bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty
Authors: Byren Ivor , Rege Shruta , Campanaro Ed , Yankelev Sara , Anastasiou Diane , Kuropatkin Gennady , Evans Richard 
Published: August 2012

ABSTRACT

The prevalence of
Staphylococcus aureus
causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.
Genome Sequencing of a Neisseria gonorrhoeae Isolate of a Successful International Clone with Decreased Susceptibility and Resistance to Extended-Spectrum Cephalosporins
Authors: Hess David , Wu Abel , Golparian Daniel , Esmaili Sarah , Pandori Will , Sena Emilee , Klausner Jeffrey D. , Barry Pennan , Unemo Magnus , Pandori Mark 
Published: August 2012

ABSTRACT

The recent emergence of
Neisseria gonorrhoeae
strains with decreased susceptibility to extended-spectrum cephalosporins is a major concern globally. We sequenced the genome of an
N. gonorrhoeae
multiantigen sequence typing (NG-MAST) ST1407 isolate (SM-3) with decreased susceptibility and resistance to oral extended-spectrum cephalosporins. The isolate was cultured in 2008 in San Francisco, CA, and possessed mosaic
penA
allele XXXIV, which is associated with an international clone that possesses decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins globally. The genome sequence of strain NCCP11945 was used as a scaffold, and our assembly resulted in 91 contigs covering 2,029,064 bp (91%; >150× coverage) of the genome. Numerous instances of suspected horizontal genetic transfer events with other
Neisseria
species were identified, and two genes,
opa
and
txf
, acquired from nongonococcal
Neisseria
species, were identified. Strains possessing mosaic
penA
alleles (
n
= 108) and nonmosaic
penA
alleles (
n
= 169) from the United States and Europe (15 countries), cultured in 2002 to 2009, were screened for the presence of these genes. The
opa
gene was detected in most (82%)
penA
mosaic-containing isolates (mainly from 2007 to 2009) but not in any
penA
nonmosaic isolates. The
txf
gene was found in all strains containing
opa
but also in several (18%)
penA
nonmosaic strains. Using
opa
and
txf
as genetic markers, we identified a strain that possesses mosaic
penA
allele XXXIV, but the majority of its genome is not genetically related to strain SM-3. This implies that
penA
mosaic allele XXXIV was transferred horizontally. Such isolates also possessed decreased susceptibility and resistance to oral extended-spectrum cephalosporins. These findings support that genetic screening for particular
penA
mosaic alleles can be a valuable method for tracking strains with decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins worldwide and that screening using only NG-MAST may not be sufficient.
Differences between Macrolide-Resistant and -Susceptible Streptococcus pyogenes: Importance of Clonal Properties in Addition to Antibiotic Consumption
Authors: Silva-Costa C. , Friães A. , Ramirez M. , Melo-Cristino J. ,   the Portuguese Group for the Study of Streptococcal Infections
Published: August 2012

ABSTRACTA steady decline in macrolide resistance amongStreptococcus pyogenes(group A streptococci [GAS]) in Portugal was reported during 1999 to 2006. This was accompanied by alterations in the prevalence of macrolide resistance phenotypes and in the clonal composition of the population. In order to test whether changes in the macrolide-resistant population reflected the same changing patterns of the overall population, we characterized both macrolide-susceptible and -resistant GAS associated with a diagnosis of tonsillo-pharyngitis recovered in the period from 2000 to 2005 in Portugal. Pulsed-field gel electrophoresis (PFGE) profiling was the best predictor ofemmtype and the only typing method that could discriminate clones associated with macrolide resistance and susceptibility within eachemmtype. Six PFGE clusters were significantly associated with macrolide susceptibility: T3-emm3-ST406, T4-emm4-ST39, T1-emm1-ST28, T6-emm6-ST382, B3264-emm89-ST101/ST408, and T2-emm2-ST55. Four PFGE clusters were associated with macrolide resistance: T4-emm4-ST39, T28-emm28-ST52, T12-emm22-ST46, and T1-emm1-ST28. We found no evidence for frequent ongoing horizontal transfer of macrolide resistance determinants. The diversity of the macrolide-resistant population was lower than that of susceptible isolates. The differences found between the two populations suggest that the macrolide-resistant population of GAS has its own dynamics, independent of the behavior of the susceptible population.
More than poverty: disruptive events among women having abortions in the USA
Authors: Jones Rachel K , Frohwirth Lori , Moore Ann M 
Published: August 2012

BackgroundIn the USA, abortion has become increasingly concentrated among poor women. For many, poverty represents difficulties meeting financial obligations, but the authors expect it is also associated with a range of potentially difficult life circumstances that may influence women's pregnancy decisions.MethodsThis mixed methods study relied on two data sources. Quantitative data came from a national sample of 9493 women obtaining abortions in 2008 and examined exposure to 11 potentially disruptive events. The authors also examined associations between disruptive events, poverty status and contraceptive use. Qualitative information from 49 in-depth interviews was used to provide insights into patterns that emerged from the quantitative analysis.ResultsMore than half (57%) of the women obtaining abortions experienced a potentially disruptive event within the last year, most commonly unemployment (20%), separation from a partner (16%), falling behind on rent/mortgage (14%) and/or moving multiple times (12%). Poverty status was significantly associated with several of the events, particularly those that could directly impact on a family's economic circumstances, for example losing a job or having a baby. Information from the in-depth interviews suggested that disruptive events interfered with contraceptive use, but the quantitative survey found no difference in contraceptive use by exposure to disruptive life events, even after controlling for poverty status.ConclusionMany abortion patients make decisions about their pregnancies in the midst of complex life circumstances.
Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death
Authors: Hamidi Tewfik , Cano Carla E. , Grasso Daniel , Garcia Maria Noé , Sandi Maria José , Calvo Ezequiel L. , Dagorn Jean-Charles , Lomberk Gwen , Urrutia Raul , Goruppi Sandro , Carracedo Arkaitz , Velasco Guillermo , Iovanna Juan L. 
Published: August 2012

AbstractPurpose: The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor.Experimental Design: Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle–associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence.Results: We showed that both Nupr1 and HIF1α are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage–dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response.Conclusions: Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress. Clin Cancer Res; 18(19); 5234–46. ©2012 AACR.
Echocardiographic Predictors of Outcome in Eisenmenger Syndrome
Authors: Moceri Pamela , Dimopoulos Konstantinos , Liodakis Emmanouil , Germanakis Ioannis , Kempny Aleksander , Diller Gerhard-Paul , Swan Lorna , Wort Stephen J. , Marino Philip S. , Gatzoulis Michael A. , Li Wei 
Published: August 2012

Background—
Eisenmenger syndrome differs significantly from other types of pulmonary arterial hypertension in its physiology and prognosis. We sought to assess the relationship between the echocardiographic characteristics of patients with Eisenmenger syndrome and mortality.

Methods and Results—

Clinical and echocardiographic variables were assessed in 181 consecutive patients with Eisenmenger syndrome, excluding those with complex congenital heart disease. Patients' mean age was 39.1±12.8 years, 59 (32.6%) were male, 122 (67.4%) were in functional class III or higher, and 74 (40.9%) were on advanced therapies. Mean oxygen saturation at rest was 85.1±7.8%, and median B-type natriuretic peptide was 55.4 ng/L. Over a median follow-up of 16.4 months, 19 patients died; the strongest predictors of mortality were tricuspid annular plane systolic excursion and peak systolic velocity, myocardial performance (expressed as total isovolumic time and ratio of systolic to diastolic duration), and elevated central venous pressure (expressed as right atrial [RA] area, RA pressure, and ratio of RA to left atrial area), even after we accounted for advanced therapies. A composite score based on the strongest echocardiographic predictors of outcome, including 1 point for each of the following: tricuspid annular plane systolic excursion <15 mm, ratio of right ventricular effective systolic to diastolic duration ≥1.5, RA area ≥25 cm
2
, ratio of RA to left atrial area ≥1.5, was highly predictive of clinical outcome (area under the curve 0.90±0.01), with no improvement when B-type natriuretic peptide and resting saturations were added into the model.

Conclusions—
Echocardiographic parameters of right ventricular function and RA area predict mortality in Eisenmenger patients. A new composite echocardiographic score, described herewith, may be incorporated into the noninvasive, periodic assessment of these patients.
Cerebral Embolization During Transcatheter Aortic Valve Implantation
Authors: Kahlert Philipp , Al-Rashid Fadi , Döttger Philipp , Mori Kathrine , Plicht Björn , Wendt Daniel , Bergmann Lars , Kottenberg Eva , Schlamann Marc , Mummel Petra , Holle Dagny , Thielmann Matthias , Jakob Heinz G. , Konorza Thomas , Heusch Gerd , Erbel Raimund , Eggebrecht Holger 
Published: August 2012

Background—
Transcatheter aortic valve implantation (TAVI) is associated with a higher risk of neurological events for both the transfemoral and transapical approach than surgical valve replacement. Cerebral magnetic resonance imaging has revealed more new, albeit clinically silent lesions from procedural embolization, yet the main source and predominant procedural step of emboli remain unclear.

Methods and Results—

Eighty-three patients underwent transfemoral (Medtronic CoreValve [MCV
TF
], n=32; Edwards Sapien [ES
TF
], n=26) and transapical (ES
TA
: n=25) TAVI. Serial transcranial Doppler examinations before, during, and 3 months after TAVI were used to identify high-intensity transient signals (HITS) as a surrogate for microembolization. Procedural HITS were detected in all patients, predominantly during manipulation of the calcified aortic valve while stent valves were being positioned and implanted. The balloon-expandable ES prosthesis caused significantly more HITS (mean [95% CI]) during positioning (ES
TF
, 259.9 [184.8–334.9]; ES
TA
, 206.1[162.5–249.7]; MCV
TF
, 78.5 [25.3–131.6];
P
<0.001) and the self-expandable MCV prosthesis during implantation (MCV
TF
, 397.1 [302.1–492.2]; ES
TF
, 88.2 [70.2–106.3]; ES
TA
, 110.7 [82.0–139.3];
P
<0.001). Overall, there were no significant differences between transfemoral and transapical TAVI or between the MCV and ES prostheses. No HITS were detected at baseline or 3-month follow-up. There was 1 major procedural stroke that resulted in death and 1 minor procedural stroke with full recovery at 3-month follow-up in the MCV group.

Conclusions—
Procedural HITS were detected by transcranial Doppler in all patients. Although no difference was observed between the transfemoral and the transapical approach with the balloon-expandable ES stent valve, transfemoral TAVI with the self-expandable MCV prosthesis resulted in the greatest number of HITS, predominantly during implantation.
T-cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing
Authors: Zhou Qi , Schneider Irene C. , Edes Inan , Honegger Annemarie , Bach Patricia , Schönfeld Kurt , Schambach Axel , Wels Winfried S. , Kneissl Sabrina , Uckert Wolfgang , Buchholz Christian J. 
Published: August 2012

AbstractTransfer of tumor-specific T-cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8+ cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8+ cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an up-regulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8+ T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as coreceptor for tumor-cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and basic research requiring CD8+ cell-specific gene delivery.
Efficient generation, purification, and expansion of CD34+ hematopoietic progenitor cells from nonhuman primate–induced pluripotent stem cells
Authors: Gori Jennifer L. , Chandrasekaran Devikha , Kowalski John P. , Adair Jennifer E. , Beard Brian C. , D'Souza Sunita L. , Kiem Hans-Peter 
Published: August 2012

AbstractInduced pluripotent stem cell (iPSC) therapeutics are a promising treatment for genetic and infectious diseases. To assess engraftment, risk of neoplastic formation, and therapeutic benefit in an autologous setting, testing iPSC therapeutics in an appropriate model, such as the pigtail macaque (Macaca nemestrina; Mn), is crucial. Here, we developed a chemically defined, scalable, and reproducible specification protocol with bone morphogenetic protein 4, prostaglandin-E2 (PGE2), and StemRegenin 1 (SR1) for hematopoietic differentiation of Mn iPSCs. Sequential coculture with bone morphogenetic protein 4, PGE2, and SR1 led to robust Mn iPSC hematopoietic progenitor cell formation. The combination of PGE2 and SR1 increased CD34+CD38−Thy1+CD45RA−CD49f+ cell yield by 6-fold. CD34+CD38−Thy1+CD45RA−CD49f+ cells isolated on the basis of CD34 expression and cultured in SR1 expanded 3-fold and maintained this long-term repopulating HSC phenotype. Purified CD34high cells exhibited 4-fold greater hematopoietic colony-forming potential compared with unsorted hematopoietic progenitors and had bilineage differentiation potential. On the basis of these studies, we calculated the cell yields that must be achieved at each stage to meet a threshold CD34+ cell dose that is required for engraftment in the pigtail macaque. Our protocol will support scale-up and testing of iPSC-derived CD34high cell therapies in a clinically relevant nonhuman primate model.
Evolutionary paths of streptococcal and staphylococcal superantigens
Authors: Okumura Kayo , Shimomura Yumi , Murayama Somay Yamagata , Yagi Junji , Ubukata Kimiko , Kirikae Teruo , Miyoshi-Akiyama Tohru 
Published: August 2012

Abstract

Background

Streptococcus pyogenes (GAS) harbors several superantigens (SAgs) in the prophage region of its genome, although speG and smez are not located in this region. The diversity of SAgs is thought to arise during horizontal transfer, but their evolutionary pathways have not yet been determined. We recently completed sequencing the entire genome of S. dysgalactiae subsp. equisimilis (SDSE), the closest relative of GAS. Although speG is the only SAg gene of SDSE, speG was present in only 50% of clinical SDSE strains and smez in none. In this study, we analyzed the evolutionary paths of streptococcal and staphylococcal SAgs.

Results
We compared the sequences of the 12–60 kb speG regions of nine SDSE strains, five speG
+ and four speG

–
. We found that the synteny of this region was highly conserved, whether or not the speG gene was present. Synteny analyses based on genome-wide comparisons of GAS and SDSE indicated that speG is the direct descendant of a common ancestor of streptococcal SAgs, whereas smez was deleted from SDSE after SDSE and GAS split from a common ancestor. Cumulative nucleotide skew analysis of SDSE genomes suggested that speG was located outside segments of steeper slopes than the stable region in the genome, whereas the region flanking smez was unstable, as expected from the results of GAS. We also detected a previously undescribed staphylococcal SAg gene, selW, and a staphylococcal SAg -like gene, ssl, in the core genomes of all Staphylococcus aureus strains sequenced. Amino acid substitution analyses, based on dN/dS window analysis of the products encoded by speG, selW and ssl suggested that all three genes have been subjected to strong positive selection. Evolutionary analysis based on the Bayesian Markov chain Monte Carlo method showed that each clade included at least one direct descendant.

Conclusions
Our findings reveal a plausible model for the comprehensive evolutionary pathway of streptococcal and staphylococcal SAgs.
Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells
Authors: Monticone Massimiliano , Daga Antonio , Candiani Simona , Romeo Francesco , Mirisola Valentina , Viaggi Silvia , Melloni Ilaria , Pedemonte Simona , Zona Gianluigi , Giaretti Walter , Pfeffer Ulrich , Castagnola Patrizio 
Published: August 2012

Abstract

Background
Most patients affected by Glioblastoma multiforme (GBM, grade IV glioma) experience a recurrence of the disease because of the spreading of tumor cells beyond surgical boundaries. Unveiling mechanisms causing this process is a logic goal to impair the killing capacity of GBM cells by molecular targeting.
We noticed that our long-term GBM cultures, established from different patients, may display two categories/types of growth behavior in an orthotopic xenograft model: expansion of the tumor mass and formation of tumor branches/nodules (nodular like, NL-type) or highly diffuse single tumor cell infiltration (HD-type).

Methods
We determined by DNA microarrays the gene expression profiles of three NL-type and three HD-type long-term GBM cultures. Subsequently, individual genes with different expression levels between the two groups were identified using Significance Analysis of Microarrays (SAM). Real time RT-PCR, immunofluorescence and immunoblot analyses, were performed for a selected subgroup of regulated gene products to confirm the results obtained by the expression analysis.

Results
Here, we report the identification of a set of 34 differentially expressed genes in the two types of GBM cultures. Twenty-three of these genes encode for proteins localized to the plasma membrane and 9 of these for proteins are involved in the process of cell adhesion.

Conclusions
This study suggests the participation in the diffuse infiltrative/invasive process of GBM cells within the CNS of a novel set of genes coding for membrane-associated proteins, which should be thus susceptible to an inhibition strategy by specific targeting.
Massimiliano Monticone and Antonio Daga contributed equally to this work