Current therapies and clinical controversies in the management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology characterized by fibrosing inflammation of the intrahepatic and extrahepatic bile ducts, leading ultimately to cirrhosis and death caused by complications from liver failure if liver transplantation is not peformed. Despite a better understanding of the natural history of the disease, no significant breakthroughs have been made into its pathogenesis. Over the past decade and a half, many clinical trials of medical therapy have been conducted; however, none have demonstrated real efficacy. This reflects our lack of understanding into the basic mechanisms of disease pathogenesis in PSC. Progress has been made in the area of orthotopic liver transplantation for PSC, and to some extent in the diagnosis and management of complications, the most grave of which is the development of cholangiocarcinoma. This review highlights the progress that has been made, describes our current deficiencies, and discusses likely developments in the future. The authors also discuss management controversies and provide current practice guidelines where applicable.     

Benzodiazepines inhibit the rate of neutrophil apoptosis

Background Benzodiazepines, which are commonly administered perioperatively, can depress immune function. Neutrophil apoptosis plays a central role in the regulation of inflammation. This is particularly important during and after surgery. Aim To examine the effects of benzodiazepines (midazolam and diazepam) on neutrophil apoptosis. Methods Venous blood samples were withdrawn from patients scheduled to undergo elective surgery, (a) immediately prior to, and 10 minutes after administration of midazolam 0.2mg/kg intravenously (n=11) and (b) immediately prior to, and 60 minutes after administration of diazepam 10mg po (n=10). Neutrophil apoptosis was measured by Annexin VFITC after 1 and 12 hours in culture. Results The percentage of apoptotic cells was significantly less after midazolam at 12% (11.9) hours in culture compared to pre-midazolam 29.7% (13.3) (p<0.05). After diazepam, the rates of neutrophil apoptosis were also significantly less after 12 hours in culture (p<0.05). Conclusion Administration of benzodiazepines in clinically relevant doses inhibits neutrophil apoptosis. In the perioperative period, this may influence the inflammatory response to surgery.     

AQP4 transfected into mouse cholangiocytes promotes water transport in biliary epithelia

Rodent cholangiocytes express 6 of the 11 known channel proteins called aquaporins (AQPs) that are involved in transcellular water transport in mammals. However, clarifying the role of AQPs in mediating water transport in biliary epithelia has been limited in part because of the absence of physiologically relevant experimental models. In this study, we established a novel AQP4-transfected polarized mouse cholangiocyte cell line suitable for functional studies of transepithelial water transport, and, using this model, we define the importance of this AQP in water transport across biliary epithelia. Polarized normal mouse cholangiocytes (NMCs) lacking endogenous AQP4 were transfected stably with functional AQP4 or cotransfected with functional AQP4 and a transport-deficient AQP4 dominant negative mutant using a retroviral delivery system. In transfected NMCs, AQP4 is expressed on both the mRNA and protein levels and is localized at both the apical and basolateral membranes. In nontransfected NMCs, the transcellular water flow, P(f), value was relatively high (i.e., 16.4 +/- 3.2 microm/sec) and likely was a reflection of endogenous expression of AQP1 and AQP8. In NMCs transfected with AQP4, P(f) increased to 75.7 +/- 1.4 microm/sec, that is, by 4.6-fold, indicating the contribution of AQP4 in channel-mediated water transport across MNCs monolayer. In cotransfected NMCs, AQP4 dominant negative reduced P(f) twofold; no changes in P(f) were observed in NMCs transfected with the empty vector. In conclusion, we developed a novel polarized mouse cholangiocyte monolayer model, allowing direct study of AQP4-mediated water transport by biliary epithelia and generated data providing additional support for the importance of AQP4 in cholangiocyte water transport.     

Solitary pulmonary nodules: CT assessment

Computed tomography (CT) was used to examine 634 solitary pulmonary nodules (SPNs). Each lesion was assessed as benign or indeterminate on the basis of CT criteria. Benign nodules made up 44% of all SPNs and 58% of the 431 that were 2 cm or less in diameter. All malignant SPNs were assessed as indeterminate, and adenocarcinoma (42%) was the most common primary malignancy. A total of 176 (63% of benign SPNs) were correctly assessed as benign by CT. Ninety SPNs assessed as diffusely calcified were not so identified by conventional tomography at outside institutions. An SPN can be reliably assessed by CT as benign if it exhibits high attenuation values, exceeding a critical level and distributed diffusely throughout a CT section through the center of the lesion and a well-defined edge. Although 38 of 283 (13.4%) primary lung cancers contained localized calcification, there was no significant overlap with the diffuse calcification of benign lesions. Central carcinoid tumors may contain focal ossification, but such lesions may be recognized by noting the proximity of larger bronchi. Assessment of SPNs by CT is most effective for lesions 2.0 cm or less in diameter. For larger lesions, the frequency of benign disease was decreased (14.3% of 203), as was the percentage of benign SPNs correctly assessed as benign by CT (37.9%).