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.

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.

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.

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.

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.

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.

Sinus node function after cardiac transplantation.

OBJECTIVES: This study aimed to examine changes over time in sinus mode function after cardiac transplantation; to determine the incidence, natural history and etiology of sinus node dysfunction in transplant recipients; and to identify any early predictors of long-term sinus node function. BACKGROUND: Bradyarrhythmias caused by sinus node dysfunction are common immediately after cardiac transplantation. Existing electrophysiologic studies have been limited by small numbers and have reported an unexpectedly high incidence of sinus node dysfunction (approximately 50%) compared with the incidence of bradyarrhythmias in other studies. There have been no previous studies reporting serial electrophysiologic data. Thus, the natural history of sinus node dysfunction after transplantation has not been adequately described. METHODS: Serial electrophysiologic studies of sinus node function and 24-h ambulatory electrocardiographic recordings were performed at 1, 2, 3 and 6 weeks and 3 and 6 months after transplantation in 40 adult recipients. RESULTS: The overall incidence of sinus node dysfunction was 17.5% (7 of 40). Six patients (15%) had sinus node dysfunction from week 1; one developed sinus node dysfunction at 3 months. Sinus node recovery time returned to normal by 6 weeks in all six patients with early sinus node dysfunction, but abnormalities of sinoatrial conduction persisted in two. Two patients who required pacing during ambulatory monitoring at 2 weeks after transplantation (temporary pacemaker 50 beats/min, demand) received a permanent pacemaker. One patient required pacing at 3 weeks and continued to require pacing 6 months after transplantation. CONCLUSIONS: The incidence of sinus node dysfunction after cardiac transplantation is lower than has been previously reported in electrophysiologic studies. Sinus node automaticity improves with time, although abnormalities of sinoatrial conduction may persist. The best predictor of permanent pacing requirements is the temporary pacing requirements during 24-h Holter monitoring 2 and 3 weeks after transplantation, with temporary pacing set at 50 beats/min on demand.

Hypothesis: epithelial-to-mesenchymal transition is a common cause of chronic allograft failure.

Renal, hepatic, and lung allografts are compromised by aggressively deteriorating function. This chronic process is produced by an overall burden of organ damage, but the pathophysiology remains poorly understood. Rates of chronic rejection in the lung, for example, have not substantially improved over the last decade, despite new immunosuppressive drugs and improvements in surgical procedure. We present a hypothesis that epithelial-to-mesenchymal transition is a common cause of chronic allograft failure. Research in this area may provide insights into chronic rejection of kidney, liver, and lung allografts that impact on future therapeutic strategies.

Circannual rhythms of ground squirrels: role of the hypothalamic paraventricular nucleus.

Female golden-mantled ground squirrels, maintained in an LD 14:10 photoperiod at 23 degrees C, sustained lesions of the paraventricular nucleus (PVN) or sham operations. Body weight and reproductive status were recorded weekly pre- and postoperatively. Bilateral lesions of the PVN did not eliminate, phase-shift, or otherwise disrupt the circannual rhythms of body mass or reproduction. Absolute levels of body weight were unaffected by PVN ablation. The PVN is not an essential component of the oscillatory system that generates circannual cycles in ground squirrels.

Pineal and photoperiodic influences on fat deposition, pelage, and testicular activity in male meadow voles.

Pinealectomy completely prevented gonadal regression as well as reduction in body weight and white adipose tissue content of the gonadal and retroperitoneal fat deposits in male meadow voles transferred from long to short day lengths. Pineal influences on pelage characteristics depended on which parameter was assessed. For instance, the increase in guard hair length observed in short-day control voles was blocked by pinealectomy; however, a similar increase in underhair length was unaffected by removal of the pineal gland. Photoperiod-dependent changes in fat deposition, testicular activity, and guard hair length presumably rely on altered pineal secretory activity to transduce the effects of day length on the neuroendocrine axis; however, mechanisms independent of pineal activity may be capable of mediating photoperiodic control of underhair growth.

Ventromedial hypothalamic mediation of photoperiodic gonadal responses in male Syrian hamsters.

Short day lengths induce testicular regression in seasonally breeding Syrian hamsters. To test whether the ventromedial hypothalamus is necessary to maintain reproductive quiescence once testicular regression has been achieved, photoregressed male hamsters were subjected to lesions of the ventromedial hypothalamus (VMHx), pinealectomy (Pinx), or sham operation (Sham). VMHx hamsters underwent accelerated gonadal recrudescence compared to Pinx and Sham hamsters. Recovery of prolactin concentrations (PRL) to values characteristic of long-day hamsters was hastened in the VMHx animals compared to Sham hamsters. Concentrations of follicle stimulating hormone (FSH) increased prematurely in both the VMHx and Pinx animals, beginning a few weeks after surgery. By the time the gonads had undergone recrudescence and the hamsters were refractory to melatonin, PRL and FSH concentrations had returned to baseline long-day values in all groups; there was no evidence of hypersecretion of either hormone in any of the animals with lesions. Melatonin concentrations of VMHx hamsters did not differ from those of sham-operated animals, but because only a single determination was made, it remains possible that VMH damage altered the duration of nightly melatonin secretion. An intact VMH appears to be essential for the continued maintenance of reproductive suppression induced by exposure to short day lengths; these and earlier findings suggest that the VMH-dorsomedial hypothalamic complex mediates regression of the reproductive apparatus during decreasing day lengths of late summer and early autumn and also is necessary to sustain regression during the winter months.

Cyclosporine-associated hypertension in cardiopulmonary transplantation. The beneficial effect of nifedipine on renal function.

In a retrospective review of fifty heart, lung, and heart-lung recipients receiving cyclosporine, forty-six (92%) were hypertensive. This hypertension was managed with either prazosin (n = 29) or nifedipine (n = 17). Renal function was assessed by creatinine clearance estimation and found to be significantly better in those patients receiving nifedipine. (creatinine clearance = 60 ml/min [SEM 5.7] vs. 49 ml/min [SEM 2.7]; P less than 0.05). This observation suggests that nifedipine should be the drug of choice for the treatment of cyclosporine-associated hypertension in cardiac and pulmonary transplant recipients.

The effect of fluid therapy on alveolar arterial oxygen gradient in brain-dead organ donors.

Lung transplantation is limited by a shortage of suitable lung donors. Fluid loading is widely used to increase blood pressure during donor maintenance. In a prospective study, we investigated the effect of fluid loading with lactated Ringers solution on pulmonary function in 26 brain-dead adult organ donors. In all patients, the initial central venous pressure (CVP) was < 6 mmHg. In 13 patients, a CVP of 8-10 mmHg was achieved and maintained for 90 min by an infusion of lactated Ringers solution. This resulted in a significant increase (P < 0.05) in the alveolar arterial oxygen gradient. In 13 patients, the CVP was maintained at 4-6 mmHg for 90 min by, if necessary, an infusion of lactated Ringers solution. In these patients, no significant change in the alveolar arterial oxygen gradient occurred. Pulmonary gas exchange has been shown to be a reliable means of evaluating donor lung function. We conclude that crystalloid fluid loading to a CVP of 8-10 mmHg may be deleterious to lung function and should be avoided in potential lung donors.

Use of low dose arginine vasopressin to support brain-dead organ donors.

In a prospective study, we documented the hemodynamic effects of conventional donor maintenance in 24 brain-dead organ donors. Patients were then randomized to receive either saline or a low dose arginine vasopressin (AVP) infusion. In the AVP group (n = 11), plasma hyperosmolality decreased (P < 0.05), blood pressure increased (P < 0.01), inotrope use decreased (P < 0.01), and cardiac output was maintained. In the control group (n = 13), plasma hyperosmolality increased (NS); no significant change in blood pressure, cardiac output, or inotrope infusion rate occurred. Myocardial ATP levels were higher in the AVP than the control group (NS). Early organ function was similar in the 2 groups. We conclude that the use of a low dose AVP infusion enables inotrope use to be reduced and recommend consideration be given to the use of a low dose AVP infusion in potential thoracic organ donors.