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Liver biopsy remains the gold standard for characterizing and evaluating treatment response in nonalcoholic fatty liver disease (NAFLD). Liver heterogeneity and sampling variability can affect the reliability of results. This study aimed to compare histological variability of intraoperative wedge and core liver biopsies from different lobes in bariatric patients, to better inform surgeons on biopsy method and guide interpretation of results.We prospectively recruited bariatric surgical patients. Intraoperative core biopsies were taken from the left and right lobe, with a wedge biopsy taken from the left. All biopsies were graded by a specialist liver pathologist, blinded to clinical details and biopsy site. Concordance of histological findings between sites was evaluated.There were 91 participants (72.2% female), mean age 46.8 ± 12.0 years, body mass index 45.9 ± 9.4 kg/mOverall diagnosis of NAFLD or NASH shows good agreement between biopsy sites, but individual components, particularly fibrosis stage, vary significantly. Clinicians should consider biopsies from varied sites, to better assess liver disease severity. These data have important implications in fibrosis assessment of NAFLD and are relevant in the interpretation of histological efficacy of investigational pharmacotherapies.ACTRN12615000875505 (Australian Clinical Trials Register).

Allogeneic stem cell transplantation (alloSCT) and graft-versus-host disease (GVHD) are characterized by systemic interleukin 6 (IL-6) dysregulation, which plays a significant role in shaping donor immune responses and T cell polarization. GVHD is a T cell-mediated disease and the severity and tissue distribution is heavily influenced by T cell-derived cytokines, therefore it is critical to understand the factors that drive T cell polarization in this context to inform therapeutic strategies. IL-6 has a unique receptor system composed of IL-6Ra and the signal transducing molecule gp130, in which signaling occurs via multiple pathways either directly (classical), indirectly via a soluble IL-6 receptor (trans), or presented via antigen presenting cells (cluster). We examined the influence of IL-6 signaling modalities on T cell polarization following allotransplantation, where we found specific targeting of these pathways modulates GVHD outcomes. Using donor grafts composed of IL-6Ra deficient T cells resulted in a profound loss of pathogenic Th17/Th22 differentiation and increased GVHD survival, demonstrating these populations are highly dependent upon classical IL-6 signaling post-transplant. Whilst targeting cluster signaling through IL-6Ra deficient DC had no effect on T cell cytokine responses, trans-signaling inhibition via soluble gp130-Fc resulted in severe skin GVHD. This effect was due to significant expansion of pathogenic donor Th22 and was prevented by donor IL-22 deficiency. These data demonstrate an important role for IL-6 trans signaling in regulating pathogenic T cell polarization pathways following allotransplantation and support IL-6 classical signaling as an important target for GVHD prevention.

Background Body mass index is associated with the risk of Barrett's oesophagus (BO). It is uncertain whether this is related to total body fat or other factors that correlate with body mass index. We aimed to quantify the association between total body fat (measured by bioelectrical impedance) and risk of BO and examine if this association was modified by gastro-oesophageal reflux (GOR) and abdominal obesity. Methods In 2007–2009, we surveyed 235 cases (69% Males, Mean age 62.1 years) and 244 age and sex matched population controls from a population based case–control study of BO. We conducted structured interviews, standard anthropometry and bioimpedance analysis of total body fat. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression analysis. Results There was a significantly increased risk of BO among those in the highest tertile of total body fat weight (OR 2.01; 95%CI 1.26–3.21) and total body fat percentage (OR 1.86; 95%CI 1.10–3.15). These risks were largely attenuated after adjustment for GOR and waist circumference. There was a significantly increased risk of BO among those in the highest tertile of waist circumference (OR 2.21; 95%CI 1.39–3.51) and this was minimally attenuated after adjustment for total body fat and moderately attenuated after adjustment for GOR. Conclusions Total body fat is associated with an increased risk of BO but this appears to be mediated via both abdominal obesity and GOR. These findings provide evidence that abdominal obesity is more important than total body fat in the development of BO.

Frequent gastroesophageal reflux (GER) causes chronic inflammation and damages esophageal mucosa, which can lead to Barrett's esophagus. It has also been consistently found to be a strong risk factor for esophageal adenocarcinoma. The prevalence of GER appears to vary; however, population-based Australian studies investigating the symptoms are limited. This study aimed to estimate the population prevalence and identify the determinants of frequent GER symptoms in the Australian population. Self-reported information on the frequency of reflux symptoms were collected from 1,580 adults from a population register. We estimated age- and sex-standardized prevalence of occasional (

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.

Splitting maps into small contiguous tiles increases the speed of Internet map distribution, improves the panning of the map, and facilitates the presentation at multiple scales. This online method of map distribution was introduced by Google in 2005 and all the major online-mapping services including Bing, Yahoo, OpenStreetMap, Nokia, and MapQuest have since adopted the technique. User-generated tiles can be overlayed on top of these maps, obscuring the standard map or satellite views. Any digital map whether a scanned historic one or a computer-generated thematic map can be converted to tiles. A multilevel overlay can be created by tiling several different maps or orthophotos. By enabling the presentation of more targeted map information, such overlays are an increasingly important method of map presentation through the Internet. A significant disadvantage of tiled overlays is that they totally obscure the underlying base map. By providing an interactive tool to control level of opacity on tiles, the cartographer can effectively combine two views. Benefits include, image comparison, map merging, and masking effects. The combination of tile mapping and opacity control provides a new way of enabling user interaction with online maps and provides a valuable new tool for the modern cartographer.

Regulatory T cells (Treg) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Treg result in diseases such as autoimmunity and graft-versus-host disease (GVHD), a serious complication of bone marrow transplantation (BMT). We recently reported that G-CSF mobilisation of stem cells in donor mice increases autophagy related genes in Treg and it is associated with an improved GVHD outcome after BMT. Autophagy is a self-degradative process for cytosolic components which promotes cell homeostasis and survival. Here, we demonstrate that the lineage-specific disruption of autophagy within FoxP3+ Treg (Atg7fl/fl.FoxP3cre+ mice) resulted in a profound loss of Treg within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and in aged mice, the development of enterocolitis and severe scleroderma. We show that the BM compartment is highly enriched in TIGIT+ Treg and that this subset is differentially lost in the absence of autophagy. Moreover, G-CSF administration to naive mice results in the mobilization of BM TIGIT+ Treg explaining the autophagy signature of peripheral Treg in G-CSF treated mice. Importantly, lethally irradiated B6D2F1 recipients of splenic grafts from G-CSF mobilized B6.Atg7fl/fl.FoxP3cre+ donors failed to reconstitute the Treg compartment within the BM. This resulted in GVHD exacerbation and reduced survival compared to recipients of B6.WT.FoxP3cre+ grafts. Collectively, these data indicate that autophagy-dependent TIGIT+ Treg in the BM are critical for the maintenance of tolerance and to control GVHD; thus the induction of autophagy may represent an attractive immune-restorative therapeutic strategy.

Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.

Heme oxygenase-1 (HO-1), a ubiquitously expressed enzyme that degrades heme, has anti-inflammatory, anti-apoptotic and anti-proliferative actions yet its role in alloreactivity is unclear. Previously we demonstrated that HO-1 mRNA levels were elevated in recipient tissues of IFNγR-/- animals resistant to acute GVHD of the GI tract. Here we demonstrate that HO-1 expression in host tissues is critical for the suppression of acute GVHD as B6.HO-1-/- recipients of allogeneic BALB/c.WT grafts developed severe acute GVHD with rapid mortality (0% survival at d10) while WT mice survived longer term (median survival 42d). This was T cell mediated since mice transplanted with T cell depleted grafts showed no evidence of acute GVHD. Histological analysis revealed B6.HO-1-/- recipients developed severe acute GVHD of the GI tract and liver. TNF and IFNγ were elevated in the sera of B6.HO-1-/- recipients and systemic IFNγ but not TNF neutralization prevented hyperacute gut GVHD. The transplantation of grafts containing luciferase+ donor T cells demonstrated increased bioluminence signals in the mesenteric lymph node, spleen and GI tract of HO-1-/- recipients. Furthermore, the absolute number of donor CD4+ and CD8+ T cells co-producing the pro-inflammatory cytokines TNF and IFNγ were increased early after BMT in the lymph nodes of B6.HO-1-/- recipients, demonstrating that HO-1 within recipient tissue controls the acquisition and expansion of donor T cell effector function after BMT.

The clinical shift toward utilizing G-CSF mobilized stem cell grafts has resulted in a striking increase in chronic GVHD after transplantation although the mechanisms involved are unclear. Comparison of cytokine expression following TCR activation of splenocytes from naïve and G-CSF treated B6 or BALB/c donors (low and high responders respectively) showed little effect of G-CSF on Th1 or Th2 cytokine production. In contrast, IL-17 production was dramatically enhanced in response to G-CSF in both strains. G-CSF induced IL-17 production occurred in both CD4 and CD8 conventional T cells and by using relevant knock-out mice or blocking reagents we demonstrated that this was independent of IL-6, TGF-beta or IL-23 signalling. However, the induction of IL-17 by G-CSF was completely dependent on IL-21 signalling and G-CSF induced IL-21 generation in CD4 T cells independent of IL-17 itself. We utilized multiple models of GVHD using G-CSF mobilized B6 or BALB/c wild-type or IL-17 deficient donors, in both MHC matched and mismatched settings. Surprisingly, IL-17 was critical for the induction of sclerodermatous chronic GVHD occurring after transplant using either donor strain. Importantly, IL-17 controlled the dramatic sequestration of macrophages into skin that coincided with the fibrogenic response. This study provides a logical explanation for the propensity of allogeneic stem cell transplantation to invoke sclerodermatous GVHD and suggests a therapeutic strategy for intervention.