Third WHO Global Consultation on regulatory requirements for xenotransplantation clinical trials, Changsha, Hunan, China December 12-14, 2018: "The 2018 Changsha Communiqué" The 10-Year Anniversary of The International Consultation on Xenotransplantation

After feedback from the working parties, the final session focused on drafting proposed revisions of the WHO documents, and resulted in the formulation of the draft “Third WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials, The 2018 Changsha Communiqué.” This draft was submitted to WHO in February 2019 for WHO and World Health Assembly consideration. If approved, the 2018 Changsha Communiqué will then be posted on the websites of WHO, IXA, and TTS, and published in Xenotransplantation. This report includes summaries of the various sessions, followed by the abstracts of invited speakers from the update sessions

Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia

BACKGROUND: Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide. CONCLUSIONS/SIGNIFICANCE: Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress

Is the expression of Gal-alpha1,3Gal on porcine pancreatic islets modified by isolation procedure?

AIM: The aim of this study was to study the Galactosyl alpha(1,3) Gal expression and the vascular tissue distribution prior to and after isolation of porcine pancreatic islets. METHODS: Biopsies of native pancreas were carried out in young (12-15 weeks; n = 4) and adult Landrace pigs (2 years old; n = 7). These pancreases were then digested (Liberase Porcine Islets [PI]) to obtain isolated pancreatic islets from each pancreas. Alpha Gal-specific biotinylated BS-1 isolectin B4 and von Willebrand's Factor (vWF) staining were performed for Galactosyl and vascular structure analysis, respectively. Quantitative Galactosyl expression as well as location of the vascular structure were determined using image analysis in pig islets of different sizes. RESULTS: Vascular structures and Galactosyl expression varied following the islet sizes but not the pig age. In large islets (>100 microm), capillaries were mainly located within the islets, whereas in small islets (<100 microm), 4-fold more vessels were situated at the periphery of the islets. Galactosyl expression followed a comparable distribution than vascular tissue in small and large islets. After isolation, a significant decrease of Gal staining (-49%) was observed, but Galactosyl expression remained positive within both small and large islets. CONCLUSIONS: Galactosyl expression is maintained within pancreatic islets after isolation procedure. Gal knock-out pigs could represent the solution to this hurdle

Impact of porcine islet size on cellular structure and engraftment after transplantation: adult versus young pigs.

OBJECTIVES: To study the impact of porcine islet size on structural properties and cellular engraftment. METHODS: The endocrine structure and collagen/vascular localization in pig islets were studied before and after enzymatic isolation on the pancreas from 6 young and 6 adult Landrace pigs. Isolated islets from both pig types were transplanted under the kidney capsula of diabetic nude rats to assess cellular engraftment. RESULTS: In comparison with adult pig pancreata, a significantly greater number of small beta cells (<100 microm) were observed before and after isolation (82% vs. 32%, respectively, P < 0.005) from young pig pancreata. Small islets (<100 microm) showed a peripheral vascular structure, whereas large islets showed a more centralized vascular organization, thereby providing protection during the enzymatic digestion procedure. The islet endocrine structure was not affected by the islet size, but a loss of glucagon cells (-7.9%, P < 0.005) was observed in large isolated islets. The purity of islet preparation was better with pancreata from adult than young donors (86% vs. 64%, respectively, P < 0.05). A lack of engraftment was observed for small islets from young pig donors as compared with large islets from adult donors. CONCLUSIONS: Large and well-structured islets, mainly found in adult pig pancreata, probably possess a better potential for cellular engraftment due to centralized vascularization and collagen distribution

EUK-134, a synthetic superoxide dismutase and catalase mimetic, protects rat kidneys from ischemia-reperfusion-induced damage.

The effect of a new synthetic superoxide dismutase and catalase mimetic was investigated on renal ischemia-reperfusion syndrome in rats. Synthetic salen-manganese complexes have characteristics that might facilitate their potential usefulness as therapeutic agents: (1) unlike proteinaceous antioxidant enzymes, synthetic complexes, due to their low molecular weight, have a better stability and bioavailability; (2) they have a catalytic activity enhancing their efficiency over noncatalytic reactive oxygen metabolite scavengers; and finally, (3) exhibiting combined superoxide dismutase and catalase activity, they destroy both superoxide anions and hydrogen peroxides, thereby enhancing their protective effect on ischemically injured tissues. One such compound, EUK-134, was tested in uninephrectomized rats that underwent a left renal artery clamping. After a 75-min left renal artery clamping, a single intravenous injection of EUK-134 at 0.2 mg/kg, just before unclamping, provided significantly better renal function recovery during the week after the ischemic insult compared with recovery of untreated animals. Two hours after several periods of renal ischemia (30, 45, 60, and 75 min of left renal artery clamping), EUK-134 given at a similar dose significantly improved the glomerular filtration rate after an acute ischemia of 30 and 45 min, as assessed by EDTA 51Cr. Overall, these results show that synthetic superoxide dismutase-catalase mimetics such as EUK-134 can protect ischemically injured rat kidneys from ischemia-reperfusion syndrome when administered just before reperfusion

Effect of 1-28 alpha-h atrial natriuretic peptide on acute renal failure in cadaveric renal transplantation.

The efficacy and safety of (1-28) alpha-human ANP in preventing acute tubular necrosis (ATN) in cadaveric renal transplantation was tested by comparing ANP infusion with a maximal hydration (MH) regimen which we previously reported as effective in lowering the incidence of ATN (1, 2). Since the production of endogenous ANP increases with volume overloading (3), we hypothesized that increased endogenous ANP production may contribute to the beneficial effects of MH in renal transplant recipients. We thus conducted an open randomized study comparing the effect on early renal allograft function of MH (control group) versus moderate hydration plus ANP infusion (ANP group). Forty patients were blindly paired in two groups of 20 according to the duration of cold ischemia time (mean +/- 2 h). The demographic characteristics of donors and recipients were similar. Using a Swan-Ganz catheter, hemodynamic parameters were monitored for 4 h after transplantation. The group receiving ANP and moderate hydration was perfused to a mean pulmonary arterial pressure (PAP) of or = 25 mmHg. In the ANP group, a bolus of 100 micrograms of ANP was infused into the graft's renal artery at the time of unclamping, followed by 24 h of continuous intravenous infusion at 0.03 microgram/kg/min. Thereafter, the patients received ANP at a rate of 0.01 microgram/kg/min until the serum creatinine reached < 2 mg/dl. As a consequence of the hydration regimen, the PAP at unclamping was lower in the ANP group than in the control group; 20 +/- 3 and 26 +/- 4 mmHg, respectively (p < 0.05). The ANP plasma levels were significantly higher during the first 3 d in the ANP group (p < 0.001). The median recovery rate of renal function was similar in both groups. No patients in the ANP group experienced ATN while 4 patients (20%) in the control group did (p = 0.125). The need for hemodialysis was markedly reduced in the ANP group compared to the control group (1 ANP-treated patient required dialysis once whereas 5 patients from the control group underwent dialysis a total of 26 times; p = 0.068). ANP administration was well-tolerated and no hypotensive episodes were reported. This preliminary study suggests that ANP infusion is at least as effective as maximal hydration in preventing ATN and represents an efficient alternative for transplantation centers which do not use maximal hydration as a standard regimen in managing kidney allograft recipients

The surgical management of congenital liver cysts : The need for a tailored approach with appropriate patient selection and proper surgical technique

BACKGROUND: Most series that report the results of surgical treatment for congenital liver cysts focus more on the technical aspects of the operation than on the late outcome of these patients. In this paper, we emphasize the importance of appropriate patient selection and adequate surgical technique for successful long-term outcome. METHODS: Twenty-four consecutive patients with congenital liver cysts were selected for surgical treatment. According to our own classification, 13 patients had simple liver cysts, nine had multicystic liver disease, and two had type I polycystic liver disease. All of these patients were treated by the fenestration technique. An open approach was used for five patients (group 1) treated between 1984 and 1990. In 19 patients (group 2) treated since 1991, a laparoscopic approach was used. The incidence of complicated liver cysts was 40% in group 1 and 68% in group 2. RESULTS: There were no treatment-related deaths in this series. The mean postoperative hospital stay was significantly shorter for patients who underwent successful laparoscopic fenestration (p < 0.05). In the open group (group 1), there were no postoperative complications, and all patients were alive and free of symptoms during a mean follow-up of 130 months, without any sign of cyst recurrence. In the laparoscopic group (group 2), four patients were converted to open surgery. One of these patients had an inaccessible posterior cyst; another had bile within the cystic cavity. A further two cases had complicated liver cysts with an uncertain diagnosis between congenital and neoplastic cysts. Four patients (21%) developed peri- or postoperative complications. During a mean follow-up time of 38.5 months, none of the patients with simple liver cysts incurred late symptoms or signs of cyst recurrence. In the six patients with multicystic liver disease, one developed disease-related cyst progression (17%) and required reoperation. One of the two patients with type I polycystic liver disease (50%) developed asymptomatic disease-related cyst progression. CONCLUSIONS: When patients are carefully selected and a proper surgical technique is employed, excellent long-term results with a low morbidity rate can be achieved in patients with congenital liver cysts. Patients with multicystic liver disease or type I polycystic liver disease are more prone to late cyst recurrence. A tailored approach is thus indicated for patients with congenital liver cystic disease. However, the laparoscopic approach appears to be the gold standard for the treatment of highly symptomatic or complicated simple liver cysts