Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl₄ administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2^−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl₄; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

Osteochondrosis is a condition involving defective endochondral ossification and retention of cartilage in subchondral bone. The pathophysiology of this condition is poorly characterized, but it has been proposed that the fundamental defect is failure of chondrocyte hypertrophy. The aim of the current study was to characterize phenotypic changes in chondrocytes associated with the initiation of osteochondrosis. Early lesions were induced in an equine model of osteochondrosis by feeding foals a high energy diet for 8 or 15 weeks. Lesions in articular‐epiphyseal growth cartilage were examined histologically and by quantitative PCR analysis of expression of a number of genes representative of pathways that regulate chondrocyte behavior during endochondral ossification. There were more cells present in clusters in the lesions compared to normal articular cartilage. Expression of matrix metalloproteinase‐13, type I collagen, type X collagen, and Runx2 mRNA was significantly greater in the lesions compared to normal cartilage from the same joint. Expression of vascular endothelial growth factor, type II collagen, connective tissue growth factor, aggrecan, Sox9, and fibroblast growth factor receptor 3 mRNA was not significantly different in lesions than in control cartilage. These observations suggest that osteochondrosis does not result from failure of chondrocytes to undergo hypertrophy. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 452–457, 2009

Information on the digestive system of the reptiles is based on relatively few studies on some of the now present 7500 reptilian species. Yet, the gap between our understanding of the major similarities and / or differences between the mammalian and reptilian digestive system does not seem satisfiable. The aim of the current study was to investigate the morphological structure of one of the most common reptilian species in Egypt, Varanus niloticus or Nile monitor. Specimens for histological examination were collected from the esophageus, stomach and small intestine of the Nile monitor and processed for paraffin embedding. Sections were stained with haematoxylin and eosin for general morpho-logy. Periodic Acid Schiff's (PAS) and Alcian Blue (AB) staining methods were applied to detect the different types of the mucous contents of the gastro-intestinal tract. Some paraffin sections were stained with Grimelius silver impregnation technique for localization of the enteroendocrine cells. The folded esophageal mucosa had ciliated columnar epithelium with muc- ous secreting goblet cells, which stained positive with PAS and AB. The esophageal mucosa was folded and the lining epithelium was ciliated columnar epithelium with mucous se- creting goblet cells, which stained posi- tive with PAS and AB. The stomach was divided into fundic and pyloric regions. The mucosa was thrown into gastric pits, into which the gastric glands opened. The surface epithelium was mucous secreting co- lumnar cells and stained positive with PAS but negative with AB. The fundic gland was made by oxynticopeptic cells and few mucous cells, while the entire pyloric gland was made by mucous cells stained positive for both PAS and AB. The small intestine showed many villi but occasional poorly developed intestinal crypts were. The intestinal mucosa was lined with absorptive columnar epithelium with goblet cells, which stained positive with PAS and AB. Enteroendocrine cells were of dif- ferent shapes; rounded, spindle, oval or pyramidal and were localized in the surface epithelium of the esophagus and small intestine, and among the cells of the gastric glands. This is the first report about the histology of the alimentary tract of the Varanus niloticus. Further studies are required for investigation the possibility of using this animal as a model for studying the regulation of the digestive processes as well as to understand the theory of development.