The diagnosis of autoimmune hepatitis (AIH) is based on a combination of biochemical, immunological and histological features and exclusion of other causes of liver disease. Typical histological features include a chronic hepatitis pattern of injury with portal inflammation and interface activity, predominance of plasma cells in the portal infiltrate, emperipolesis, and hepatocellular rosette formation. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation is now recognised in the histological spectrum of AIH and may represent an early stage of the disease. Liver histology plays a major role in clinical diagnostic scoring systems and is important to confirm or support the clinical diagnosis of AIH. This review focuses on the role of histopathology in AIH and highlights the contribution of histological interpretation to the diagnosis of AIH, differential diagnosis from other entities, recognition of concurrent liver disease, and identification of the so-called overlap or variant syndromes, and addresses the importance of liver biopsy in the management and prognosis of patients with AIH.

A 25-carboxylic ester analog of 1␣,25-dihydroxyvitamin D 3 [1␣,25(OH) 2 D 3 ], ZK159222 (compound 1), was recently described as a novel type of antagonist of 1␣,25(OH) 2 D 3 signaling. In this study five derivatives of compound 1 (compounds 2-6) were selected because of their sensitivity in facilitating complex formation between the 1␣,25(OH) 2 D 3 receptor (VDR) and the retinoid X receptor on a 1␣,25(OH) 2 D 3 response element that was comparable to that of the natural hormone (0.2-0.9 nM). Most derivatives of compound 1 reacted as typical agonists, because they were able to promote ligand-dependent interaction of the VDR with the coactivator TIF2, stabilized the VDR preferentially in its agonistic conformation c1 LPD , and stimulated VDR-dependent gene activity with a potency similar to 1␣,25(OH) 2 D 3 . In contrast, only compound 2 showed the antagonistic profile of compound 1, which includes the incompetence to induce a VDR-TIF2 contact, the stabilization of the antagonistic conformation c2 LPD , and only a very weak and insensitive functional activity. Accordingly, only compounds 1 and 2, but not compounds 3 to 6, showed prominent antagonistic effects in cellular systems. The comparison of the structures of the compounds indicates that the essential requirements for an antagonistic function are a cyclopropyl ring at carbon 25, a hydroxy group at carbon 24, and at least a butylester. Interestingly, compound 2 was an approximately 3 times more sensitive antagonist than compound 1 and even displayed a lower residual agonistic activity. In conclusion, only a very limited number of structural variations of compound 1 are possible to keep its antagonistic profile, but the tools presented here for their in vitro evaluation allow an accurate prediction of the effects and are suited to screening for even more potent 1␣,25(OH) 2 D 3 antagonists.The nuclear hormone 1␣,25-dihydroxyvitamin D 3 [1␣,25(OH) 2 D 3 ] is the natural agonist of the vitamin D 3 receptor (VDR) (Pike, 1991). VDR is a member of the nuclear receptor transcription factor superfamily (Mangelsdorf et al., 1995) and acts preferentially as a heterodimer with the retinoid X receptor (RXR; Carlberg, 1996) on specific DNA sequences in promoter regions of 1␣,25(OH) 2 D 3 target genes, referred to as 1␣,25(OH) 2 D 3 response elements (VDREs) (Carlberg, 1995). The VDR contains a DNA-binding domain (DBD), which is formed by two zinc-finger motifs that are characteristic of the nuclear receptor superfamily (Glass, 1994), and a ligand-binding domain (LBD) that is formed by 12 ␣-helical structures, of which the last one, helix 12, contains a short transactivation function 2 (AF-2) domain (Moras and Gronemeyer, 1998). VDR-RXR-VDRE complexes are the molecular core of DNA-dependent 1␣,25(OH) 2 D 3 -signaling pathways (Carlberg and Polly, 1998) and should be able to explain the physiological actions of 1␣,25(OH) 2 D 3 , which are the regulation of calcium homeostasis and bone mineralization (DeLuca et al., 1990) and the control of cellular growth, different...

Background:Colorectal cancers (CRCs) detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen-detected cancers. The aim was to identify whether this was solely due to the earlier stage shift of these cancers, or whether other factors were involved.Methods:A combination of a regional CRC registry (Northern Colorectal Cancer Audit Group) and the BCSP database were used to identify screen-detected and interval cancers (diagnosed after a negative faecal occult blood test, before the next screening round), diagnosed between April 2007 and March 2010, within the North East of England. For each Dukes' stage, patient demographics, tumour characteristics, and survival rates were compared between these two groups.Results:Overall, 322 screen-detected cancers were compared against 192 interval cancers. Screen-detected Dukes' C and D CRCs had a superior survival rate compared with interval cancers (P=0.014 and P=0.04, respectively). Cox proportional hazards regression showed that Dukes' stage, tumour location, and diagnostic group (HR 0.45, 95% CI 0.29–0.69, P<0.001 for screen-detected CRCs) were all found to have a significant impact on the survival of patients.Conclusions:The improved survival of screen-detected over interval cancers for stages C and D suggest that there may be a biological difference in the cancers in each group. Although lead-time bias may have a role, this may be related to a tumour's propensity to bleed and therefore may reflect detection through current screening tests.

MC903 (calcipotriol) is a synthetic, low calcemic analog of the nuclear hormone 1alpha,25-dihydroxyvitamin D3 and used in the treatment of psoriasis. The beneficial effects of MC903 on psoriasis are based on gene regulatory events. The genomic actions of 1alpha,25-dihydroxyvitamin D3 and its analogs are primarily mediated by a complex of the vitamin D3 receptor and the retinoid X receptor bound to a 1alpha,25-dihydroxyvitamin D3 response element that can be considered as the molecular switch of 1alpha,25-dihydroxyvitamin D3 signaling. In this study, the interaction of MC903 and two new analogs, GS1500 and EB1213, with this molecular switch was compared with that of 1alpha,25-dihydroxyvitamin D3. In DNA-dependent limited protease digestion assays, ligand-dependent gel shift assays and mammalian-one-hybrid assays, all four ligands appeared to be equally sensitive VDR agonists that activated vitamin D3 receptor-retinoid X receptor-1alpha,25-dihydroxyvitamin D3 response element complexes at a concentration of approximately 0.2 nM. The analyzed VDR agonists, however, also showed individual molecular properties, such as a reduced sensitivity in HaCaT cells (MC903), a selectivity for DNA-bound vitamin D3 receptor-retinoid X receptor heterodimers (GS1500) and a long-lasting stabilization of vitamin D3 receptor-retinoid X receptor-1alpha,25-dihydroxyvitamin D3 response element complexes (EB1213). This molecular evaluation demonstrated that the sensitivity in activating the vitamin D3 receptor is already optimal for MC903, but the analog may not be ideal in keeping the receptor active and in selectively triggering 1alpha,25-dihydroxyvitamin D3 signaling pathways.