Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group.

Non-alcoholic fatty liver disease (NAFLD) is common, affecting approximately 25% of the general population. The evidence base for the investigation and management of NAFLD is large and growing, but there is currently little practical guidance to support development of services and delivery of care. To address this, we produced a series of evidence-based quality standard recommendations for the management of NAFLD, with the aim of improving patient care. A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group produced the recommendations, which cover: management of people with, or at risk of, NAFLD before the gastroenterology or liver clinic; assessment and investigations in secondary care; and management in secondary care. The quality of evidence for each recommendation was evaluated by the Grading of Recommendation Assessment, Development and Evaluation tool. An anonymous modified Delphi voting process was conducted individually by each member of the group to assess the level of agreement with each statement. Statements were included when agreement was 80% or greater. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice. It is hoped that services will review their practice against our recommendations and key performance indicators and institute service development where needed to improve the care of patients with NAFLD.

Hepatic stellate cells: central modulators of hepatic carcinogenesis.

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90% of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC.

Genetics of ulcerative colitis.

Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.

Unbiased screening of polymer libraries to define novel substrates for functional hepatocytes with inducible drug metabolism.

Maintaining stable differentiated somatic cell function in culture is essential to a range of biological endeavors. However, current technologies, employing, for example, primary hepatic cell culture (essential to the development of a bio-artificial liver and improved drug and toxicology testing), are limited by supply, expense, and functional instability even on biological cell culture substrata. As such, novel biologically active substrates manufacturable to GMP standards have the potential to improve cell culture-based assay applications. Currently hepatic endoderm (HE) generated from pluripotent stem cells is a genotypically diverse, cheap, and stable source of "hepatocytes"; however, HE routine applications are limited due to phenotypic instability in culture. Therefore a manufacturable subcellular matrix capable of supporting long-term differentiated cell function would represent a step forward in developing scalable and phenotypically stable hESC-derived hepatocytes. Adopting an unbiased approach we screened polymer microarrays and identified a polyurethane matrix which promoted HE viability, hepatocellular gene expression, drug-inducible metabolism, and function. Moreover, the polyurethane supported, when coated on a clinically approved bio-artificial liver matrix, long-term hepatocyte function and growth. In conclusion, our data suggest that an unbiased screening approach can identify cell culture substrate(s) that enhance the phenotypic stability of primary and stem cell-derived cell resources.

Video-assisted thoracoscopic surgery management of spontaneous pneumothorax--long-term results.

OBJECTIVE: Although widely adopted, there is lack of immediate and long-term follow-up data for patients undergoing video-assisted thoracoscopic surgery (VATS) management of pneumothorax. Therefore, we have reviewed our experience with both primary (PSP) and secondary (SSP) spontaneous pneumothorax to assess the perioperative outcomes and long-term efficacy associated with different VATS operative strategies. METHODS: A retrospective case series review was undertaken on all patients undergoing VATS procedures for PSP or SSP over a 17-year period. RESULTS: A total of 644 VATS pneumothorax procedures were performed between 1992 and 2008 on 569 patients, of which 550 procedures were performed for PSP and 94 for SSP. Mean age for PSP and SSP groups were 28.4 ± 10.4 and 58.2 ± 14.2 years, respectively. Surgical technique used bullectomy in combination with abrasion (273), poudrage (246) and pleurectomy (46). Isolated poudrage was used in 72 cases. Median postoperative stay was 3 and 4 days, respectively. Major complications occurred in 25 (4.6%) PSP and 18 (19.2%) SSP patients. Two patients in the SSP group died (2.1%). Median follow-up was 73 months. Freedom from further surgery for the two populations was PSP: 98.1% at 5 years (confidence interval (C.I.): 96.9-99.4) and 97.8% at 10 years (C.I.: 96.5-99.2); SSP: 96.1% at 5 years (C.I.: 91.5-1.006) and 96.1% at 10 years (C.I.: 91.5-1.006). Freedom from further operation at 10 years was independent of the pleurodesis technique employed: abrasion 96.4%, poudrage 98.9% and pleurectomy 97.5% (p=0.22). CONCLUSIONS: VATS management of both PSP and SSP offers good short-term results and excellent long-term freedom from repeat surgery. In combination with bullectomy, results of abrasion and poudrage do not significantly differ from pleurectomy. We recommend abrasion for pleurodesis in young patients reserving poudrage for the elderly. Pleurectomy may not be necessary.