bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating confidence intervals for information transfer analysis of confusion matrices
Authors: Azadpour Mahan , McKay Colette M. , Smith Robert L.
Published: February 2014

A non-parametric bootstrapping statistical method is introduced and investigated for estimating confidence intervals resulting from information transfer (IT) analysis of confusion matrices. Confidence intervals can be used to statistically compare ITs from two or more confusion matrices obtained in an experiment. Information transfer is a nonlinear analysis and does not satisfy many of the assumptions of a parametric method. The bootstrapping method accurately estimated IT confidence intervals as long as the confusion matrices contained a sufficiently large number of presentations per stimulus category, which is also a condition for reduced bias in IT analysis.
Action Monitoring and Medial Frontal Cortex: Leading Role of Supplementary Motor Area
Authors: Bonini Francesca , Burle Boris , Liégeois-Chauvel Catherine , Régis Jean , Chauvel Patrick , Vidal Franck
Published: February 2014

Oops, That's Not Right…

Evaluating our actions, and detecting our errors, is crucial for adaptive behavior. These fundamental executive functions are intensively studied in cognitive and social neuroscience, but their anatomical basis remains poorly characterized. Using intracerebral electroencephalography in patients being prepared for epilepsy surgery,

Bonini
et al.

(p.
888
) found that, contrary to what is widely assumed, the supplementary motor area, and not the anterior cingulate cortex, plays a leading role in these processes. The data provide a precise spatio-temporal description of the cortical network underlying action monitoring and error processing.
Unraveling a Flavivirus Enigma
Authors: Shi Pei-Yong
Published: February 2014

The structure of a flavirirus nonstructural protein provides mechanistic understanding for many of its functions.

[Also see Report by

Akey
et al.

]
FDA Considers Trials of 'Three-Parent Embryos'
Authors: Vogel Gretchen
Published: February 2014

An experimental technique that manipulates a woman's DNA could spare her from passing on a potentially deadly disease to her children, but the technique breaks new and ethically fraught ground.
Antarctic Scientists Continue to Reel From Shutdown
Authors: Mervis Jeffrey
Published: February 2014

U.S. scientists working in Antarctica continue to feel the negative effects of last fall's government shutdown.
Atlantic Current Can Shut Down for Centuries, Disrupting Climate
Authors: Kerr Richard A.
Published: February 2014

Researchers now have hard evidence that the circulation that helps warm the North Atlantic did indeed abruptly slow or perhaps even stop for centuries at a time more than 100,000 years ago.
Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant
Authors: Feinen Brandon , Petrovsky Nikolai , Verma Anita , Merkel Tod J.
Published: February 2014

Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized
Bacillus anthracis
Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to
B. anthracis
as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by
in vivo
imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.
Assessment of Etest as an Alternative to Agar Dilution for Antimicrobial Susceptibility Testing of Neisseria gonorrhoeae
Authors: Liu Hsi , Taylor Thomas H. , Pettus Kevin , Trees David
Published: February 2014

We studied whether the Etest can be used as an alternative to agar dilution to determine antimicrobial susceptibilities of ceftriaxone, cefixime, and cefpodoxime in
Neisseria gonorrhoeae
surveillance. One hundred fifteen clinical and laboratory isolates of
N. gonorrhoeae
were tested following the Clinical Laboratory Improvement Amendments (CLIA)-approved CLSI standard agar dilution method and, separately, by the Etest according to the manufacturer's recommendations. The MICs were determined and compared. Ten laboratory-generated mutants were used to simulate substantially nonsusceptible specimens. The Etest and agar dilution methods were well correlated. Statistical tests produced regression
R
2
values of 88%, 82%, and 85% and Pearson correlation coefficients of 92%, 91%, and 92% for ceftriaxone, cefixime, and cefpodoxime, respectively. When paired comparisons were made, the two tests were 88.7%, 80%, and 87% within 1 log
2
dilution from each other for ceftriaxone, cefixime, and cefpodoxime, respectively. The within-2-log
2
agreements were 99.1%, 98.3%, and 94.8% for ceftriaxone, cefixime, and cefpodoxime, respectively. Notwithstanding the good correlations and the within-2-log
2
general agreement, the Etest results produced slightly lower MICs than the agar dilution results. In conclusion, we found that the Etest can be effectively used as an alternative to agar dilution testing to determine the susceptibility of
N. gonorrhoeae
to ceftriaxone, cefixime, and cefpodoxime, although we recommend further research into extremely resistant isolates. For isolates within the typical range of clinical MICs, reexamination of the Etest interpretation of susceptible and nonsusceptible categories would likely allow for successful transition from agar dilution to the Etest.
Premarket Evaluations of the IMDx C. difficile for Abbott
m
2000 Assay and the BD Max Cdiff Assay
Authors: Stellrecht K. A. , Espino A. A. , Maceira V. P. , Nattanmai S. M. , Butt S. A. , Wroblewski D. , Hannett G. E. , Musser K. A.
Published: February 2014

Clostridium difficile
-associated diarrhea is a well-recognized complication of antibiotic use. Historically, diagnosing
C. difficile
has been difficult, as antigen assays are insensitive and culture-based methods require several days to yield results. Nucleic acid amplification tests (NAATs) are quickly becoming the standard of care. We compared the performance of two automated investigational/research use only (IUO/RUO) NAATs for the detection of
C. difficile
toxin genes, the IMDx
C. difficile
for Abbott
m
2000 Assay (IMDx) and the BD Max Cdiff Assay (Max). A prospective analysis of 111 stool specimens received in the laboratory for
C. difficile
testing by the laboratory's test of record (TOR), the BD GeneOhm Cdiff Assay, and a retrospective analysis of 88 specimens previously determined to be positive for
C. difficile
were included in the study. One prospective specimen was excluded due to loss to follow-up discrepancy analysis. Of the remaining 198 specimens, 90 were positive by all three methods, 9 were positive by TOR and Max, and 3 were positive by TOR only. One negative specimen was initially inhibitory by Max. The remaining 95 specimens were negative by all methods. Toxigenic
C. difficile
culture was performed on the 12 discrepant samples. True
C. difficile
-positive status was defined as either positive by all three amplification assays or positive by toxigenic culture. Based on this definition, the sensitivity and specificity were 96.9% and 95% for Max and 92.8% and 100% for IMDx. In summary, both highly automated systems demonstrated excellent performance, and each has individual benefits, which will ensure that they will both have a niche in clinical laboratories.
Potential for Use of the Seegene Anyplex MTB/NTM Real-Time Detection Assay in a Regional Reference Laboratory
Authors: Perry Michael D. , White P. Lewis , Ruddy Michael
Published: February 2014

Requests for direct molecular diagnosis of mycobacterial disease are increasingly warranted. The Anyplex MTB/NTM assay demonstrates sensitivities, specificities, and positive and negative predictive values of 1.00, 0.96, 0.93, and 1.00 for
Mycobacterium tuberculosis
complex (MTBC) and 1.00, 0.97, 0.75, and 1.00 for nontuberculous mycobacteria (NTM) detection, respectively, making it a suitable screening test for mycobacterial detection.
Inhibition of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by HIV-1 Nef and Cellular MicroRNA hsa-miR-1258
Authors: Yan Qin , Ma Xinting , Shen Chenyou , Cao Xu , Feng Ninghan , Qin Di , Zeng Yi , Zhu Jianzhong , Gao Shou-Jiang , Lu Chun
Published: February 2014

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several AIDS-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. The interaction of human immunodeficiency virus type 1 (HIV-1) and KSHV has a central role in promoting the aggressive manifestations of AIDS-KS. We have previously shown that negative factor (Nef), a secreted HIV-1 protein, synergizes with KSHV viral interleukin-6 (vIL-6) to promote angiogenesis and tumorigenesis by activating the AKT pathway (X. Zhu, et al., Oncogene, 22 April 2013,
http://dx.doi.org/10.1038/onc.2013.136
). Here, we further demonstrated the role of soluble and ectopic Nef in the regulation of KSHV latency. We found that both soluble Nef protein and ectopic expression of Nef by transfection suppressed the expression of KSHV viral lytic mRNA transcripts and proteins and the production of infectious viral particles. MicroRNA (miRNA) microarray analysis identified a number of Nef-regulated miRNAs. Bioinformatics and luciferase reporter analyses showed that one of the Nef-upregulated miRNAs, cellular miRNA 1258 (hsa-miR-1258), directly targeted a seed sequence in the 3′ untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls KSHV reactivation from latency. Ectopic expression of hsa-miR-1258 impaired RTA synthesis and enhanced Nef-mediated inhibition of KSHV replication, whereas repression of hsa-miR-1258 has the opposite effect. Mutation of the seed sequence in the RTA 3′UTR abolished downregulation of RTA by hsa-miR-1258. Collectively, these novel findings demonstrate that, by regulating cellular miRNA, Nef may inhibit KSHV replication to promote viral latency and contribute to the pathogenesis of AIDS-related malignancies.

IMPORTANCE
This study found that Nef, a secreted HIV-1 protein, suppressed KSHV lytic replication to promote KSHV latency. Mechanistic studies indicated that a Nef-upregulated cellular miRNA, hsa-miR-1258, inhibits KSHV replication by directly targeting a seed sequence in the KSHV RTA 3′UTR. These results illustrate that, in addition to viral miRNAs, cellular miRNAs also play an important role in regulating the life cycle of KSHV. Overall, this is the first study to report the involvement of Nef in KSHV latency, implying its likely important role in the pathogenesis of AIDS-related malignancies.
CD4
+
Memory Stem Cells Are Infected by HIV-1 in a Manner Regulated in Part by SAMHD1 Expression
Authors: Tabler Caroline O. , Lucera Mark B. , Haqqani Aiman A. , McDonald David J. , Migueles Stephen A. , Connors Mark , Tilton John C.
Published: February 2014

CD4
+
and CD8
+
memory T cells with stem cell-like properties (T
SCM
cells) have been identified in mice, humans, and nonhuman primates and are being investigated for antitumor and antiviral vaccines and immunotherapies. Whether CD4
+
T
SCM
cells are infected by human immunodeficiency virus (HIV) was investigated by using a combination HIV reporter virus system
in vitro
and by direct staining for HIV p24 antigen
ex vivo
. A proportion of T
SCM
cells were found to express the HIV coreceptors CCR5 and CXCR4 and were infected by HIV both
in vitro
and
in vivo
. Analysis of viral outcome following fusion using the combination reporter virus system revealed that T
SCM
cells can become productively or latently infected, although the vast majority of T
SCM
cells are abortively infected. Knockdown of the HIV restriction factor SAMHD1 using Vpx-containing simian immunodeficiency virus (SIV) virion-like particles enhanced the productive infection of T
SCM
cells, indicating that SAMHD1 contributes to abortive infection in these cells. These results demonstrate that CD4
+
T
SCM
cells are targets for HIV infection, that they become productively or latently infected at low levels, and that SAMHD1 expression promotes abortive infection of this important memory cell subset.

IMPORTANCE
Here we demonstrate the susceptibility of CD4
+
memory stem cells (T
SCM
cells) to infection by HIV
in vitro
and
in vivo
, provide an in-depth analysis of coreceptor expression, demonstrate the infection of naïve and memory CD4
+
T cell subsets with both CCR5- and CXCR4-tropic HIV, and also perform outcome analysis to calculate the percentage of cells that are productively, latently, or abortively infected. Through these outcome studies, we determined that the vast majority of T
SCM
cells are abortively infected by HIV, and we demonstrate that knockdown of SAMHD1 significantly increases the frequency of infection of this CD4
+
T cell subset, indicating that SAMHD1 is an active restriction factor in T
SCM
cells.
Lymphocyte Gene Expression and JC Virus Noncoding Control Region Sequences Are Linked with the Risk of Progressive Multifocal Leukoencephalopathy
Authors: Marshall Leslie J. , Ferenczy Michael W. , Daley Elizabeth L. , Jensen Peter N. , Ryschkewitsch Caroline F. , Major Eugene O.
Published: February 2014

Progressive multifocal leukoencephalopathy (PML)-derived noncoding control region (NCCR) sequences permitted greater early viral gene expression than kidney-associated NCCR sequences. This was driven in part by binding of the transcription factor Spi-B to unique PML-associated Spi-B binding sites. Spi-B is upregulated in developing B cells in response to natalizumab therapy, a known risk factor for PML. Naturally occurring JCV sequence variation, together with drug treatment-induced cellular changes, may synergize to create an environment leading to an increased risk of PML.
Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread
Authors: Barretto Naina , Sainz Bruno , Hussain Snawar , Uprichard Susan L.
Published: February 2014

Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, “cell-free” entry of infectious extracellular virions that have been released by infected cells and direct “cell-to-cell” transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread. In contrast, the very low density lipoprotein (VLDL) pathway, which is required for the secretion of cell-free infectious virus and thus has been identified as an antiviral target for blocking cell-free virus secretion/spread, is not required for cell-to-cell spread. Noting that HCV cell-free and cell-to-cell spread share some common factors but not others, we tested the therapeutic implications of these observations and demonstrate that inhibitors that target cell factors required for both forms of HCV spread exhibit synergy when used in combination with interferon (a representative inhibitor of intracellular HCV production), while inhibitors that block only cell-free spread do not. This provides insight into the mechanistic basis of synergy between interferon and HCV entry inhibitors and highlights the broader, previously unappreciated impact blocking HCV cell-to-cell spread can have on the efficacy of HCV combination therapies.

IMPORTANCE
HCV can spread to naive cells using distinct mechanisms: “cell-free” entry of extracellular virus and direct “cell-to-cell” transmission. Herein, we identify the host cell HCV entry factor NPC1L1 as also being required for HCV cell-to-cell spread, while showing that the VLDL pathway, which is required for the secretion of cell-free infectious virus, is not required for cell-to-cell spread. While both these host factors are considered viable antiviral targets, we demonstrate that only inhibitors that block factors required for both forms of HCV entry/spread (i.e., NPC1L1) exhibit synergy when used in combination with interferon, while inhibitors that block factors required only for cell-free spread (i.e., VLDL pathway components) do not. Thus, this study advances our understanding of HCV cell-to-cell spread, provides mechanistic insight into the basis of drug synergy, and highlights inhibition of HCV spread as a previously unappreciated consideration in HCV therapy design.
Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection
Authors: Johnston Christine , Zhu Jia , Jing Lichen , Laing Kerry J. , McClurkan Christopher M. , Klock Alexis , Diem Kurt , Jin Lei , Stanaway Jeffrey , Tronstein Elizabeth , Kwok William W. , Huang Meei-li , Selke Stacy , Fong Youyi , Magaret Amalia , Koelle David M. , Wald Anna , Corey Lawrence
Published: February 2014

Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4
+
and CD8
+
T cells were quantified by immunofluorescence, and HSV-specific CD4
+
T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (
P
< 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8
+
T cells compared to control tissue (27 versus 13 cells/mm
2
,
P
= 0.03) and identified HSV-specific CD4
+
T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract.

IMPORTANCE
This detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8
+
T cells compared to control tissue, and HSV-specific CD4
+
T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract.
Identification and Characterization of a Proteolytically Primed Form of the Murine Coronavirus Spike Proteins after Fusion with the Target Cell
Authors: Wicht Oliver , Burkard Christine , de Haan Cornelis A. M. , van Kuppeveld Frank J. M. , Rottier Peter J. M. , Bosch Berend Jan
Published: February 2014

Enveloped viruses carry highly specialized glycoproteins that catalyze membrane fusion under strict spatial and temporal control. To prevent premature activation after biosynthesis, viral class I fusion proteins adopt a locked conformation and require proteolytic cleavage to render them fusion-ready. This priming step may occur during virus exit from the infected cell, in the extracellular milieu or during entry at or in the next target cell. Proteolytic processing of coronavirus spike (S) fusion proteins during virus entry has been suggested but not yet formally demonstrated, while the nature and functionality of the resulting subunit is still unclear. We used a prototype coronavirus—mouse hepatitis virus (MHV)—to develop a conditional biotinylation assay that enables the specific identification and biochemical characterization of viral S proteins on virions that mediated membrane fusion with the target cell. We demonstrate that MHV S proteins are indeed cleaved upon virus endocytosis, and we identify a novel processing product S2* with characteristics of a fusion-active subunit. The precise cleavage site and the enzymes involved remain to be elucidated.

IMPORTANCE
Virus entry determines the tropism and is a crucial step in the virus life cycle. We developed an approach to characterize structural components of virus particles after entering new target cells. A prototype coronavirus was used to illustrate how the virus fusion machinery can be controlled.
Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis
Authors: Campion Eva M. , Hakimjavadi Roya , Loughran Sinéad T. , Phelan Susan , Smith Sinéad M. , D'Souza Brendan N. , Tierney Rosemary J. , Bell Andrew I. , Cahill Paul A. , Walls Dermot
Published: February 2014

The Epstein-Barr virus (EBV) establishes a lifelong latent infection in humans. EBV infection of primary B cells causes cell activation and proliferation, a process driven by the viral latency III gene expression program, which includes EBV nuclear proteins (EBNAs), latent membrane proteins, and untranslated RNAs, including microRNAs. Some latently infected cells enter the long-lived memory B-cell compartment and express only EBNA1 transiently (Lat I) or no EBV protein at all (Lat 0). Targeting the molecular machinery that controls B-cell fate decisions, including the Bcl-2 family of apoptosis-regulating proteins, is crucial to the EBV cycle of infection. Here, we show thatBIK(also known asNBK), which encodes a proapoptotic “sensitizer” protein, is repressed by the EBNA2-driven Lat III program but not the Lat I program.BIKrepression occurred soon after infection of primary B cells by EBV but not by a recombinant EBV in which the EBNA2 gene had been knocked out. Ectopic BIK induced apoptosis in Lat III cells by a mechanism dependent on its BH3 domain and the activation of caspases. We show that EBNA2 repressesBIKin EBV-negative B-cell lymphoma-derived cell lines and that this host-virus interaction can inhibit the proapoptotic effect of transforming growth factor β1 (TGF-β1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-β1-associated regulatory SMAD proteins were bound to theBIKpromoter in response to EBV Lat III or ectopic EBNA2. These data are evidence of an additional mechanism used by EBV to promote B-cell survival, namely, the transcriptional repression of the BH3-only sensitizerBIK.

IMPORTANCEOver 90% of adult humans are infected with the Epstein-Barr virus (EBV). EBV establishes a lifelong silent infection, with its DNA residing in small numbers of blood B cells that are a reservoir from which low-level virus reactivation and shedding in saliva intermittently occur. Importantly, EBV DNA is found in some B-cell-derived tumors in which viral genes play a key role in tumor cell emergence and progression. Here, we report for the first time that EBV can shut off a B-cell gene calledBIK. When activated by a molecular signal called transforming growth factor β1 (TGF-β1),BIKplays an important role in killing unwanted B cells, including those infected by viruses. We describe the key EBV–B-cell molecular interactions that lead toBIKshutoff. These findings further our knowledge of how EBV prevents the death of its host cell during infection. They are also relevant to certain posttransplant lymphomas where unregulated cell growth is caused by EBV genes.
3C
pro
of Foot-and-Mouth Disease Virus Antagonizes the Interferon Signaling Pathway by Blocking STAT1/STAT2 Nuclear Translocation
Authors: Du Yijun , Bi Jingshan , Liu Jiyu , Liu Xing , Wu Xiangju , Jiang Ping , Yoo Dongwan , Zhang Yongguang , Wu Jiaqiang , Wan Renzhong , Zhao Xiaomin , Guo Lihui , Sun Wenbo , Cong Xiaoyan , Chen Lei , Wang Jinbao
Published: February 2014

Foot-and-mouth disease virus (FMDV) causes a highly contagious, debilitating disease in cloven-hoofed animals with devastating economic consequences. To survive in the host, FMDV has evolved to antagonize the host type I interferon (IFN) response. Previous studies have reported that the leader proteinase (L
pro
) and 3C
pro
of FMDV are involved in the inhibition of type I IFN production. However, whether the proteins of FMDV can inhibit type I IFN signaling is less well understood. In this study, we first found that 3C
pro
of FMDV functioned to interfere with the JAK-STAT signaling pathway. Expression of 3C
pro
significantly reduced the transcript levels of IFN-stimulated genes (ISGs) and IFN-stimulated response element (ISRE) promoter activity. The protein level, tyrosine phosphorylation of STAT1 and STAT2, and their heterodimerization were not affected. However, the nuclear translocation of STAT1/STAT2 was blocked by the 3C
pro
protein. Further mechanistic studies demonstrated that 3C
pro
induced proteasome- and caspase-independent protein degradation of karyopherin α1 (KPNA1), the nuclear localization signal receptor for tyrosine-phosphorylated STAT1, but not karyopherin α2, α3, or α4. Finally, we showed that the protease activity of 3C
pro
contributed to the degradation of KPNA1 and thus blocked STAT1/STAT2 nuclear translocation. Taken together, results of our experiments describe for the first time a novel mechanism by which FMDV evolves to inhibit IFN signaling and counteract host innate antiviral responses.

IMPORTANCE
We show that 3C
pro
of FMDV antagonizes the JAK-STAT signaling pathway by blocking STAT1/STAT2 nuclear translocation. Furthermore, 3C
pro
induces KPNA1 degradation, which is independent of proteasome and caspase pathways. The protease activity of 3C
pro
contributes to the degradation of KPNA1 and governs the ability of 3C
pro
to inhibit the JAK-STAT signaling pathway. This study uncovers a novel mechanism evolved by FMDV to antagonize host innate immune responses.
Capacity for Infectious HIV-1 Virion Capture Differs by Envelope Antibody Specificity
Authors: Liu Pinghuang , Williams LaTonya D. , Shen Xiaoying , Bonsignori Mattia , Vandergrift Nathan A. , Overman R. Glenn , Moody M. Anthony , Liao Hua-Xin , Stieh Daniel J. , McCotter Kerrie L. , French Audrey L. , Hope Thomas J. , Shattock Robin , Haynes Barton F. , Tomaras Georgia D.
Published: February 2014

Antibody capacity to recognize infectious virus is a prerequisite of many antiviral functions. We determined the infectious virion capture index (IVCI) of different antibody specificities. Whereas broadly neutralizing antibodies (bNAbs), except for an MPER bNAb, selectively captured infectious virions, non-bNAbs and mucosal human immunodeficiency virus type 1 (HIV-1)-positive IgG captured subsets of both infectious and noninfectious virions. Infectious virion capture was additive with a mixture of antibodies, providing proof of concept for vaccine-induced antibodies that together have improved capacity to recognize infectious virions.
The Safety of Acupuncture during Pregnancy: A Systematic Review
Authors: Park Jimin , Sohn Youngjoo , White Adrian R , Lee Hyangsook
Published: February 2014

Objective

Although there is a growing interest in the use of acupuncture during pregnancy, the safety of acupuncture is yet to be rigorously investigated. The objective of this review is to identify adverse events (AEs) associated with acupuncture treatment during pregnancy.

Methods

We searched Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED) and five Korean databases up to February 2013. Reference lists of relevant articles were screened for additional reports. Studies were included regardless of their design if they reported original data and involved acupuncture needling and/or moxibustion treatment for any conditions in pregnant women. Studies of acupuncture for delivery, abortion, assisted reproduction or postpartum conditions were excluded. AE data were extracted and assessed in terms of severity and causality, and incidence was determined.

Results

Of 105 included studies, detailed AEs were reported only in 25 studies represented by 27 articles (25.7%). AEs evaluated as certain, probable or possible in the causality assessment were all mild/moderate in severity, with needling pain being the most frequent. Severe AEs or deaths were few and all considered unlikely to have been caused by acupuncture. Total AE incidence was 1.9%, and the incidence of AEs evaluated as certainly, probably or possibly causally related to acupuncture was 1.3%.

Conclusions

Acupuncture during pregnancy appears to be associated with few AEs when correctly applied.
Acute large bowel obstruction secondary to stage 4 colonic carcinoma in an elderly man with severe aortic stenosis: a therapeutic challenge
Authors: Prabhu Raghunath , Kumar Neha , Sadhu Sakshi , Natarajan Arjun
Published: February 2014

Colonic adenocarcinoma is a common gastrointestinal malignancy affecting the elderly, and has a multifactorial aetiology. Depending on the individual circumstances, surgical resection is the treatment of choice for colon cancer even for oligometastasis. Metastatic evidence as well as presence of comorbidities, particularly in the elderly, make surgical management difficult and often present a clinical challenge for clinicians. This is a case report exploring the treatment options for an 80-year-old male patient presenting with acute large bowel obstruction secondary to colonic adenocarcinoma with disseminated metastases and severe aortic stenosis.
Functional paraganglioma
Authors: Balasubramanian Gokulakrishnan , Nellaiappan Vallikantha
Published: February 2014

Paraganglioma are tumours arising from neural crest cells of the sympathetic and parasympathetic paraganglia. Functional paraganglioma presents with symptoms of catecholamine excess that includes hypertension, flushing, diaphoresis, etc. Non-functional paraganglioma are usually found incidentally during imaging studies. Early diagnoses of functional paraganglioma are important because their removal is often curative. We present the case of a young man who presented with hypertensive crisis and severe headache, who was later found to have functional paraganglioma.
Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures
Authors: Mannion Sasha , Mtintsilana Asanda , Posthumus Michael , van der Merwe Willem , Hobbs Hayden , Collins Malcolm , September Alison V
Published: February 2014

Background

Genetic variants within genes involved in fibrillogenesis have previously been implicated in anterior cruciate ligament (ACL) injury susceptibility. Proteoglycans also have important functions in fibrillogenesis and maintaining the structural integrity of ligaments. Genes encoding proteoglycans are plausible candidates to be investigated for associations with ACL injury susceptibility; polymorphisms within genes encoding the proteoglycans aggrecan (ACAN), biglycan (BGN), decorin (DCN), fibromodulin (FMOD) and lumican (LUM) were examined.

Methods

A case–control genetic association study was conducted. 227 participants with surgically diagnosed ACL ruptures (ACL group) and 234 controls without any history of ACL injury were genotyped for 10 polymorphisms in 5 proteoglycan genes. Inferred haplotypes were constructed for specific regions.

Results

The G allele ofACANrs1516797 was significantly under-represented in the controls (p=0.024; OR=0.72; 95% CI 0.55 to 0.96) compared with the ACL group. ForDCNrs516115, the GG genotype was significantly over-represented in female controls (p=0.015; OR=9.231; 95%CI 1.16 to 73.01) compared with the ACL group and the AA genotype was significantly under-represented in controls (p=0.013; OR=0.33; 95% CI 0.14 to 0.78) compared with the female non-contact ACL injury subgroup. Haplotype analyses implicated regions overlappingACAN(rs2351491 C>T-rs1042631 T>C-rs1516797 T>G),BGN(rs1126499 C>T-rs1042103 G>A) andLUM-DCN(rs2268578 T>C-rs13312816 A>T-rs516115 A>G) in ACL injury susceptibility.

Conclusions

These independent associations and haplotype analyses suggest that regions withinACAN,BGN,DCNand a region spanningLUM–DCNare associated with ACL injury susceptibility. Taking into account the functions of these genes, it is reasonable to propose that genetic sequence variability within the genes encoding proteoglycans may potentially modulate the ligament fibril properties.
CORKSCREW 2013 CORK study of children's realistic estimation of weight
Authors: Skrobo Darko , Kelleher Gemma
Published: February 2014

Background

In a resuscitation situation involving a child (age 1–15 years) it is crucial to obtain a weight as most interventions and management depend on it. The APLS formula, ‘2×(age+4)’, is taught via the APLS course and is widely used in Irish hospitals. As the prevalence of obesity is increasing the accuracy of the formula has been questioned and a newer formula has been suggested, the Luscombe and Owens (LO) formula, ‘(3×age)+7’.

Aims and Objectives

To gather data on the weights and ages of the Cork paediatric population (ages 1–15 years) attending services at the Cork University Hospital (CUH), and to identify which of the two age-based weight estimation formulae has best diagnostic accuracy.

Setting

CUH, Ireland’s only level one trauma centre.

Methods

Retrospective data collection from charts in the Emergency Department, Paediatric Assessment Unit and the Paediatric wards of CUH.

Results

3155 children aged 1–15 years were included in the study. There were 1344 girls and 1811 boys. The formula weight=‘2×(age+4)’ underestimated children’s weights by a mean of 20.3% (95% CI 19.7% to 20.9%) for the ages of 1–15 years. The LO formula weight=‘(3×age)+7’ showed a mean underestimation of 4.0% (95% CI 3.3% to 4.6%) for the same age range.

Conclusions

The LO formula has been validated in several studies and proven to be a superior age-based weight estimation formula in many western emergency departments. This study shows that the LO formula leads to less underestimation of weights in Irish children than the APLS formula. It is a simple, safe and more accurate age-based estimation formula that can be used over a large age range (1–15 years).
Sensitivity and specificity of CT scanning for determining the number of internally concealed packages in ‘body-packers’
Authors: Asha Stephen Edward , Higham Matthew , Child Peter
Published: February 2014

Introduction

If package counts on abdominal CTs of body-packers were known to be accurate, follow-up CTs could be avoided. The objective was to determine the accuracy of CT for the number of concealed packages in body-packers, and the reliability of package counts reported by body-packers who admit to concealing drugs.

Methods

Suspected body-packers were identified from the emergency departments (ED) database. The medical record and radiology reports were reviewed for package counts determined by CT, patient-reported and physically retrieved. The last method was used as the reference standard. Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were calculated for CT package count accuracy. Reliability of patient-reported package counts was assessed using Pearson's correlation coefficient.

Results

There were 50 confirmed body-packers on whom 104 CT scans were performed. Data for the index and reference tests were available for 84 scans. The sensitivity, specificity, PPV and NPV for CT package count were 63% (95% CI 46% to 77%), 82% (95% CI 67% to 92%), 76% (95% CI 58% to 89%) and 71% (95% CI 56% to 83%) respectively. For CTs with a package count <15, the sensitivity, specificity, PPV and NPV for CT package count were 96% (95% CI 80% to 99%), 95% (95% CI 82% to 99%), 93% (95% CI 76% to 99%) and 97% (95% CI 86% to 100%), respectively. Correlation between patient-reported package counts and the number of packages retrieved was high (r=0.90, p<0.001, R2=81%).

Conclusions

The accuracy of CT for determining the number of concealed packages is poor, although when applied to patients with few concealed packages accuracy is high and is useful as a rule-out test. Among patients who have admitted to drug concealment, the number of packages reported to be concealed is reliable.
Thromboembolic complications with Pipeline Embolization Device placement: impact of procedure time, number of stents and pre-procedure P2Y12 reaction unit (PRU) value
Authors: Tan Lee A , Keigher Kiffon M , Munich Stephan A , Moftakhar Roham , Lopes Demetrius K
Published: February 2014

Background

Thromboembolic events after Pipeline Embolization Device (PED) placement remain a feared complication among neuroendovascular surgeons. This study aimed to investigate potential risk factors for thromboembolic events in patients undergoing PED placement.

Methods

Medical records of patients who underwent PED placement from April 2011 to August 2013 were reviewed. Variables including pre-procedure P2Y12 reaction unit (PRU) value, procedure time, number of PEDs deployed and perioperative neurovascular complications were recorded. Multivariate analysis was performed to identify risk factors for perioperative thromboembolic complications.

Results

Seventy-four patients were identified. Six patients (8.1%) had changes in neurological status after PED placement including five (6.8%) thromboembolic complications and one (1.4%) delayed intracranial hemorrhage; 50.9% of patients had diffusion-weighted imaging (DWI) changes on post-procedural MRI. Longer procedure time (>116 min) and multiple PED placements (>1) were statistically significant risk factors for symptomatic thromboembolic events (p<0.01). A pre-procedural PRU value >208 had an OR of 11.32 (95% CI 0.06 to 212.57) for symptomatic thromboembolic complications, but the result was not statistically significant.

Conclusions

DWI changes on MRI occurred at a much higher rate than new neurological symptoms following PED placement. Longer procedure time and multiple PED deployment are associated with higher risks of new neurological changes due to thromboembolic events. There was a trend for an increased risk of a symptomatic thromboembolic event in patients with pre-procedural PRU values >208. Reloading (clopidogrel 600 mg) patients with preoperative PRU >208 was safe and may have a protective effect on thromboembolic events.
Efficacy of vaccination againstActinobacillus pleuropneumoniaein two Belgian farrow‐to‐finish pig herds with a history of chronic pleurisy
Authors: Del Pozo Sacristán R. , Michiels A. , Martens M. , Haesebrouck F. , Maes D.
Published: February 2014

The efficacy of anActinobacillus pleuropneumoniaesubunit vaccine based on ApxIA, ApxIIA, ApxIIIA and OMP‐2 (Porcilis App, MSD) was investigated in two farrow‐to‐finish pig herds (A and B) affected by chronic pleurisy. In total, 1161 pigs were included. At three weeks of age, the pigs were randomly allocated to non‐vaccinated control (NV; n=580) and vaccinated (V; n=581) groups. At 6 and 10 weeks of age, pigs were injected with Porcilis‐APP (V group) or adjuvant (NV group). At slaughter (26 weeks), pleurisy and pneumonia lesions were assessed. All pigs were weighed individually at 6 and 26 weeks of age, and average daily weight gain (ADG; g/pig/day) was calculated. Mortality and days of additional treatment (DAT) were registered during the whole experiment. Data were analysed using binary logistic regression or analysis of variance for proportions or continuous variables, respectively. The prevalence of pleurisy and pneumonia was (NV‐A=19.3, V‐A=7.9, (P=0.000); NV‐B=17.9, V‐B=0.7, (P=0.000)) and (NV‐A=42.4, V‐A=21.2, (P=0.000); NV‐B=46.7, V‐B=19.0, (P=0.000)), respectively. The ADG was NV‐A=632±157, V‐A=647±91, (P=0.162); NV‐B=660±115, V‐B=670±82, (P=0.232). The mortality during the experiment was NV‐A=5.7, V‐A=1.8, (P=0.015); NV‐B=2.3, V‐B=1.0, (P=0.170) per cent. The DAT was: NV‐A=15.04±1.41, V‐A=14.95±0.67, (P=0.010); NV‐B=21.68±2.43, V‐B=16.99±0.62, (P=0.000). The present study showed a significant reduction of the prevalence of pleurisy and pneumonia, and antimicrobial use in V pigs from both herds, and in mortality in V pigs from one herd.
Accuracy of aggregate 2- and 3-component models of body composition relative to 4-component for the measurement of changes in fat mass during weight loss in overweight and obese subjects
Authors: Lara Jose , Johnstone Alexandra M. , Wells Jonathan , Jebb Susan , Siervo Mario
Published: February 2014

The 4-component (4-C) model is the reference method to measure fat mass (FM). Simpler 2-component (2-C) models are widely used to assess FM. We hypothesised that an aggregate 2-C model may improve accuracy of FM assessment during weight loss (WL). One hundred and six overweight and obese men and women were enrolled in different WL programs (fasting, very low energy diet, low energy diet). Body density, bone mineral content, and total body water were measured. FM was calculated using 2-C, 3-C, and 4-C models. Aggregate equations for 2-C, 3-C, and 4-C models were calculated, with the aggregate 4-C model assumed as the reference method. The aggregate approach postulates that the average of the individual estimates obtained from each model is more accurate than the best single measurement. The average WL was −7.5 kg. The agreement between 3-C and 4-C models for FM change was excellent (R2= 0.99). The aggregate 2-C equation was more accurate than individual 2-C estimates in measuring changes in FM. The aggregate model was characterised by a lower measurement error at baseline and post-WL. The relationship between the aggregate 3-C and 4-C component models was highly linear (R2= 0.99), whereas a lower linearity was found for the aggregate 2-C and 4-C model (R2= 0.72). The aggregate 2-C model is characterised by a greater accuracy than commonly applied 2-C equations for the measurement of FM during WL in overweight and obese men and women.
Practical approaches to probiotics use
Authors: Taibi Amel , Comelli Elena M.
Published: February 2014

Probiotics are microorganisms exerting beneficial effects on the host. They can be ingested through foods or supplements and their inclusion in these products is regulated in Canada by the Health Canada Health Products and Food Branch. The aim of this article is to summarize current evidence from randomized controlled trials and guidelines from Health Canada, the World Health Organization, and internationally recognized expert committees in the hope that it will help practitioners and professionals recommending probiotics to healthy and diseased patients, with a focus on the Canadian setting. From a general perspective, probiotics can be recommended for prevention of diseases that are associated to altered intestinal ecology. Specifically, they can be recommended for prevention of upper respiratory tract infections and pouchitis, for prevention and management of necrotizing enterocolitis, bacterial vaginosis and antibiotic associated diarrhea, including Clostridium difficile infection, and for treatment of atopic eczema in cow’s milk allergy and of infectious diarrhea. Additional substantiated probiotic benefits include prevention of hypercholesterolemia, management of constipation, reduction of recurrent urinary tract infections, improvement of irritable bowel syndrome symptoms, and reduction of antibiotics side effects in Helicobacter pylori eradication. Because probiotics are generally recognized as safe and can be removed with antimicrobial agents, their use should be considered in patients of all ages.
A screening strategy for phenotypic detection of carbapenemase in the clinical laboratory
Authors: Yan Yu-Zhong , Sun Kang-De , Pan Li-Hong , Fan Hui-Qin , Yang Huan-Zhang , Lu Yan-Chun , Shi Yi
Published: February 2014

Nosocomial infections caused by carbapenemase-producing Enterobacteriaceae have emerged as an important challenge worldwide and represent a great limitation for antimicrobial therapy. Detection of carbapenemase in Enterobacteriaceae species also remains challenging. Although the modified Hodge test is recommended, it lacks specificity and is unable to distinguish between carbapenemase types. Here, we demonstrated a screening strategy for the phenotypic detection of carbapenemases among Enterobacteriaceae isolates in the clinical laboratory by using ethylenediaminetetraacetic acid and phenylboronic acid. This strategy displayed an overall 100% sensitivity and 98.6% specificity for carbapenemase detection in Enterobacteriaceae, which was superior to that of the modified Hodge test (98.0% sensitivity and 84.3% specificity), and it also discriminated the carbapenemase phenotypes of KPC-2, VIM-1, and OXA-48.
Self-Replicating Patterns in 2D Linear Cellular Automata
Authors: Uguz Selman , Sahin Uḡur , Akin Hasan , Siap Irfan
Published: February 2014

This paper studies the theoretical aspects of two-dimensional cellular automata (CAs), it classifies this family into subfamilies with respect to their visual behavior and presents an application to pseudo random number generation by hybridization of these subfamilies. Even though the basic construction of a cellular automaton is a discrete model, its macroscopic behavior at large evolution times and on large spatial scales can be a close approximation to a continuous system. Beyond some statistical properties, we consider geometrical and visual aspects of patterns generated by CA evolution. The present work focuses on the theory of two-dimensional CA with respect to uniform periodic, adiabatic and reflexive boundary CA (2D PB, AB and RB) conditions. In total, there are 512 linear rules over the binary field ℤ2for each boundary condition and the effects of these CA are studied on applications of image processing for self-replicating patterns. After establishing the representation matrices of 2D CA, these linear CA rules are classified into groups of nine and eight types according to their boundary conditions and the number of neighboring cells influencing the cells under consideration. All linear rules have been found to be rendering multiple self-replicating copies of a given image depending on these types. Multiple copies of any arbitrary image corresponding to CA find innumerable applications in real life situation, e.g. textile design, DNA genetics research, statistical physics, molecular self-assembly and artificial life, etc. We conclude by presenting a successful application for generating pseudo numbers to be used in cryptography by hybridization of these 2D CA subfamilies.