Endotoxin and CD14 in the progression of biliary atresia

<p>Abstract</p> <p>Background</p> <p>Biliary atresia (BA) is a typical cholestatic neonatal disease, characterized by obliteration of intra- and/or extra-hepatic bile ducts. However, the mechanisms contributing to the pathogenesis of BA remain uncertain. Because of decreased bile flow, infectious complications and damaging endotoxemia occur frequently in patients with BA. The aim of this study was to investigate endotoxin levels in patients with BA and the relation of these levels with the expression of the endotoxin receptor, CD14.</p> <p>Methods</p> <p>The plasma levels of endotoxin and soluble CD14 were measured with a pyrochrome Limulus amebocyte lysate assay and enzyme-linked immunosorbent assay in patients with early-stage BA when they received the Kasai procedure (KP), in patients who were jaundice-free post-KP and followed-up at the outpatient department, in patients with late-stage BA when they received liver transplantation, and in patients with choledochal cysts. The correlation of CD14 expression with endotoxin levels in rats following common bile duct ligation was investigated.</p> <p>Results</p> <p>The results demonstrated a significantly higher hepatic CD14 mRNA and soluble CD14 plasma levels in patients with early-stage BA relative to those with late-stage BA. However, plasma endotoxin levels were significantly higher in both the early and late stages of BA relative to controls. In rat model, the results demonstrated that both endotoxin and CD14 levels were significantly increased in liver tissues of rats following bile duct ligation.</p> <p>Conclusions</p> <p>The significant increase in plasma endotoxin and soluble CD14 levels during BA implies a possible involvement of endotoxin stimulated CD14 production by hepatocytes in the early stage of BA for removal of endotoxin; whereas, endotoxin signaling likely induced liver injury and impaired soluble CD14 synthesis in the late stages of BA.</p

TLR7 and TLR8 Gene Variations and Susceptibility to Hepatitis C Virus Infection

Toll-like receptors (TLRs) play pivotal roles in the innate immune system and control inflammatory responses and adaptive immunity. We previously evaluated associations between TLR7 and TLR8 gene SNPs and susceptibility to hepatitis C virus (HCV) infection. Our results suggested that TLR7IVS2-151G and TLR8-129G alleles were present at higher frequency in males of an HCV-infected group as compared to a control group (24.1% vs. 14.4%, p = 0.028; 17.6% vs. 6.8%, p = 0.004, respectively). Based upon their recognition of single stranded viral RNA, this suggested that TLR7 and TLR8 played a significant role in anti-HCV immune responses. Here, we studied the functional effects of these polymorphisms by analyzing the mRNA expressions of TLR7 and TLR8 and cytokine production induced ex vivo by TLR7- and TLR8-specific agonists using whole blood of subjects with different genotypes. The percentage of CD14+ cells from those with an AG haplotype that expressed TLR7 and TLR8 was significantly lower, but higher in intensity compared to cells from those with GG and AC haplotypes. Cells from those with an AG haplotype produced more IFN-α and less amounts of pro-inflammatory cytokines upon stimulation. This suggests that variations in TLR7 and TLR8 genes might impair immune responses during HCV infection

Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Cholestasis is frequently related to endotoxemia and inflammatory response. Our previous investigation revealed a significant increase in plasma endotoxin and CD14 levels during biliary atresia. We therefore propose that lipopolysacharides (LPS) may stimulate CD14 production in liver cells and promote the removal of endotoxins. The aims of this study are to test the hypothesis that CD14 is upregulated by LPS and investigate the pathophysiological role of CD14 production during cholestasis. Using Western blotting, qRT-PCR, and promoter activity assay, we demonstrated that LPS was associated with a significant increase in CD14 and MD2 protein and mRNA expression and CD14 promoter activity in C9 rat hepatocytes but not in the HSC-T6 hepatic stellate cell line in vitro. To correlate CD14 expression and endotoxin sensitivity, in vivo biliary LPS administration was performed on rats two weeks after they were subjected to bile duct ligation (BDL) or a sham operation. CD14 expression and endotoxin levels were found to significantly increase after LPS administration in BDL rats. These returned to basal levels after 24 h. In contrast, although endotoxin levels were increased in sham-operated rats given LPS, no increase in CD14 expression was observed. However, mortality within 24 h was more frequent in the BDL animals than in the sham-operated group. In conclusion, cholestasis and LPS stimulation were here found to upregulate hepatic CD14 expression, which may have led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and death in BDL rats

Experimental Phage Therapy in Treating Klebsiella pneumoniae-Mediated Liver Abscesses and Bacteremia in Mice▿

Intragastric inoculation of mice with Klebsiella pneumoniae can cause liver abscesses, necrosis of liver tissues, and bacteremia. A newly isolated phage (φNK5) with lytic activity for K. pneumoniae was used to treat K. pneumoniae infection in an intragastric model. Both intraperitoneal and intragastric administration of a single dose of φNK5 lower than 2 × 108 PFU at 30 min after K. pneumoniae infection was able to protect mice from death in a dose-dependent manner, but the efficacy achieved with a low dose of φNK5 by intragastric treatment provided the more significant protection. Phage φNK5 administered as late as 24 h after K. pneumoniae inoculation was still protective, while intraperitoneal treatment with phage was more efficient than intragastric treatment as a result of the dissemination of bacteria into the circulation at 24 h postinfection. Surveys of bacterial counts for mice treated with φNK5 by the intraperitoneal route revealed that the bacteria were eliminated effectively from both blood and liver tissue. K. pneumoniae-induced liver injury, such as liver necrosis, as well as blood levels of aspartate aminotransferase and alanine aminotransferase and inflammatory cytokine production, was significantly inhibited by φNK5 treatment. These data suggest that a low dose of φNK5 is a potential therapeutic agent for K. pneumoniae-induced liver infection

Percutaneous Ultrasound-guided Radiofrequency Ablation of Intrahepatic Cholangiocarcinoma

This study evaluated the clinical applications, treatment effects, and complications of percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) of intrahepatic cholangiocarcinoma. Ten patients (6 men and 4 women) with histologically proven cholangiocarcinoma underwent US-guided percutaneous RFA. Tumor diameters ranged from 1.9 to 6.8 cm. There were 12 sessions of RFA for 10 solitary cholangiocarcinomas. Eight patients were treated at a single session and two patients had two treatment sessions. The efficacy of RFA was evaluated using contrast-enhanced dynamic computed tomography 1 month after treatment and then every 3 months. Complete necrosis was defined as lack of contrast enhancement of the treated region. There was complete necrosis in eight tumors. In two patients with large tumors (4.7 and 6.8 cm in diameter), enhancement of residual tissue was observed after RFA treatment, indicating residual tumor. Complete necrosis was seen in all five tumors (100%) with diameters of 3.0 cm or less, two of three tumors (67%) with diameters of 3.1-5.0 cm, and one of two tumors (50%) with diameters of more than 5.0 cm. A large biloma was found in one patient after treatment. No serious complications occurred in the other nine patients. In conclusion, percutaneous RFA is effective and successful in the treatment of intrahepatic cholangiocarcinoma of 3 cm or less and satisfactory for tumors of 3-5 cm. The rate of serious complications after RFA is low. Further follow-up is necessary to determine long-term efficacy

Percutaneous Radiofrequency Ablation of Renal Cell Carcinoma

Preliminary data regarding the use of percutaneous radiofrequency ablation (RFA) for the treatment of renal cell carcinoma (RCC) are encouraging, and show the technique to be associated with minimal morbidity. Thus, the current study was designed to evaluate the clinical applications, treatment efficacy, and complications of percutaneous RFA in RCC. Methods: From February 2003 to February 2004, 12 consecutive patients with histopathologically proven RCC underwent imaging-guided percutaneous RFA. The mean age of the patients (8 men and 4 women) was 76 years (range, 56-87 years), and mean tumor diameter was 3.7 cm (range, 2.2-8.0 cm). The efficacy of RFA was evaluated with contrast-enhanced, dynamic computed tomography (CT) performed 1 month after treatment, and then every 3 months. A Radionics device with an internally cooled electrode was used in 7 patients, and a radiofrequency interstitial tissue ablation (RITA) device with an expandable needle electrode was used in 5. Complete necrosis was defined as a lack of contrast enhancement in the treated region on follow-up CT studies. Results: Overall, 16 sessions of RFA were performed for 12 solitary renal tumors in 12 patients: 8 patients underwent a single RFA session, whereas 4 had 2 sessions. Dynamic CT after RFA showed complete necrosis in 9 of 12 tumors. In 3 patients with tumors of 4.5-8.0 cm in diameter, enhancement of residual tissue was observed after RFA treatment, thus indicating residual tumor. Complete tumor necrosis was seen in all 5 tumors (100%) of diameter = 3.0 cm; 3 of 4 tumors (75%) of diameter 3.1-5.0 cm; and 1 of 3 tumors (33%) of diameter > 5.0 cm. A big subcapsular hematoma, which was found in 1 patient after RFA, resolved completely within 10 months without treatment; no serious complications occurred in the other 11 patients. Conclusion: Percutaneous RFA is effective in the treatment of RCC. It is most successful for tumors not larger than 3 cm in diameter, and has a satisfactory success rate in tumors of 3-5 cm in diameter. The rate of serious complications of RFA is low. Further studies are necessary to determine the long-term efficacy of RFA in RCC

Effects of Mind–Body Movements on Balance Function in Stroke Survivors: A Meta-Analysis of Randomized Controlled Trials

Objective: We performed a systematic review with meta-analysis and meta-regression to determine if mind&ndash;body movements (MBM) could be effective in rehabilitating balance function among stroke survivors. Methods: A literature search was conducted using major Chinese and English electronic databases from an inception until January 2018. Randomized controlled studies were included in our meta-analysis. Data was independently extracted by two review authors using a pre-developed table and confirmed by a third party to reach a consensus. Pooled effect size (Hedge&rsquo;s g) was computed while the random-effect model was set. Results: The meta-analytic results showed a significant benefit of the MBM intervention on increased balance function compared to the control groups (Hedge&rsquo;s g = 1.59, CI 0.98 to 2.19, p &lt; 0.001, I2 = 94.95%). Additionally, the meta-regression indicated that the total number of sessions (&beta; = 0.00142, 95% CI 0.0039 to 0.0244, p = 0.0067) and dose of weekly training (&beta; = 0.00776, 95% CI 0.00579 to 0.00972, p = 0.00) had significantly positive effects on balance function. Conclusions: The study encouraging findings indicate the rehabilitative effect of a MBM intervention for balance function in stroke survivors. However, there were significant limitations in the design among several of the included trials. Additional studies with more robust methodologies are needed to provide a more definitive conclusion