bluuebunny/crossref_metadata_2025_split huggingface dataset:
Barriers to care and treatment for patients with chronic viral hepatitis in Europe: a systematic review
Authors: Papatheodoridis George V. , Tsochatzis Emmanuel , Hardtke Svenja , Wedemeyer Heiner 
Published: April 2014

AbstractBackground & AimsDespite the availability of effective therapies for hepatitis B (HBV) and C virus (HCV), only a minority of these patients receive treatment. We systematically reviewed published data on barriers to management for chronic HBV/HCV patients in Europe.MethodsLiterature search to identify studies including adult patients with chronic HBV/HCV infection from European countries and data on barriers to treatment.ResultsTwenty‐five studies including 6253 chronic HBV and 19 014 HCV patients were identified, of which only two were from Eastern Europe. The mean rate of no treatment in HBV patients was 42% being higher in North‐Western European countries than Italy (56% vs. 39%, P < 0.001). Immigrants represented the most common barrier to HBV treatment. The mean rate of no treatment in HCV RNA‐positive patients was 57%, being highest in Romania (89%), intermediate in France (79%) and lower though still high in other European countries (52%, P < 0.001). The predominant barriers to HCV treatment were lack of financial resources in Romania and direct/indirect limitations of interferon‐alfa and/or parenteral drug and alcohol abuse in other countries. The mean rate of no treatment was highest in HCV RNA‐positive parenteral drug users (72%) and intermediate in those with HCV–HIV co‐infection (64%).ConclusionsA substantial proportion of diagnosed chronic HBV and the majority of diagnosed HCV patients remain untreated. The rates and most importantly the reasons of barriers to treatment in chronic HBV/HCV patients vary widely among European countries supporting the need for country‐specific national strategies, resource allocation and implementation of global management policies.
VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride‐induced cirrhosis
Authors: Sánchez Elisabet , Nieto Juan C. , Boullosa Ana , Vidal Silvia , Sancho Francesc J. , Rossi Giacomo , Sancho‐Bru Pau , Oms Rosa , Mirelis Beatriz , Juárez Cándido , Guarner Carlos , Soriano Germán 
Published: April 2014

AbstractBackground & AimsProbiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis.MethodsForty‐six Sprague‐Dawley rats with CCl4‐induced cirrhosis were randomized into two groups: VSL#3 group (n = 22) that received VSL#3 in drinking water, and water group (n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin‐2 and 4, β‐defensin‐1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines.ResultsMortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) (P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group (P = 0.03 vs. VSL#3 group) and 0/11 in the control group (P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF‐α were lower in the VSL#3 group than in the water group (P < 0.05).ConclusionsVSL#3 decreases bacterial translocation, the pro‐inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis.
The pan‐caspase inhibitor Emricasan (IDN‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis
Authors: Barreyro Fernando J. , Holod Silvia , Finocchietto Paola V. , Camino Alejandra M. , Aquino Jorge B. , Avagnina Alejandra , Carreras María C. , Poderoso Juan J. , Gores Gregory J. 
Published: April 2014

AbstractBackground & AimsHepatocyte apoptosis, the hallmark of non‐alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis ofNASH, the final common step of apoptosis is executed by a family of cysteine‐proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan‐caspase inhibitor, ameliorates liver injury and fibrosis in a murine model ofNASH.MethodsC57/BL6J‐mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan.ResultsMice fed a HFD diet demonstrate a five‐fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5‐fold and 1.3‐fold increase in caspase‐3 and‐8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD‐Em). Likewise, liver injury and inflammation were reduced in mice fed HFD‐Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1‐β, TNF‐α, monocyte chemoattractant protein (MCP‐1) and C‐X‐C chemokine ligand‐2 (CXCL2) quantitative reverse‐transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR.ConclusionIn conclusion, these data demonstrate that in a murine model ofNASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy inNASH.
Transient depletion of specific immune cell populations to improve adenovirus‐mediated transgene expression in the liver
Authors: Alzuguren Pilar , Hervas‐Stubbs Sandra , Gonzalez‐Aseguinolaza Gloria , Poutou Joanna , Fortes Puri , Mancheno Uxua , Bunuales Maria , Olagüe Cristina , Razquin Nerea , Van Rooijen Nico , Enguita Monica , Hernandez‐Alcoceba Ruben 
Published: April 2014

AbstractBackground & AimsAdenoviral (Ad) vectors are currently one of the most efficient tools for in vivo gene transfer to the liver. However, anti‐Ad immune responses limit the safety and efficacy of these vectors. The initial inflammatory reaction is a concern in terms of toxicity, and it favours the development of cellular and humoral responses leading to short transgene persistence and inefficient vector re‐administrations. Therefore, safe and simple ways to interfere with these processes are needed. Study ways to deplete specific immune cell populations and their impact on liver‐directed gene transfer.MethodsFirst‐generation Ad vectors encoding reporter genes (luciferase or β‐galactosidase) were injected intravenously into Balb/c mice. Kupffer cells and splenic macrophages were depleted by intravenous administration of clodronate liposomes. B lymphocytes, CD4+, CD8+ T lymphocytes or NK cells were depleted by intraperitoneal injection of anti‐M plus anti‐D, anti‐CD4, anti‐CD8 or anti‐asialo‐GM1 antibodies respectively. Long‐term evolution of luciferase expression in the liver was monitored by bioluminescence imaging.ResultsThe anti‐CD4 monoclonal antibody impaired cellular and humoral immune responses, leading to efficient vector re‐administration. Clodronate liposomes had no impact on humoral responses but caused a 100–1000 fold increase in liver transduction, stabilized transgene expression, reduced the concentration of inflammatory cytokines, and inhibited lymphocyte activation.ConclusionsTransient CD4+ T‐cell depletion using antibodies is a clinically feasible procedure that allows efficient Ad redosing. Systemic administration of clodronate liposomes may further increase the safety and efficacy of vectors.
Yttrium‐90 radioembolization vs sorafenib for intermediate‐locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis
Authors: Gramenzi Annagiulia , Golfieri Rita , Mosconi Cristina , Cappelli Alberta , Granito Alessandro , Cucchetti Alessandro , Marinelli Sara , Pettinato Cinzia , Erroi Virginia , Fiumana Silvia , Bolondi Luigi , Bernardi Mauro , Trevisani Franco ,   BLOG (Bologna Liver Oncology Group)
Published: April 2014

AbstractBackground & AimsSorafenib and transarterial 90Y‐radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate‐advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single‐centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy.MethodsSeventy‐four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child–Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy.ResultsMedian overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3–24.5) in sorafenib and 13.2 months (95% CI: 6.1–20.2) in TARE patients, with 1‐, 2‐ and 3‐year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down‐staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2–25.9) and TARE patients (11.2 months; 95% CI: 6.7–15.7), with comparable 1‐, 2‐ and 3‐year survival rates.ConclusionsIn cirrhotic patients with intermediate‐advanced or not‐otherwise‐treatable HCC, sorafenib and TARE provide similar survivals. Down‐staging allowing liver transplantation only occurred after TARE.
Natural selection and the genetic basis of osmoregulation in heteromyid rodents as revealed byRNA‐seq
Authors: Marra Nicholas J. , Romero Andrea , DeWoody J. Andrew 
Published: April 2014

AbstractOne adaptation of ecological and evolutionary interest is the extraordinary ability of desert rodents to retain water during waste production. Much is known regarding the unique kidney physiology of kangaroo rats (Dipodomysspp.) and their ability to retain water during waste production, yet the genetic basis of these physiological adaptations is relatively unknown. Herein, we utilizedRNA‐seq data to conduct a comparative study to identify osmoregulatory genes expressed in heteromyid rodents. We sequenced kidney tissue from two temperate desert species (Dipodomys spectabilisandChaetodipus baileyi) from two separate subfamilies of theHeteromyidae and compared these transcriptomes to a tropical mesic species (Heteromys desmarestianus) from a third subfamily. The evolutionary history of these subfamilies provided a robust phylogenetic control that allowed us to separate shared evolutionary history from convergence. Using two methods to detect differential expression (DE), we identified 1890 genes that showed consistent patterns ofDEbetween the arid and mesic species. A three‐species reciprocalBLASTanalysis revealed 3511 sets of putative orthologues that, upon comparison to knownMus musculussequences, revealed 323 annotated and full‐length genic regions. Selection tests displayed evidence of positive selection (dn/ds > 1) on six genes in the two desert species and remained significant for one of these genes after correction for multiple testing. Thus, our data suggest that both the coding sequence and expression of genes have been shaped by natural selection to provide the genetic architecture for efficient osmoregulation in desert‐adapted heteromyid rodents.
A conserved and essential basic region mediates tRNA binding to the Elp1 subunit of the Saccharomyces cerevisiae Elongator complex
Authors: Di Santo Rachael , Bandau Susanne , Stark Michael J. R. 
Published: April 2014

SummaryElongator is a conserved, multi‐protein complex discovered in Saccharomyces cerevisiae, loss of which confers a range of pleiotropic phenotypes. Elongator in higher eukaryotes is required for normal growth and development and a mutation in the largest subunit of human Elongator (Elp1) causes familial dysautonomia, a severe recessive neuropathy. Elongator promotes addition of mcm5 and ncm5 modifications to uridine in the tRNA anticodon ‘wobble’ position in both yeast and higher eukaryotes. Since these modifications are required for the tRNAs to function efficiently, a translation defect caused by hypomodified tRNAs may therefore underlie the variety of phenotypes associated with Elongator dysfunction. The Elp1 carboxy‐terminal domain contains a highly conserved arginine/lysine‐rich region that resembles a nuclear localization sequence (NLS). Using alanine substitution mutagenesis, we show that this region is essential for Elongator's function in tRNA wobble uridine modification. However, rather than acting to determine the nucleo‐cytoplasmic distribution of Elongator, we find that the basic region plays a critical role in a novel interaction between tRNA and the Elp1 carboxy‐terminal domain. Thus the conserved basic region in Elp1 may be essential for tRNA wobble uridine modification by acting as tRNA binding motif.
The relationship of the lipoprotein SsaB, manganese and superoxide dismutase in Streptococcus sanguinis virulence for endocarditis
Authors: Crump Katie E. , Bainbridge Brian , Brusko Sarah , Turner Lauren S. , Ge Xiuchun , Stone Victoria , Xu Ping , Kitten Todd 
Published: April 2014

SummaryStreptococcus sanguinis colonizes teeth and is an important cause of infective endocarditis. Our prior work showed that the lipoprotein SsaB is critical for S. sanguinis virulence for endocarditis and belongs to the LraI family of conserved metal transporters. In this study, we demonstrated that an ssaB mutant accumulates less manganese and iron than its parent. A mutant lacking the manganese‐dependent superoxide dismutase, SodA, was significantly less virulent than wild‐type in a rabbit model of endocarditis, but significantly more virulent than the ssaB mutant. Neither the ssaB nor the sodA mutation affected sensitivity to phagocytic killing or efficiency of heart valve colonization. Animal virulence results for all strains could be reproduced by growing bacteria in serum under physiological levels of O2. SodA activity was reduced, but not eliminated in the ssaB mutant in serum and in rabbits. Growth of the ssaB mutant in serum was restored upon addition of Mn2+ or removal of O2. Antioxidant supplementation experiments suggested that superoxide and hydroxyl radicals were together responsible for the ssaB mutant's growth defect. We conclude that manganese accumulation mediated by the SsaB transport system imparts virulence by enabling cell growth in oxygen through SodA‐dependent and independent mechanisms.
The role of pain modulators in esophageal disorders – no pain no gain
Authors: Dickman R. , Maradey‐Romero C. , Fass R. 
Published: April 2014

AbstractPain modulators have been primarily used for the management of functional esophageal disorders. Recently, these drugs have also been used for the management of other esophageal disorders, such as non‐erosive reflux disease, the hypersensitive esophagus, and heartburn that is not responsive to proton pump inhibitor treatment. Several etiologies have been identified in patients with functional esophageal disorders, and these include esophageal hypersensitivity due to peripheral and/or central sensitisation, altered central processing of peripheral stimuli, altered autonomic activity, and psychological comorbidity such as depression and anxiety. Different antidepressants have been used as pain modulators and have demonstrated a beneficial effect on patients with the aforementioned esophageal disorders. Tricyclic antidepressants are the most commonly used class of drugs in clinical practice. Other antidepressants that have been used, some with more clinical success than others, include selective serotonin reuptake inhibitors, serotonin‐norepinephrine reuptake inhibitors, and trazodone. Other medications that have been used as pain modulators in esophageal disorders include adenosine antagonists, serotonin agonists, antiepileptics, and medications that ameliorate peripheral neuropathy. The mechanism by which many of the pain modulators confer their visceral analgesic effect remains to be fully elucidated. Regardless, their role and value in treating esophageal disorders have markedly increased in the last decade.
Genome‐wide association implicates numerous genes underlying ecological trait variation in natural populations of Populus trichocarpa
Authors: McKown Athena D. , Klápště Jaroslav , Guy Robert D. , Geraldes Armando , Porth Ilga , Hannemann Jan , Friedmann Michael , Muchero Wellington , Tuskan Gerald A. , Ehlting Jürgen , Cronk Quentin C. B. , El‐Kassaby Yousry A. , Mansfield Shawn D. , Douglas Carl J. 
Published: April 2014

Summary

In order to uncover the genetic basis of phenotypic trait variation, we used 448 unrelated wild accessions of black cottonwood (Populus trichocarpa) from much of its range in western North America. Extensive data from large‐scale trait phenotyping (with spatial and temporal replications within a common garden) and genotyping (with a 34 K Populus single nucleotide polymorphism (SNP) array) of all accessions were used for gene discovery in a genome‐wide association study (GWAS).

We performed GWAS with 40 biomass, ecophysiology and phenology traits and 29 355 filtered SNPs representing 3518 genes. The association analyses were carried out using a Unified Mixed Model accounting for population structure effects among accessions.

We uncovered 410 significant SNPs using a Bonferroni‐corrected threshold (P < 1.7 × 10−6). Markers were found across 19 chromosomes, explained 1–13% of trait variation, and implicated 275 unique genes in trait associations. Phenology had the largest number of associated genes (240 genes), followed by biomass (53 genes) and ecophysiology traits (25 genes).

The GWAS results propose numerous loci for further investigation. Many traits had significant associations with multiple genes, underscoring their genetic complexity. Genes were also identified with multiple trait associations within and/or across trait categories. In some cases, traits were genetically correlated while in others they were not.
Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome
Authors: Ohyama K , Moriyama M , Hayashida J‐N , Tanaka A , Maehara T , Ieda S , Furukawa S , Ohta M , Imabayashi Y , Nakamura S 
Published: April 2014

ObjectivesRecently, the use of saliva as a diagnostic tool has gained considerable attention because it is non‐invasive and easy to perform repeatedly. In this study, we focused on soluble molecules in saliva to establish a new diagnostic method for xerostomia.Materials and MethodsSaliva was obtained from 90 patients with Sjögren's syndrome (SS), 22 patients with xerostomia associated with neurogenic/neuropsychiatric disorders and drugs (XND), 30 patients with radiation‐induced xerostomia (RX), and 36 healthy controls. Concentrations of helper T (Th) cytokines in saliva were measured by flow cytometric analysis. Concentrations of secretory IgA (SIgA) and chromogranin A (CgA) were measured by ELISA.ResultsUnstimulated and stimulated whole saliva from patients with SS, XND, and RX was significantly reduced compared with controls. Th1 and Th2 cytokines from SS patients were significantly higher than controls. Furthermore, Th2 cytokines were closely associated with strong lymphocytic accumulation in salivary glands from SS patients, while Th1 and Th17 cytokines were negatively associated. SIgA levels were not significantly different between all patient groups and controls. CgA levels from XND patients were significantly higher than controls.ConclusionsThe measurement of cytokines, CgA, and SIgA in saliva is suggested to be useful for the diagnosis of xerostomia and also to reveal disease status.
Lowe's Argument Against the Psychoneural Token Identity Thesis
Authors: Paprzycka Katarzyna 
Published: April 2014

AbstractE. J. Lowe argues that the mental event token cannot be identical to the complex neural event token for they have different counterfactual properties. If the mental event had not occurred, the behavior would not have ensued, while if the neural event had not occurred, the behavior would have ensued albeit slightly differently. Lowe's argument for the neural counterfactual relies on standard possible world semantics, whose evaluation of such counterfactuals is problematic. His argument for the mental counterfactual relies on a premise that is plausibly false. My arguments support other counterfactuals, which are consistent with identity theories.
Cinematic magnetic resonance enterography for non‐organic abdominal pain in infants and children
Authors: Watanabe Yoshio , Takasu Hidemi , Sumida Wataru , Ohshima Kazuo 
Published: April 2014

AbstractBackgroundRecurrent non‐organic abdominal pain is the most commonly diagnosed medical problem in children. However, excluding small bowel disease remains a challenge. We evaluated our exclusion criteria for organic small intestinal diseases in pediatric patients with recurrent non‐organic abdominal pain using cinematic magnetic resonance (cine‐MR) enterography.MethodsThe non‐intestinal organic (non‐IO) group as classified by the Rome III criteria system and the intestinal organic (IO) group consisted of 81 and 19 patients, with 35 and 12 male and 46 and 7 female patients with an age range of 5–18 and 4–15 years (average 10.5 and 10.5 years), respectively. Cine‐MR enterography was performed by dynamically balanced first‐field‐echo imaging with thick‐slice water‐selective excitation without breath holding. In our original small intestinal motility test, cine‐MR enterography was taken at three different times (fasting state [P1], immediately after [P2] and 30 min after [P3] drinking liquid material), with images taken sequentially for 5 min at each time‐point to evaluate the motion of water in the gastrointestinal tract. Positive findings for organic intestinal problems were concluded when persistent visible intestinal loops appeared in both the P1 and P2 phases.ResultsCine‐MR enterography showed 6/81 (7.4%) and 18/19 (94.7%) (P < 0.01) positive cases of organic intestinal problems in the non‐IO and IO groups, respectively. Positive and negative predictive values of this examination were 78.3% and 97.4%, respectively.ConclusionsThe unique capabilities of cine‐MR enterography technology in this clinical setting render it an important additional diagnostic tool when specific disease management issues must be addressed.