bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient Single Tobamoviral Vector-Based Bioproduction of Broadly Neutralizing Anti-HIV-1 Monoclonal Antibody VRC01 in Nicotiana benthamiana Plants and Utility of VRC01 in Combination Microbicides
Authors: Hamorsky Krystal Teasley , Grooms-Williams Tiffany W. , Husk Adam S. , Bennett Lauren J. , Palmer Kenneth E. , Matoba Nobuyuki 
Published: February 2013

ABSTRACTBroadly neutralizing monoclonal antibodies (bnMAbs) may offer powerful tools for HIV-1 preexposure prophylaxis, such as topical microbicides. However, this option is hampered due to expensive MAb biomanufacturing based on mammalian cell culture. To address this issue, we developed a new production system for bnMAb VRC01 inNicotiana benthamianaplants using a tobamovirus replicon vector. Unlike conventional two-vector-based expression, this system was designed to overexpress full-length IgG1 from a single polypeptide by means of kex2p-like enzyme recognition sites introduced between the heavy and light chains. An enzyme-linked immunosorbent assay (ELISA) revealed that gp120-binding VRC01 IgG1 was maximally accumulated on 5 to 7 days following vector inoculation, yielding ∼150 mg of the bnMAb per kg of fresh leaf material. The plant-made VRC01 (VRC01p) was efficiently purified by protein A affinity followed by hydrophobic-interaction chromatography. ELISA, surface plasmon resonance, and an HIV-1 neutralization assay demonstrated that VRC01p has gp120-binding affinity and HIV-1-neutralization capacity virtually identical to the human-cell-produced counterpart. To advance VRC01p's use in topical microbicides, we analyzed combinations of the bnMAb with other microbicide candidates holding distinct antiviral mechanisms in an HIV-1 neutralization assay. VRC01p exhibited clear synergy with the antiviral lectin griffithsin, the CCR5 antagonist maraviroc, and the reverse transcriptase inhibitor tenofovir in multiple CCR5-tropic HIV-1 strains from clades A, B, and C. In summary, VRC01p is amenable to robust, rapid, and large-scale production and may be developed as an active component in combination microbicides with other anti-HIV agents such as antiviral lectins, CCR5 antagonists, and reverse transcriptase inhibitors.
Prolonged NF-κB Activation by a Macrophage Inhibitory Cytokine 1-Linked Signal in Enteropathogenic Escherichia coli-Infected Epithelial Cells
Authors: Choi Hye Jin , Kim Juil , Do Kee Hun , Park Seong-Hwan , Moon Yuseok 
Published: February 2013

ABSTRACT

Intestinal epithelial activation of nuclear factor kappa B (NF-κB) exerts both detrimental and beneficial functions in response to various luminal insults, including ones associated with mucosa-associated pathogens. Gastrointestinal infection with enteropathogenic
Escherichia coli
(EPEC) causes severe injuries in epithelial integrity and leads to watery diarrhea. The present study was conducted to investigate the prolonged epithelial responses to persistent EPEC infection via NF-κB activation. EPEC infection led to sustained activation of NF-κB signal in mouse intestinal epithelial cells
in vivo
and
in vitro
, which was positively associated with a type III secretion system, whereas early NF-κB is regulated. Moreover, prolonged NF-κB activation was found to be a part of macrophage inhibitory cytokine 1 (MIC-1)-mediated signaling activation, a novel link between NF-κB signaling and infection-associated epithelial stress. EPEC infection induced gene expression of MIC-1, a member of the transforming growth factor β (TGF-β) superfamily, which then activated TGF-β-activated kinase 1 and consequently led to NF-κB activation. Functionally, both EPEC-induced MIC-1 and NF-κB signaling mediated epithelial survival by enhancing the expression of cyclin D1, a target of NF-κB. In summary, the results of the present study suggest that MIC-1 serves as a mediator of prolonged NF-κB activation, which is critical in maintaining gut epithelial integrity in response to infection-induced injuries.
Relationship of Sudden Cardiac Death to New-Onset Atrial Fibrillation in Hypertensive Patients With Left Ventricular Hypertrophy
Authors: Okin Peter M. , Bang Casper N. , Wachtell Kristian , Hille Darcy A. , Kjeldsen Sverre E. , Dahlöf Björn , Devereux Richard B. 
Published: February 2013

Background—
Prevalent atrial fibrillation (AF) is associated with a higher sudden cardiac death (SCD) rate in some populations, and incident AF predicts increased mortality risk in the general population and after myocardial infarction. However, the relationship of SCD to new-onset AF is unclear.

Methods and Results—

The relationship of SCD to new-onset AF was evaluated in 8831 hypertensive patients with electrocardiographic left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. During 4.7±1.1 years mean follow-up, new-onset AF occurred in 701 patients (7.9%) and SCD in 151 patients (1.7%). In univariate Cox analyses, new-onset AF was associated with a >4-fold higher risk of SCD (hazard ratio, 4.69; 95% CI interval, 2.96–7.45;
P
<0.001). In multivariate Cox analyses adjusting for age, sex, race, diabetes mellitus, history of heart failure, myocardial infarction, ischemic heart disease, stroke, smoking, serum high-density lipoprotein cholesterol, creatinine, glucose, and urine albumin/creatinine ratio as standard risk factors, and for incident myocardial infarction, in-treatment use of digoxin, systolic and diastolic pressure, heart rate, QRS duration, Cornell voltage-duration product, and Sokolow-Lyon voltage left ventricular hypertrophy treated as time-varying covariates, new-onset AF remained associated with a >3-fold increased risk of SCD (hazard ratio, 3.13; 95% confidence interval, 1.87–5.24;
P
<0.001).

Conclusions—
Development of new-onset AF identifies hypertensive patients at increased risk of SCD.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00338260.
Native Myocardial T1 Mapping by Cardiovascular Magnetic Resonance Imaging in Subclinical Cardiomyopathy in Patients With Systemic Lupus Erythematosus
Authors: Puntmann Valentina O. , D’Cruz David , Smith Zachary , Pastor Ana , Choong Peng , Voigt Tobias , Carr-White Gerry , Sangle Shirish , Schaeffter Tobias , Nagel Eike 
Published: February 2013

Background—
Increased systemic inflammation has been linked to myocardial dysfunction and heart failure in patients with systemic lupus erythematosus (SLE). Accurate detection of early myocardial changes may be able to guide preventive intervention. We investigated whether multiparametric imaging by cardiovascular magnetic resonance can detect differences between controls and asymptomatic SLE patients.

Methods and Results—

A total of 33 SLE predominantly female patients (mean age, 40±9 years) underwent cardiovascular magnetic resonance for routine assessment of myocardial perfusion, function, and late gadolinium enhancement. T1 mapping was performed in single short-axis slice before and after 15 minutes of gadolinium administration. Twenty-one subjects with a low pretest probability and normal cardiovascular magnetic resonance served as a control group. Both groups had similar left ventricular volumes and mass and normal global systolic function. SLE patients had significantly reduced longitudinal strain (controls versus SLE, −20±2% versus −17±3%;
P
<0.01) and showed intramyocardial and pericardial late gadolinium enhancement. SLE patients had significantly increased native myocardial T1 (1056±27 versus 1152±46 milliseconds;
P
<0.001) and extracellular volume fraction (26±5% versus 30±6%;
P
=0.007) and reduced postcontrast myocardial T1 (454±53 versus 411±62 milliseconds;
P
=0.01). T1-derived indices were associated with longitudinal strain (
r
=0.37–0.47) but not with the presence of late gadolinium enhancement. Native myocardial T1 values showed the greatest concordance with the presence of clinical diagnosis of SLE.

Conclusions—
In patients with SLE and free of cardiac symptoms, there is evidence of subclinical perimyocardial impairment. We further demonstrate that T1 mapping may have potential to detect subclinical myocardial involvement in patients with SLE.
Randomized Comparison of Sirolimus-Eluting and Everolimus-Eluting Coronary Stents in the Treatment of Total Coronary Occlusions
Authors: Moreno Raul , García Eulogio , Teles Rui , Rumoroso Jose-Ramon , Carvalho Henrique Cyrne , Goicolea Francisco Javier , Moreu José , Mauri Josefa , Sabaté Manel , Mainar Vicente , Patricio Lino , Valdés Mariano , Fernández Vázquez Felipez , Sánchez-Recalde Angel , Galeote Guillermo , Jimenez-Valero Santiago , Almeida Manuel , de Sa Esteban Lopez , Calvo Luis , Plaza Ignacio , Lopez-Sendón Jose-Luis , Martín Jose-Luis R. ,   for the CIBELES Investigators
Published: February 2013

Background—
Patients with coronary total occlusions are at especially high risk for restenosis and new revascularizations. Sirolimus-eluting stents dramatically improved the clinical outcome of this subset of patients in randomized trials, but other drug-eluting stents, mainly the everolimus-eluting stent (currently the most frequently used stent), have not yet been evaluated in patients with coronary total occlusions. The objective was to compare the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent in patients with coronary total occlusions.

Methods and Results—

A total of 207 patients with coronary total occlusions and estimated time since occlusion >2 weeks were randomized to everolimus- or sirolimus-eluting stent. The primary end point was in-stent late loss at 9-month angiographic follow-up (noninferiority trial). Clinical follow-up was performed at 1 and 12 months. In-stent late loss at 9 months was 0.29±0.60 versus 0.13±0.69 mm in patients allocated to sirolimus- and everolimus-eluting stent, respectively. The observed difference in in-stent late loss between both groups was –0.16 mm (95% confidence interval, 0.04 to –0.36 mm;
P
for noninferiority <0.01). The rate of binary angiographic restenosis was 10.8% and 9.1% in patients allocated to sirolimus- and everolimus-eluting stent, respectively (
P
=0.709), whereas the rate of vessel reocclusion was 3.2% and 1.1%, respectively (
P
=0.339). At 12 months, the rate of major adverse events was 15.9% versus 11.1% with sirolimus- and everolimus-eluting stent, respectively (
P
=0.335), and probable or definitive stent thrombosis occurred in 3.0% and 0.0% of patients, respectively (
P
=0.075).

Conclusions—
In patients with coronary total occlusions, everolimus-eluting stent is as effective as sirolimus-eluting stent.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00793221.
Outcomes of Stent Implantation for Obstruction of Intracardiac Lateral Tunnel Fontan Pathways
Authors: Mets Joseph M. , Bergersen Lisa , Mayer John E. , Marshall Audrey C. , McElhinney Doff B. 
Published: February 2013

Background—
Factors associated with obstruction of the cavopulmonary pathway in patients with a lateral tunnel (LT) intracardiac Fontan connection and outcomes of percutaneous stent implantation for this complication have not been characterized.

Methods and Results—

Between 1999 and 2011, 51 patients underwent stent implantation for LT pathway stenosis at a median age of 10.2 years and a median of 6.9 years after Fontan completion. Compared with control patients undergoing catheterization for other indications, patients had significantly higher inferior vena cava pressures (15.6 versus 13.7 mm Hg;
P
=0.007), but only 18 (35%) had a measurable pressure gradient in the catheterization laboratory. The morphology of the obstructions varied considerably and was not amenable to straightforward classification. Stenting increased mean diameter of the LT stenosis from 8.5 to 14.2 mm (
P
<0.001) and eliminated the pressure gradient when present. After stenting, 1 patient developed a significant new baffle leak that was treated with surgical Fontan revision 1.2 months later. A trivial baffle leak was observed in 1 other patient after stenting but required no treatment. Eight patients (16%) underwent successful redilation of the LT stent because of patient growth, symptomatic presentation, or during catheterization for other indications, but 1 developed a new baffle leak during redilation.

Conclusions—
It was possible to enlarge the narrowed LT baffle substantially in patients with a variety of forms of obstruction, with few adverse events. The physiological implications of LT narrowing and target size for stenting deserve further investigation.
Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension
Authors: Hoeper Marius M. , Barst Robyn J. , Bourge Robert C. , Feldman Jeremy , Frost Adaani E. , Galié Nazzareno , Gómez-Sánchez Miguel Angel , Grimminger Friedrich , Grünig Ekkehard , Hassoun Paul M. , Morrell Nicholas W. , Peacock Andrew J. , Satoh Toru , Simonneau Gérald , Tapson Victor F. , Torres Fernando , Lawrence David , Quinn Deborah A. , Ghofrani Hossein-Ardeschir 
Published: February 2013

Background—
By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH).

Methods and Results—

Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm
−5
symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52;
P
=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm
−5
(95% confidence interval, −502 to − 255;
P
<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation.

Conclusions—
Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
Asymptomatic Carotid Artery Stenosis and the Risk of Ischemic Stroke According to Subtype in Patients With Clinical Manifest Arterial Disease
Authors: den Hartog Anne G. , Achterberg Sefanja , Moll Frans L. , Kappelle L. Jaap , Visseren Frank L.J. , van der Graaf Yolanda , Algra Ale , de Borst Gert Jan 
Published: February 2013

Background and Purpose—
Because best medical treatment is improving, the risk of stroke in asymptomatic carotid artery stenosis (ACAS) may decline. We evaluated the risk of ischemic stroke and stratified it according to stroke subtype in patients with ACAS during long-term follow-up.

Methods—
In total, 4319 consecutive patients in the Second Manifestations of Arterial disease study with clinically manifest arterial disease or specific risk factors, but without a history of cerebrovascular disease, were included. Degree of stenosis was evaluated with duplex ultrasound scanning. Strokes during follow-up were classified according to subtype. Cox-proportional hazard-regression models were used to evaluate the relationship between ACAS and future stroke.

Results—
We identified 293 (6.8%) patients with ACAS 50% to 99%, of whom 193 had 70% to 99% stenosis. In these subgroups, mean follow-up was 6.2 and 6.0 years, respectively. In total, 94 ischemic strokes occurred, of which 8 in ACAS 50% to 99% patients. The any territory annual ischemic stroke risk was 0.4% in 50% to 99% ACAS and 0.5% per year for 70% to 99% ACAS patients. The risk of ischemic stroke was not significantly increased in patients with ACAS 70% to 99% (hazard ratio, 1.5; 95% confidence interval, 0.7–3.5). Patients with ACAS 50% to 99% and ACAS 70% to 99% tended to have nonsignificantly more large vessel disease strokes (hazard ratio, 1.5; 95% confidence interval, 0.5–4.2 and hazard ratio, 1.7; 95% confidence interval, 0.5–5.6).

Conclusions—
Patients with clinically manifest arterial disease or type 2 diabetes mellitus have a low risk of developing ischemic stroke, irrespective of its subtype and independent of the degree of ACAS stenosis.
Nailing Down and Tying Up: Lessons in Intertextual Impossibility from the Martyrdom of Polycarp
Authors: Moss Candida R. 
Published: February 2013

Abstract
This paper addresses scholarly approaches to the function of allusions and intertextuality in the Martyrdom of Polycarp. It argues that scholarship on this question has operated with and been hampered by unspoken assumptions about the historicity and authenticity of the account, the development of canon, the use of scriptural sources, and the function of allusions. Attention to the function of intertextuality in the account reveals both that it is difficult to identify concretely the sources of the account and that, as a result, it is impossible to speak authoritatively about the author’s intent with respect to the use of these sources.
Evaluation of the effects of reflexology on quality of life and symptomatic relief in multiple sclerosis patients with moderate to severe disability; a pilot study
Authors: Miller L , McIntee E , Mattison P 
Published: February 2013

Objective: To examine the feasibility of delivering reflexology to people moderately to severely affected by multiple sclerosis and to investigate the effect on a range of symptoms. Methods: A pilot single-blind randomized placebo controlled trial. Setting: An outpatient multiple sclerosis rehabilitation centre. Subjects: Twenty people moderately to severely affected by multiple sclerosis were randomized into one of two groups receiving either reflexology or sham reflexology. Intervention: Each participant received 8 weeks, 1 hour per week of either reflexology or sham reflexology. Main measures: Primary outcome measure was the Multiple Sclerosis Impact Scale (MSIS29). Secondary measures assessed a range of symptoms at baseline, 8 weeks and 16 weeks. Results: There were no statistically significant differences between the two groups at either 8 ( P = 0.538) or 16 ( P = 0.112) weeks for the primary outcome measure; however, both groups demonstrated small improvements from 92.3 (SD 20.9) to 75.6 (SD 3.3) with reflexology, and 91.3 (SD 29.9) to 81.5 (±18.5) with sham reflexology group after 8 weeks of treatment. Small improvements were noted in most of the secondary outcome measures at 8 weeks. There was no difference between the groups at 8 weeks except for bladder function ( P = 0.003) and most scores returned to baseline at follow-up. Conclusions: The results do not support the use of reflexology for symptom relief in a more disabled multiple sclerosis population and are strongly suggestive of a placebo response. This study demonstrates, however, that reflexology can be delivered and is well tolerated by people who are moderately to severely affected by multiple sclerosis.
Cluster-like headache and a cystic hypothalamic tumour as first presentation of sarcoidosis
Authors: der Vlist Steven HM van , Hummelink Bernard JCM , Westerga Johan , Boogerd Willem 
Published: February 2013

Introduction Sarcoidosis is a granulomatous, multisystem inflammatory disease of unknown cause, which presents with a wide variety of symptoms. We describe a rare case of a newly diagnosed sarcoidosis, with cluster-like headache as a presenting symptom. Case A 31-year-old man presented with cluster headache with a cystic lesion in the hypothalamus. A non-caseating granuloma consistent with the diagnosis sarcoidosis was found at biopsy. Pulmonary involvement was confirmed on positron electron tomography-computed tomography (PET-CT). Treatment with prednisone led to regression of the hypothalamic lesion. Headache attacks did not recur. Discussion Cluster-like headache with a cystic hypothalamic lesion as first presentation of sarcoidosis has never been reported. Their possible relationship seems to underline the role of the hypothalamus in the central pain-regulatory areas in the brain, but is not undisputed. This case clearly demonstrates once again the relevance of neuroimaging in new-onset cluster-like headache.
Humoral immune response to HTLV-1 basic leucine zipper factor (HBZ) in HTLV-1-infected individuals
Authors: Enose-Akahata Yoshimi , Abrams Anna , Massoud Raya , Bialuk Izabela , Johnson Kory R , Green Patrick L , Maloney Elizabeth M , Jacobson Steven 
Published: February 2013

Abstract

Background
Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system.

Results
Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4+ T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients.

Conclusions
This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection.