SUMMARYDelayed cerebellar development is a hallmark of Zellweger syndrome (ZS), a severe neonatal neurodegenerative disorder. ZS is caused by mutations in PEX genes, such as PEX13, which encodes a protein required for import of proteins into the peroxisome. The molecular basis of ZS pathogenesis is not known. We have created a conditional mouse mutant with brain-restricted deficiency of PEX13 that exhibits cerebellar morphological defects. PEX13 brain mutants survive into the postnatal period, with the majority dying by 35 days, and with survival inversely related to litter size and weaning body weight. The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very-long-chain fatty acids are normal. PEX13 brain mutants exhibit defects in reflex and motor development that correlate with impaired cerebellar fissure and cortical layer formation, granule cell migration and Purkinje cell layer development. Astrogliosis and microgliosis are prominent features of the mutant cerebellum. At the molecular level, cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show enhanced apoptosis together with mitochondrial dysfunction. PEX13 brain mutants show increased levels of MnSOD in cerebellum. Our findings suggest that PEX13 deficiency leads to mitochondria-mediated oxidative stress, neuronal cell death and impairment of cerebellar development. Thus, PEX13-deficient mice provide a valuable animal model for investigating the molecular basis and treatment of ZS cerebellar pathology.

Globally, a large proportion of donor livers are discarded due to concerns over inadequate organ quality. Normothermic machine perfusion (NMP) allows for hepatocellular and biliary viability assessment prior to transplantation and might therefore enable the safe use of these orphan donor livers. We describe here the first Australasian experience of NMP-preserved liver transplants using a 'backto-base' approach, where NMP was commenced at the recipient hospital following initial static cold storage. In the preclinical phase, 10 human donor livers declined for transplantation (7 from donation after circulatory death [DCD] and 3 from donation after brain death [DBD]) were perfused using a custom-made NMP setup. Subsequently, 10 orphan donor livers (5 from DCD and 5 from DBD) underwent NMP and viability assessment on the OrganOx metra device (OrganOx Limited, Oxford, United Kingdom). Both hepatocellular and biliary viability criteria were used. The median donor risk index was 1.53 (1.16-1.71), and the median recipient Model for End-Stage Liver Disease score was 17 (11-21). In the preclinical phase, 'back-to-base' NMP was deemed suitable and feasible. In the clinical phase, each graft met predefined criteria for implantation during NMP and was subsequently transplanted. Five (50%) recipients developed early allograft dysfunction based on peak aspartate aminotransferase. To date, all grafts function satisfactorily, and none of the 5 recipients who received a DCD liver have developed cholangiopathy. The OrganOx metra using a backto-base approach has enabled the safe use of 10 high-risk orphan donor livers with 100% 6-month patient and graft survival. NMP improved surgeon confidence to use orphan donor livers and has enabled a safe expansion of the donor pool.

Rodent and cell‐culture models support a role for iron‐related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD. Paired serum samples at baseline and 6 months (end of treatment) in controls (n = 28) and patients who had venesection (n = 23) were assayed for adiponectin, leptin, resistin, retinol binding protein‐4, tumor necrosis factor α, and interleukin‐6, using a Quantibody, customized, multiplexed enzyme‐linked immunosorbent assay array. Hepatic iron concentration (HIC) was determined using MR FerriScan. Unexpectedly, analysis revealed a significant positive correlation between baseline serum adiponectin concentration and HIC, which strengthened after correction for age, sex, and body mass index (rho = 0.36; P = 0.007). In addition, there were significant inverse correlations between HIC and measures of insulin resistance (adipose tissue insulin resistance (Adipo‐IR), serum insulin, serum glucose, homeostasis model assessment of insulin resistance, hemoglobin A1c, and hepatic steatosis), whereas a positive correlation was noted with the insulin sensitivity index. Changes in serum adipokines over 6 months did not differ between the control and venesection groups. Conclusion: HIC positively correlates with serum adiponectin and insulin sensitivity in patients with NAFLD. Further study is required to establish causality and mechanistic explanations for these associations and their relevance in the pathogenesis of insulin resistance and NAFLD. (Hepatology Communications 2018;2:644‐653)