Chronic Hepatitis C Therapy in Liver Cirrhosis Complicated by Telaprevir-Induced DRESS

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare yet severe adverse drug-induced reaction with up to 10% mortality rate. Recent clinical trials reported an association between DRESS and telaprevir (TVR), an NS3/4A protease inhibitor of chronic hepatitis C (CHC) virus genotype 1. Its diagnosis is challenging given the variable pattern of cutaneous eruption and the myriad internal organ involvement. We present two patients who are middle-aged, obese, and white with CHC cirrhosis. They both developed a progressive diffuse, painful pruritic maculopapular rash at weeks 8 and 10 of CHC therapy with TVR, Peg-Interferon alfa-2a, and Ribavirin. They had no exposures to other medications that can cause this syndrome. Physical exam and labs and skin biopsy supported a “Definite” clinical diagnosis of DRESS, per RegiSCAR criteria. Thus Telaprevir-based triple therapy was discontinued and both patients experienced rapid resolution of the systemic symptoms with gradual improvement of eosinophilia and the skin eruption. These two cases illustrate the paramount importance of having a high index of suspicion for TVR-induced DRESS, critical for early diagnosis. Immediate discontinuation of TVR is essential in prevention of a potentially life-threatening complication. Risk factors for development of DRESS in patients receiving TVR remain to be elucidated

A Ribosomal S-6 Kinase–Mediated Signal to C/EBP-β Is Critical for the Development of Liver Fibrosis

BACKGROUND: In response to liver injury, hepatic stellate cell (HSC) activation causes excessive liver fibrosis. Here we show that activation of RSK and phosphorylation of C/EBPbeta on Thr217 in activated HSC is critical for the progression of liver fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: Chronic treatment with the hepatotoxin CCl(4) induced severe liver fibrosis in C/EBPbeta(+/+) mice but not in mice expressing C/EBPbeta-Ala217, a non-phosphorylatable RSK-inhibitory transgene. C/EBPbeta-Ala217 was present within the death receptor complex II, with active caspase 8, and induced apoptosis of activated HSC. The C/EBPbeta-Ala217 peptides directly stimulated caspase 8 activation in a cell-free system. C/EBPbeta(+/+) mice with CCl(4)-induced severe liver fibrosis, while continuing on CCl(4), were treated with a cell permeant RSK-inhibitory peptide for 4 or 8 weeks. The peptide inhibited RSK activation, stimulating apoptosis of HSC, preventing progression and inducing regression of liver fibrosis. We found a similar activation of RSK and phosphorylation of human C/EBPbeta on Thr266 (human phosphoacceptor) in activated HSC in patients with severe liver fibrosis but not in normal livers, suggesting that this pathway may also be relevant in human liver fibrosis. CONCLUSIONS/SIGNIFICANCE: These data indicate that the RSK-C/EBPbeta phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target

A Synoptical Classification of the Bivalvia (Mollusca)

The following classification summarizes the suprageneric taxono-my of the Bivalvia for the upcoming revision of the Bivalvia volumes of the Treatise on Invertebrate Paleontology, Part N. The development of this classification began with Carter (1990a), Campbell, Hoeks-tra, and Carter (1995, 1998), Campbell (2000, 2003), and Carter, Campbell, and Campbell (2000, 2006), who, with assistance from the United States National Science Foundation, conducted large-scale morphological phylogenetic analyses of mostly Paleozoic bivalves, as well as molecular phylogenetic analyses of living bivalves. Dur-ing the past several years, their initial phylogenetic framework has been revised and greatly expanded through collaboration with many students of bivalve biology and paleontology, many of whom are coauthors. During this process, all available sources of phylogenetic information, including molecular, anatomical, shell morphological, shell microstructural, bio- and paleobiogeographic as well as strati-graphic, have been integrated into the classification. The more recent sources of phylogenetic information include, but are not limited to, Carter (1990a), Malchus (1990), J. Schneider (1995, 1998a, 1998b, 2002), T. Waller (1998), Hautmann (1999, 2001a, 2001b), Giribet and Wheeler (2002), Giribet and Distel (2003), Dreyer, Steiner, and Harper (2003), Matsumoto (2003), Harper, Dreyer, and Steiner (2006), Kappner and Bieler (2006), Mikkelsen and others (2006), Neulinger and others (2006), Taylor and Glover (2006), Kříž (2007), B. Morton (2007), Taylor, Williams, and Glover (2007), Taylor and others (2007), Giribet (2008), and Kirkendale (2009). This work has also benefited from the nomenclator of bivalve families by Bouchet and Rocroi (2010) and its accompanying classification by Bieler, Carter, and Coan (2010).This classification strives to indicate the most likely phylogenetic position for each taxon. Uncertainty is indicated by a question mark before the name of the taxon. Many of the higher taxa continue to undergo major taxonomic revision. This is especially true for the superfamilies Sphaerioidea and Veneroidea, and the orders Pectinida and Unionida. Because of this state of flux, some parts of the clas-sification represent a compromise between opposing points of view. Placement of the Trigonioidoidea is especially problematic. This Mesozoic superfamily has traditionally been placed in the order Unionida, as a possible derivative of the superfamily Unionoidea (see Cox, 1952; Sha, 1992, 1993; Gu, 1998; Guo, 1998; Bieler, Carter, & Coan, 2010). However, Chen Jin-hua (2009) summarized evi-dence that Trigonioidoidea was derived instead from the superfamily Trigonioidea. Arguments for these alternatives appear equally strong, so we presently list the Trigonioidoidea, with question, under both the Trigoniida and Unionida, with the contents of the superfamily indicated under the Trigoniida.Fil: Carter, Joseph G.. University of North Carolina; Estados UnidosFil: Altaba, Cristian R.. Universidad de las Islas Baleares; EspañaFil: Anderson, Laurie C.. South Dakota School of Mines and Technology; Estados UnidosFil: Araujo, Rafael. Consejo Superior de Investigaciones Cientificas. Museo Nacional de Ciencias Naturales; EspañaFil: Biakov, Alexander S.. Russian Academy of Sciences; RusiaFil: Bogan, Arthur E.. North Carolina State Museum of Natural Sciences; Estados UnidosFil: Campbell, David. Paleontological Research Institution; Estados UnidosFil: Campbell, Matthew. Charleston Southern University; Estados UnidosFil: Chen, Jin Hua. Chinese Academy of Sciences. Nanjing Institute of Geology and Palaeontology; República de ChinaFil: Cope, John C. W.. National Museum of Wales. Department of Geology; Reino UnidoFil: Delvene, Graciela. Instituto Geológico y Minero de España; EspañaFil: Dijkstra, Henk H.. Netherlands Centre for Biodiversity; Países BajosFil: Fang, Zong Jie. Chinese Academy of Sciences; República de ChinaFil: Gardner, Ronald N.. No especifica;Fil: Gavrilova, Vera A.. Russian Geological Research Institute; RusiaFil: Goncharova, Irina A.. Russian Academy of Sciences; RusiaFil: Harries, Peter J.. University of South Florida; Estados UnidosFil: Hartman, Joseph H.. University of North Dakota; Estados UnidosFil: Hautmann, Michael. Paläontologisches Institut und Museum; SuizaFil: Hoeh, Walter R.. Kent State University; Estados UnidosFil: Hylleberg, Jorgen. Institute of Biology; DinamarcaFil: Jiang, Bao Yu. Nanjing University; República de ChinaFil: Johnston, Paul. Mount Royal University; CanadáFil: Kirkendale, Lisa. University Of Wollongong; AustraliaFil: Kleemann, Karl. Universidad de Viena; AustriaFil: Koppka, Jens. Office de la Culture. Section d’Archéologie et Paléontologie; SuizaFil: Kříž, Jiří. Czech Geological Survey. Department of Sedimentary Formations. Lower Palaeozoic Section; República ChecaFil: Machado, Deusana. Universidade Federal do Rio de Janeiro; BrasilFil: Malchus, Nikolaus. Institut Català de Paleontologia; EspañaFil: Márquez Aliaga, Ana. Universidad de Valencia; EspañaFil: Masse, Jean Pierre. Universite de Provence; FranciaFil: McRoberts, Christopher A.. State University of New York at Cortland. Department of Geology; Estados UnidosFil: Middelfart, Peter U.. Australian Museum; AustraliaFil: Mitchell, Simon. The University of the West Indies at Mona; JamaicaFil: Nevesskaja, Lidiya A.. Russian Academy of Sciences; RusiaFil: Özer, Sacit. Dokuz Eylül University; TurquíaFil: Pojeta, John Jr.. National Museum of Natural History; Estados UnidosFil: Polubotko, Inga V.. Russian Geological Research Institute; RusiaFil: Pons, Jose Maria. Universitat Autònoma de Barcelona; EspañaFil: Popov, Sergey. Russian Academy of Sciences; RusiaFil: Sanchez, Teresa Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Sartori, André F.. Field Museum of National History; Estados UnidosFil: Scott, Robert W.. Precision Stratigraphy Associates; Estados UnidosFil: Sey, Irina I.. Russian Geological Research Institute; RusiaFil: Signorelli, Javier Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico; ArgentinaFil: Silantiev, Vladimir V.. Kazan Federal University; RusiaFil: Skelton, Peter W.. Open University. Department of Earth and Environmental Sciences; Reino UnidoFil: Steuber, Thomas. The Petroleum Institute; Emiratos Arabes UnidosFil: Waterhouse, J. Bruce. No especifica;Fil: Wingard, G. Lynn. United States Geological Survey; Estados UnidosFil: Yancey, Thomas. Texas A&M University; Estados Unido

Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Background: The limited availability of microbiology services in sub-Saharan Africa impedes accurate diagnosis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia among hospitalized children in The Gambia and to identify factors associated with bacteremia and mortality. Methods: We prospectively studied children presenting wit

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Hepatic stellate cells:central modulators of hepatic carcinogenesis

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90 % of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC

Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study

Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p<0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%]), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%]), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis. Interpretation: Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals