify factors associated with intraoperative blood loss. RESULTS A total of 175 patients were studied, of whom 95 (54%) underwent resection of three or more segments. Median blood loss was 782 ml. Greater blood loss occurred during major resections and prolonged surgery and was associated with an increase in postoperative complications (P= 0.026). Peak central venous pressure (CVP) of >10 cm H(2)O was associated with increased blood loss (P= 0.01). Although no differences in case mix were identified, blood loss varied significantly among anaesthetists, as did intraoperative volumes of i.v. fluids and transfusion practices. CONCLUSIONS This study confirms a relationship between CVP and blood loss in hepatic resection. Intraoperative CVP values were higher than those described in other studies. There was variation in the intraoperative management of patients. Collaboration between surgical and anaesthesia teams is required to minimize blood loss and the standardization of intraoperative anaesthesia practice may improve outcomes following liver surgery.

Age at first anal sex and HIV/STI vulnerability among gay men in Australia

Objectives To determine whether there is a link between age at first anal intercourse (AFAI) and gay mens HIV/sexually transmissible infection (STI) vulnerability, including tendencies to engage in higher risk sexual behaviour. Methods A nationwide cross-sectional survey was conducted online involving 845 Australian gay men born between 1944 and 1993. Results Median AFAI fell from 35 years for men born between 1944 and 1953 to 18 years for men born between 1984 and 1993. Of those who reported having had anal intercourse (N=822), HIV-positive men were found to be significantly younger on average when they first had anal intercourse compared with HIV-negative men (18.5 vs 21.3 years, p<0.001). Men with a history of other STIs were also significantly younger. Engaging in higher risk sexual behaviour is a likely factor, with AFAI generally younger among men who reported >10 sexual partners in the past year (p<0.001) and who engaged in group sex (p<0.001), receptive anal intercourse (p=0.008) or were drug or alcohol affected (p=0.06) during their most recent sexual encounter. Conclusions There appears to be a strong link between AFAI and infection with HIV/STIs, as well as tendencies to engage in higher risk sexual behaviour. While further research is needed to understand this link, these findings highlight a need for sexuality education aimed at gay-identified youth to ensure their sexual debut does not lead to poorer sexual health outcomes.

Versatility and HIV Vulnerability: Investigating the Proportion of Australian Gay Men Having Both Insertive and Receptive Anal Intercourse

INTRODUCTION There is a lack of recent data on the extent to which gay men engage in insertive anal intercourse (IAI) and receptive anal intercourse (RAI). Accurate assessments of the overall risk of infection from HIV and other sexually transmitted infections (STIs) require such data because versatile men who engage in both roles have heightened vulnerability for becoming infected and infecting others. AIM To investigate the extent to which gay men are versatile with regard to having IAI and RAI. MAIN OUTCOME MEASURES Percentages of gay men who reported engaging in IAI, RAI, or both during the past 12 months and in their most recent sexual encounter. METHODS Eight hundred fifty-six Australian gay men completed an online survey to retrospectively report on their sexual practices over the past 12 months. RESULTS Of men who had anal intercourse in the past 12 months, 83% had both IAI and RAI, of whom 57% were highly versatile in that they had approximately equal numbers of partners for IAI and RAI. Of men who had anal intercourse in their most recent sexual encounter, as many as one in five (20%) had reciprocal anal intercourse, having both IAI and RAI with the same partner in a single encounter. Condom use was significantly less likely with reciprocal (38%) than nonreciprocal anal intercourse (50%; P = 0.04). While highly versatile men were less likely to know their HIV status, practices at most recent sexual encounter such as reciprocal anal intercourse and condom use were not significantly related to either their HIV status or that of their partner. CONCLUSIONS Engaging in both IAI and RAI appears to be common among gay men. HIV/STI prevention strategies would benefit from paying attention to the implications of high rates of versatile sexual practices, particularly the tendency for condoms to be used less often when having reciprocal anal intercourse.

Now, later or never? Challenges associated with hepatitis C treatment

Background and Aims: Of the 259,000 Australians estimated to have a hepatitis C virus infection, very few have received antiviral therapy. This study identifies personal, psychological and structural barriers associated with decisions to begin treatment and the challenges associated with adhering to a demanding treatment regimen.