Elevated Plasma IL-6 Associates with Increased Risk of Advanced Fibrosis and Cholangiocarcinoma in Individuals Infected by Opisthorchis viverrini

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection

Spatial Distribution of, and Risk Factors for, Opisthorchis viverrini Infection in Southern Lao PDR

The liver fluke Opisthorchis viverrini mainly occurs in Lao PDR and Thailand. Humans become infected through the consumption of raw or insufficiently cooked freshwater fish. Chronic infections may lead to severe liver (bile duct) diseases that eventually develop into a bile duct cancer with extremely poor prognosis. Current control efforts aim at preventing heavy morbidity and mortality. In recent years, spatial modeling, using data from well designed surveys, has been employed to better understand the distribution and determinants of parasitic diseases for guiding subsequent control. However, a spatial modeling approach has not been used for O. viverrini before. The purpose of the current study was to map the distribution of O. viverrini infection in Champasack province in southern Lao PDR, to identify risk factors of infection, and to predict the distribution at non-surveyed locations. We found that the risk of O. viverrini infection is higher for people living in close proximity to freshwater bodies, whereas the lack of sanitation sustained environmental contamination and transmission. High risk zones in Champasack province are concentrated in the Mekong River corridor, and hence control efforts should be targeted along the Mekong River

Unlocking the Transcriptomes of Two Carcinogenic Parasites, Clonorchis sinensis and Opisthorchis viverrini

The two parasitic trematodes, Clonorchis sinensis and Opisthorchis viverrini, have a major impact on the health of tens of millions of humans throughout Asia. The greatest impact is through the malignant cancer ( = cholangiocarcinoma) that these parasites induce in chronically infected people. Therefore, both C. sinensis and O. viverrini have been classified by the World Health Organization (WHO) as Group 1 carcinogens. Despite their impact, little is known about these parasites and their interplay with the host at the molecular level. Recent advances in genomics and bioinformatics provide unique opportunities to gain improved insights into the biology of parasites as well as their relationships with their hosts at the molecular level. The present study elucidates the transcriptomes of C. sinensis and O. viverrini using a platform based on next-generation (high throughput) sequencing and advanced in silico analyses. From 500,000 sequences, >50,000 sequences were assembled for each species and categorized as biologically relevant based on homology searches, gene ontology and/or pathway mapping. The results of the present study could assist in defining molecules that are essential for the development, reproduction and survival of liver flukes and/or that are linked to the development of cholangiocarcinoma. This study also lays a foundation for future genomic and proteomic research of C. sinensis and O. viverrini and the cancers that they are known to induce, as well as novel intervention strategies

Sarcopenia: etiology, clinical consequences, intervention, and assessment

The aging process is associated with loss of muscle mass and strength and decline in physical functioning. The term sarcopenia is primarily defined as low level of muscle mass resulting from age-related muscle loss, but its definition is often broadened to include the underlying cellular processes involved in skeletal muscle loss as well as their clinical manifestations. The underlying cellular changes involve weakening of factors promoting muscle anabolism and increased expression of inflammatory factors and other agents which contribute to skeletal muscle catabolism. At the cellular level, these molecular processes are manifested in a loss of muscle fiber cross-sectional area, loss of innervation, and adaptive changes in the proportions of slow and fast motor units in muscle tissue. Ultimately, these alterations translate to bulk changes in muscle mass, strength, and function which lead to reduced physical performance, disability, increased risk of fall-related injury, and, often, frailty. In this review, we summarize current understanding of the mechanisms underlying sarcopenia and age-related changes in muscle tissue morphology and function. We also discuss the resulting long-term outcomes in terms of loss of function, which causes increased risk of musculoskeletal injuries and other morbidities, leading to frailty and loss of independence

Induction of cytochrome P450 2A6 expression in humans by the carcinogenic parasite infection, opisthorchiasis viverrini

The purpose of this study was to examine in vivo the activity of cytochrome P450 (CYP) 2A6, an enzyme capable of activating carcinogens, including N-nitrosodimethylamine, in humans with the carcinogenic liver fluke infection, opisthorchiasis viverrini, before and after treatment with the antiparasitic agent, praziquantel. Coumarin hydroxylase activity of CYP 2A6 was assessed by administering a probe drug, coumarin, and measuring its metabolite, 7-hydroxycoumarin, in urines collected between 0-2 h and 2-4 h of 106 people with varying intensities of Opisthorchis viverrini infection. Five individuals who did not excrete any detectable 7-hydroxy coumarin (and have a genetic defect probably leading to an absence of catalytic activity of the CYP 2A6 protein) were excluded from analysis. Infected people excreted an average of 22.7 mumol of 7-hydroxycoumarin in the first 2 h after taking the drug, whereas the mean of the uninfected group was 19.4 mumol; this difference did not reach statistical significance (P = 0.10). However, a highly significant increase in CYP 2A6-related activity was observed in infected individuals who also had radiological evidence of biliary fibrosis (28.1 mumol) compared to those without (19.4 mumol; P = 0.01). Reassessments of coumarin hydroxylase activity of CYP 2A6 made 2 months after praziquantel treatment showed highly significant reductions in the amount of 7-hydroxycoumarin excreted among the infected groups but no difference in the uninfected group. These results suggest that expression of CYP 2A6 is induced among chronically infected people who also have fibrosis of the intrahepatic bile duct. As already demonstrated in an animal model and now observed in humans for the first time, this increase in CYP 2A6-related enzyme activity may represent an important mechanistic link between inflammatory products of chronic liver fluke infection (e.g., DNA alkylation damage from endogenously formed N-nitrosamines) and the high risk of cholangiocarcinoma faced by infected individuals

Immune responsiveness and parasite-specific antibody levels in human hepatobiliary disease associated with Opisthorchis viverrini infection.

Opisthorchis viverrini infection is associated with human hepatobiliary disease and cholangiocarcinoma, but the role of the immune response in the pathogenesis of infection is unclear. Here ultrasonography was used to examine the biliary tracts of residents from an endemic community. Delayed-type hypersensitivity responses to unrelated antigens, and fluke-specific IgG and IgA levels in serum of this group were also examined. Relationships between immunological parameters, intensity of infection and radiologically measured variables are reported. Immune responsiveness to unrelated antigens did not vary with intensity of parasite infection or disease status. Of all the variables, IgG levels were most markedly elevated in disease cases compared with normal subjects and were closely associated with gall bladder size and dysfunction. This is consistent with the hypothesis that an immunopathologic mechanism is involved in opisthorchiasis and suggests that antibody levels may be useful in screening populations for fluke-associated hepatobiliary disease

Relationships between the synthesis of N-nitrosodimethylamine and immune responses to chronic infection with the carcinogenic parasite, Opisthorchis viverrini, in men

This study investigated the relationship between immune responses to infection with the liver fluke, Opisthorchis viverrini , and the synthesis of the carcinogen, N-nitrosodimethylamine (NDMA) in humans. it also examined associations between synthesis of nitric oxide (NO) and nitrosation of amines, in vivo . Antibody and T cell responses to fluke antigens and post-alcohol urinary NDMA excretion were assessed among three groups of 40-50 men with no, moderate and heavy liver fluke infection. Markers of NO synthesis (nitrate, nitrite) and nitrosation (nitrosamino acids) were also measured in biological fluids. Assessments were carried out under controlled conditions which minimised intake of exogenous nitrate and nitrite and were carried out at two time points, namely before and 4 months after elimination of the infection with praziquantel treatment. No statistically significant variation was observed in the amount of NDMA excreted between the 3 groups. However, during active infection, a strong negative association was observed between in vitro lymphoproliferative responses to some liver fluke antigens and NDMA excretion. After treatment this association was reduced. Multivariate statistical models revealed a highly significant relationship between NDMA levels and urinary nitrate, stimulation indices for two T cell responses to two parasite antigens (MW 37 kDa and 110 kDa) and gall bladder dimension. NDMA levels after treatment were best described by the ratio between parasite-specific IgG2 and IgE, background levels of T cell proliferation, a urinary marker of nitrosation (N-nitrosothioproline) and usual level of alcohol consumption. These results suggest that individual background immunologic activity, parasite-specific responses and/or parasite products and NO synthesis are important determinants of endogenous generation of nitrosamines in O.viverrini -infected humans

Relationships between the synthesis of N-nitrosodimethylamine and immune responses to chronic infection with the carcinogenic parasite, Opisthorchis viverrini, in men

This study investigated the relationship between immune responses to infection with the liver fluke. Opisthorchis viverrini, and the synthesis of the carcinogen, N-nitrosodimethylamine (NDMA) in humans. It also examined associations between synthesis of nitric oxide (NO) and nitrosation of amines, in vivo. Antibody and T cell responses to fluke antigens and post-alcohol urinary NDMA excretion were assessed among three groups of 40-50 men with no, moderate and heavy liver fluke infection. Markers of NO synthesis (nitrate, nitrite) and nitrosation (nitrosamino acids) were also measured in biological fluids. Assessments were carried out under controlled conditions which minimised intake of exogenous nitrate and nitrite and were carried out at two time points, namely before and 4 months after elimination of the infection with praziquantel treatment. No statistically significant variation was observed in the amount of NDMA excreted between the 3 groups. However, during active infection, a strong negative association was observed between in vitro lymphoproliferative responses to some liver fluke antigens and NDMA excretion. After treatment this association was reduced. Multivariate statistical models revealed a highly significant relationship between NDMA levels and urinary nitrate, stimulation indices for two T cell responses to two parasite antigens (MW 37 kDa and 110 kDa) and gall bladder dimensions. NDMA levels after treatment were best described by the ratio between parasite-specific IgG2 and IgE, background levels of T cell proliferation, a urinary marker of nitrosation (N-nitrosothioproline) and usual level of alcohol consumption. These results suggest that individual background immunologic activity, parasite-specific responses and/or parasite products and NO synthesis are important determinants of endogenous generation of nitrosamines in O.viverrini-infected humans

Lubiprostone plus polyethylene glycol electrolyte lavage solution (PEG-ELS) versus PEG-ELS for bowel preparation in chronic constipation: a randomized controlled trial

Abstract Colonoscopy is considered the standard procedure for early detection and prevention of colorectal cancer. Adequate bowel cleansing is an important determinant of the efficacy of colonoscopy screening. Currently, there is no standard method of bowel preparation for patients with chronic constipation. The aim was to access the rate of adequate bowel cleansing achieved using split-dose polyethylene glycol electrolyte lavage solution (PEG-ELS) plus lubiprostone in comparison with split-dose PEG-ELS alone. A single-centre, endoscopist-blinded, randomized controlled trial was conducted. Seventy-eight constipated patients aged 18–75 years who were indicated for colonoscopy in the gastroenterology unit of Srinagarind Hospital, Khon Kaen University, between February 2020 and February 2021 were randomly allocated to receive either split-dose PEG-ELS in combination with lubiprostone (N = 39) or split-dose PEG-ELS alone (N = 39) before colonoscopy. Adequate bowel cleansing was defined as an Ottawa bowel preparation score ≤ 7. The rate of adequate bowel cleansing was comparable between the PEG-ELS plus lubiprostone group and the PEG-ELS alone group (50% vs. 52.9%, p value = 0.81) with a relative risk of 1.13 (95% CI = 0.43–2.91). There were no significant differences in adenoma detection rate (41.2% vs. 35.3%, p value = 0.62), adverse events, acceptance, compliance, or patient satisfaction between the 2 groups. No additional benefit to successful bowel preparation was achieved by the combination of lubiprostone and PEG-ELS in chronic constipation patients undergoing colonoscopy