Levels of 8-OxodG Predict Hepatobiliary Pathology in Opisthorchis viverrini Endemic Settings in Thailand.

Opisthorchis viverrini is distinct among helminth infections as it drives a chronic inflammatory response in the intrahepatic bile duct that progresses from advanced periductal fibrosis (APF) to cholangiocarcinoma (CCA). Extensive research shows that oxidative stress (OS) plays a critical role in the transition from chronic O. viverrini infection to CCA. OS also results in the excision of a modified DNA lesion (8-oxodG) into urine, the levels of which can be detected by immunoassay. Herein, we measured concentrations of urine 8-oxodG by immunoassay from the following four groups in the Khon Kaen Cancer Cohort study: (1) O. viverrini negative individuals, (2) O. viverrini positive individuals with no APF as determined by abdominal ultrasound, (3) O. viverrini positive individuals with APF as determined by abdominal ultrasound, and (4) O. viverrini induced cases of CCA. A logistic regression model was used to evaluate the utility of creatinine-adjusted urinary 8-oxodG among these groups, along with demographic, behavioral, and immunological risk factors. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive accuracy of urinary 8-oxodG for APF and CCA. Elevated concentrations of 8-oxodG in urine positively associated with APF and CCA in a strongly dose-dependent manner. Urinary 8-oxodG concentrations also accurately predicted whether an individual presented with APF or CCA compared to O. viverrini infected individuals without these pathologies. In conclusion, urinary 8-oxodG is a robust \u27candidate\u27 biomarker of the progression of APF and CCA from chronic opisthorchiasis, which is indicative of the critical role that OS plays in both of these advanced hepatobiliary pathologies. The findings also confirm our previous observations that severe liver pathology occurs early and asymptomatically in residents of O. viverrini endemic regions, where individuals are infected for years (often decades) with this food-borne pathogen. These findings also contribute to an expanding literature on 8-oxodG in an easily accessible bodily fluid (e.g., urine) as a biomarker in the multistage process of inflammation, fibrogenesis, and infection-induced cancer

Microproteinuria during Opisthorchis viverrini infection: A biomarker for advanced renal and hepatobiliary pathologies from chronic Opisthorchiasis

Approximately 680 million people are at risk of infection with Opisthorchis viverrini (OV) andClonorchis sinensis, with an estimated 10 million infected with OV in Southeast Asia alone. While opisthorchiasis is associated with hepatobiliary pathologies, such as advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), animal models of OV infection show that immune-complex glomerulonephritis is an important renal pathology that develops simultaneously with hepatobiliary pathologies. A cardinal sign of immune-complex glomerulonephritis is the urinary excretion of immunoglobulin G (IgG) (microproteinuria). In community-based studies in OV endemic areas along the Chi River in northeastern Thailand, we observed that over half of the participants had urine IgG against a crude OV antigen extract (OV antigen). We also observed that elevated levels of urine IgG to OV antigen were not associated with the intensity of OV infection, but were likely the result of immune-complex glomerulonephritis as seen in animal models of OV infection. Moreover, we observed that urine IgG to OV antigen was excreted at concentrations 21 times higher in individuals with APF and 158 times higher in individuals with CCA than controls. We also observed that elevated urine IgG to OV antigen could identify APF+ and CCA+ individuals from non-cases. Finally, individuals with urine IgG to OV antigen had a greater risk of APF as determined by Odds Ratios (OR = 6.69; 95%CI: 2.87, 15.58) and a greater risk of CCA (OR = 71.13; 95%CI: 15.13, 334.0) than individuals with no detectable level of urine IgG to OV antigen. Herein, we show for the first time the extensive burden of renal pathology in OV endemic areas and that a urine biomarker could serve to estimate risk for both renal and hepatobiliary pathologies during OV infection, i.e., serve as a “syndromic biomarker” of the advanced pathologies from opisthorchiasis

Distinct antibody response in susceptible and non-susceptible hosts of the carcinogenic liver fluke Opisthorchis viverrini infection

Opisthorchis viverrini is a carcinogenic parasite that can cause bile duct cancer called cholangiocarcinoma. A study of the immune response of this parasite in susceptible and non-susceptible hosts may provide a clue to develop vaccines and immunodiagnostic markers, which are currently not available. Here, we compared the antibody response in susceptible Golden Syrian hamsters and non-susceptible BALB/c mice infected by the liver fluke. In mice, the antibody was detected between 1 and 2 weeks post-infection, whereas it was positive between 2 and 4 weeks post-infection in hamsters. Immunolocalization revealed that the antibody from mice reacts strongly with the tegumental surface and gut epithelium of the worm, while hamster antibody showed a weak signal in the tegument and a comparable signal in the gut of the worm. Immunoblot of the tegumental proteins demonstrated that while hamster antibody showed a broad specificity, mice strongly reacted with a single protein band. Mass spectrometry revealed these immunogenic targets. Recombinant proteins of the reactive targets were produced in the bacterial expression system. The immunoblot of these recombinant proteins confirm the reactivity of their native form. In summary, there is a different antibody response against O. viverrini infection in susceptible and non-susceptible hosts. The non-susceptible host reacts quicker and stronger than the susceptible host

High macrophage activities are associated with advanced periductal fibrosis in chronic Opisthorchis viverrini infection

Liver fluke infection caused by Opisthorchis viverrini induces several hepatobiliary conditions including advanced periductal fibrosis (APF ) and cholangiocarcinoma (CCA ), but >25% of the infected population develops APF and 1% develop CCA . The innate immune response is the first line of defence, and macrophages are critical regulators of fibrosis. We hypothesized that macrophages from infected individuals have different capacities to either promote or suppress periductal fibrosis. We compared phagocytic activities of macrophages of healthy individuals and O viverrini‐ infected individuals ± APF , and found that macrophages from infected individuals with APF ingested significantly higher numbers of beads compared with healthy controls and O viverrini‐ infected individuals without APF . To further investigate proteolytic activity, we monitored real‐time phagosomal proteolysis of beads conjugated to DQ ‐BODIPY ‐BSA using live cell imaging. We show that macrophages from O viverrini‐ infected individuals with APF also have elevated phagosomal proteolysis activity, which is consistent with their increased phagocytic activity. Additionally, stimulated ROS production by blood monocytes was higher in individuals with APF compared with healthy controls and infected individuals without APF . These results suggest that during O viverrini infection, macrophages with high phagocytic and proteolytic activities together with elevated ROS production are the phenotypes that can promote tissue damage, which results in periductal fibrosis

Opisthorchiasis-Induced Cholangiocarcinoma: How Innate Immunity May Cause Cancer

Innate, inflammatory responses towards persistent Opisthorchis viverrini (OV) infection are likely to contribute to the development of cholangiocarcinoma (CCA), a liver cancer that is rare in the West but prevalent in Greater Mekong Subregion countries in Southeast Asia. Infection results in the infiltration of innate immune cells into the bile ducts and subsequent activation of inflammatory immune responses that fail to clear OV but instead may damage local tissues within the bile ducts. Not all patients infected with OV develop CCA, and so tumourigenesis may be dependent on multiple factors including the magnitude of the inflammatory response that is activated in infected individuals. The purpose of this review is to summarize how innate immune responses may promote tumourigenesis following OV infection and if such responses can be used to predict CCA onset in OV-infected individuals. It also hypothesizes on the role that Helicobacterspp., which are associated with liver fluke infections, may play in activation of the innate the immune system to promote tissue damage and persistent inflammation leading to CCA

Human intestinal capillariasis in Thailand

Intestinal capillariasis caused by Capillaria philippinensis appeared first in the Philippines and subsequently in Thailand, Japan, Iran, Egypt and Taiwan; major outbreaks have occurred in the Philippines and Thailand. This article reviews the epidemiology, history and sources of C. philippinensis infection in Thailand. The annual epidemiological surveillance reports indicated that 82 accumulated cases of intestinal capillariasis were found in Thailand from 1994-2006. That made Thailand a Capillaria-prevalent area. Sisaket, in northeast Thailand, was the first province which has reported intestinal capillariasis. Moreover, Buri Ram presented a high prevalence of intestinal capillariasis, totaling 24 cases from 1994-2006. About half of all cases have consumed raw or undercooked fish. However, even if the numbers of the intestinal capillariasis cases in Thailand is reduced, C. philippinensis infection cases are still reported. The improvement of personal hygiene, specifically avoiding consumption of undercooked fish and promoting a health education campaign are required. These strategies may minimize or eliminate C. philippinensis infection in Thailand

Fluid-Structure Interaction Analysis for Hydrodynamic Parameters in Semi-Submerged Axisymmetric Buoy

The dynamic heave responses of the semi-submerged axisymmetric buoy of two different geometries to the excitations equivalent to impulse excitation technique were represented by mechanical single-degree-of-freedom models. Founded on linear and 2-dimensional potential flow theory, the fluid-structure interactions were modeled and simulated with finite element approach. The numerical results obtained in transient harmonic oscillations were implemented with the frequency analysis tools and scaled by the input force spectrum. The records of the frequency response receptance were used in the assessment of hydrodynamic added mass and damping coefficients at the apparent linear resonance frequency. The buoyancy stiffness was calculated with relation to the hydrostatic pressure. Comparison with the experimental and analytical results lent validity to the numerical models

Fluid-Structure Interaction Analysis for Hydrodynamic Parameters in Semi-Submerged Axisymmetric Buoy

The dynamic heave responses of the semi-submerged axisymmetric buoy of two different geometries to the excitations equivalent to impulse excitation technique were represented by mechanical single-degree-of-freedom models. Founded on linear and 2-dimensional potential flow theory, the fluid-structure interactions were modeled and simulated with finite element approach. The numerical results obtained in transient harmonic oscillations were implemented with the frequency analysis tools and scaled by the input force spectrum. The records of the frequency response receptance were used in the assessment of hydrodynamic added mass and damping coefficients at the apparent linear resonance frequency. The buoyancy stiffness was calculated with relation to the hydrostatic pressure. Comparison with the experimental and analytical results lent validity to the numerical models