Caroli's Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model

Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD). It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF). The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK) rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats

Elevated circulating level of P2X7 receptor is related to severity of coronary artery stenosis and prognosis of acute myocardial infarction

Background: Acute myocardial infarction (AMI) is a severely life-threatening cardiovascular disease. Previous research has identified an association between the P2X7 receptor (P2X7R) and the development of atherosclerosis. However, the correlation of its expression with the clinical prognosis of patients with AMI remains unclear. The present study aimed to investigate the potential role of P2X7R in Chinese patients with AMI. Methods: Seventy-nine patients with AMI and 48 controls were consecutively enrolled in this prospective observational study. Circulating P2X7R mRNA expression levels and other clinical variables were determined upon admission to the hospital. Patients were followed up for 360 days, and the end-point was considered as the occurrence of major adverse cardiovascular events (MACE). Results: Circulating P2X7R mRNA expression level in peripheral blood mononuclear cells of patients with AMI were significantly higher than those in controls and had promising diagnostic ability of AMI with an area under the curve of 0.928. Furthermore, P2X7R was demonstrated to be correlated positively with the severity of coronary artery stenosis. Additionally, this is the first study to indicate that higher P2X7R mRNA expression is associated with a higher rate of MACE within 360 days after AMI. Conclusions: The present study showed that the circulating level of P2X7R was elevated in AMI patients and was closely associated with the severity of coronary artery stenosis and prognosis of AMI

Roles of moisture and cyclic loading in microstructures and their effects on mechanical properties for typical Chinese bituminous coals

This work aimed at studying the roles of moisture and cyclic loading in microstructures and their effects on mechanical properties for typical Chinese bituminous coals. Different relative moisture contents (100%, 75%, 50%, 25%, and 0%) for Shenmu coal (SM), Hongshaquan coal (HSQ), and Wucaiwan coal (WCW) were chosen to study the effects of moisture. The raw SM was then further selected to investigate the effects of cyclic loading. Images of coals surfaces and mechanical properties during simulated crushing process were recorded and combined to be analyzed. The results showed that the moisture possessed significant effects on coal mechanical properties, which strongly depended on their porosities. As for low porosity coal (SM), the adsorption of moisture can soften and lubricate the microstructures, weakening mechanical properties. While the drying process would destroy the microstructures and decease mechanical properties for high porosity coals (HSQ and WCW). Under the cyclic loading process, the cumulative effects of strain showed a step-up state and the first cyclic loading can typically cause the biggest change of microstructures and produce the largest strain under different stress levels. Finally, a normalized quantitative relationship ([fórmula]) between the relative fractal dimension and relative stress was built

Complications after radical gastrectomy following FOLFOX7 neoadjuvant chemotherapy for gastric cancer

<p>Abstract</p> <p>Background</p> <p>This study assessed the postoperative morbidity and mortality occurring in the first 30 days after radical gastrectomy by comparing gastric cancer patients who did or did not receive the FOLFOX7 regimen of neoadjuvant chemotherapy.</p> <p>Methods</p> <p>We completed a retrospective analysis of 377 patients after their radical gastrectomies were performed in our department between 2005 and 2009. Two groups of patients were studied: the SURG group received surgical treatment immediately after diagnosis; the NACT underwent surgery after 2-6 cycles of neoadjuvant chemotherapy.</p> <p>Results</p> <p>There were 267 patients in the SURG group and 110 patients in the NACT group. The NACT group had more proximal tumours (P = 0.000), more total/proximal gastrectomies (P = 0.000) and longer operative time (P = 0.005) than the SURG group. Morbidity was 10.0% in the NACT patients and 17.2% in the SURG patients (P = 0.075). There were two cases of postoperative death, both in the SURG group (P = 1.000). No changes in complications or mortality rate were observed between the SURG and NACT groups.</p> <p>Conclusion</p> <p>The FOLFOX7 neoadjuvant chemotherapy is not associated with increased postoperative morbidity, indicating that the FOLFOX7 neoadjuvant chemotherapy is a safe choice for the treatment of local advanced gastric cancer.</p

Optimization of a Fuel Assembly for Supercritical Water-Cooled Reactor CSR1000

As one of the Generation IV nuclear reactors, the SCWR (supercritical water-cooled reactor) has high economy and safety margin, good mechanical properties for its high thermal efficiency, and simplified structure design. As the key component of nuclear reactor, the fuel assembly has always been the main issue for the design of the SCWR. The design of the fuel assembly for CSR1000 proposed by the Nuclear Power Institute of China (NPIC) has been optimized and presented in this study, which is composed of four subassemblies welded by four filler strips and guide thimbles arranged close together in the cross-shaped passage. Aiming at improving the hydraulic buffer performance of the cruciform control rod, the scram time and terminal velocity of control rod assembly were calculated to assess the scram performance based on the computational fluid dynamics and dynamic mesh method, and the mechanical property and neutronic performance of assemblies were also investigated. It has been demonstrated that the optimized fuel assembly had good feasibility and performance, which was a promising design for CSR1000

Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: Molecular mechanism of IgG4 reaction in cancer tissue

IgG4 reactions consisting of marked infiltration by immunoglobulin G4 (IgG4)-positive plasma cells in affected organs is found in cancer patients as well as patients with IgG4-related diseases. Notably, extrahepatic cholangiocarcinomas accompanying marked IgG4 reactions clinicopathologically mimic IgG4-related sclerosing cholangitis. The regulatory cytokine interleukin (IL)-10 is thought to induce the differentiation of IgG4-positive cells. In this study, to clarify the mechanism of the IgG4 reaction in extrahepatic cholangiocarcinoma, we investigated nonprofessional antigen-presenting cells (APCs) generating IL-10-producing regulatory T cells (anergy T cells) and Foxp3-positive regulatory cells producing IL-10. Immunohistochemistry targeting IgG4, HLA-DR, CD80, CD86, and Foxp3 was performed using 54 cholangiocarcinoma specimens from 24 patients with gallbladder cancer, 22 patients with common bile duct cancer, and eight patients with cancer of the Papilla of Vater. Moreover, a molecular analysis of Foxp3 and IL-10 was performed using a cultured human cholangiocarcinoma cell line. Consequently, 43% of the cholangiocarcinomas were found to be abundant in IgG4. Those expressing HLA-DR but lacking costimulatory molecules (CD80 and CD86) and those expressing Foxp3 detected by an antibody recognizing the N terminus accounted for 54% and 39% of cases, respectively. Moreover, the number of IgG4-positive cells was larger in these cases than in other groups. In cultured cells, the presence of a splicing variant of Foxp3 messenger RNA and the expression of IL-10 were demonstrated. Conclusion: Extrahepatic cholangiocarcinoma is often accompanied by significant infiltration of IgG4-positive cells. Cholangiocarcinoma cells could play the role of nonprofessional APCs and Foxp3-positive regulatory cells, inducing IgG4 reactions via the production of IL-10 indirectly and directly, respectively. © 2012 American Association for the Study of Liver Diseases

A systemic administration of liposomal curcumin inhibits radiation pneumonitis and sensitizes lung carcinoma to radiation

Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application

Case of telangiectatic/inflammatory hepatocellular adenoma arising in a patient with primary sclerosing cholangitis

Hepatocellular adenomas (HCA) have been recently identified as a heterogeneous group, differing based on genotypic as well as morphological characteristics. HCA are most frequently found in women on oral contraception. A type of HCA, inflammatory HCA, is also known as telangiectatic HCA and was previously referred to as telangiectatic focal nodular hyperplasia. We present the first case of HCA arising from the liver with primary sclerosing cholangitis (PSC). This case is a 30-year-old man with a past medical history of PSC, ulcerative colitis and diabetes mellitus. A routine ultrasonography for PSC detected the gradually enlarged intrahepatic mass. Liver biopsy could reveal the diagnosis of telangiectatic/ inflammatory HCA by morphological and immunohistochemical analyses. Partial hepatectomy was performed and the resected liver was pathologically diagnosed as the telangiectatic/inflammatory HCA arising in PSC. This is the first case report of such an association and here we review the current developments and published work of this rare tumor and the association with an activated inflammatory related tumorogenic pathway and PSC. © 2012 The Japan Society of Hepatology

Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis

金沢大学医薬保健研究域医学系Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011