bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ephrin‐A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia
Authors: Yang Jinshan , Luo Xiang , Huang Xiaojiang , Ning Qin , Xie Minjie , Wang Wei 
Published: July 2014

AbstractIncreasing evidence indicates that the Eph receptors and their ephrin ligands are involved in the regulation of interactions between neurons and astrocytes. Moreover, astrocytic ephrin‐A3 reverse signaling mediated by EphA4 receptors is necessary for controlling the abundance of glial glutamate transporters. However, the role of ephrin‐A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. In the present study, we found that the EphA4 receptor and its ephrin‐A3 ligand, which were distributed in neurons and astrocytes, respectively, in the hippocampus showed a coincident up‐regulation of protein expression in the early stage of ischemia. Application of clustered EphA4 decreased the expressions of astrocytic glutamate transporters together with astrocytic glutamate uptake capacity through activating ephrin‐A3 reverse signaling. In consequence, neuronal loss was aggravated in the CA1 region of the hippocampus accompanied by impaired hippocampus‐dependent spatial memory when clustered EphA4 treatment was administered prior to transient global ischemia. These findings indicate that EphA4‐mediated ephrin‐A3 reverse signaling is a crucial mechanism for astrocytes to control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions.
image
Astrocytic ephrin‐A3 reverse signaling mediated by EphA4 receptor is necessary for controlling the abundance of glial glutamate transporters under physiological conditions. However, the role of ephrin‐A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. We found EphA4‐mediated ephrin‐A3 reverse signaling to be a crucial mechanism for astrocytes to control glial glutamate transporters and protect hippocampal neurons from glutamate excitotoxicity under ischemic conditions, this cascade representing a potential therapeutic target for stroke.
High flow nasal cannula for continuous positive airway pressure weaning in preterm neonates: A single‐centre experience
Authors: Sasi Arun , Malhotra Atul 
Published: July 2014

AimHigh flow nasal cannula therapy (HFNC) is an emerging method of non‐invasive respiratory support therapy for premature infants. Recent evidence around its safety and efficacy for post‐extubation respiratory support is encouraging. However, its effect on long‐term respiratory outcomes is not known. The aim of this study is to determine the effect of HFNC on respiratory outcomes (chronic lung disease (CLD), need for home oxygen) when used to wean babies from continuous positive airway pressure (CPAP).MethodsThis retrospective study compared respiratory outcomes in infants born <32 weeks gestation needing any respiratory support at birth in two epochs – epoch I (2004–2007) verus epoch II (2008–2011). HFNC was available to be used as a CPAP weaning modality in epoch II.ResultsA total of 1286 infants (epoch I: 597 vs. epoch II: 689), mean (standard deviation) gestation, 28.1 (2.2) versus 28.5 (2.3) weeks were enrolled, with 222 (32%) receiving HFNC in epoch II. Overall median duration of respiratory support increased by 150 h in epoch II (P = 0.03), primarily as HFNC hours. A reduction in duration of invasive ventilation and CPAP along with 6% (P = 0.01) reduction in CLD rates was observed in epoch II. No change in home oxygen therapy rates was noted. In logistic regression, HFNC had no significant effect on rates of CLD or home oxygen.ConclusionsIntroduction of HFNC for weaning nasal CPAP seems to have a minimal effect on CLD rates. The effect of HFNC on long‐term outcomes needs to be further evaluated.
Management of treatment‐naïve chronic hepatitisCgenotype 1 patients: a cost‐effectiveness analysis of treatment options
Authors: Cortesi P. A. , Ciaccio A. , Rota M. , Lim J. K. , De Salvia S. , Okolicsanyi S. , Vinci M. , Belli L. S. , Mantovani L. G. , Strazzabosco M. 
Published: July 2014

SummaryNew and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment inCHCG1 patients. We performed a cost‐effectiveness analysis of boceprevir (BOC)‐ and telaprevir (TVR)‐based triple therapy according to different patients’ selection strategies. A semi‐Markov model ofCHCnatural history and progression towards end‐stage liver disease was built. We considered 3 selection strategies based onMETAVIRfibrosis stage: (i) treat all patients with F1–F4 fibrosis, (ii) only F2–F4 and (iii) only F3–F4. For each strategy,TVRinterleukin‐28B‐guided (IL28B‐guided) andBOCrapid virologic response‐guided (RVR‐guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5‐year time horizon, and adopting the Italian National Health System perspective. The incremental cost‐effectiveness ratio (ICER) for F1–F4 strategy relative to F3–F4 was €5132 per quality‐adjusted life years gained, acrossTVR IL‐28B‐guided therapy, and €7042 in theBOC RVR‐guided therapy. Conversely, in the 5‐year scenario, theICERfor F1–F4 strategy relative to F3–F4 was €1 818 679 (TVR IL28B‐guided) and €1 866 437 (BOC RVR‐guided) per end‐stage liver disease or death (ESLD‐D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis withTVRorBOCcould represent the most cost‐effective strategy to optimize resource utilization.
microRNA‐122 regulates hypoxia‐inducible factor‐1 and vimentin in hepatocytes and correlates with fibrosis in diet‐induced steatohepatitis
Authors: Csak Timea , Bala Shashi , Lippai Dora , Satishchandran Abishek , Catalano Donna , Kodys Karen , Szabo Gyongyi 
Published: July 2014

AbstractBackground & AimsmiR‐122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non‐alcoholic fatty liver disease, is regulated by hypoxia‐inducible factor‐1α (HIF‐1α). Here, we hypothesized that reduced miR‐122 has a pathogenic role in steatohepatitis.MethodsmiR‐122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine–choline‐deficient (MCD) or methionine–choline‐supplemented (MCS) diet.ResultsLiver and hepatocyte miR‐122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR‐122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR‐122 target gene, was induced at all stages of non‐alcoholic steatohepatitis (NASH; 3–8 weeks) only at the mRNA level. Increased NF‐κB activation was found in MCD diet‐fed mice and MAP3K3 regulated the NF‐κB DNA binding in naive hepatocytes. HIF‐1α mRNA and DNA binding and expression of the HIF‐1α target gene, profibrotic lysyl oxidase, was increased in advanced steatohepatitis (8 weeks). In addition, increase in vimentin and Sirius red staining (liver fibrosis) was found at 8 weeks of MCD diet. Using miR‐122 overexpression and inhibition approaches, we confirmed that HIF‐1α, vimentin and MAP3K3 are novel miR‐122 targets in hepatocytes. We report transcriptional repression of miR‐122 in NASH. Decreased liver miR‐122 was associated with elevated circulating miR‐122 in both exosome‐rich and protein‐rich serum fractions.ConclusionsOur novel data suggest that decreased liver miR‐122 contributes to upregulation of modulators of tissue remodelling (HIF‐1α, vimentin and MAP3K3) and might play a role in NASH‐induced liver fibrosis.
MicroRNA‐425‐3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma
Authors: Vaira Valentina , Roncalli Massimo , Carnaghi Carlo , Faversani Alice , Maggioni Marco , Augello Claudia , Rimassa Lorenza , Pressiani Tiziana , Spagnuolo Gaia , Di Tommaso Luca , Fagiuoli Stefano , Rota Caremoli Elena , Barberis Massimo , Labianca Roberto , Santoro Armando , Bosari Silvano 
Published: July 2014

AbstractBackground & AimsSorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients.MethodsWe profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set). Formalin‐fixed paraffin‐embedded tumour and cirrhotic liver biopsies were used for RNA extraction and miRNAs profiling with TaqMan Arrays technology. Statistical analyses were used to correlate miRNA levels with clinical outcome, including time to progression (TTP), progression free (PFS), and overall survival. Cell viability and cell motility of HuH‐7 or HepG2 HCC cells were tested in vitro after transfection with specific miRNA precursor, inhibitor or controls and sorafenib treatment.ResultsSix miRNAs were significantly associated with clinical variables in the training set and only miR‐425‐3p could be further validated. Higher levels of miR‐425‐3p were associated with longer TTP and PFS (P = 0.0008; HR = 0.4; 95% CI = 0.2–0.7 and P = 0.007; HR = 0.5; 95% CI = 0.3–0.9 respectively). Multivariate analysis confirmed the predictive significance of miR‐425‐3p. Furthermore, an association between increased miR‐425‐3p, cell death and reduced cell motility was defined in vitro in HCC cell lines treated with sorafenib.ConclusionsAssessment of miR‐425‐3p levels in liver biopsies could help in stratifying patients with advanced HCC for sorafenib treatment. These promising results need to be confirmed in a large prospective study.
Burden of HIV and hepatitis C co‐infection: the changing epidemiology of hepatitis C in HIV‐infected patients in France
Authors: Cacoub Patrice , Dabis François , Costagliola Dominique , Almeida Kayigan , Lert France , Piroth Lionel , Semaille Caroline 
Published: July 2014

AbstractBackground & AimsTo better evaluate the HIV–HCV co‐infection burden in the context of new effective HCV treatment.MethodsWe reviewed all the epidemiological data available on HCV‐related disease in HIV‐infected patients in France. Sources of data have been selected using the following criteria: (i) prospective cohorts or cross‐sectional surveys; (ii) conducted at a national level; (iii) in the HIV‐infected population; (iv) able to identify HCV co‐infection and chronic active hepatitis C (HCV RNA positive); and (v) conducted during the period 2003–2012.ResultsThe overall prevalence of HIV–HCV co‐infection has decreased from 22–24% to 16–18%. This prevalence decreased from 93% to 87% among injecting drug users while it increased from 4% to 6% among men who have sex with men. The characteristics of patients have changed: decrease in the proportion of patients with chronic active hepatitis C (HCV RNA positive) from 77% to 63% and in the genotypes 2 and 3 HCV infection; increase in the proportion of HCV genotype 1 (from 45–50% to 58%) and genotype 4 (from 15% to 22%). The proportion of patients treated with highly active antiretroviral therapy increased from 76% to 95%, with higher rates of undetectable HIV viral load (47% in 2004 vs. 85% in 2012).ConclusionThe decreasing prevalence and the change in patients profile in HIV–HCV co‐infection underline the importance of continuing efforts to educate physicians and patients. This should increase the benefit of viral risk reduction policies and increase the access of co‐infected patients to HCV treatment.
Studying the dynamics of autonomic activity during emotional experience
Authors: Golland Yulia , Keissar Kobi , Levit‐Binnun Nava 
Published: July 2014

AbstractRecent theories emphasize the dynamic aspects of emotions. However, the physiological measures and the methodological approaches that can capture the dynamics of emotions are underdeveloped. In the current study, we investigated whether moment‐to‐moment changes in autonomic nervous system (ANS) activity are reliably associated with the unfolding of emotional experience. We obtained cardiovascular and electrodermal signals from participants while they viewed emotional movies. We found that theANSsignals were temporally aligned across individuals, indicating a reliable stimulus‐driven response. The degree of response reliability was associated with the emotional time line of the movie. Finally, individual differences inANSresponse reliability were strongly correlated with the subjective emotional responses. The current research offers a methodological approach for studying physiological responses during dynamic emotional situations.
Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog
Authors: Christopherson Pete W. , Bacek Lenore M. , King Kevin B. , Boudreaux Mary K. 
Published: July 2014

BackgroundHemophilia A is an X‐linked disorder caused by a deficiency in coagulation factor VIII. Over 2300 unique mutations in the gene‐encoding factor VIII have been documented in people, but limited information is known in dogs. An 11‐week‐old male Boxer and a 5‐year‐old male German Shepherd were diagnosed with hemophilia A based on diminished factor VIII activity.ObjectiveThe purpose of the study was to identify genetic mutations associated with hemophilia A in both dogs.MethodsGenomic DNA was isolated from EDTA blood samples from the affected German Shepherd and Boxer, the Boxer's dam, 3 female siblings, and one asymptomatic male sibling. Primers were designed in noncoding regions to amplify the 26 exons of the factor VIII gene via PCR.ResultsThe affected Boxer sequence revealed a single nucleotide change, cytosine to guanine, at nucleotide position 1412 (1412C>G) in exon 10. The change is predicted to result in the substitution of arginine for proline at amino acid 471 (P471R) in the A2 domain of factor VIII. The dam and female siblings were carriers, the male sibling did not have the mutation. The German Shepherd dog had a single nucleotide change of a guanine to adenine at position 1643 (1643G>A) in exon 11, predicting the substitution of tyrosine for cysteine at amino acid 548 (C548Y) in the A2 domain.ConclusionsHere we document 2 mutations associated with canine hemophilia A associated with < 1% factor VIII activity, similar to that in people. Another related Boxer with the P471R mutation was later identified.
Diagnosis of Pneumocystis jirovecii Pneumonia in Immunocompromised Patients by Real-Time PCR: a 4-Year Prospective Study
Authors: Robert-Gangneux Florence , Belaz Sorya , Revest Matthieu , Tattevin Pierre , Jouneau Stéphane , Decaux Olivier , Chevrier Sylviane , Le Tulzo Yves , Gangneux Jean-Pierre 
Published: July 2014

ABSTRACT

Pneumocystis jirovecii
pneumonia (PCP) is a life-threatening infection in immunocompromised patients. Quantitative real-time PCR (qPCR) is more sensitive than microscopic examination for the detection of
P. jirovecii
but also detects colonized patients. Hence, its positive predictive value (PPV) needs evaluation. In this 4-year prospective observational study, all immunocompromised patients with acute respiratory symptoms who were investigated for PCP were included, totaling 659 patients (814 bronchoalveolar lavage fluid samples). Patients with negative microscopy but positive qPCR were classified through medical chart review as having retained PCP, possible PCP, or colonization, and their clinical outcomes were compared to those of patients with microscopically proven PCP. Overall, 119 patients were included for analysis, of whom 35, 41, and 43 were classified as having retained PCP, possible PCP, and colonization, respectively. The 35 patients with retained PCP had clinical findings similar to those with microscopically proven PCP but lower fungal loads (
P
< 0.001) and were mainly non-HIV-infected patients (
P
< 0.05). Although the mean amplification threshold was higher in colonized patients, it was not possible to determine a discriminant qPCR cutoff. The PPV of qPCR in patients with negative microscopy were 29.4% and 63.8% when considering retained PCP and retained plus possible PCP, respectively. Patients with possible PCP had a higher mortality rate than patients with retained PCP or colonization (63% versus 3% and 16%, respectively); patients who died had not received co-trimoxazole. In conclusion, qPCR is a useful tool to diagnose PCP in non-HIV patients, and treatment might be better targeted through a multicomponent algorithm including both clinical/radiological parameters and qPCR results.
Rapid Expansion of CD8
+
T Cells in Wild-Type and Type I Interferon Receptor-Deficient Mice Correlates with Protection after Low-Dose Emergency Immunization with Modified Vaccinia Virus Ankara
Authors: Volz Asisa , Langenmayer Martin , Jany Sylvia , Kalinke Ulrich , Sutter Gerd 
Published: July 2014

ABSTRACT

Immunization with modified vaccinia virus Ankara (MVA) can rapidly protect mice against lethal ectromelia virus (ECTV) infection, serving as an experimental model for severe systemic infections. Importantly, this early protective capacity of MVA vaccination completely depends on virus-specific cytotoxic CD8
+
T cell responses. We used MVA vaccination in the mousepox challenge model using ECTV infection to investigate the previously unknown factors required to elicit rapid protective T cell immunity in normal C57BL/6 mice and in mice lacking the interferon alpha/beta receptor (IFNAR
−/−
). We found a minimal dose of 10
5
PFU of MVA vaccine fully sufficient to allow robust protection against lethal mousepox, as assessed by the absence of disease symptoms and failure to detect ECTV in organs from vaccinated animals. Moreover, MVA immunization at low dosage also protected IFNAR
−/−
mice, indicating efficient activation of cellular immunity even in the absence of type I interferon signaling. When monitoring for virus-specific CD8
+
T cell responses in mice vaccinated with the minimal protective dose of MVA, we found significantly enhanced levels of antigen-specific T cells in animals that were MVA vaccinated and ECTV challenged compared to mice that were only vaccinated. The initial priming of naive CD8
+
T cells by MVA immunization appears to be highly efficient and, even at low doses, mediates a rapid
in vivo
burst of pathogen-specific T cells upon challenge. Our findings define striking requirements for protective emergency immunization against severe systemic infections with orthopoxviruses.

IMPORTANCE
We demonstrate that single-shot low-dose immunizations with vaccinia virus MVA can rapidly induce T cell-mediated protective immunity against lethal orthopoxvirus infections. Our data provide new evidence for an efficient protective capacity of vaccination with replication-deficient MVA. These data are of important practical relevance for public health, as the effectiveness of a safety-tested, next-generation smallpox vaccine based on MVA is still debated. Furthermore, producing sufficient amounts of vaccine is expected to be a major challenge should an outbreak occur. Moreover, prevention of other infections may require rapidly protective immunization; hence, MVA could be an extremely useful vaccine for delivering heterologous T cell antigens, particularly for infectious diseases that fit a scenario of emergency vaccination.
Detailed Study of the Interaction between Human Herpesvirus 6B Glycoprotein Complex and Its Cellular Receptor, Human CD134
Authors: Tang Huamin , Wang Junjie , Mahmoud Nora F. , Mori Yasuko 
Published: July 2014

ABSTRACT
Recently, we identified a novel receptor, CD134, which interacts with the human herpesvirus 6B (HHV-6B) glycoprotein (g)H/gL/gQ1/gQ2 complex and plays a key role in the entry of HHV-6B into target cells. However, details of the interaction between the HHV-6B gH/gL/gQ1/gQ2 complex and CD134 were unknown. In this study, we identified a cysteine-rich domain (CRD), CDR2, of CD134 that is critical for binding to the HHV-6B glycoprotein complex and HHV-6B infection. Furthermore, we found that the expression of HHV-6B gQ1 and gQ2 subunits was sufficient for CD134 binding, which is different from the binding of human herpesvirus 6A (HHV-6A) to its receptor, CD46. Finally, we identified a region in gQ1 critical for HHV-6B gQ1 function. These results contribute much to our understanding of the interaction between this ligand and receptor.

IMPORTANCE
We identified the domain in HHV-6B entry receptor CD134 and the components in the HHV-6B gH/gL/gQ1/gQ2 complex required for ligand-receptor binding during HHV-6B infection. Furthermore, we identified domains in gQ1 proteins of HHV-6A and -6B and a key amino acid residue in HHV-6B gQ1 required for its function. These data should be the basis for further investigation of ligand-receptor interaction in the study of HHV-6A and -6B.
Type III Interferon Attenuates a Vesicular Stomatitis Virus-Based Vaccine Vector
Authors: Guayasamin Ryann C. , Reynolds Tracy D. , Wei Xin , Fujiwara Mai , Robek Michael D. 
Published: July 2014

ABSTRACT

Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture.
In vivo
, IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications.

IMPORTANCE
Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.