Iron and non-alcoholic fatty liver disease

The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.     

Cathepsin S inhibitors: 2004-2010

INTRODUCTION: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. AREAS COVERED: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. EXPERT OPINION: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 - 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.     

Treatment of ultralong-segment Barrett’s using focal and balloon-based radiofrequency ablation

Introduction  

Endoscopic radiofrequency ablation (ERFA) is being evaluated as definitive treatment for patients with Barrett’s esophagus (BE). Guidelines have yet to be developed for the application of this technology to patients with ultralong-segment BE (ULBE, ≥8 cm). This study reports a single institution’s experience with ERFA of ULBE.     

Association test of multiallelic gene copy numbers in family trios

While recent genomic surveys reveal growing numbers of di‐allelic copy number variations, it is genes with multiallelic (>2) copy numbers that have shown association with distinct phenotypes. Current high‐throughput laboratory methods are restricted to enumerating total gene copy numbers (GCNs) per individual and not the “genotype,” i.e. gene copy per chromosome. Thus, association studies of multiallelic GCNs have been limited to comparison of median copies in different groups. Our new nonparametric statistical approach is based on GCN information within a trio‐based study design. We present theoretical derivation of the statistics and results of simulation studies that show robustness of our approach and power under several genetic models. Genet. Epidemiol. 34:2–6, 2010. © 2009 Wiley‐Liss, Inc.     

CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome

Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1 , FGFR1 , PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7 . In retrospect, these three CHD7 -positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.