Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells.

Acute hepatitis C virus (HCV) infection culminates in viral persistence in the majority of cases. Abs that recognize the envelope glycoproteins E1 and E2 are generated during the late stages of acute infection, yet their contribution to spontaneous viral clearance remains controversial. Investigation of the humoral responses during acute HCV infection have been limited by the inability to directly identify and characterize HCV-specific B cells. In this study we describe the development of a novel tetramer of the E2 glycoprotein ectodomain (J6, genotype 2a strain), which allowed us to visualize E2-specific B cells longitudinally in the peripheral blood of HCV-infected individuals. HCV-specific class-switched memory B cells were detected in 3 out of 7 participants during late acute infection, with a mean frequency of 0.63% for positive samples (range 0.16-0.67%) and in 7 out of 7 participants with chronic infection with a mean frequency of 0.47% (range 0.20-0.78%). In a cross-sectional study, E2 tetramer positive population was detected in 28 out of 31 chronically infected individuals. Deep sequencing of the BCR from E2-specific class-switched memory B cells sorted from two independent participants revealed a focused repertoire suggestive of clonal selection. Tetramer-specific B cells exhibited skewed CDR3 length distribution and increased mutation frequency compared with naive B cells. This BCR profile is indicative of clonal expansion and affinity maturation. E2 tetramer allows for specific and sensitive ex vivo characterization of rare HCV-specific B cells in infected individuals, and will enable researchers to gain a better understanding of humoral immunity in HCV infection.

Transarterial embolization therapies for the treatment of hepatocellular carcinoma: CEPO review and clinical recommendations.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and its incidence rate has consistently increased over the past 15 years in Canada. Although transarterial embolization therapies are palliative options commonly used for the treatment of HCC, their efficacy is still controversial. The objective of this guideline is to review the efficacy and safety of transarterial embolization therapies for the treatment of HCC and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to October 2013 was performed. A total of 38 studies were included. RECOMMENDATIONS: Considering the evidence available to date, the CEPO recommends the following: (i) transarterial chemoembolization therapy (TACE) be considered a standard of practice for the palliative treatment of HCC in eligible patients; (ii) drug-eluting beads (DEB)-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities; (iii) the decision to treat with TACE or DEB-TACE be discussed in tumour boards; (iv) bland embolization (TAE) not be considered for the treatment of HCC; (v) radioembolization (TARE) not be considered outside of a clinical trial setting; and (vi) sorafenib combined with TACE not be considered outside of a clinical trial setting.

Organochlorine pesticides in green mussel, Perna viridis, from the Cienfuegos Bay, Cuba.

The green mussel, Perna viridis, was used to measure bioaccumulated levels of organochlorine pesticides in the marine environment of Cuba. Samples were collected in the Cienfuegos Bay between January and December 2010. The organochlorine pesticides (i.e. DDT, Dieldrin, Chlordane, Endosulfan, HCB, Aldrin, Heptachlor and Lindane) were quantified by gas chromatography. The sum of all organochlorine pesticides in P. viridis was 6.31 ng g(-1). The concentration ranged from 3.53 to 4.42 ng g(-1) dry weight (dw) for DDTs (i.e. sum of pp' DDT, pp' DDD, op' DDE and pp' DDE); 1.7-1.9 ng g(-1) dw for Dieldrin; 0.17-0.20 ng g(-1) dw for Chlordanes; 0.14-0.16 ng g(-1) dw for Endosulfan; 0.11-0.17 ng g(-1) dw for HCB; 0.07-0.11 ng g(-1) dw for Aldrin; 0.046-0.054 ng g(-1) dw for Heptachlor and 0.035-0.039 ng g(-1) dw for Lindane. These levels can be considered as low when compared to reported values from similar studies conducted elsewhere in the world. The concentrations of all organochlorines residues detected in this study fell below the EU Maximum Residue Limits.

A real-world experience of SARS-CoV-2 infection in a tertiary referral centre of Montréal: Unexpected low prevalence and low mortality.

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with chronic liver disease (CLD) and liver transplant (LT) recipients remains a concern. The aim of this study was to report the impact of coronavirus disease 2019 (COVID-19) infection among patients at the tertiary health care centre Centre hospitalier de l'Université de Montréal (CHUM) during the first wave of the SARS-CoV-2 pandemic. METHODS: This real-world, retrospective cohort included all patients admitted to our liver unit and/or seen as an outpatient with CLD with or without cirrhosis and/or LT recipients who tested positive to SARS-CoV-2 infection. Cases were considered positive as defined by the detection of SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. RESULTS: Between April 1 and July 31, 2020, 5,637 were admitted to our liver unit and/or seen as outpatient. Among them, 42 were positive for SARS-CoV-2. Twenty-two patients had CLD without cirrhosis while 16 patients had cirrhosis at the time of the infection (13, 2, and 1 with Child-Pugh A, B, and C scores, respectively). Four were LT recipients. Overall, 15 of 42 patients (35.7%) were hospitalized; among them, 7 of 42 (16.7%) required respiratory support and 4 of 42 (9.5%) were transferred to the intensive care unit. Only 4 of 42 (9.5%) patients died: 2 with CLD without cirrhosis and 2 with CLD with cirrhosis. Overall survival was 90.5%. CONCLUSION: This real-world study demonstrates an unexpectedly low prevalence and low mortality in the context of SARS-CoV-2 infection among patients with CLD with or without cirrhosis and LT recipients.

PCBs in sediments and oysters of Manila Bay, the Philippines.

Polychlorinated biphenyls (PCBs) were analyzed in sediment and oyster samples from coastal sites inside Manila Bay. Concentrations for 13 individual PCB congeners and total PCBs are reported herein. Median SigmaPCB concentration in sediments was 0.46 ng g(-1) dry weight (range 0.10-1.5 ng g(-1)) and in oysters it was 15 ng g(-1) dry weight (range 7-73 ng g(-1)). The most contaminated areas of the bay were the coastal zones of Metropolitan Manila and Bulacan province. A significant correlation (p < 0.01) was found between SigmaPCB concentrations in oysters and in sediments. PCB concentrations measured in the bay sediments were below acute toxic levels to marine biota. Nevertheless, consumption of oysters by human population living around the bay might originate SigmaPCB intake rates estimated at about 2.5 times lower than the tolerance limit. Further environmental surveillance is recommended in order to prevent public health risks that may be posed by these chemicals.

Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells.

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.

Ecological risk assessment of PCBs and other organic contaminant residues in Laguna de Terminos, Mexico.

Laguna de Terminos, a wide coastal lagoon system in Campeche, Mexico, was investigated for the contamination by polychlorobiphenyls (PCBs). Distribution of these industrial chemical contaminants along with pesticide residues in the lagoon, as well as their sediment-water partitioning and bioaccumulation by oysters and fish were assessed. Contaminant concentrations in the lagoon were compared with toxicity data for aquatic organisms and the ecotoxicological risks discussed. Current contaminant concentrations generally were several orders of magnitude below acute toxic levels for the most sensitive aquatic species and this seems compatible with the status of nature reserve and functions aimed at Laguna de Terminos. In particular, Penaeidae shrimp species that are the most valuable fisheries resources of Campeche with important populations in the Laguna are not impaired with the current low levels of these contaminants. Nevertheless, due to known environmental persistence, the surveillance of chlorinated contaminant levels in the lagoon ecosystems is recommended.

Organic contaminants in the marine environment of Manila Bay, Philippines.

Organochlorine pesticides (OCs) and polychlorobiphenyls (PCBs) were determined in sediments and oysters' soft tissues (Cassostrea gigas) collected in selected sites of Manila Bay. Overall, the concentration levels were very low. In sediments, PCBs were the compounds present in higher concentrations, with Sigma13PCB congeners averaging 0.69 +/- 0.46 ng/g (dry weight), followed by SigmaDDT averaging 0.53 +/- 0.28 ng/g and Sigmachlordane with 0.26 +/- 0.28 ng/g. Concentrations measured in oysters averaged 20 +/- 17 ng/g (dry weight) for Sigma13PCB and were higher than SigmaDDT, with 9.5 +/- 2.4 ng/g, and Sigmachlordane, with 3.8 +/- 3.1 ng/g. No dissolved residues of polar compounds, such as herbicides, and organophosphorous and organochlorine pesticides were found in the bay water. In general, results showed that concentrations of organochlorine pesticide residues, such as DDT, hexachlorocyclohexane, chlordane, lindane, endosulfan, and heptachlor in sediments and oysters were low in comparison with other coastal areas in Asia, although PCB concentrations in oysters were relatively high in some zones of Manila Bay and indicative of loose control of industrial chemical waste discharges into the bay. Nevertheless, current concentrations of persistent organochlorine contaminants in sediments were under threshold effect levels (TELs) and chronic toxic effects are, thus, unlikely to generate impairment of marine biota in Manila Bay.

Gastric antral vascular ectasia is more frequent in patients with non-alcoholic steatohepatitis-induced cirrhosis.

Background: Gastric antral vascular ectasia (GAVE) is an uncommon cause of occult gastrointestinal (GI) bleeding. Based on clinical observations, we hypothesized that GAVE was more common in patients with non-alcoholic steatohepatitis (NASH) cirrhosis. Methods: We performed this retrospective study at Centre Hospitalier de l'Université de Montréal (CHUM). We included all cirrhotic patients who had undergone an esophagogastroduodenoscopy (EGD) between 2009 and 2011. GAVE was diagnosed based on a typical endoscopic appearance. NASH cirrhosis was diagnosed in patients with a metabolic syndrome after excluding other causes of liver disease. GAVE was considered symptomatic if it required treatment. Results: We included 855 cirrhotic patients in the study. The median age was 58 (range 19-88) years. The etiology of cirrhosis was as follows: NASH in 18% (n = 154), autoimmune diseases in 15.1% (n = 129), hepatitis B virus (HBV) in 6.3% (n = 54), hepatitis C virus (HCV) in 19.4% (n = 166), alcohol in 25.7% (n = 220), alcohol plus HCV in 7.8% (n = 67), cryptogenic in 2.8% (n = 24), and other etiologies in 4.8% (n = 41). GAVE was more frequently observed among patients with NASH cirrhosis than in cirrhosis of other etiologies (29.2% vs. 9.4%, respectively; p < 0.001). In multivariate analysis, NASH was strongly associated with GAVE with an odds ratio (OR) of 3.73 (95% CI 2.36 to 5.90, p < 0.001), and the association was stronger with symptomatic GAVE (OR 5.77, 95% CI 2.93 to 11.38). Conclusions: NASH cirrhosis is a major risk factor for GAVE and symptomatic GAVE.

Type 3 cytokines IL-17A and IL-22 drive TGF-ß-dependent liver fibrosis.

Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor-ß signaling in HSCs in a p38 mitogen-activated protein kinase-dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.

Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada.

Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.

Coplanar and non-coplanar congener-specificity of PCB bioaccumulation and immunotoxicity in sea stars.

The sea star Asterias rubens (L.), a representative species of the North Sea benthic environment, was exposed to a mixture of 10 selected PCB congeners (3 coplanar or c-PCBs, and 7 non-coplanar) via experimentally contaminated sediments. Both the degree of bioaccumulation and subsequent immunotoxic effects of these PCBs were determined. A strong congener-specificity for both bioaccumulation and immunotoxicity was found as well as a probable induction of a congener-specific detoxification mechanism resulting in the dramatic decrease in body levels of the three coplanar congeners tested (PCBs 77, 126 and 169). Moreover, a correlation was found between the bioaccumulation of c-PCBs and their immunotoxic effects. These findings suggest that coplanar congeners should be included in the list of congeners recommended to be analyzed for biological impact-oriented marine monitoring programmes.

The natural history of chronic hepatitis B virus infection.

Under most circumstances, HBV is not cytopathic and it is the immune response of the host that determines the outcome of infection. The most complete immune response is associated with the most severe liver injury and the greatest likelihood of viral clearance, whereas an immature immune response leads to chronic hepatitis. The natural history of chronic hepatitis B is similar to that of acute HBV infection except for the different time frame, and can be viewed in four stages. The first stage is characterized by high viral loads and immune tolerance. In acute infection, this corresponds to the incubation period, but with neonatal chronic infection, this period often lasts for decades. In the second stage, an immunologic response develops leading to hepatocyte necrosis. In patients with chronic infection, stage 2 may persist for 10-20 years and lead to cirrhosis and its complications. When the immune response decreases the number of infected cells, a third stage begins with low viral replication, referred to as the inactive carrier state. In this stage, HBeAg is no longer detectable, a marked decrease in HBV viral load is observed, and aminotransferase levels become normal. During stage 3, some patients continue to have high levels of serum HBV DNA and amino-transferases (referred to as HBeAg-negative chronic hepatitis), because of HBV variants that prevent the production of HBeAg. In the fourth stage, patients become negative for HBeAg and positive for anti-HBs, and HBV DNA is usually no longer detectable in serum, although still present in liver tissue. Immune clearance occurs at a rate of about 1% per year in chronic carriers of HBV During stage 4, some patients can reactivate their hepatitis B when given chemotherapy or immuno-suppressive treatment. Patients with active HBV replication are at increased risk for cirrhosis, hepatic decompensation and hepatocellular carcinoma compared to inactive carriers. Available evidence indicates that control of HBV replication with antiviral agents decreases the incidence of these complications.

Chlorinated hydrocarbons in marine biota and coastal sediments from the Gulf and Gulf of Oman.

The spatial distribution of various organochlorinated compounds was investigated in the Gulf and Gulf of Oman based on marine biota (fish and various bivalves) and coastal sediment collected in Bahrain, Oman, Qatar and the United Arab Emirates (UAE) during 2000-2001. Several potential organic contaminants from agricultural (e.g., DDT and its breakdown products, lindane, endrin, dieldrin, endosulfan) and industrial (PCBs) sources were measured. Sediment burdens for all compounds, even for an apparent hot spot near a refinery in Bahrain, were amongst the lowest reported for surface sediments from other seas. Concentrations of DDTs were low in the muscle and liver of all fish (orange spotted grouper and the spangled emperor) analysed. Similarly, the levels of chlorinated hydrocarbons were low in the various bivalve species, notably rock oysters and pearl oysters. These results contribute to the sparse regional database for organochlorinated compounds in the marine environment. Moreover, they can be used as the most recent end point for elucidating temporal trends. Whereas the levels, albeit relatively low, SigmaDDTs in the rock oysters from the Gulf of Oman have remained uniform, there has been an irregular but generally decreasing trend in concentrations of summation SigmaPCBs during the last two decades.

Aliphatic and aromatic hydrocarbons in marine biota and coastal sediments from the Gulf and the Gulf of Oman.

The composition and spatial distribution of aliphatic and polycyclic aromatic hydrocarbons (PAHs) were investigated in biota and coastal sediments from four countries surrounding the Gulf (Bahrain, Qatar, United Arab Emirates and Oman). The levels of total petroleum hydrocarbons (TPH), aliphatic unresolved mixture and PAHs in sediments and biota were relatively low compared to world-wide locations reported to be chronically contaminated by oil. Only in the case of the sediments collected near the BAPCO oil refinery in Bahrain, having concentrations of 779 microg g(-1) total petroleum hydrocarbon equivalents and 6.6 microg g(-1) Sigma PAHs, can they be categorized as chronically contaminated. Some evidence of oil contamination was also apparent in sediments and bivalves around Akkah Head and Abu Dhabi in the UAE, and near Mirbat in Oman. Contaminant patterns in sediments and biota indicated that the PAHs were mainly from fossil sources, with the exception of the high PAH concentrations in sediments near the BAPCO refinery that contained substantial concentrations of carcinogenic PAH combustion products.

Etiology and outcome of acute liver failure: experience from a liver transplantation centre in Montreal.

BACKGROUND: Acute liver failure is a rare condition in which massive liver injury is associated with the rapid development of hepatic encephalopathy. Although viral hepatitis and drug-induced liver injury are the most common causes, no specific etiology is found in a substantial proportion of cases reported from Europe and the United States. AIM: To determine the etiology and outcome of patients with acute liver failure in the authors' institution. PATIENTS AND METHODS: The charts of 81 consecutive patients admitted to Saint-Luc between 1991 and 1999 were reviewed. RESULTS: The etiology was viral in 27 cases (33.2%), toxic or drug-induced in 22 (27.2%), of unknown origin in 22 (27.2%) and due to various causes in 10 (12.3%) (autoimmune, vascular, cancer). Of the 81 patients, 16% survived without liver transplantation, and 84% died or underwent liver transplantation. Survival without liver transplantation differed according to the mode of presentation: the survival rate was 27% in patients with hyperacute liver failure, 7% in those with acute liver failure and 0% in those with subacute liver failure. Among the 38 patients who underwent liver transplantation, survival one year after transplantation was 71%. In the 30 patients who died without liver transplantation, the main causes of death were cerebral edema and sepsis. CONCLUSIONS: Acute liver failure is associated with a high mortality, and liver transplantation is the treatment of choice. In a significant proportion of cases, the etiology remains undetermined and is probably related to yet unidentified hepatotropic viruses.

The management of chronic viral hepatitis: a Canadian consensus conference 2004.

Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

Organochlorinated compounds in Caspian Sea sediments.

Several organochlorinated contaminants, including numerous pesticides, were determined in coastal sediments from the Caspian Sea. The most important contaminants were p,p'-DDT (up to 7400 pg g(-1)) and its breakdown products, p,p'-DDD (up to 3400 pg g(-1)) and p,p'-DDE (up to 1300 pg g(-1)). Although the contamination was most severe in Azerbaijan, the sediment concentrations and percentage distribution of the three DDT-related compounds indicated that such contamination constitutes a contemporary and ubiquitous problem in the Caspian Sea. Lindane represented the second most significant contaminant, particularly in the Russian Federation, with concentrations up to 609 pg g(-1). The concentrations of HCB and other chlorinated pesticides (cis- and trans-chlordane, methoxychlor, heptachlor, heptachlor epoxide, aldrin, endrin, and endosulfans) were lower and not generally of concern, but the pesticides did demonstrate markedly different distributions reflecting differing agricultural usage in the region. The concentrations of Sigma PCBs were also quite low and ranged from 0.03 to 6.4 ng g(-1), with the highest amounts in the Russian Federation and Azerbaijan.

Aliphatic and aromatic hydrocarbons in coastal Caspian Sea sediments.

This investigation represents the first extensive study of the spatial distribution and sources of aliphatic (n-alkanes and unresolved complex mixture of fossil hydrocarbons) and polycyclic aromatic hydrocarbons (PAHs) in coastal sediments from the Caspian Sea. PAH concentrations, n-alkanes and biomarker profiles all suggested that there was limited petrogenic contamination in the shallow North Caspian Sea sediments, which are coarse with a low total organic carbon content. In contrast, moderate to high petrogenic contamination was found in the South Caspian Sea, in particular in the offshore oil fields near Baku, Azerbaijan. Contaminant patterns indicated that the PAHs were mainly from fossil sources, with higher contributions of pyrolytic only near industrialized and urban areas. A high contribution of perylene, a geochemically derived PAH, to the total PAHs was found in the west and south at sites influenced by the Kura, Safid Rud, Terek, Sulak and Samur Rivers.

The management of chronic viral hepatitis: A Canadian consensus conference 2004.

Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.