A bio-functional polymer that prevents retinal scarring through modulation of NRF2 signalling pathway.

One common cause of vision loss after retinal detachment surgery is the formation of proliferative and contractile fibrocellular membranes. This aberrant wound healing process is mediated by epithelial-mesenchymal transition (EMT) and hyper-proliferation of retinal pigment epithelial (RPE) cells. Current treatment relies primarily on surgical removal of these membranes. Here, we demonstrate that a bio-functional polymer by itself is able to prevent retinal scarring in an experimental rabbit model of proliferative vitreoretinopathy. This is mediated primarily via clathrin-dependent internalisation of polymeric micelles, downstream suppression of canonical EMT transcription factors, reduction of RPE cell hyper-proliferation and migration. Nuclear factor erythroid 2-related factor 2 signalling pathway was identified in a genome-wide transcriptomic profiling as a key sensor and effector. This study highlights the potential of using synthetic bio-functional polymer to modulate RPE cellular behaviour and offers a potential therapy for retinal scarring prevention.

Antiangiogenic Nanomicelles for the Topical Delivery of Aflibercept to Treat Retinal Neovascular Disease.

The traditional intravitreal injection delivery of antivascular endothelial growth factor (anti-VEGF) to the posterior segment of the eye for treatment of retinal diseases is invasive and associated with sight-threatening complications. To avoid such complications, there has been significant interest in developing polymers for topical drug delivery to the retina. This study reports a nanomicelle drug delivery system made of a copolymer EPC (nEPCs), which is capable of delivering aflibercept to the posterior segment topically through corneal-scleral routes. EPC is composed of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and polycaprolactone (PCL) segments. In this study, aflibercept-loaded nEPCs (nEPCs + A) are capable of penetrating the cornea in ex vivo porcine eye models and deliver a clinically significant amount of aflibercept to the retina in laser-induced choroidal neovascularization (CNV) murine models, causing CNV regression. nEPCs + A also demonstrate biocompatibility in vitro and in vivo. Interestingly, this study also suggests that nEPCs have intrinsic antiangiogenic properties. The ability to deliver anti-VEGF drugs and the intrinsic antiangiogenic properties of nEPCs may result in synergistic effects, which can be harnessed for effective therapeutics. nEPCs may be a promising topical anti-VEGF delivery platform for the treatment of retinal diseases.

Dual en bloc technique for adult renal transplantation.

INTRODUCTION: We describe and provide follow-up for a novel simplified technique permitting dual en bloc (DEB) transplantation of adult organs using single in situ arterial and venous anastomoses. METHODS: Twenty-two adult DEB transplants were performed at our center between 2001 and 2012, utilizing 44 kidneys en bloc. Results were compared with 20 solitary transplants from expanded criteria donors (ECD) associated with lower terminal serum creatinines and Remuzzi biopsy scores vs DEB group. Adult DEB implants had donor inferior vena cava connected to recipient external iliac vein and "Y" arterial interposition graft anastomosed to the recipient iliac artery. Ureters were conjoined prior to implantation as a single patch into the recipient bladder. RESULTS: Mean operative time was 206±57 minutes in DEB vs 180±30 minutes in single transplants (P<.05). Delayed graft function rate was 23% vs 25% in both groups. At 12-month follow-up, mean serum creatinine was 152±66 µmol/L vs in 154±52 µmol/L DEB and single kidney transplant recipients, respectively (P=NS). Three-year overall and graft specific survival were 86% and 84% in the DEB group, respectively (P=NS). Complication rates were similar between groups. CONCLUSIONS: This DEB renal transplantation technique is safe and effective in adults. By employing techniques used to conjoin organ vasculature ex vivo, the number of in situ anastomoses is reduced, thereby minimizing operative ischemic time and potential for complications associated with extensive vascular dissection.

The pattern of urologic care among traumatic spinal cord injured patients.

INTRODUCTON: We assessed the urologic care patterns of traumatic spinal cord injury (TSCI) patients. METHODS: This was a retrospective cohort study of adult TSCI patients injured between 2002 and 2012. The primary outcome was urologic consultation. The primary exposure was the year of injury. Measured covariates included lesion level, age, gender, comorbidity burden, and socioeconomic status. RESULTS: We identified 1551 incident TSCI patients who were discharged from a rehabilitation hospital in Ontario between 2002 and 2012. The median follow-up time of this cohort was 5.0 (inter-quartile range [IQR] 2.9-7.5) years. Within this cohort, 74% were male, and the mean age was 48 (IQR 33-63) years. In total, 66% of patients (1022/1551) were seen by a urologist in a median of 0.7 (IQR 0.2-3.0) years after the SCI. Over the study period, there was no change in the proportion of TSCI patients being assessed by a urologist within 1 year of their initial injury (median 55.1%, p = 0.92 for the trend). An adjusted Cox proportional hazards model demonstrated that TSCI patients who were female (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.66-0.92) or over 65 years of age (HR 0.70, 95% CI 0.57-0.85) were significantly less likely to be referred to a urologist. CONCLUSIONS: Urologists are often not involved in the care of TSCI patients, and this has not changed significantly over the last 10 years. Females and older patients are significantly less likely to be referred to a urologist.

Carbon monoxide releasing molecules inhibit cell death resulting from renal transplantation related stress.

PURPOSE: Organ cold storage and subsequent transplantation are associated with significant ischemia-reperfusion injury, leading to cell death, graft inflammation and decreased graft function. MATERIALS AND METHODS: CORM-3s reduce oxidative stress and prevent inflammation in kidneys stored at 4C and subsequently transplanted. Graft survival and function are markedly improved compared to kidneys preserved and stored in University of Wisconsin solution alone. We determined whether CORM-3 has direct antiapoptotic effects on in vitro preparations of human HUVECs exposed to anoxic conditions. We also determined whether direct administration of CORM-3 to renal grafts before and/or after cold storage would prevent renal damage during the transplantation process. RESULTS: CORM-3 supplementation led to a significantly increased frequency of live cells (mean ± SD 72.3% ± 1.9%, p <0.01), reduced apoptosis (14.9% ± 6.1%, p <0.01) and decreased mitochondrial transmembrane potential (40.2% ± 7.2%, p <0.05) in HUVECs exposed to 20 hours of cold storage compared to controls (11.6% ± 3.5%, 82.2% ± 2.3% and 78.2% ± 3.2%, respectively). In keeping with this antiapoptotic effect CORM-3 supplementation led to a mean 7.4 ± 2.1-fold up-regulation in Bcl-2 gene expression. CORM-3 supplementation in standard preservation solution was most beneficial at initial ischemic injury and before cold storage exposure. However, additional reflushing before vascular reperfusion showed an additive benefit to graft survival and function after transplantation. This was confirmed by decreased glomerular and tubular necrosis, and apoptosis in double flushed grafts. CONCLUSIONS: CORM-3 supplementation in standard University of Wisconsin solution has a significant impact on decreasing cellular and graft injury, and improving survival through its antiapoptotic effects, which are likely mediated through mitochondrial membrane stabilization.

Impact of evolving strategy on clinical outcomes and central pulmonary artery growth in patients with bilateral superior vena cava undergoing a bilateral bidirectional cavopulmonary shunt.

OBJECTIVE: We reported a high incidence of thrombosis, central pulmonary artery hypoplasia, and mortality for bilateral bidirectional cavopulmonary shunts. We hypothesized that technical modifications in the cavopulmonary anastomosis and anticoagulation would limit thrombus and central pulmonary artery hypoplasia, and thereby improve outcomes. METHODS: Sixty-one patients (median age, 8.4 months; weight, 6.6 kg) underwent bilateral bidirectional cavopulmonary shunt from 1990 to 2007. The cohort was divided into 2 groups: 1) the conventional group (1990-1999, n = 37) and 2) the V-shaped group, with a hemi-Fontan or modification in which the cavae were anastomosed to the pulmonary artery adjacent to each other so they formed the appearance of a V (1999-2007, n = 24). Central and branch pulmonary artery growth, survival, and reinterventions were determined. RESULTS: The pre-Fontan study showed equivalent superior venae cavae and Nakata indices. The central pulmonary artery index and central pulmonary artery/Nakata index ratio were significantly higher in the V-shaped group (P < .05). There were no differences in freedom from death or transplant (conventional 69% vs V-shaped 75% at 3 years, P = .5), and a nonsignificant trend toward improving freedom from reinterventions (63% vs 81% at 3 years, P = .15) and thrombosis (82% vs 95% at 1 year, P = .11) was observed in the V-shaped group. Multivariate analysis showed anastomotic strategy, low saturation, and thrombosis were predictors for death. Anastomotic strategy, lack of anticoagulation, thrombosis, and small superior venae cavae were predictors for reintervention (P < .05). Predictors for thrombus included small superior venae cavae, Nakata index, and low saturation (P < .03). CONCLUSIONS: Surgical modifications for bilateral bidirectional cavopulmonary shunts were associated with the larger central pulmonary artery size. Lack of anticoagulation and anastomotic strategy affected reintervention. Anastomotic strategy and postoperative thrombus affected mortality.

The functional intraoperative pulmonary blood flow study is a more sensitive predictor than preoperative anatomy for right ventricular pressure and physiologic tolerance of ventricular septal defect closure after complete unifocalization in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collaterals.

BACKGROUND: The objective was to determine if intraoperative pulmonary artery (PA) flow studies after complete unifocalization correlate with postrepair hemodynamics for pulmonary atresia (PA), ventricular septal defects (VSD), and major aortopulmonary collaterals. METHODS AND RESULTS: Twenty patients (median age, 8 months; weight, 7.9 kg) underwent unifocalization between 2003 and 2008. A functional PA flow study was achieved by cannulating the unifocalized central PA before intracardiac repair and increasing flow incrementally to 2.5 L/min per m(2). Mean PA pressure (mPAP) was measured. The intent was to close the VSD for a mPAP of <30 mm Hg. Right ventricular systolic pressure (RVSP) and systemic systolic pressure were recorded. Total incorporated pulmonary segments, pulmonary segment artery ratio (ratio of incorporated segments to 18), and total neopulmonary artery index (the sum of major aortopulmonary collaterals and native PA index) were calculated. The VSD was successfully closed in 18 patients (90%). One attempted closure required an intraoperative fenestration. The study mPAP correlated with RVSP (rho=0.72; P=0.0027) and RVSP/systemic systolic pressure (rho=0.67; P=0.0063). Total neopulmonary artery index had a nonsignificant negative correlation with RVSP (rho=-0.42; P=0.079). Total incorporated pulmonary segments and pulmonary segment artery ratio were not correlated. Flow study mPAP had the highest accuracy in predicting successful VSD closure: area under the receiver-operator curve (0.83) versus total neopulmonary artery index (0.42), pulmonary segments (0.35), and pulmonary segment artery ratio (0.33). CONCLUSIONS: The intraoperative pulmonary flow study predicted postoperative physiology significantly better than did standard anatomic measures. Conventional measures should be used with caution when determining the possibility for complete repair.