Spontaneous remission of obstructive jaundice in rats: Selection of experimental models.

The aim of the present study was to evaluate the prevalence and causes of spontaneous remission of obstructive jaundice in rats. Healthy male and female Wistar rats (180-220 g) were randomly assigned to receive common bile duct ligation (CBDL) and transection (group A), CBDL only (group B), or CBD dissection without ligation or transection (control group C; n=36 in each group). There was a difference in eye and skin jaundice prevalence between groups A and B from 14 days after surgery. The level of total bilirubin (TB) did not continue to increase in group A and began to decrease in the majority of rats in group B (P<0.05 vs. group B). At day 21 after surgery, the TB level returned to normal in group B and no significant difference was observed compared with group C. At day 21 after surgery, significant dilatation of bile ducts above the ligature was observed in group A following cholangiography with 38% meglumine diatrizoate and this contrast agent did not spread to other sites. Slight dilatation of the proximal bile ducts was observed in group B and the contrast agent entered the intestinal lumen through the omental ducts adhering to the porta hepatis. After 14 days of surgery, there were 36 rats in group A and B, and 17 rats exhibited spontaneous regression of jaundice. Overall, 47.2% (17/36) of rats experienced spontaneous remission of obstructive jaundice, 82.4% (14/17) of which underwent ligation only. The spontaneous remission of jaundice may have been caused by shunting through very small bile ducts or omental ducts adhering to the porta hepatis. If a model of biliary obstruction is to be established in future research, a model of CBDL and transection is preferable. In this case, jaundice reduction surgery should be performed 14 days after establishment of the model.

Causes of peripheral cytopenia in hepatitic cirrhosis and portal hypertensive splenomegaly.

The clinical data of 183 patients with hepatitic cirrhosis and portal hypertensive splenomegaly complicated by peripheral cytopenia were retrospectively analyzed to investigate the causes of peripheral cytopenia, as well as the proportion of the causes in these patients. All patients underwent splenectomy. Before operation, these patients had one or more types of peripheral cytopenia (cumulative cytopenia: 390 patient-times). After splenectomy, blood counts in 79.2% (309/390) returned to normal, while in 15.9% (62/390) they increased but failed to reach to normal levels, and in 4.9% (19/390) they became lower than before the operations. For the last group of patients ( n = 19), long-term follow-up showed that blood counts returned to normal in five patients. In other words, in 80.5% [(309 + 5)/390 or 314/390] of patient-times, the peripheral cytopenia was due to hypersplenism, in 15.9% it was due to a combination of factors, and in 3.6% [14/390] it had nothing to do with the hypersplenism. Thus, hypersplenism is a major cause, but not the only cause, of peripheral cytopenia in patients with hepatic cirrhosis and portal hypertensive splenomegaly, and splenectormy is an effective treatment for these patients. Impact statement For a long time, the development of peripheral cytopenias as a complication to cirrhotic portal hypertension has been attributed to hypersplenism; however, this has never been fully demonstrated. Dameshek summarized that hypersplenism should be diagnosed by the presence of four conditions: (a) mono- or multi-lineage peripheral cytopenias; (b) compensatory hyperplasia of bone marrow; (c) splenomegaly; and (d) correction of cytopenias after splenectomy. We retrospectively analyzed the clinical data from 183 surgical patients, and found that 80.5% of peripheral cytopenias was caused by hypersplenism, 16% by a combination of factors, and 3.5% by other factors unrelated to hypersplenism. As the first quantitative findings in this field, our results verify that hypersplenism is a major, but not exclusive, cause of peripheral cytopenias, and provides important clinical evidence for investigating the cause of peripheral cytopenias.

Hypersplenism: History and current status.

Hypersplenism is a common disorder characterized by an enlarged spleen which causes rapid and premature destruction of blood cells. This review summarizes the history of hypersplenism, discuss its classification and pathogenesis, and examines its diagnosis and treatment options. We performed a comprehensive literature search using PubMed, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) database, reviewed hypersplenism-related articles and summarized the major findings. According to its etiological causes, hypersplenism is characterized by splenomegaly and peripheral cytopenias. It can be classified into three categories: i) primary hypersplenism; ii) secondary hypersplenism; and iii) occult hypersplenism. A number of mechanisms causing hypersplenism have been identified, and mainly involve retention in the spleen, phagocytosis, and autoimmunity. Treatment options for hypersplenism include etiological treatment, non-surgical treatment, total splenectomy and liver transplantation. In any case, treatment should be individualized for each patient.

Chlorogenic acid protects against cholestatic liver injury in rats.

The aim of this study was to investigate the protective effect of chlorogenic acid (CA) on liver injury caused by bile duct ligation (BDL), as well as the potential mechanism. Permanent bile duct ligation induced liver injury was evaluated by liver index, liver function and pathological observation. Oral administration of CA for 3 weeks markedly attenuated liver swelling and fibrosis. Blood biochemistry results revealed that CA decreased alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin and total bile acid. PCR analysis indicated that collagen I, collagen III, transforming growth factor and vascular endothelial growth factor mRNA were increased markedly by BDL treatment but these increases were suppressed by CA. Additionally, CA effectively alleviated the expression of α-smooth muscle actin induced by BDL. Taken together, our data indicate that CA can efficiently inhibit BDL-induced liver injury in rats, which is a candidate drug for preventing liver injury against cholestasis.

Grading of peripheral cytopenias caused by nonalcoholic cirrhotic portal hypertension and its clinical significance.

This study investigates peripheral cytopenias in patients with splenomegaly caused by nonalcoholic cirrhotic portal hypertension. Data from 330 splenomegaly cases caused by nonalcoholic cirrhotic portal hypertension were collected and analyzed using univariate and multivariate analysis. The cytopenias were scored and graded according to the F value of the multiple linear regression equation. Based on the severity of thrombocytopenia, cytopenia was graded as mild, moderate, or severe, and determined by a score of <2 points, 2-3 points, and >3 points. 30 % of the patients had monolineage cytopenias, 35.8 % had bilineage cytopenias, and 34.2 % had trilineage cytopenias. All patients were treated surgically. In the univariate analysis, the severity of erythropenia was different in the surgical outcome when compared to the intra-group (P < 0.05). In the multivariate analysis, thrombocytopenia was different in the surgical outcomes when compared with leukopenia and erythropenia (P < 0.05). There was a significant difference in surgical outcomes between the three grades (mild, moderate, and severe) of cytopenia (P < 0.05). Peripheral cytopenias have a significant impact on the clinical outcomes. The more severe the cytopenias, the worse the surgical outcomes are. Thrombocytopenia is a major factor influencing surgical outcomes. The thrombocytopenia-based three-level grading of cytopenias provides a basis for analyzing individual cases, planning treatment, and assessing prognosis in clinical practice.

Clinical study on the relationship between hematocytopenia and splenomegaly caused by cirrhotic portal hypertension.

This clinical study was designed to evaluate the presence of hematocytopenia in patients with splenomegaly caused by non-alcoholic cirrhotic portal hypertension. For this purpose, we randomly selected 358 patients with splenomegaly caused by non-alcoholic cirrhotic portal hypertension and admitted to the clinical data in our hospital between January 1991 and June 2009. Among these 358 patients, 322 patients (90.0 %) showed hematocytopenia, including multi-hemocyte decrease in 206 patients (i.e., 89 patients with a decrease in white blood cell count (WBC) + red blood cell count (RBC) + platelets count (PLT)); 52 patients with WBC + PLT decrease; 29 patients with RBC + PLT decrease; and 36 patients with WBC + RBC decrease) and single-hemocyte decrease in 116 patients (i.e., 31 cases with single PLT decrease; 29 cases with single WBC decrease; and 56 patients with single RBC decrease). After splenectomy, 36 patients (10.0 %) with hematocytopenia presented a statistical improvement of blood cell to normal level (P < 0.05), while 32 patients did not have any change as compared to pre-operative one (P > 0.05). It has to be noted that 4 patients did not received any surgery. Hematocytopenia was not detected in all the patients with splenomegaly caused by cirrhotic portal hypertension, thus it is probably a complication of splenomegaly but not an inevitable manifestation. It was concluded that splenectomy could be an effective treatment for splenomegaly associated with hematocytopenia, but patients without hematocytopenia could choose a non-surgical alternative treatment.

Peripheral blood cell variations in cirrhotic portal hypertension patients with hypersplenism.

OBJECTIVE: To explore peripheral blood cell variations in hepatic cirrhosis portal hypertension patients with hypersplenism. METHODS: Clinical data of 322 hypersplenism patients with decreased peripheral blood cells, admitted with cirrhotic portal hypertension, was retrospectively studied over the last 17 years. RESULTS: In 64% (206/322) of patients, more than 2 kinds of blood cell were decreased, including 89 cases of pancytopenia (43.2%), 52 cases of WBC + PLT decrease (25.2%), 29 cases of RBC + PLT decrease (14.1%), and 36 cases of WBC + RBC decrease (17.5%); in 36% (116/322) of patients, single type blood cell decrease occurred, including 31 cases of PLT decrease (26.7%), 29 cases of WBC decrease (25%) and 56 cases of RBC decrease (48.3%). Of 227 routine bone marrow examinations, bone marrow hyperplasia was observed in 118 cases (52.0%), the remainder showed no hyperplasia. For the distinct scope and extent of peripheralblood cell decreases, preoperative blood component transfusions were carried out, then treated by surgery, after whole group splenectomy, the peripheral blood cell count was significantly higher (P<0.05). CONCLUSIONS: Of portal hypertensive patients with splenomegaly and hypersplenism, 64% have simultaneous decrease in various blood cells, 36% have decrease in single type blood cells, 52% of patients have bone marrow hyperplasia. A splenectomy can significantly increase the reduction of peripheral blood cells.

Gemcitabine resistance induced by interaction between alternatively spliced segment of tenascin-C and annexin A2 in pancreatic cancer cells.

Pancreatic cancer is the fourth leading cause of cancer-related death in the western countries and it is resistant to almost all cytotoxic drugs. In the current study, we explored the gemcitabine resistance induced by the interaction between Annexin A2 (ANXA2) and alternatively spliced segment of tenascin-C (TNfnA-D). In the pancreatic cancer cell culture system in vitro, it was proved that exogenous recombinant TNfnA-D combined with the cell surface ANXA2 specifically and their interaction suppressed gemcitabine-induced cytotoxicity on pancreatic cancer cells in a dose-dependent manner. Meanwhile, the TNfnA-D/ANXA2 interaction increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, inhibitory kappaB (IkappaB) kinase alpha/beta (IKKalpha/beta), IkappaBalpha, and p65 nuclear factor-kappaB (NF-kappaB) significantly. Inhibition of Akt and PI3K with their specific inhibitors partially reversed the suppression of gemcitabine-induced cytotoxicity elicited by TNfnA-D/ANXA2 interaction. Activation of p65 NF-kappaB was dependent on the phosphorylation of PI3K/Akt. The phosphorylated IKKalpha/beta induced the phosphorylation and degradation of IkappaBalpha, the sequential phosphorylation, nuclear translocation and activation of p65 NF-kappaB. Pyrrolidine dithiocarbamate (PDTC) effectively blocked the activity of p65 NF-kappaB in response to TNfnA-D. Down-regulation of p65 NF-kappaB with its specific small interfering RNA (siRNA) restored the gemcitabine-induced cytotoxicity suppressed by TNfnA-D/ANXA2 interaction. For the first time, this study show that ANXA2/TNfnA-D interaction induced gemcitabine resistance via the canonical PI3K/Akt/NF-kappaB signaling pathways in pancreatic cancer cells. Therefore, therapy targeting ANXA2/TNfnA-D and/or p65 NF-kappaB may have potential clinical application for patients with pancreatic cancers.

[Historical review of Portal Hypertension].

It has been more than 100 years since the nomenclature Portal Hypertension was put forward, during which the treatment of Portal Hypertension in medical circles experienced a gradual perfection. Reviewing the developmental progress can help to improve the treatment of Portal Hypertension.

Effect of L-arginine on calcium in hepatic mitochondrion in rats with obstructive jaundice.

BACKGROUND: There is much debate over the regulation of mitochondrial calcium overload and reducing the impairment of energy metabolism in hepatic cells. It has not been reported whether L-arginine (L-Arg) can affect hepatic mitochondrial calcium overload. This study was undertaken to investigate the protective effect of L-Arg on Ca2+ handling of hepatic mitochondrion in rats with obstructive jaundice and to clarify its possible mechanism. METHODS: Seventy-two male SD rats were randomly divided into 3 groups: sham operation+normal saline group (SO group), common bile duct ligation+normal saline group (BDL group), and common bile duct ligation+ L-Arg group (L-Arg group). The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and Ca2+ in rat hepatic mitochondrion were examined at the 7th, 14th and 21st day after operation. RESULTS: The Ca2+ and MDA levels of hepatic mitochondrion increased significantly but their SOD content decreased markedly at each time point in the BDL group. Except at the 21st day, the Ca2+ and MDA, contents of hepatic mitochondrion were significantly lower, and SOD concentrations were higher in the L-Arg group than those in the BDL group at the 7th and 14th day (P<0.01). CONCLUSION: L-Arg has a protective effect on mitochondrion in the early and mid stages of obstructive jaundice.