bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tadalafil for the Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign Prostatic Hyperplasia: Results from a 12‐week Placebo‐controlled Dose‐finding Study with a 42‐week Open‐label Extension
Authors: TAKEDA Masayuki , NISHIZAWA Osamu , IMAOKA Takeshi , MORISAKI Yoji , VIKTRUP Lars 
Published: March 2012

Objectives: To examine the efficacy, safety, and dose response of tadalafil once daily in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH‐LUTS).Methods: Men ≥45 years with moderate‐to‐severe BPH‐LUTS were randomized to once‐daily placebo (N = 140), tadalafil 2.5 mg (N = 142), or tadalafil 5.0 mg (N = 140), in a 12‐week double‐blind phase, followed by a 42‐week, tadalafil 5.0 mg open‐label extension (OLE) phase (N = 394). The primary outcome was total International Prostate Symptom Score (IPSS) change from baseline to last available observation in the double‐blind phase.Results: The least squares (LS) mean difference between placebo and tadalafil in total IPSS change from baseline was −0.7 (P = 0.201) and −1.1 (P = 0.062) for tadalafil 2.5 and 5 mg, respectively (ANCOVA; a dose‐dependent improvement in placebo‐adjusted total IPSS for tadalafil 5 mg versus 2.5 mg of 57%). Repeated‐measures analyses identified a significant total IPSS change for tadalafil 5 mg (LS mean difference between placebo and tadalafil 5 mg: −1.2; P = 0.035), but not tadalafil 2.5 mg, at week 12. Significant improvements for tadalafil 5 mg were demonstrated (ANCOVA) for IPSS obstructive subscore (P = 0.033) and IPSS quality of life index (P = 0.022). Numerical improvements in IPSS scores were maintained over the OLE phase. Tadalafil was well tolerated with no unexpected adverse events.Conclusion: Tadalafil (5.0 mg) had a favorable benefit‐to‐risk profile, supporting further investigation of tadalafil (5.0 mg) in Japanese men with BPH‐LUTS.
COHERENTISM AND THE EPISTEMIC JUSTIFICATION OF MORAL BELIEFS: A CASE STUDY IN HOW TO DO PRACTICAL ETHICS WITHOUT APPEAL TO A MORAL THEORY
Authors: ENGEL JR. MYLAN 
Published: March 2012

abstractThis paper defends a coherentist approach to moral epistemology. In “The Immorality of Eating Meat” (2000), I offer a coherentist consistency argument to show that our own beliefs rationally commit us to the immorality of eating meat. Elsewhere, I use our own beliefs as premises to argue that we have positive duties to assist the poor (2004) and to argue that biomedical animal experimentation is wrong (2012). The present paper explores whether this consistency‐based coherentist approach of grounding particular moral judgments on beliefs we already hold, with no appeal to moral theory, is a legitimate way of doing practical ethics. I argue (i) that grounding particular moral judgments on our core moral convictions and other core nonmoral beliefs is a legitimate way to justify moral judgments, (ii) that these moral judgments possess as much epistemic justification and have as much claim to objectivity as moral judgments grounded on particular ethical theories, and (iii) that this internalistic coherentist method of grounding moral judgments is more likely to result in behavioral guidance than traditional theory‐based approaches to practical ethics. By way of illustrating the approach, I briefly recapitulate my consistency‐based argument for ethical vegetarianism. I then defend the coherentist approach implicit in the argument against a number of potentially fatal metatheoretical attacks.
Performance of the QuantiFERON-Cytomegalovirus (CMV) Assay for Detection and Estimation of the Magnitude and Functionality of the CMV-Specific Gamma Interferon-Producing CD8+T-Cell Response in Allogeneic Stem Cell Transplant Recipients
Authors: Clari María Ángeles , Muñoz-Cobo Beatriz , Solano Carlos , Benet Isabel , Costa Elisa , Remigia María José , Bravo Dayana , Amat Paula , Navarro David 
Published: March 2012

ABSTRACTThe performance of the QuantiFERON-cytomegalovirus (CMV) assay was compared to that of a flow cytometry intracellular cytokine staining (ICS) method for the detection of CMV-specific gamma interferon (IFN-γ)-producing CD8+T-cell responses in allogeneic stem cell transplant (allo-SCT) recipients and for estimations of their magnitude and functionality. A total of 90 whole-blood specimens from 23 allo-SCT recipients was analyzed by both methods. Overall, the percentage of specimens that yielded concordant results by both methods was 68.8% (κ = 0.691; 95% confidence interval [CI], 0.548 to 0.835), and the sensitivity of the QuantiFERON-CMV assay for the detection of positive IFN-γ T-cell responses (>0.2 IU/ml), taking the ICS method as the reference, was 76.3%. The magnitude of IFN-γ-producing CD8+T-cell responses to CMV-specific peptides measured with the QuantiFERON-CMV assay correlated significantly (σ = 0.695;P= <0.001) with that of the total IFN-γ-producing CD8+T cells and dual-functional (IFN-γ/tumor necrosis factor alpha [TNF-α] [σ = 0.652;P= <0.001] and IFN-γ/CD107a [σ = 0.690;P= <0.001]) and trifunctional (IFN-γ/TNF-α/CD107a [σ = 0.679;P= >0.001]) CMV-specific CD8+T-cell responses, as quantitated by ICS. In summary, the data indicated that the QuantiFERON-CMV assay is less sensitive than the ICS method for the detection of CMV-specific IFN-γ-producing CD8+T-cell responses in the allo-SCT setting. Nevertheless, it allowed the estimation of the total and polyfunctional CMV-specific IFN-γ-producing CD8+T-cell responses in specimens that tested positive by both methods.
Dexamethasone Treatment Has No Effect on the Formation of Pneumococcal Antibodies during Community-Acquired Pneumonia
Authors: van Mens Suzan P. , Meijvis Sabine C. A. , Grutters Jan C. , Vlaminckx Bart J. M. , Bos Willem J. W. , Rijkers Ger T. 
Published: March 2012

ABSTRACTIn this study, the effect of dexamethasone on the formation of pneumococcal antibodies during community-acquired pneumonia (CAP) was investigated. No differences between CAP patients receiving dexamethasone as additional therapy and patients receiving a placebo were found with respect to immune response rates and mean baseline and convalescent-phase antibody concentrations.
Detection of Resistance to Second-Line Antituberculosis Drugs by Use of the Genotype MTBDR
sl
Assay: a Multicenter Evaluation and Feasibility Study
Authors: Ignatyeva Olga , Kontsevaya Irina , Kovalyov Alexander , Balabanova Yanina , Nikolayevskyy Vladislav , Toit Kadri , Dragan Anda , Maxim Daniela , Mironova Svetlana , Kummik Tiina , Muntean Ionela , Koshkarova Ekaterina , Drobniewski Francis 
Published: March 2012

ABSTRACT

The rate of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has been steadily increasing in countries of the former USSR. The availability of rapid and reliable methods for the detection of drug resistance to second-line drugs is vital for adequate patient management. We evaluated the performance of the Genotype MTBDR
sl
assay compared to that of phenotypic drug susceptibility testing (Becton Dickinson Bactec MGIT 960 system) with a test panel of 200
Mycobacterium tuberculosis
isolates at four sites in Eastern Europe. The interpretability of the Genotype MTBDR
sl
assay was over 95%. The sensitivity for the detection of resistance to fluoroquinolones, ethambutol, amikacin, and capreomycin varied between 77.3% and 92.3%; however, it was much lower for kanamycin (42.7%). The sensitivity for the detection of XDR TB was 22.6%. The test specificity was over 82% for all drugs. The assay presents a good screening tool for the rapid detection of resistance to individual second-line drugs and can be recommended for use in countries with a high burden of MDR/XDR TB. The sensitivity for the detection of kanamycin resistance needs improvement.
Dimethyl Sulfoxide Enhances Effectiveness of Skin Antiseptics and Reduces Contamination Rates of Blood Cultures
Authors: Tarrand Jeffrey J. , LaSala Paul R. , Han Xiang-Yang , Rolston Kenneth V. , Kontoyiannis Dimitrios P. 
Published: March 2012

ABSTRACT

Effective skin antisepsis is of central importance in the prevention of wound infections, colonization of medical devices, and nosocomial transmission of microorganisms. Current antiseptics have a suboptimal efficacy resulting in substantial infectious morbidity, mortality, and increased health care costs. Here, we introduce an
in vitro
method for antiseptic testing and a novel alcohol-based antiseptic containing 4 to 5% of the polar aprotic solvent dimethyl sulfoxide (DMSO). The DMSO-containing antiseptic resulted in a 1- to 2-log enhanced killing of
Staphylococcus epidermidis
and other microbes
in vitro
compared to the same antiseptic without DMSO. In a prospective clinical validation, blood culture contamination rates were reduced from 3.04% for 70% isopropanol–1% iodine (control antiseptic) to 1.04% for 70% isopropanol–1% iodine–5% DMSO (
P
< 0.01). Our results predict that improved skin antisepsis is possible using new formulations of antiseptics containing strongly polarized but nonionizing (polar aprotic) solvents.
Evaluation of the Cepheid Xpert Flu Assay for Rapid Identification and Differentiation of Influenza A, Influenza A 2009 H1N1, and Influenza B Viruses
Authors: Novak-Weekley S. M. , Marlowe E. M. , Poulter M. , Dwyer D. , Speers D. , Rawlinson W. , Baleriola C. , Robinson C. C. 
Published: March 2012

ABSTRACT
The Xpert Flu Assay cartridge is a next-generation nucleic acid amplification system that provides multiplexed PCR detection of the influenza A, influenza A 2009 H1N1, and influenza B viruses in approximately 70 min with minimal hands-on time. Six laboratories participated in a clinical trial comparing the results of the new Cepheid Xpert Flu Assay to those of culture or real-time PCR with archived and prospectively collected nasal aspirate-wash (NA-W) specimens and nasopharyngeal (NP) swabs from children and adults. Discrepant results were resolved by DNA sequence analysis. After discrepant-result analysis, the sensitivities of the Xpert Flu Assay for prospective NA-W specimens containing the influenza A, influenza A 2009 H1N1, and influenza B viruses compared to those of culture were 90.0%, 100%, and 100%, respectively, while the sensitivities of the assay for prospective NP swabs compared to those of culture were 100%, 100%, and 100%, respectively. The sensitivities of the Xpert Flu Assay for archived NA-W specimens compared to those of Gen-Probe ProFlu+ PCR for the influenza A, influenza A 2009 H1N1, and influenza B viruses were 99.4%, 98.4%, and 100%, respectively, while the sensitivities of the Xpert Flu Assay for archived NP swabs compared to those of ProFlu+ were 98.1%, 100%, and 93.8%, respectively. The sensitivities of the Xpert Flu Assay with archived NP specimens compared to those of culture for the three targets were 97.5%, 100%, and 93.8%, respectively. We conclude that the Cepheid Xpert Flu Assay is an accurate and rapid method that is suitable for on-demand testing for influenza viral infection.
The Bovine Immunodeficiency Virus Rev Protein: Identification of a Novel Nuclear Import Pathway and Nuclear Export Signal among Retroviral Rev/Rev-Like Proteins
Authors: Gomez Corredor Andrea , Archambault Denis 
Published: March 2012

ABSTRACT

The Rev protein is essential for the replication of lentiviruses. Rev is a shuttling protein that transports unspliced and partially spliced lentiviral RNAs from the nucleus to the cytoplasm via the nucleopore. To transport these RNAs, the human immunodeficiency virus type 1 (HIV-1) Rev uses the karyopherin β family importin β and CRM1 proteins that interact with the Rev nuclear localization signal (NLS) and nuclear exportation signal (NES), respectively. Recently, we reported the presence of new types of bipartite NLS and nucleolar localization signal (NoLS) in the bovine immunodeficiency virus (BIV) Rev protein. Here we report the characterization of the nuclear import and export pathways of BIV Rev. By using an
in vitro
nuclear import assay, we showed that BIV Rev is transported into the nucleus by a cytosolic and energy-dependent importin α/β classical pathway. Results from glutathione
S
-transferase (GST) pulldown assays that showed the binding of BIV Rev with importins α3 and α5 were in agreement with those from the nuclear import assay. We also identified a leptomycin B-sensitive NES in BIV Rev, which indicates that the protein is exported via CRM1 like HIV-1 Rev. Mutagenesis experiments showed that the BIV Rev NES maps between amino acids 109 to 121 of the protein. Remarkably, the BIV Rev NES was found to be of the cyclic AMP (cAMP)-dependent protein kinase inhibitor (PKI) type instead of the HIV-1 Rev type. In summary, our data showed that the nuclear import mechanism of BIV Rev is novel among Rev proteins characterized so far in lentiviruses.
Signature Biochemical Properties of Broadly Cross-Reactive HIV-1 Neutralizing Antibodies in Human Plasma
Authors: Sajadi Mohammad M. , Lewis George K. , Seaman Michael S. , Guan Yongjun , Redfield Robert R. , DeVico Anthony L. 
Published: March 2012

ABSTRACTThe common properties of broadly cross-reactive HIV-1 neutralization antibodies found in certain HIV-1-infected individuals holds significant value for understanding natural and vaccine-mediated anti-HIV immunity. Recent efforts have addressed this question by deriving neutralizing monoclonal anti-envelope antibodies from memory B cell pools of selected subjects. However, it has been more difficult to identify whether broadly neutralizing antibodies circulating in plasma possess shared characteristics among individuals. To address this question, we used affinity chromatography and isoelectric focusing to fractionate plasma immunoglobulin from 10 HIV-1-infected subjects (5 subjects with broad HIV-1 neutralizing activity and 5 controls). We find that plasma neutralizing activity typically partitions into at least two subsets of antibodies. Antibodies with restricted neutralization breadth have relatively neutral isoelectric points and preferentially bind to envelope monomers and trimers versus core antigens from which variable loops and other domains have been deleted. In comparison, broadly neutralizing antibodies account for a minor fraction of the total anti-envelope response. They are consistently distinguished by more basic isoelectric points and specificity for epitopes shared by monomeric gp120, gp120 core, or CD4-induced structures. Such biochemical properties might be exploited to reliably predict or produce broad anti-HIV immunity.
Widespread Impact of HLA Restriction on Immune Control and Escape Pathways of HIV-1
Authors: Carlson Jonathan M. , Listgarten Jennifer , Pfeifer Nico , Tan Vincent , Kadie Carl , Walker Bruce D. , Ndung'u Thumbi , Shapiro Roger , Frater John , Brumme Zabrina L. , Goulder Philip J. R. , Heckerman David 
Published: March 2012

ABSTRACTThe promiscuous presentation of epitopes by similar HLA class I alleles holds promise for a universal T-cell-based HIV-1 vaccine. However, in some instances, cytotoxic T lymphocytes (CTL) restricted by HLA alleles with similar or identical binding motifs are known to target epitopes at different frequencies, with different functional avidities and with different apparent clinical outcomes. Such differences may be illuminated by the association of similar HLA alleles with distinctive escape pathways. Using a novel computational method featuring phylogenetically corrected odds ratios, we systematically analyzed differential patterns of immune escape across all optimally defined epitopes in Gag, Pol, and Nef in 2,126 HIV-1 clade C-infected adults. Overall, we identified 301 polymorphisms in 90 epitopes associated with HLA alleles belonging to shared supertypes. We detected differential escape in 37 of 38 epitopes restricted by more than one allele, which included 278 instances of differential escape at the polymorphism level. The majority (66 to 97%) of these resulted from the selection of unique HLA-specific polymorphisms rather than differential epitope targeting rates, as confirmed by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISPOT) data. Discordant associations between HLA alleles and viral load were frequently observed between allele pairs that selected for differential escape. Furthermore, the total number of associated polymorphisms strongly correlated with average viral load. These studies confirm that differential escape is a widespread phenomenon and may be the norm when two alleles present the same epitope. Given the clinical correlates of immune escape, such heterogeneity suggests that certain epitopes will lead to discordant outcomes if applied universally in a vaccine.
Carboxyl-Terminal Amino Acids 1052 to 1082 of the Latency-Associated Nuclear Antigen (LANA) Interact with RBP-Jκ and Are Responsible for LANA-Mediated RTA Repression
Authors: Jin Yi , He Zhiheng , Liang Deguang , Zhang Quanzhi , Zhang Hongxing , Deng Qiang , Robertson Erle S. , Lan Ke 
Published: March 2012

ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is closely associated with several malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV can establish lifelong latency in the host, but the mechanism is not fully understood. Previous studies have proposed a feedback model in which the viral replication and transcription activator (RTA) can induce the expression of the latency-associated nuclear antigen (LANA) during early infection. LANA, in turn, represses transcription and RTA function to establish and maintain KSHV latency. The interaction between LANA and the recombination signal sequence binding protein Jκ (RBP-Jκ, also called CSL), a major transcriptional repressor of the Notch signaling pathway, is essential for RTA repression. In the present study, we show that the LANA carboxyl-terminal amino acids 1052 to 1082 are responsible for the LANA interaction with RBP-Jκ. The secondary structure of the LANA carboxyl terminus resembles the RBP-Jκ-associated module (RAM) of Notch receptor. Furthermore, deletion of the region of LANA residues 1052 to 1082 resulted in aberrant expression of RTA, leading to elevated viral lytic replication. For the first time, we dissected a conserved RBP-Jκ binding domain in LANA and demonstrated that this domain was indispensable for LANA-mediated repression of KSHV lytic genes, thus helping the virus maintain latency and control viral reactivation.
UCLA1, a Synthetic Derivative of a gp120 RNA Aptamer, Inhibits Entry of Human Immunodeficiency Virus Type 1 Subtype C
Authors: Mufhandu Hazel T. , Gray Elin S. , Madiga Maphuti C. , Tumba Nancy , Alexandre Kabamba B. , Khoza Thandeka , Wibmer Constantinos Kurt , Moore Penny L. , Morris Lynn , Khati Makobetsa 
Published: March 2012

ABSTRACT

Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by the virion surface envelope (Env) glycoproteins, making it a desirable target for antiretroviral entry inhibitors. We previously isolated a family of gp120 binding RNA aptamers and showed that they neutralized the infectivity of HIV-1. In this study, we assessed the activity of a shortened synthetic derivative of the B40 aptamer, called UCLA1, against a large panel of HIV-1 subtype C viruses. UCLA1 tightly bound to a consensus HIV-1 subtype C gp120 and neutralized isolates of the same subtype with 50% inhibitory concentrations (IC
50
s) in the nanomolar range. The aptamer had little toxicity in tests with cell lines and primary cells. Furthermore, it exhibited high therapeutic indices, suggesting that it may be effective at very low doses. Mapping of UCLA1 binding sites on gp120 revealed eight amino acid residues that modulated neutralization resistance. This included residues within the coreceptor binding site, at the base of the V3 loop, and in the bridging sheet within the conserved V1/V2 stem-loop of gp120. The aptamer was also shown to have synergistic effects with T20, a gp41 fusion inhibitor, and IgG1b12 (b12), an anti-CD4 binding site monoclonal antibody. These results suggest that UCLA1 may be suitable for development as a potent HIV-1 entry inhibitor.
Retroviral Cyclin Enhances Cyclin-Dependent Kinase-8 Activity
Authors: Rovnak Joel , Brewster Connie D. , Quackenbush Sandra L. 
Published: March 2012

ABSTRACTAlterations in the functional levels of cyclin-dependent kinase-8 (CDK8) or its partner, cyclin C, have been clearly associated with cancers, including colon cancer, melanoma, and osteosarcoma. Walleye dermal sarcoma virus encodes a retroviral cyclin (RV-cyclin) that localizes to interchromatin granule clusters and binds CDK8. It also binds to the Aα subunit (PR65) of protein phosphatase 2A (PP2A). Binding to the Aα subunit excludes the regulatory B subunit, but not the catalytic C subunit, in a manner similar to that of T antigens of the small DNA tumor viruses. The expression of the RV-cyclin enhances the activity of immune affinity-purified CDK8in vitrofor RNA polymerase II carboxy-terminal domain (CTD) and histone H3 substrates. PP2A also enhances CDK8 kinase activityin vitrofor the CTD but not for histone H3. The PP2A enhancement of CDK8 is independent of RV-cyclin expression and likely plays a role in the normal regulation of CDK8. The manipulation of endogenous PP2A activity by inhibition, amendment, or depletion confirmed its role in CDK8 activation by triggering CDK8 autophosphorylation. Although RV-cyclin and PP2A both enhance CDK8 activity, their actions are uncoupled and additive in kinase reactions. PP2A may be recruited to CDK8 in the Mediator complex by a specific PP2A B subunit or additionally by the RV-cyclin in infected cells, but the RV-cyclin appears to activate CDK8 directly and in a manner independent of its physical association with PP2A.
Mechanisms of cervical spine injury in rugby union: a systematic review of the literature
Authors: Kuster Daniel , Gibson Alastair , Abboud Rami , Drew Tim 
Published: March 2012

BackgroundSevere cervical spine injury in rugby union (rugby) exerts a major impact on the individual who sustains the injury and on the broader society. Since the late 1970s, authors of rugby case report studies have postulated that the underlying mechanism of cervical spine injury is hyperflexion of the neck. However, this is in conflict with findings from more recent experimental studies. These have shown that it is more likely that the majority of cervical spine injuries occur due to buckling of the cervical spinal column.ObjectiveTo investigate the primary mechanism of cervical spine injury in rugby.MethodsA comprehensive and systematic review of the literature was undertaken. Six key factors were identified and subsequently used to investigate the two principally postulated mechanisms of cervical spine injury: hyperflexion and buckling.ResultsFacet dislocations, in particular bilateral facet dislocations, were identified as the most common types of cervical spine injury in rugby. Trauma occurred most often at lower cervical spinal levels, notably the C4/5 and C5/6 motion segments. Experimental studies demonstrate that bilateral facet dislocations occurring at the lower cervical spinal levels are primarily produced via buckling.ConclusionOur analysis of key factors for cervical spine injury in rugby shows that it is unlikely that the majority of injuries occur after hyperflexion of the neck. It appears more likely that they are the result of buckling of the cervical spinal column.