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Objectives: This scoping review was undertaken to identify risk prediction models and pre-operative predictors of surgical site infection (SSI) in adult cardiac surgery. A particular focus was on the identification of novel predictors that could underpin the future development of a risk prediction model to identify individuals at high risk of SSI, and therefore guide a national SSI prevention strategy., Methods: A scoping review to systematically identify and map out existing research evidence on pre-operative predictors of SSI was conducted in two stages. Stage 1 reviewed prediction modelling studies of SSI in cardiac surgery. Stage 2 identified primary studies and systematic reviews of novel cardiac SSI predictors., Results: The search identified 7887 unique reports; 7154 were excluded at abstract screening and 733 were selected for full-text assessment. Twenty-nine studies (across 30 reports) were included in Stage 1 and reported the development (N=14), validation (N=13), or both development and validation (N=2) of 52 SSI risk prediction models including 67 different pre-operative predictors. The remaining 703 reports were re-assessed in Stage 2; 49 studies met the inclusion criteria, and 56 novel pre-operative predictors that have not been assessed previously in models were identified., Conclusions: This review identified 123 pre-operative predictors of the risk of SSI following cardiac surgery, 56 of which have not been included previously in the development of cardiac SSI risk prediction models. These candidate predictors will be a valuable resource in the future development of risk prediction scores, and may be relevant to prediction of the risk of SSI in other surgical specialities., Competing Interests: Conflict of interest statement None declared., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Interview and questionnaire studies have identified barriers and challenges to preventing surgical site infections (SSIs) by focusing on compliance with recommendations and care bundles using interviews, questionnaires and expert panels. This study proposes a more comprehensive investigation by using observations of clinical practice plus interviews which will enable a wider focus., Aim: To comprehensively identify the factors which affect SSI prevention using cardiac surgery as an exemplar., Methods: The study consisted of 130 h of observed clinical practice followed by individual semi-structured interviews with 16 surgeons, anaesthetists, theatre staff, and nurses at four cardiac centres in England. Data were analysed thematically., Findings: The factors were complex and existed at the level of the intervention, the individual, the team, the organization, and even the wider society. Factors included: the attributes of the intervention; the relationship between evidence, personal beliefs, and perceived risk; power and hierarchy; leadership and culture; resources; infrastructure; supplies; organization and planning; patient engagement and power; hospital administration; workforce shortages; COVID-19 pandemic; 'Brexit'; and the war in Ukraine., Conclusion: This is one of the first studies to provide a comprehensive overview of the factors affecting SSI prevention. The factors are complex and need to be fully understood when trying to reduce SSIs. A strong evidence base was insufficient to ensure implementation of an intervention., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 μg.l -1 ; functional iron deficiency as ferritin 30-100 μg.l -1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l -1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l -1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay., (© 2022 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: The aim of this systematic review was to summarize the results of trials evaluating interventions for the reduction of sarcopenia in patients undergoing surgery., Methods: Searches were conducted using the Cochrane Central Register of Controlled Trials, MEDLINE and Embase. RCTs evaluating exercise, dietary or pharmacological interventions to address sarcopenia in the perioperative period were included. Treatment effect estimates were expressed as standardized mean differences (MDs) with confidence intervals, and heterogeneity was expressed as I2 values., Results: Seventy trials including 3402 participants were selected for the data synthesis. Exercise interventions significantly increased muscle mass (MD 0.62, 95 per cent c.i. 0.34 to 0.90; P < 0.001), muscle strength (MD 0.55, 0.39 to 0.71; P < 0.001), measures of gait speed (MD 0.42, 0.05 to 0.79; P = 0.03), and reduced time for completion of set exercises (MD -0.76, -1.12 to -0.40; P < 0.001) compared with controls. Subgroup analysis showed that interventions in the early postoperative period were more likely to have a positive effect on muscle mass (MD 0.71, 0.35 to 1.07; P < 0.001) and timed tests (MD -0.70, -1.10 to -0.30; P = 0.005) than preoperative interventions. Treatment effects on muscle mass (MD 0.09, -0.31 to 0.49; P = 0.66) and strength (MD 0.46, -0.01 to 0.92; P = 0.05) were attenuated by the presence of cancer. Results of analyses restricted to nine trials at low risk of allocation concealment bias and fourteen trials at low risk of attrition bias were comparable to those of the primary analysis. Risk-of-bias assessment showed that most trials were at high risk of incomplete outcome and attrition bias, thus reducing the estimate of certainty of the evidence according to the GRADE assessment tool., Conclusion: Exercise interventions appear beneficial in reducing the impact of sarcopenia. Because of the high risk of bias and low certainty of the current evidence, large RCTs using standardized measures of muscle mass should be undertaken., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Objectives: To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design., Methods: Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop., Results: Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability., Conclusion: A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

Background: The aim was to investigate whether preoperative weight loss results in improved clinical outcomes in surgical patients with clinically significant obesity., Methods: This was a systematic review and aggregate data meta-analysis of RCTs and cohort studies. PubMed, MEDLINE, Embase and CINAHL Plus databases were searched from inception to February 2018. Eligibility criteria were: studies assessing the effect of weight loss interventions (low-energy diets with or without an exercise component) on clinical outcomes in patients undergoing any surgical procedure. Data on 30-day or all-cause in-hospital mortality were extracted and synthesized in meta-analyses. Postoperative thromboembolic complications, duration of surgery, infection and duration of hospital stay were also assessed., Results: A total of 6060 patients in four RCTs and 12 cohort studies, all from European and North American centres, were identified. Most were in the field of bariatric surgery and all had some methodological limitations. The pooled effect estimate suggested that preoperative weight loss programmes were effective, leading to significant weight reduction compared with controls: mean difference -7·42 (95 per cent c.i. -10·09 to -4·74) kg (P < 0·001). Preoperative weight loss interventions were not associated with a reduction in perioperative mortality (odds ratio 1·41, 95 per cent c.i. 0·24 to 8·40; I 2 = 0 per cent, P = 0·66) but the event rate was low. The weight loss groups had shorter hospital stay (by 27 per cent). No differences were found for morbidity., Conclusion: This limited preoperative weight loss has advantages but may not alter the postoperative morbidity or mortality risk., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background and Objectives: To review preclinical and clinical studies that have evaluated the effects of red cell rejuvenation in vivo and in vitro and to assess the potential risks and benefits from their clinical use., Materials and Methods: A systematic review and narrative synthesis of the intervention of red cell rejuvenation using a red cell processing solution containing inosine, pyruvate, phosphate and adenine. Outcomes of interest in vitro were changes in red cell characteristics including adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG), deformability and the accumulation of oxidized lipids and other reactive species in the red cell supernatant. Outcomes in vivo were 24-h post-transfusion survival and the effects on oxygen delivery, organ function and inflammation in transfused recipients., Results: The literature search identified 49 studies evaluating rejuvenated red cells. In vitro rejuvenation restored cellular properties including 2,3-DPG and ATP to levels similar to freshly donated red cells. In experimental models, in vivo transfusion of rejuvenated red cells improved oxygen delivery and myocardial, renal and pulmonary function when compared to stored red cells. In humans, in vivo 24-h survival of rejuvenated red cells exceeded 75%. In clinical studies, rejuvenated red cells were found to be safe, with no reported adverse effects. In one adult cardiac surgery trial, transfusion of rejuvenated red cells resulted in improved myocardial performance., Conclusion: Transfusion of rejuvenated red cells reduces organ injury attributable to the red cell storage lesion without adverse effects in experimental studies in vivo. The clinical benefits of this intervention remain uncertain., (© 2018 International Society of Blood Transfusion.)

Background: We assessed whether a near-infrared spectroscopy (NIRS)-based algorithm for the personalized optimization of cerebral oxygenation during cardiopulmonary bypass combined with a restrictive red cell transfusion threshold would reduce perioperative injury to the brain, heart, and kidneys., Methods: In a randomized controlled trial, participants in three UK centres were randomized with concealed allocation to a NIRS (INVOS 5100; Medtronic Inc., Minneapolis, MN, USA)-based 'patient-specific' algorithm that included a restrictive red cell transfusion threshold (haematocrit 18%) or to a 'generic' non-NIRS-based algorithm (standard care). The NIRS algorithm aimed to maintain cerebral oxygenation at an absolute value of > 50% or at > 70% of baseline values. The primary outcome for the trial was cognitive function measured up to 3 months postsurgery., Results: The analysis population comprised eligible randomized patients who underwent valve or combined valve surgery and coronary artery bypass grafts using cardiopulmonary bypass between December 2009 and January 2014 ( n =98 patient-specific algorithm; n =106 generic algorithm). There was no difference between the groups for the three core cognitive domains (attention, verbal memory, and motor coordination) or for the non-core domains psychomotor speed and visuo-spatial skills. The NIRS group had higher scores for verbal fluency; mean difference 3.73 (95% confidence interval 1.50, 5.96). Red cell transfusions, biomarkers of brain, kidney, and myocardial injury, adverse events, and health-care costs were similar between the groups., Conclusions: These results do not support the use of NIRS-based algorithms for the personalized optimization of cerebral oxygenation in adult cardiac surgery., Clinical Trial Registration: http://www.controlled-trials.com , ISRCTN 23557269., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Viscoelastic point-of-care tests are commonly used to provide prompt diagnosis of coagulopathy and allow targeted treatments in bleeding patients. We updated existing meta-analyses that have evaluated the clinical effectiveness of viscoelastic point-of-care tests vs the current standard of care for the management of cardiac surgery patients at risk of coagulopathic bleeding. Randomized controlled trials comparing viscoelastic point-of-care diagnostic testing with standard care in cardiac surgery patients were sought. All-cause mortality, blood loss, reoperation, blood transfusion, major morbidity, and intensive care unit and hospital length of stay were analysed using random-effects modelling. Fifteen trials that randomized a total of 8737 participants were included for the analysis. None of the trials was classified as low risk of bias. The use of thromboelastography- (TEG®) or thromboelastometry (ROTEM®)-guided algorithms did not reduce mortality [risk ratio (RR) 0.55, 95% confidence interval (CI) 0.28-1.10] without heterogeneity (I2=1%), reoperation for bleeding, stroke, ventilation time, or hospital length of stay compared with standard care. Use of TEG® or ROTEM® resulted in reductions in the frequency of red blood cell (Risk Ratio 0.88, 95% Confidence Interval 0.79-0.97; I2=43%) and platelet transfusion (Risk Ratio 0.78, 95% Confidence Interval 0.66-0.93; I2=0%). Group Reading Assessment and Diagnostic Evaluation (GRADE) assessment demonstrated that the quality of the evidence was low or very low for all estimated outcomes. Routine use of viscoelastic point-of-care tests did not improve important clinical outcomes beyond transfusion in adults undergoing cardiac surgery., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.)

Background: Experimental studies suggest that mechanical cell washing to remove pro-inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients., Methods: Cardiac surgery patients at increased risk of large-volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin-8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects., Results: Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2-5.5) RBC units, stored for a mean of 21 ( sd 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC-derived microvesicles but increased cell-free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin-8 values [adjusted mean difference 0.239 (95% confidence intervals -0.231, 0.709), P =0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury., Conclusions: These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery., Clinical Trial Registration: ISRCTN 27076315., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.)

Objective: To assess the incremental cost and cost-effectiveness of a restrictive versus a liberal red blood cell transfusion threshold after cardiac surgery., Design: A within-trial cost-effectiveness analysis with a 3-month time horizon, based on a multicentre superiority randomised controlled trial from the perspective of the National Health Service (NHS) and personal social services in the UK., Setting: 17 specialist cardiac surgery centres in UK NHS hospitals., Participants: 2003 patients aged >16 years undergoing non-emergency cardiac surgery with a postoperative haemoglobin of <9 g/dL., Interventions: Restrictive (transfuse if haemoglobin <7.5 g/dL) or liberal (transfuse if haemoglobin <9 g/dL) threshold during hospitalisation after surgery., Main Outcome Measures: Health-related quality of life measured using the EQ-5D-3L to calculate quality-adjusted life years (QALYs)., Results: The total costs from surgery up to 3 months were £17 945 and £18 127 in the restrictive and liberal groups (mean difference is -£182, 95% CI -£1108 to £744). The cost difference was largely attributable to the difference in the cost of red blood cells. Mean QALYs to 3 months were 0.18 in both groups (restrictive minus liberal difference is 0.0004, 95% CI -0.0037 to 0.0045). The point estimate for the base-case cost-effectiveness analysis suggested that the restrictive group was slightly more effective and slightly less costly than the liberal group and, therefore, cost-effective. However, there is great uncertainty around these results partly due to the negligible differences in QALYs gained., Conclusions: We conclude that there is no clear difference in the cost-effectiveness of restrictive and liberal thresholds for red blood cell transfusion after cardiac surgery., Trial Registration Number: ISRCTN70923932; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Introduction: It has been suggested that removal of proinflammatory substances that accumulate in stored donor red cells by mechanical cell washing may attenuate inflammation and organ injury in transfused cardiac surgery patients. This trial will test the hypotheses that the severity of the postoperative inflammatory response will be less and postoperative recovery faster if patients undergoing cardiac surgery receive washed red cells compared with standard care (unwashed red cells)., Methods and Analysis: Adult (≥16 years) cardiac surgery patients identified at being at increased risk for receiving large volume red cell transfusions at 1 of 3 UK cardiac centres will be randomly allocated in a 1:1 ratio to either red cell washing or standard care. The primary outcome is serum interleukin-8 measured at 5 postsurgery time points up to 96 h. Secondary outcomes will include measures of inflammation, organ injury and volumes of blood transfused and cost-effectiveness. Allocation concealment, internet-based randomisation stratified by operation type and recruiting centre, and blinding of outcome assessors will reduce the risk of bias. The trial will test the superiority of red cell washing versus standard care. A sample size of 170 patients was chosen in order to detect a small-to-moderate target difference, with 80% power and 5% significance (2-tailed)., Ethics and Dissemination: The trial protocol was approved by a UK ethics committee (reference 12/EM/0475). The trial findings will be disseminated in scientific journals and meetings., Trial Registration Number: ISRCTN 27076315.

Background: There is uncertainty regarding the safety of different volume replacement solutions. The aim of this study was systematically to review evidence of crystalloid versus colloid solutions, and to determine whether these results are influenced by trial design or clinical setting., Methods: PubMed, Embase and the Cochrane Central Register of Controlled Trials were used to identify randomized clinical trials (RCTs) that compared crystalloids with colloids as volume replacement solutions in patients with traumatic injuries, those undergoing surgery and in critically ill patients. Adjusted odds ratios (ORs) for mortality and major morbidity including renal injury were pooled using fixed-effect and random-effects models., Results: Some 59 RCTs involving 16 889 patients were included in the analysis. Forty-one studies (69 per cent) were found to have selection, detection or performance bias. Colloid administration did not lead to increased mortality (32 trials, 16 647 patients; OR 0·99, 95 per cent c.i. 0·92 to 1·06), but did increase the risk of developing acute kidney injury requiring renal replacement therapy (9 trials, 11 648 patients; OR 1·35, 1·17 to 1·57). Sensitivity analyses that excluded small and low-quality studies did not substantially alter these results. Subgroup analyses by type of colloid showed that increased mortality and renal replacement therapy were associated with use of pentastarch, and increased risk of renal injury and renal replacement therapy with use of tetrastarch. Subgroup analysis indicated that the risks of mortality and renal injury attributable to colloids were observed only in critically ill patients with sepsis., Conclusion: Current general restrictions on the use of colloid solutions are not supported by evidence., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: The aim of this study was to develop two novel risk prediction scores for transfusion and bleeding that would be used to inform treatment decisions, quality assurance, and clinical trial design in cardiac surgery., Methods: Clinical data prospectively collected from 26 UK cardiac surgical centres and a single European centre were used to develop two risk prediction models: one for any red blood cell (RBC) transfusion, and the other for large volume blood transfusion (≥4 RBC units; LVBT), an index of severe blood loss. 'Complete case' data were available for 24 749 patients. Multiple imputation was used for missing covariate data (typically <5% per variable), with the imputed data set containing 39 970 patients. Risk models were developed in the complete case data set, with internal validation using leave-one-centre-out cross-validation. The final selected models were fitted to the imputed data set. Final risk scores were then compared with the performance of three existing scores: the Transfusion Risk and Clinical Knowledge score (TRACK), the Transfusion Risk Understanding Scoring Tool (TRUST), and the Papworth Bleeding Risk Score (BRiSc)., Results: The area under the receiver operating characteristic curve (AUC) was 0.77 (95% confidence interval 0.77-0.77) for the any RBC transfusion score and AUC 0.80 (0.79-0.80) for the LVBT score in the imputed data set. The LVBT model also showed excellent discrimination (Hosmer-Lemeshow P=0.32). In the imputed data set, the AUCs for the TRACK and TRUST scores for any RBC transfusion were 0.71 and 0.71, respectively, and for LVBT the AUC for the BRiSc score was 0.69., Conclusions: Two new risk scores for any RBC transfusion or LVBT among cardiac surgery patients have excellent discrimination, and could inform clinical decision making., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: We evaluated, in a randomized controlled trial, the safety and effectiveness of intraoperative cell salvage and autotransfusion of washed salvaged red blood cells after first-time coronary artery bypass grafting performed on the beating heart., Methods: Sixty-one patients undergoing off-pump coronary artery bypass grafting surgery were prospectively randomized to autotransfusion (n = 30; receiving autotransfused washed blood from intraoperative cell salvage) or control (n = 31; receiving homologous blood only as blood-replacement therapy). Homologous blood was given according to unit protocols., Results: The groups were well matched with respect to demographic and comorbid characteristics. Patients in the autotransfusion group had a significantly higher 24-hour postoperative hemoglobin concentration (11.9 g/dL; SD, 1.41 g/dL) than those in the control group (10.5 g/dL; SD, 1.37 g/dL) (mean difference, 1.02 g/dL; 95% confidence interval, 1.60-0.44 g/dL; P = .0007), as well as a 20% reduction in the frequency of homologous blood product use (11/31 vs 5/30; P = .095). Autotransfusion of washed red blood cells was not associated with any derangement of thromboelastograph values or laboratory measures of clotting pathway function (prothrombin time, activated partial thromboplastin time, and fibrinogen levels), increased postoperative bleeding, fluid requirements, or adverse clinical events. There was no statistical difference between groups in the total operation, hospitalization, and management costs per patient (median difference, USD 1015.90; 95% confidence interval, -USD 2260 to USD 206; P = .11). Conclusions Intraoperative cell salvage and autotransfusion was associated with higher postoperative hemoglobin concentrations, a modest reduction in transfusion requirements, no adverse clinical or coagulopathic effects, and no significant increase in cost compared with controls. This study supports its routine use in off-pump coronary artery bypass grafting surgery.

Aim: Intimal hyperplasia remains the leading cause of late graft failure following heart transplantation. The immunosuppressive drug mycophenolate mofetil has been shown to inhibit the development of intimal hyperplasia. This study aimed to assess the efficacy of a combination of mycophenolate mofetil, calcineurin inhibition, and sirolimus on the development of intimal hyperplasia., Methods: Male Sprague-Dawley rats received mycophenolate mofetil (30 mg/kg per day) and either tacrolimus (0.1 mg/kg per day), cyclosporine (5 mg/kg per day), or sirolimus (0.05 mg/kg per day) and were compared to an untreated control group. All animals underwent left common carotid artery balloon angioplasty. Morphometric analysis was performed on representative transverse sections, and intima medial ratios calculated at 2 weeks. Profibrotic gene expression was assessed with competitive RT-PCR at 2 weeks for metalloproteinase-2, metalloproteinase-9, TIMP-1, collagen III, and TGF-beta. Sections were stained with sirius red, and extracellular matrix deposition was quantified., Results: Mycophenolate mofetil in combination with rapamycin was associated with the greatest reduction in intimal thickening (intima medial ratio 0.79; range 0.45-0.86), compared to its combination with either cyclosporine (1.41; range 1.06-1.68, P < .02) or tacrolimus (0.93; range 0.81-1.37, P < .05) and controls (1.47; range 1.02-2.04, P < .005). Mycophenolate mofetil and rapamycin significantly inhibited all profibrotic genes studied compared to controls (P < .01) but there were no differences between tacrolimus and cyclosporine. Mycophenolate mofetil and sirolimus significantly attenuated extracellular matrix deposition compared to tacrolimus and cyclosporin (P < .023)., Conclusion: The benefits of mycophenolate mofetil in combination with sirolimus are preferential over those with cyclosporine or tacrolimus. Randomised trials are warranted to assess if mycophenolate mofetil should be an alternative agent to calcineurin-inhibitors when used in combination with sirolimus.

Despite many years of clinical and experimental research, the contribution of cardiopulmonary bypass (CPB) and cardioplegic arrest to morbidity and mortality following cardiac surgery remains unclear. This is due, in part, to lack of suitable control group against which bypass and cardioplegic arrest can be compared. The recent success of beating heart coronary artery bypass grafting has, however, for the first time, provided an opportunity to compare the same operation, in similar patient groups, with, or without CPB and cardioplegic arrest. CPB is associated with an acute phase reaction of protease cascades, leucocyte, and platelet activation that result in tissue injury. This is largely manifest as subclinical organ dysfunction that produces a clinical effect in those patients that generate an excessive inflammatory response or in those with limited functional reserve. The contribution of myocardial ischemia/reperfusion, secondary to aortic cross-clamping, and cardioplegic arrest, to the systemic inflammatory response and wider organ dysfunction is unknown, and requires further evaluation in clinical trials.

Heart disease is a leading cause of maternal death. The aim of this study is to review the most common causes of cardiac disease, highlight factors that should be recognized by the clinician, and address recent advances in the anaesthetic management of these patients. Incipient cardiac disease, including peripartum cardiomyopathy, myocardial infarction and aortic dissection, accounts for approximately one in six maternal deaths. The keys to successful diagnosis and management of incipient disease are: a high index of suspicion, particularly in women with known risk factors for cardiovascular disease; a low threshold for radiological investigations; early cardiology input; and invasive monitoring during labour and delivery. Echocardiography is a safe, non-invasive test, under-used in pregnancy. Management of pregnant women with pre-existing cardiac problems should be undertaken by multidisciplinary teams in tertiary centres. In women with pre-existing cardiac disease wishing to proceed to term, cardiac status must be optimized preoperatively and planned elective delivery is preferable. Vaginal delivery is preferable, and with careful incremental regional anaesthesia is safe in most women with cardiac disease. The presence of adequate systems for early detection, appropriate referral to specialist centres, and timely delivery with multidisciplinary support can minimize the serious consequences of poorly controlled heart disease in pregnancy.

Background: The aim of this study was to compare the effect of Neoral cyclosporin- and tacrolimus-based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial., Methods: A total of 102 patients undergoing renal transplantation were randomized to immunosuppression with either microemulsion cyclosporin (Neoral; 15 mg per kg per day adjusted to whole-blood trough concentrations of 200-300 ng/ml) or tacrolimus (0.2 mg per kg per day adjusted to whole-blood trough levels of 8-15 ng/ml) in conjunction with steroids, or at a lower dose (7 mg per kg per day and 0.1 mg per kg per day respectively) with the addition of azathioprine for non-heart-beating renal transplant recipients. Renal transplant interstitial fibrosis was quantified using computerized histomorphometric measurement of picrosirius red-stained 1-year protocol renal transplant biopsies. Levels of interstitial fibrosis were compared in relation to observed efficacy and toxicity profiles of the two drugs., Results: There was a significant increase in allograft interstitial fibrosis in the patients treated with Neoral compared with those given tacrolimus. There was no significant difference in the demographic characteristics between the patient groups or in the incidence of acute rejection (Neoral 36 per cent versus tacrolimus 35 per cent) or steroid-resistant rejection (both 10 per cent) between the two drugs. There was a higher incidence of insulin resistance in the tacrolimus group (post-transplant diabetes mellitus, glucose tolerance testing) but this was not statistically significant. Neoral was associated with a significant increase in total cholesterol (P = 0.030) and low-density lipoprotein (P = 0.021) levels, which persisted throughout the study period., Conclusion: Despite equivalent efficacy and pretransplantation risk factors for CAN, Neoral was associated with increased allograft fibrosis and significantly higher serum low-density lipoprotein cholesterol levels compared with tacrolimus., (Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Atrial fibrillation (AF) is the most common complication following cardiac surgery and is associated with significant increases in postoperative morbidity, length of stay and cost of care. In a randomized study we assessed the impact of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) (off-pump, n = 100), compared to conventional (on-pump, n = 100) CABG, on the frequency of postoperative AF. Arrhythmias were detected using an automated arrhythmia detector for the first 72 hours following surgery and by four hourly clinical observations thereafter. AF was defined as an irregular narrow complex rhythm (in the absence of bundle branch block) with absence of discrete P waves lasting greater then 10 minutes. There was a significant reduction in the incidence of postoperative AF in the off-pump group (11% versus 45%, P < 0.001) in addition to significant reductions in blood usage, postoperative pneumonia, inotrope requirements, and hospital and intensive care unit stay. Univariate analysis identified all these variables as risk factors for AF, however multivariate regression analysis identified CPB and cardioplegic arrest as the only independent predictor of postoperative AF (OR 7.4; 95% CI 3.4 to 17.9). This study therefore suggests that the inflammatory response to bypass, myocardial ischaemia and atrial cannulation are significant contributory factors to the development of AF following cardiac surgery. In the light of more recent trials it is apparent that this benefit may be most marked in patients with multiple perioperative risk factors for postoperative AF.

Background: Rapamycin inhibits extracellular matrix (ECM) accumulation (fibrosis) and vascular remodeling in experimental models of chronic allograft dysfunction (CAD) by poorly understood mechanisms. The aim of this study was to assess the effect of rapamycin on the expression of fibrosis-associated genes and correlate this with observed changes in ECM remodeling in an experimental of model allograft vasculopathy., Methods: Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerized histomorphometry of F344-to-Lewis rat aortic allograft sections harvested at serial timepoints. Expression of fibrosis associated genes was studied by means of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR)., Results: Rapamycin (0.5 mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intragraft gelatinase, collagen III and tissue inhibitor of metalloproteinase 1 (TIMP 1) mRNA levels. At a lower dosage (0.25 mg/kg/day), rapamycin inhibited intimal hyperplasia and medial ECM accumulation, but there was a lesser effect on vascular remodeling. Lower dose allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intragraft matrix metalloproteinase 9 (MMP 9) mRNA than those treated with the higher dose., Conclusions: These data suggest that, in addition to the tissue response to injury, the alloimmune injury itself may contribute directly to the vascular remodeling that occurs in allograft vasculopathy. Rapamycin at higher but not lower doses inhibited both of these pathologic processes.

Objective: The aim of this study was to examine the effect of age on the outcome of surgical treatment for carcinoma of the oesophagus and gastric cardia., Methods: From 1979 to 1999, 596 patients underwent gastro-oesophagectomy with two-field lymph node clearance for cancer under the care of a single surgeon. The clinicopathologic characteristics and survival of patients aged between 45 and 63 years (n=198, Group 1), 63 and 71 years (n=199, Group 2) and 71 and 89 years (n=199, Group 3) were compared., Results: Thirty-day mortality for the first 300 patients (1979-1993) in this consecutive series was 5, 8 and 18% for Groups 1, 2 and 3, respectively, and 6, 6 and 6% for Groups 1, 2 and 3, respectively, in the second consecutive 296 patients (1993-1999, P=0.006, chi(2)). Tumours were poorly differentiated in 55.7, 59.1 and 53.4% of patients in Groups 1, 2 and 3, respectively, for 1979-1993 and 64.7, 53.2 and 40.2% of tumours in Groups 1, 2 and 3, respectively, for 1993-1999 (P=0.02, chi(2)). Adjuvant therapy was significantly more common in younger patients (P=0.006, chi(2)). Five-year survival in the first period was 22, 15 and 11% for Groups 1, 2 and 3, respectively, (P=0.02 log-rank) and 18, 16 and 14% for Groups 1, 2 and 3 in the second period (P=NS, log-rank)., Conclusions: Elderly patients now have equivalent short and long-term outcomes compared to younger patients following gastro-oesophagectomy. Five-year survival, even in younger patients receiving adjuvant therapy remains poor, however, at approximately 20%. New therapeutic modalities are required to improve long-term survival following surgical treatment of gastro-oesophageal carcinoma.

Background: Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition., Methods: Male Sprague-Dawley rats received rapamycin 0.05 mg/kg daily and either tacrolimus 0.1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima : media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase-polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red., Results: The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0.02)., Conclusion: The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin.

Background: The provision and maintenance of vascular access remains a major cost to end stage renal failure programmes. There are few reports regarding the surgical revision of the failing native elbow arteriovenous fistula (AVF)., Patients and Methods: A retrospective case note review was performed on all patients identified from the hospital vascular access database as having undergone construction of an autogeneous vein elbow AVF. Over a seven year period 282 autogeneous vein AVFs were fashioned in 232 patients using the brachial artery as the in-flow conduit. Of these 208 were brachiocephalic fistulas, or a variant thereof, and 74 were fashioned using the transposed autologous basilic vein (136 male: 96 female; median age 60 years, range 14-94 years)., Results: Of 282 elbow fistulas 197 were successfully used for dialysis (70%). Cumulative primary patency of elbow fistulas using autogeneous vein in this series was 68%, 54%, and 44% at one, two, and three years respectively. A further 34 revision procedures were performed on 28 fistulas to maintain fistula function, and cumulative secondary patency after surgical revision was 75%, 60%, and 46% at one, two, and three years. Overall 21 out of 34 procedures (62%) successfully restored fistula function and cumulative primary patency of the revised fistulas was 56% at one year. Eighteen AVFs (brachiocephalic, n=12; autologous basilar vein, n=6) required revision for access dysfunction secondary to a short stenoses within 4 cm of the arteriovenous anastomoses. Of these 18 AVFs eight were revised by excision of the stenosed segment and either primary anastomoses of the two cut ends of arterialised vein or reanastomoses of the proximal venous limb proximally on the brachial artery. In another nine fistulas the excised segment was replaced with a short interposition graft (polytetrafluoroethylene, n=7; native basilic vein, n=1; bovine carotid artery, n=1). One fistula with postanastomotic stenoses and a more proximal needle site stenoses was revised using two vein patches. Overall 100% were patent at 24 hours, 13 provided successful dialysis (72%), and cumulative primary patency was 67% and 50% at six months and one year respectively., Conclusions: Successful surgical revision of failing native elbow fistulas can restore patency and improve cumulative secondary patency with potential benefits in terms of patient morbidity and mortality. These results compare favourably to published patency rates after fistula salvage using interventional radiological techniques.

Background: Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterized by histological evidence of extracellular matrix (ECM) accumulation (fibrosis). The aim of this study was to characterize the changes in fibrosis-associated gene expression in an experimental model of CAD and to measure the effect of the immunosuppressant cyclosporin on these changes., Methods: Lewis recipients of F344 rat thoracic to abdominal transplants were administered cyclosporin or no treatment. Vascular remodelling and ECM accumulation (picrosirius red) were measured using computerized histomorphometry. Fibrosis-associated gene expression was studied by semiquantitative reverse transcription-polymerase chain reaction., Results: Cyclosporin inhibited medial ECM accumulation and vascular remodelling in allografts. This was associated with an attenuation of the graft inflammatory infiltrate and a reduction in intragraft matrix metalloproteinase (MMP) 2 and MMP-9 messenger RNA (mRNA) levels. There was a significant negative correlation between neoadventitial ECM density and MMP-9 expression, as well as with vessel circumference. Neoadventitial ECM density was significantly higher in the cyclosporin-treated group than in animals with untreated allografts, as were mRNA levels of collagen 3 and tissue inhibitor of metalloproteinase 1., Conclusion: The alloimmune injury itself may contribute directly to vascular remodelling and fibrosis in allograft vasculopathy. Cyclosporin attenuated this component of the pathophysiology of CAD effectively.

Background: The success of infragenicular revascularisation for lower limb ischaemia is limited by the high proportion of patients without ipsilateral long saphenous vein (LSV) of adequate length or quality. The aim of this study was to report the results of an autogenous vein only policy for infragenicular revascularisation utilising contralateral LSV when ipsilateral LSV is inadequate. The treatment and outcome of infection of autogenous grafts with methicillin resistant Staphylococcus aureus (MRSA) is also reported., Patients and Methods: The vascular audit database and patient case notes were reviewed retrospectively for patients with arterial occlusive disease requiring infragenicular reconstruction. There were 68 critically ischaemic legs in 65 patients of whom 48 were male: median age (range) 74 years (41-94), over a three year period., Results: Thirty six patients (53%) underwent revascularisation (eight infragenicular femoropopliteal bypass, 28 femorodistal), 24 (35%) underwent primary amputation and a further eight (12%) were found to have unsuitable distal vessels for revascularisation after tibial vessel exploration and intraoperative angiography. Thirty three grafts (92%) utilised LSV and three (8%) were polytetrafluoroethylene grafts. Thirteen patients (39%) lacked adequate ipsilateral LSV of whom 12 had the contralateral leg explored providing suitable LSV in 10/12 (83%). Contralateral LSV was used as a single length conduit in two cases and as a venovenous composite graft in eight cases. Primary, primary assisted, and secondary patency rates at two years were 38%, 77%, and 81% respectively. Actuarial limb survival and patient survival rates at two years were 86% and 61% respectively. Eleven patients developed ipsilateral wound complications (30%) including seven (21%) who developed MRSA infection of the ipsilateral leg wound. MRSA wound infection was treated successfully in all cases by antibiotic therapy (intravenous vancomycin). No patient subsequently required saphenous vein harvesting for a secondary reconstruction or coronary artery bypass graft., Conclusion: Excellent long term results can be achieved using autogenous vein for infragenicular revascularisation and the contralateral LSV is an excellent alternative in the absence of suitable ipsilateral LSV. Autogenous vein may confer some protection against severe complications observed with MRSA infection seen in vascular patients and therefore its use is recommended.

Objectives: diabetes mellitus is an increasingly common cause of end stage renal failure (ESRF) and the establishment of adequate permanent vascular access for dialysis is a major cause of morbidity and mortality in these patients. The aim of this study was to compare the availability of suitable vein, maturation rates, patency and complication rates of autogeneous elbow fistulas in diabetics and non-diabetics at a single centre where an autogeneous vein only policy is employed., Design: retrospective series., Patients and Methods: two hundred and ninety-three elbow fistulas were attempted in 232 patients over a seven year period, [median age 60 years (range 14-94 years)], of which 210 were in non-diabetic and 83 were in diabetic patients. The diabetic group had a significantly higher proportion of male patients (p < 0.05), peripheral vascular disease and established ESRF., Results: there was a trend towards a higher technical success rate in the non-diabetic group (98% versus 93% p = 0.057). There was no significant difference between the primary failure rate, fistula maturation rate, revision rate or incidence of complications between the two groups. Diabetes had no effect on cumulative secondary fistula patency even when stratified for Type 1/Type 2 diabetes, female sex, old age or primary versus subsequent procedures., Conclusion: diabetes mellitus has no significant detrimental effect on outcome following formation of autogeneous elbow fistulas for haemodialysis., (Copyright 2002 Elsevier Science Ltd.)

Aims: intimal hyperplasia is mediated by smooth muscle cell proliferation, migration and deposition of extracellular matrix. The anti-fibrotic agent pirfenidone has been shown to inhibit pro-fibrotic growth factors in non-vascular inflammatory models. This study investigated the effect of the novel anti-fibrotic agent pirfenidone on the development of neointima., Methods: male Sprague-Dawley rats received either standard diet or diet supplemented with pirfenidone (250, 500, 1000 mg/kg/day). Animals underwent left common carotid balloon angioplasty and were explanted at 4, 8, 14 and 28 days and analysed for intimal thickening, pro-fibrotic gene expression, extracellular matrix deposition and metalloproteinase activity., Results: neointimal thickness was significantly reduced in a dose-dependent manner at 14 days; pirfenidone 250 mg/kg (p<0.005), pirfenidone 500 mg/kg (p<0.001), pirfenidone 1 g/kg ( p<0.001). There were no significant differences in intimal thickening at 28 days. Expression of MMP-2, MMP-9, TIMP-1, collagen III and TGF-beta were all significantly inhibited at 14 days. Both collagen III expression and ECM deposition were reduced at 28 days ( p<0.05 and <0.002 respectively)., Conclusion: pirfenidone reduces expression of MMPs governing smooth muscle cell proliferation and migration (MMP-2 and 9), and genes favouring ECM accumulation (TIMP-1 and collagen III). This study shows that inhibition of MMP activity is not sufficient to inhibit late lesion size., (Copyright 2002 Harcourt Publishers Limited.)

GSH-dependent prostaglandin D(2) synthase (PGDS) enzymes represent the only vertebrate members of class Sigma glutathione S-transferases (GSTs) identified to date. Complementary DNA clones encoding the orthologous human and rat GSH-dependent PGDS (hPGDS and rPGDS, respectively) have been expressed in Escherichia coli, and the recombinant proteins isolated by affinity chromatography. The purified enzymes were both shown to catalyse specifically the isomerization of prostaglandin (PG) H(2) to PGD(2). Each transferase also exhibited GSH-conjugating and GSH-peroxidase activities. The ability of hPGDS to catalyse the conjugation of aryl halides and isothiocyanates with GSH was found to be less than that of the rat enzyme. Whilst there is no difference between the enzymes with respect to their K(m) values for 1-chloro-2,4-dinitrobenzene, marked differences were found to exist with respect to their K(m) for GSH (8 mM versus 0.3 mM for hPGDS and rPGDS, respectively). Using molecular modelling techniques, amino acid substitutions have been identified in the N-terminal domain of these enzymes that lie outside the proposed GSH-binding site, which may explain these catalytic differences. The tissue-specific expression of PGDS also varies significantly between human and rat; amongst the tissues examined, variation in expression between the two species was most apparent in spleen and bone marrow. Differences in catalytic properties and tissue-specific expression of hPGDS and rPGDS appears to reflect distinct physiological roles for class Sigma GST between species. The evolution of divergent functions for the hPGDS and rPGDS is discussed in the context of the orthologous enzyme from chicken.

NMDA receptors (NMDARs) typically contribute to excitatory synaptic transmission in the CNS. While Ca(2+) influx through NMDARs plays a critical role in synaptic plasticity, direct actions of NMDAR-mediated Ca(2+) influx on neuronal excitability have not been well established. Here we show that Ca(2+) influx through NMDARs is directly coupled to activation of BK-type Ca(2+)-activated K+ channels in outside-out membrane patches from rat olfactory bulb granule cells. Repetitive stimulation of glutamatergic synapses in olfactory bulb slices evokes a slow inhibitory postsynaptic current (IPSC) in granule cells that requires both NMDARs and BK channels. The slow IPSC is enhanced by glutamate uptake blockers, suggesting that extrasynaptic NMDARs underlie the response. These findings reveal a novel inhibitory action of extrasynaptic NMDARs in the brain.

Insulin resistance is of major pathogenic importance in several common human disorders, but the underlying mechanisms are unknown. The stroke-prone spontaneously hypertensive (SHRSP) rat is a model of human insulin resistance and is characterized by reduced insulin-mediated glucose disposal and defective fatty acid metabolism in isolated adipocytes (Collison et al. [Diabetes 49:2222-2226, 2000]). In this study, we have examined skeletal muscle and cultured skeletal muscle myoblasts for defects in insulin action in the male SHRSP rat model compared with the normotensive, insulin-sensitive control strain, Wistar-Kyoto (WKY). We show that skeletal muscle from SHRSP animals exhibits a marked decrease in insulin-stimulated glucose transport compared with WKY animals (fold increase in response to insulin: 1.4 +/- 0.15 in SHRSP, 2.29 +/- 0.22 in WKY; n = 4, P = 0.02), but the stimulation of glucose transport in response to activation of AMP-activated protein kinase was similar between the two strains. Similar reductions in insulin-stimulated glucose transport were also evident in myoblast cultures from SHRSP compared with WKY cultures. These differences were not accounted for by a reduction in cellular GLUT4 content. Moreover, analysis of the levels and subcellular distribution of insulin receptor substrates 1 and 2, the p85alpha subunit of phosphatidylinositol 3'-kinase, and protein kinase B (PKB)/cAKT in skeletal muscle did not identify any differences between the two strains; the insulin-dependent activation of PKB/cAKT was not different between the two strains. However, the total cellular levels of caveolin and flotillin, proteins implicated in insulin signal transduction/compartmentalization, were markedly elevated in skeletal muscles from SHRSP compared with WKY animals. Increased cellular levels of the soluble N-ethylmaleimide attachment protein receptor (SNARE) proteins syntaxin 4 and vesicle-associated membrane protein (VAMP)-2 were also observed in the insulin-resistant SHRSP strain. Taken together, these data suggest that the insulin resistance observed in the SHRSP is manifest at the level of skeletal muscle, that muscle cell glucose transport exhibits a blunted response to insulin but unchanged responses to activation of AMP-activated protein kinase, that alterations in key molecules in both GLUT4 trafficking and insulin signal compartmentalization may underlie these defects in insulin action, and that the insulin resistance of these muscles appears to be of genetic origin rather than a paracrine or autocrine effect, since the insulin resistance is also observed in cultured myoblasts over several passages.

Introduction: The decline in heart-beating brainstem dead organ donors has necessitated the search for other organ sources. In the field of renal transplantation one alternative source currently available, but little used, is that of kidneys from non-heart-beating donors (NHBD). Reticence to use NHBD kidneys is in part due to concerns over the effect that warm ischemic may have subsequent graft function. Presented here are the results of the NHBD renal transplants at the Leicester transplant unit, and compared with matched heart-beating donor transplants as a case control analysis., Methods: In order to analyze any differences in graft performance between the two organ sources, the confounding effect of other variables known to influence the outcome of renal transplantation was minimized by matching NHBD and HBD transplants for the following criteria: donor age and sex, first or re-transplant, anastomosis and cold times, tissue match and PRA sensitisation. Transplant performance was assessed primarily by graft survival, the statistical evaluation of which was by log rank analysis of Kaplan-Meier curves., Results: 72 NHBD and 192 HBD transplants were performed over an eight year period. Of the 192 HBD transplants, 105 matched one or more of the NHBD by the criteria outlined above, and thus constituted the control group for comparison. There was no significant difference in overall graft survival between the two groups. The 5 year survival for the NHBD was 73% compared with 65% for HBD kidneys. When death with a functioning graft is treated as censored data, then these figures become 75% and 81% respectively, again without statistical significance., Conclusion: NHBD kidneys are a valuable additional source of organs for transplantation, with long-term survival, comparable to transplants from HBD.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) infection is emerging as a major problem in vascular surgical practice. The aim of this study was to review the management of patients with MRSA infection complicating vascular surgical operations., Methods: Data were obtained from the vascular audit, case notes, intensive therapy unit (ITU) notes, high dependency unit (HDU) notes and microbiological records of patients who underwent either arterial reconstruction (n = 464) or limb amputation (n = 110) between April 1994 and October 1998., Results: Forty-nine vascular surgical patients developed clinical MRSA infection (9%). Clinical MRSA infection in patients who had undergone aorto-iliac reconstruction (n = 18) was associated with a 56% mortality (n = 10) and the most common infections were bacteraemia (55%) and pneumonia (50%). MRSA infection occurred in 17 patients who had undergone infra-inguinal bypass and was associated with a 29% mortality (n = 5). The most common site of MRSA infection was the groin wound (76%) leading to anastomotic dehiscence and death in one patient (11%) and necessitating wound debridement in 4 patients (22%). MRSA infection of the groin wound in the presence of a prosthetic graft (n = 3) led to anastomotic dehiscence in 2 patients, and graft excision in 2 patients. Similar complications were not observed in the presence of an underlying autogeneous long saphenous vein graft (n = 16). MRSA infection following major lower limb amputation (n = 14) was associated with death in 5 patients (36%). Wound infection in 10 amputees (71%) led to revision of the amputation to a higher level in 2 (14%) and wound debridement in 2 (14%)., Conclusions: MRSA infection has a high mortality in vascular surgical patients in general, and following aorto-iliac reconstruction in particular. Autogeneous vein may confer some protection against local complications following groin wound infection. Strategies aimed at reducing the incidence of infection, including strict adherence to infection control procedures, may reduce the severity of this problem.

Image stability during self motion depends on the combined actions of the vestibuloocular and optokinetic reflexes (VOR and OKR, respectively). Neurons in the medial vestibular nucleus (MVN) participate in the VOR and OKR by firing in response to both head and image motion. Their intrinsic spike-generating properties enable MVN neurons to modulate firing rates linearly over a broad range of input amplitudes and frequencies such as those that occur during natural head and image motion. This study examines the postnatal development of the intrinsic spike-generating properties of rat MVN neurons with respect to maturation of peripheral vestibular and visual function. Spike generation was studied in a brain stem slice preparation by recording firing responses to current injected intracellularly through whole cell patch electrodes. MVN neurons fired spontaneously and modulated their firing rate in response to injected current at all postnatal ages. However, the input-output properties of the spike generator changed dramatically during the first two postnatal weeks. Neurons younger than postnatal day 10 could not fire faster than 80 spikes/s, modulated their firing rates over a limited range of input amplitudes, and tended to exhibit a nonlinear relationship between input current and mean evoked firing rate. In response to sustained depolarization, firing rates declined significantly in young neurons. Response gains tended to be highest in the first few postnatal days but varied widely across neurons and were not correlated with age. By about the beginning of the third postnatal week, MVN neurons could fire faster than 100 spikes/s in response to a broad range of input amplitudes, exhibited predominantly linear current-firing rate relationships, and adapted little in response to sustained depolarization. Concomitant decreases in action potential width and the time course of the afterhyperpolarization suggest that changes in potassium currents contribute to the maturation of the MVN neuronal spike generator. The results demonstrate that developmental changes in intrinsic membrane properties enable MVN neurons to fire linearly in response to a broad range of stimuli in time for the onset of visual function at the beginning of the third postnatal week.

Mpl is the thrombopoietin (TPO) receptor. The current molecular understanding of how Mpl activation stimulates proliferation of megakaryocyte-lineage cells is based largely on the engineered expression of Mpl in nonmegakaryocyte-lineage cell lines. However, the relevance of these findings to Mpl signaling in primary megakaryocyte-lineage cells remains largely unknown. Therefore, a system was developed to study Mpl function in primary mpl(-/-) megakaryocyte-lineage cells. Expressing avian retroviral receptors on the surfaces of mammalian cells overcomes their natural block to avian retroviral infection; 815 bp of human GPIIb regulatory sequence was used to generate transgenic mice with megakaryocyte-lineage expression of the subgroup A avian leukosis virus receptor, TVA. Avian retroviral infection of unfractionated bone marrow from these mice is restricted to megakaryocyte-lineage cells. The transgenic mice were crossed to an mpl(-/-) background generating GPIIb-tva+mpl(-/-) mice. By using avian retroviruses to express wild-type or mutant Mpl on the surfaces of primary megakaryocyte-lineage cells, it was demonstrated that (1) the 10 membrane-proximal, cytoplasmic amino acids of Mpl are required for TPO-induced proliferation; (2) Y582F mutation confers a proliferative advantage over wild-type Mpl and imparts a constitutive anti-apoptotic signal; (3) truncating the 50 C-terminal Mpl amino acids reduces but does not eliminate TPO-induced mitogen-activated protein kinase activation, yet it does not alter the synergistic effect of stem cell factor on TPO-induced proliferation; and (4) TPO-induced proliferation of early, primary megakaryocyte-lineage cells does not require Stat-5 phosphorylation. The system reported provides an improved approach for Mpl structure-function studies, and the method can be applied to any hematopoietic lineage.

Background: Primary thrombosis and chronic allograft nephropathy are important causes of early and late graft loss, respectively, following renal transplantation. This study examined the potential for aspirin therapy to reduce these complications., Methods: A consecutive series of 105 cadaveric renal transplants treated with aspirin 150 mg daily for the first 3 months after transplantation was compared with an untreated historical control group (n = 121). Protocol needle-core biopsies were performed on all transplants in both groups at 1 week and 12 months after transplantation. Needle-core allograft biopsies were performed at 3, 6 and 12 months after transplantation, and serum creatinine was measured at each outpatient attendance for the duration of follow-up., Results: There was a significantly lower rate of primary allograft thrombosis in patients treated with aspirin (none of 105) compared with that in the control group (six (5 per cent) of 121; P = 0.03). There were no differences in renal function or 2-year allograft survival between the two groups. Aspirin-treated patients had a lower incidence of chronic allograft nephropathy at 1 year than controls although this did not reach statistical significance (16 versus 26 per cent; P = 0.075). There were no major bleeding complications in either group in association with peptic ulcer disease or following renal transplant biopsy., Conclusion: Aspirin reduced the rate of early graft thrombosis of renal transplants in this series but did not improve renal function or graft survival. A trend towards a lower rate of chronic allograft nephropathy was noted with aspirin treatment. These findings require confirmation in a prospective randomized trial.

The recent development of a novel class of insulin-sensitizing drugs, the thiazolidinediones (TZDs), represents a significant advance in antidiabetic therapy. One key mechanism by which these drugs exert their effects is by activation of the peroxisome proliferator activated receptor gamma (PPAR-gamma), a member of the nuclear receptor family. Evidence supporting this mechanism of action of the TZDs will be reviewed in this article. Recent data suggests that PPAR-gamma agonists might also have therapeutic potential in the treatment of inflammatory diseases and certain cancers.

Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3., Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase., Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

Background: The recent expansion of renal replacement therapy programmes has been associated with an increase in the number and complexity of patients requiring permanent vascular access. The introduction of strategies designed to maximize secondary access patency is, therefore, increasingly important as a means of prolonging patient survival on dialysis, reducing morbidity and reducing the escalating cost of such programmes., Methods: A review of the current literature on the planning of vascular access, access surveillance methods and treatment of the most common complications was performed., Results: Multidisciplinary vascular access planning, increased use of preoperative imaging and the preferential use of autogeneous vein are essential to obtain the best long-term results. While vascular access surveillance, in particular protocols involving direct measurement of access flow, enables the prospective detection and treatment of venous stenosis, the precise indications for treating venous stenosis remain unclear. Surgical revision remains the gold standard for the treatment of failing arteriovenous fistulas, but recent advances in interventional radiological techniques along with the suitability of arteriovenous fistulas for percutaneous intervention may offer an effective alternative. The effect of both these interventions on access patency requires comparison in a randomized trial., Conclusion: The introduction of strategies to improve access patency rates will change vascular access surgical practice away from the construction of new fistulas towards an increase in outpatient percutaneous intervention and surgical revisional procedures. The role of surgical interventions requires clearer definition.

Background: The ethical and medical implications of live kidney donation result in a comprehensive work-up process. The aim of this study was to determine the magnitude of the workload and the yield of renal transplants generated by a live donor programme., Methods: Referrals to the Leicester live donor programme over the five-year period 1994-1998 were retrospectively assessed. These were initiated by nephrology referral and subsequently investigated in a stepwise manner. Patients were counselled and baseline tests performed prior to consultant surgeon review and assessment of donor renal function/anatomy., Results: One hundred and fifty referrals consisting of 150 recipients with 269 potential donors were originally made. This resulted in 32/120 (27%) related and 3/30 (10%) unrelated recipients (P=0.06) and 32/220 (15%) related and 3/49 (6%) unrelated donors proceeding to live donor transplantation, with a mean work-up time (+/-SD) of 9 (+/-7) months. One hundred and fifteen recipients (77%) and 234 (87%) donors failed to proceed at various stages of assessment, for a variety of immunological, medical and social reasons. A large number of expensive immunological investigations were required for potential donors, the majority of which did not proceed to transplantation. However as a result of performing these in the early stages of assessment the number of more invasive tests is kept to a minimum., Conclusions: There is a relatively low yield of transplants from live donor referrals, particularly those between unrelated individuals. The vast majority of referrals fail to proceed for legitimate reasons, but as a result, create a significant workload with notable staffing and financial implications.

Background: The transposed autologous basilic vein to brachial artery arteriovenous fistula provides vascular access in the absence of adequate superficial vein. The long-term patency and complication rates of this conduit are largely unreported., Patients and Methods: Seventy-four brachiobasilic fistulas were performed in 65 patients. This was a secondary or tertiary access procedure in 84 per cent of patients., Results: Of the 74 fistulas performed, 50 were successfully used for dialysis (68 per cent) and 24 (32 per cent) were never used, including 13 fistulas that failed without being used for dialysis. Of the 74 fistulas, 46 per cent failed (n = 34), 10 patients died with a functioning fistula (n = 10) and five were transplanted. The 30-day secondary patency was 73 per cent at 1 year, 53 per cent at 2 years and 43 per cent at 3 years rate was 96 per cent. Cumulative secondary patency was 73 per cent at 1 year, 53 per cent at 2 years and 43 per cent at 3 years. Nineteen (26 per cent) fistulas underwent a further 19 operative procedures. Fifty-one (69 per cent) fistulas developed complications. The most common complications were arm oedema (24 per cent), thrombosis (22 per cent) and bleeding (18 per cent)., Conclusion: In high-risk patients the autologous transposed brachiobasilic fistula has equivalent patency and lower complication rates than those reported for polytetrafluoroethylene interposition grafts.

Insulin stimulation of adipose and muscle cells results in the translocation of GLUT4 from an intracellular location to the plasma membrane; this translocation is defective in insulin resistance. Studies have suggested an important role for synaptobrevin and syntaxin homologues in this event, particularly the v-soluble N-ethylmaleimide attachment protein receptors (SNAREs) cellubrevin and vesicle-associated membrane protein-2 (VAMP-2) and the t-SNARE syntaxin 4, but the expression of these proteins has not been studied in insulin-resistant tissues. Therefore, we examined SNARE protein content in skeletal muscle from Zucker diabetic fatty (ZDF) rats compared with lean controls and determined the effect of the thiazolidinedione insulin sensitizer rosiglitazone on these proteins. GLUT4 levels in skeletal muscle from ZDF rats were similar to those in lean control animals. In contrast, cellubrevin, VAMP-2, and syntaxin 4 protein levels were elevated (2.8-fold, P = 0.02; 3.7-fold, P = 0.01; and 2.2-fold, P < 0.05, respectively) in skeletal muscle from ZDF rats compared with lean controls. Restoration of normoglycemia and normoinsulinemia in ZDF rats with rosiglitazone (30 micromol/kg) normalized cellubrevin, VAMP-2, and syntaxin 4 protein to levels approaching those observed in lean control animals. These data show that elevated v- and t-SNARE protein levels are associated with insulin resistance in skeletal muscle and that these increases may be reversed by rosiglitazone treatment concomitant with a restoration of glycemic control. Such increases in SNARE protein levels were not observed in streptozotocin-induced diabetic rats, which suggests that hyperinsulinemia rather than hyperglycemia may be more important in modulating SNARE protein expression in rodent models of insulin resistance. Consistent with this hypothesis, elevated levels of SNARE proteins were also observed in 3T3-L1 adipocytes chronically treated with insulin (500 nmol/l for 24 h). These data argue that SNARE protein levels may be altered in insulin-resistant states and that the levels of these proteins are modulated by agents that increase insulin sensitivity. Moreover, these data demonstrate for the first time altered expression of proteins known to regulate GLUT4 translocation in a model of diabetes.

Objective: To develop a monoclonal antibody that recognises an epitope of the native beta3-adrenoceptor expressed on the extracellular surface of human cells and tissues., Design: A high affinity monoclonal antibody, Mab72c, was raised against the human beta3-adrenoceptor expressed on a transfected mammalian cell line., Results: In CHO (Chinese hamster ovary) cells transfected with beta3-adrenoceptor cDNA, antibody labelling was found to be proportional to receptor density measured by the binding of the radiolabelled beta-adrenoceptor antagonist, [125I]-iodocyanopindolol. The use of Mab 72c has demonstrated the expression of the beta3-adrenoceptor in a variety of human tissues, including gall bladder, prostate and colon, where a mRNA signal had been detected previously. This study also provides the first direct demonstration of the expression of beta3-adrenoceptors in human skeletal muscle, atrium and adipose tissue., Conclusion: The development of this antibody represents an important addition to the armentarium of reagents that are available to study the localisation of beta3-adrenoceptors in human tissues.