System Xc- Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine.

The cystine/glutamate antiporter system Xc- (SXc-) mediates the exchange of intracellular L-glutamate (L-Glu) with extracellular L-cystine (L-Cys2). Both the import of L-Cys2 and the export of L-Glu take on added significance in CNS cells, especially astrocytes. When the relative activity of SXc- overwhelms the regulatory capacity of the EAATs, the efflux of L-Glu through the antiporter can be significant enough to trigger excitotoxic pathology, as is thought to occur in glioblastoma. This has prompted considerable interest in the pharmacological specificity of SXc- and the development of inhibitors. The present study explores a series of analogues that are structurally related to sulfasalazine, a widely employed inhibitor of SXc-. We identify a number of novel aryl-substituted amino-naphthylsulfonate analogues that inhibit SXc- more potently than sulfasalazine. Interestingly, the inhibitors switch from a competitive to noncompetitive mechanism with increased length and lipophilic substitutions, a structure-activity relationship that was previously observed with aryl-substituted isoxazole. These results suggest that the two classes of inhibitors may interact with some of the same domains on the antiporter protein and that the substrate and inhibitor binding sites may be in close proximity to one another. Molecular modeling is used to explore this possibility.

Dual temperature multi-organ recovery from a Maastricht category III donor after circulatory death.

Donation after circulatory death (DCD) makes a significant contribution to the transplant activity but is associated with significantly lower organ recovery rates and poorer function for the abdominal extra-renal organs compared with donation after brain death. Traditionally, DCD organ recovery involves cold thoracic and abdominal perfusion with a rapid removal of organs in order to minimize the ischemic damage. Novel approaches to organ recovery and preservation include the use of normothermic regional perfusion in the donor and ex vivo organ preservation. We report a new technique for multi-organ recovery from Maastricht category III donors with abdominal normothermic perfusion and concomitant cold lung flushing which allows a rapid removal of the lungs with preservation of the abdominal normothermic circulation throughout the thoracic procurement. This approach could lead to an increased organ recovery and better function for the abdominal organs.

Lymph node status as a prognostic indicator after preoperative neoadjuvant chemoradiotherapy of rectal cancer.

AIM: The primary aim of this study was to examine lymph node status after neoadjuvant chemoradiotherapy (CRT) using a novel scoring system describing the pathological lymph node regression grade. The proposed scoring system was based on the percentage of fibrosis and the presence of residual tumour amount. The secondary aim of the study was to assess the oncological impact of this scoring system. METHOD: The project was a retrospective cohort study over a 10-year period. Two hundred and two patients with rectal cancer who had received CRT followed by curative surgery were included. A histopathologist prospectively scored each specimen and the impact of the scoring system on survival and recurrence was analysed. RESULTS: One hundred and ninety patients completed long-course preoperative CRT and formed the basis of the study. Overall, 40 recurrences (local and distant) were observed over a median follow-up of 36 months. The lymph node regression score was a significant predictor of tumour recurrence (hazard ratio 1.273, 95% CI 1.048-1.548; P = 0.015). The overall mortality rate was 21%, and a lower lymph node regression score was correlated with an improved survival curve (P = 0.01). CONCLUSION: The results demonstrate that lymph node response to neoadjuvant CRT based on a nodal regression scoring system is related to recurrence.

Simultaneous liver resection and double cardiac valve replacement. A case report.

INTRODUCTION: We present a rare case in which both a double cardiac valve replacement was performed as well as a hepatic resection. PRESENTATION OF CASE: We report the case of a 36 year old patient who presented with intra abdominal bleeding thought to have been caused by a liver haemangioma she also had severe autoimmune cardiac valve disease. She underwent a simultaneous right hepatectomy with cardiac valve replacement. DISCUSSION: Management of this challenging case is discussed. CONCLUSION: We advocate the possibility of performing combined operations where both valve replacement and hepatic resection is required.

Factors predicting stomal wound closure infection rates.

BACKGROUND: Stoma closure is associated with high wound infection rates. The aim of this study was to evaluate risk factors for infection rates in such wounds, with particular emphasis on assessing the importance of the stomal wound closure technique. METHODS: A retrospective analysis of 142 patients who had undergone ileostomy or colostomy closure between 2002 and 2011 was performed. Postoperative outcome as measured by wound infection rate was recorded. Three different closure techniques were identified: primary closure (PC), primary closure with penrose drain (PCP) and purse-string circumferential wound approximation technique (PSC). Other factors such as age, sex, ASA score, type of prophylactic antibiotics used, diabetes, smoking and obesity were also analysed. All other techniques were excluded. RESULTS: Our series consisted of 142 stomal closures (90 ileostomy and 52 colostomy closures). The patients had a median age of 63.5 years with an interquartile range of 50.1-73.2 years. The overall wound infection rate was 10.7%. PC, PCP and PSC were associated with wound infection rates of 17.9, 10.5 and 3.6%, respectively. Compared to PSC, PC and PCP were associated with significantly higher wound infection rates (p = 0.027 and p = 0.068, respectively). Obesity was a significant risk factor for wound infection (p = 0.024). Use of triple-agent antibiotics prophylactically had a protective effect on the infection rate (p = 0.012). CONCLUSIONS: To reduce stomal wound closure infection rates, we recommend institution of closure techniques other than PC with or without a drain. Risk factors such as obesity should be addressed, and prophylactic triple antibiotics should be administered.

Anti-reflux surgery in lung transplant recipients: outcomes and effects on quality of life.

Fundoplication may improve survival after lung transplantation. Little is known about the effects of fundoplication on quality of life in these patients. The aim of this study was to assess the safety of fundoplication in lung transplant recipients and its effects on quality of life. Between June 1, 2008 and December 31, 2010, a prospective study of lung transplant recipients undergoing fundoplication was undertaken. Quality of life was assessed before and after surgery. Body mass index (BMI) and pulmonary function were followed up. 16 patients, mean ± sd age 38 ± 11.9 yrs, underwent laparoscopic Nissen fundoplication. There was no peri-operative mortality or major complications. Mean ± SD hospital stay was 2.6 ± 0.9 days. 15 out of 16 patients were satisfied with the results of surgery post fundoplication. There was a significant improvement in reflux symptom index and DeMeester questionnaires and gastrointestinal quality of life index scores at 6 months. Mean BMI decreased significantly after fundoplication (p = 0.01). Patients operated on for deteriorating lung function had a statistically significant decrease in the rate of lung function decline after fundoplication (p = 0.008). Laparoscopic fundoplication is safe in selected lung transplant recipients. Patient benefit is suggested by improved symptoms and satisfaction. This procedure is acceptable, improves quality of life and may reduce deterioration of lung function.

Organ transplantation: historical perspective and current practice.

Over the course of the last century, organ transplantation has overcome major technical limitations to become the success it is today. The breakthroughs include developing techniques for vascular anastomoses, managing the immune response (initially by avoiding it with the use of identical twins and subsequently controlling it with chemical immunosuppressants), and devising preservation solutions that enable prolonged periods of ex vivo storage while preserving function. One challenge that has remained from the outset is to overcome the shortage of suitable donor organs. The results of organ transplantation continue to improve, both as a consequence of the above innovations and the improvements in peri- and postoperative management. This review describes some of the achievements and challenges of organ transplantation.

Cardiac transplantation in adults with congenital heart disease.

BACKGROUND: Due to increasing success with repair or palliation in childhood, there is a rapidly growing population of adult patients with complex congenital heart disease who may require transplantation. There remains little data on outcomes of cardiac transplantation in this group. METHODS: 38 orthotopic cardiac transplants were performed in 37 patients (18 men) > or =18 years of age with congenital heart disease (CHD) from 1988 to 2009 in our institution. Outcomes were reviewed using medical records and transplant databases. RESULTS: 15 patients (41%) had univentricular and 22 (59%) biventricular physiology. The biggest group was transposition of the great arteries following atrial switch in eight patients (22%). Six (16%) had no previous surgical intervention. Mean age at transplant was 33.5 years (range 19.1-59.9 years). 11 patients (30%) required additional surgical procedures at transplant. 16 (43%) died, 12 early and 4 late deaths (1.8, 2.4, 2.7 and 7 years). Survival was 70% at 30 days, 68% at 1 year, 58% at 5 years and 53% at 10 and 15 years. Outcome improved in later eras with reduction in 30-day mortality from 50% to 18% and increase in 5-year survival from 50% to 69%. Two patients developed post-transplant lymphoproliferative disease. None required long-term renal replacement therapy. One patient was re-transplanted for cardiac allograft vasculopathy. CONCLUSIONS: While operative mortality following cardiac transplantation for adult congenital heart disease is higher than for other diagnostic groups, long-term survival is good and comparable to patients without CHD. Disappointing early results are improved with increasing experience.

Targeting allograft injury and inflammation in the management of post-lung transplant bronchiolitis obliterans syndrome.

Chronic allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is the major cause of morbidity and mortality in human lung transplant recipients. While alloimmunity has a definite role, there is increasing interest in overall allograft injury and subsequent inflammation and remodeling. This review deals with nonalloimmune factors that may potentiate alloimmune injury. We discuss infection and reflux/aspiration as examples of allograft injury, which may lead to chronic loss of graft function and BOS. Surgical and nonsurgical treatments aimed at preventing these insults and improving survival are considered. The need for further evidence, including randomized-controlled trials, to evaluate the role of medical and surgical therapies is emphasized by the current literature.

Circulating endothelial progenitor cell numbers are not associated with donor organ age or allograft vasculopathy in cardiac transplant recipients.

INTRODUCTION: Increasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages. METHODS: We identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR). RESULTS: There were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers. CONCLUSIONS: We suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.

Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation.

In the present study, 4 patients with cystic fibrosis undergoing lung transplantation (from a total of 137) who developed fulminant pseudomembranous colitis are described. Initial presentation was variable and the mortality rate was 50% despite urgent colectomy. In one case the presenting abdominal distension was thought to be due to meconium ileus equivalent. It is concluded that Clostridium difficile colitis may be a difficult diagnosis in patients with cystic fibrosis and follows a fulminant course after lung transplantation.

Mitral valve dysfunction and repair following orthotopic heart transplantation: a case report.

Mitral valve dysfunction after orthotopic heart transplantation may cause symptoms refractory to medical therapy. In this report, we present a patient who underwent mitral annuloplasty for severe symptomatic mitral valve insufficiency 9 years after heart transplantation, and we critically appraise the literature available for mitral valve dysfunction in this setting. Mitral valve repair, when feasible, should be considered for mitral insufficiency after transplantation to improve functional status and reduce the risk of retransplantation--this is particularly prudent in view of chronic donor shortage.

Outcomes of lung transplantation for cystic fibrosis in a large UK cohort.

BACKGROUND: Lung transplantation is an important option to treat patients with advanced cystic fibrosis (CF) lung disease. The outcomes of a large UK cohort of CF lung transplantation recipients is reported. METHODS: Retrospective review of case notes and transplantation databases. RESULTS: 176 patients with CF underwent lung transplantation at our centre. The majority (168) had bilateral sequential lung transplantation. Median age at transplantation was 26 years. Diabetes was common pretransplantation (40%). Polymicrobial infection was common in individual recipients. A diverse range of pathogens were encountered, including the Burkholderia cepacia complex (BCC). The bronchial anastomotic complication rate was 2%. Pulmonary function (forced expiratory volume in 1 s % predicted) improved from a pretransplantation median of 0.8 l (21% predicted) to 2.95 l (78% predicted) at 1 year following transplantation. We noted an acute rejection rate of 41% within the first month. Our survival values were 82% survival at 1 year, 70% at 3 years, 62% at 5 years and 51% at 10 years. Patients with BCC infection had poorer outcomes and represented the majority of those who had a septic death. Data are presented on those free from these infections. Bronchiolitis obliterans syndrome (BOS) and sepsis were common causes of death. Freedom from BOS was 74% at 5 years and 38% at 10 years. Biochemical evidence of renal dysfunction was common although renal replacement was infrequently required (<5%). CONCLUSION: Lung transplantation is an important therapeutic option in patients with CF even in those with more complex microbiology. Good functional outcomes are noted although transplantation associated morbidities accrue with time.

Smoking after cardiac transplantation.

Although smoking cessation is a prerequisite prior to listing for cardiac transplantation, some patients return to smoking after recovery. We have covertly assessed the smoking habits of our cardiac transplant recipients (with ethical approval) since 1993 by measuring urinary cotinine: a level of >500 ng/mL signifying continued tobacco use. We retrospectively analyzed survival, causes of death and the development of graft coronary artery disease (GCAD) with respect to the number of positive and negative cotinine levels. One hundred four of 380 (27.4%) patients tested positive for active smoking at some point posttransplant, and 57 (15.0%) tested positive repeatedly. Smokers suffered significantly more deaths due to GCAD (21.2% vs. 12.3%, p < 0.05), and due to malignancy (16.3% vs. 5.8%, p < 0.001). In univariate analysis, smoking after heart transplantation shortened median survival from 16.28 years to 11.89 years. After correcting for the effects of pretransplant smoking in time-dependent multivariate analysis, posttransplant smoking remained the most significant determinant of overall mortality (p < 0.00001). We conclude that tobacco smoking after cardiac transplantation significantly impacts survival by accelerating the development of graft vasculopathy and malignancy. We hope that this information will deter cardiac transplant recipients from relapsing, and intensify efforts in improving cessation rates.

Early hemodynamic injury during donor brain death determines the severity of primary graft dysfunction after lung transplantation.

Sympathetic discharge and hypertensive crisis often accompany brain death, causing neurogenic pulmonary edema. Progressive systemic inflammatory response develops, which can injure the lung further. We investigated whether (a) early hemodynamic injury during donor brain death increases reperfusion injury after lung transplantation and (b) delaying lung recovery would augment reperfusion injury further, because of the progressive systemic inflammatory response in the donor. Brain death was induced by intracranial balloon inflation in rats, with or without alpha-adrenergic blockade pretreatment to prevent the hypertensive crisis. Another group of rats had a sham procedure. Lungs were retrieved 15 min after brain death or sham procedure and reperfused using recipient rats. In a fourth group, brain death was induced and the lungs were retrieved 5 h after brain death and reperfused. Postreperfusion, lungs retrieved early from untreated brain-dead donors developed more severe reperfusion injury, as assessed by functional parameters and inflammatory markers, than those from sham or alpha-blockade-treated donors. Lungs retrieved late from brain-dead donors had similar inflammatory markers after reperfusion to those retrieved early, but significantly lower pulmonary vascular resistance. Early hemodynamic damage during donor brain death increases reperfusion injury after lung transplantation. Delaying retrieval may allow the lung to recover from the hemodynamic injury.

Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation.

Pseudomembranous colitis is an uncommon complication in patients with cystic fibrosis, despite the use of multiple high-dose antibiotic regimens and the frequency of hospital admissions. Four patients from a total of 137 patients with cystic fibrosis undergoing lung transplantation are described who developed fulminant pseudomembranous colitis. Initial presentation was variable and the mortality rate was 50% despite urgent colectomy. In one case the presenting abdominal distension was thought to be due to meconium ileus equivalent. It is concluded that Clostridium difficile colitis may be a difficult diagnosis in patients with cystic fibrosis and follows a fulminant course after lung transplantation.

Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts.

BACKGROUND: A biologically plausible link between gastro-oesophageal reflux (GOR), aspiration, and lung allograft dysfunction has been suggested, but there is no systematic evidence indicating the presence of gastric contents in the lung. We have tested the hypothesis that pepsin, as a marker of aspiration, is detectable in bronchoalveolar lavage (BAL) fluid of allograft recipients who had not reported symptoms of GOR. METHODS: Standardised 3 x 60 ml surveillance BAL fluid samples from 13 chronologically sequential stable lung allograft recipients without chronic rejection (10 patients treated with a prophylactic proton pump inhibitor) were studied. Lavage supernatants were assayed by an ELISA based on a monospecific goat antibody for pepsin/pepsinogen. Pepsin levels were compared with those from four normal volunteer controls. RESULTS: Pepsin levels were measurable in all allograft recipients, in keeping with gastric aspiration (median 109 ng/ml (range 35-1375)). In the control group the pepsin levels were below the limit of detection. Treatment with a proton pump inhibitor was not correlated with pepsin levels. There was no correlation between BAL fluid neutrophils and pepsin levels. CONCLUSION: These data demonstrate lung epithelial lining fluid concentrations of pepsin in lung allograft recipients which are much higher than blood reference levels, with no detectable pepsin in controls. This provides direct evidence of gastric aspiration, which is potentially injurious to the allograft.