bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MerR-Like Regulator BrlR Confers Biofilm Tolerance by Activating Multidrug Efflux Pumps in Pseudomonas aeruginosa Biofilms
Authors: Liao Julie , Schurr Michael J. , Sauer Karin 
Published: May 2013

ABSTRACT

A defining characteristic of biofilms is antibiotic tolerance that can be up to 1,000-fold greater than that of planktonic cells. In
Pseudomonas aeruginosa
, biofilm tolerance to antimicrobial agents requires the biofilm-specific MerR-type transcriptional regulator BrlR. However, the mechanism by which BrlR mediates biofilm tolerance has not been elucidated. Genome-wide transcriptional profiling indicated that
brlR
was required for maximal expression of genes associated with antibiotic resistance, in particular those encoding the multidrug efflux pumps MexAB-OprM and MexEF-OprN. Chromatin immunoprecipitation (ChIP) analysis revealed a direct regulation of these genes by BrlR, with DNA binding assays confirming BrlR binding to the promoter regions of the
mexAB-oprM
and
mexEF-oprN
operons. Quantitative reverse transcriptase PCR (qRT-PCR) analysis further indicated BrlR to be an activator of
mexAB-oprM
and
mexEF-oprN
gene expression. Moreover, immunoblot analysis confirmed increased MexA abundance in cells overexpressing
brlR
. Inactivation of both efflux pumps rendered biofilms significantly more susceptible to five different classes of antibiotics by affecting MIC but not the recalcitrance of biofilms to killing by bactericidal agents. Overexpression of either efflux pump in a Δ
brlR
strain partly restored tolerance of Δ
brlR
biofilms to antibiotics. Expression of
brlR
in mutant biofilms lacking both efflux pumps partly restored antimicrobial tolerance of biofilms to wild-type levels. Our results indicate that BrlR acts as an activator of multidrug efflux pumps to confer tolerance to
P. aeruginosa
biofilms and to resist the action of antimicrobial agents.
Which is the most useful patient-reported outcome in femoroacetabular impingement? Test–retest reliability of six questionnaires
Authors: Hinman Rana S , Dobson Fiona , Takla Amir , O'Donnell John , Bennell Kim L 
Published: May 2013

Background/aimsThe most reliable patient-reported outcomes (PROs) for people with femoroacetabular impingement (FAI) is unknown because there have been no direct comparisons of questionnaires. Thus, the aim was to evaluate the test–retest reliability of six existing PROs in a single cohort of young active people with hip/groin pain consistent with a clinical diagnosis of FAI.MethodsYoung adults with clinical FAI completed six PRO questionnaires on two occasions, 1–2 weeks apart. The PROs were modified Harris Hip Score, Hip dysfunction and Osteoarthritis Score, Hip Outcome Score, Non-Arthritic Hip Score, International Hip Outcome Tool, Copenhagen Hip and Groin Outcome Score.Results30 young adults (mean age 24 years, SD 4 years, range 18–30 years; 15 men) with stable symptoms participated. Intraclass correlation coefficient(3,1)values ranged from 0.73 to 0.93 (95% CI 0.38 to 0.98) indicating that most questionnaires reached minimal reliability benchmarks. Measurement error at the individual level was quite large for most questionnaires (minimal detectable change (MDC95) 12.4–35.6, 95% CI 8.7 to 54.0). In contrast, measurement error at the group level was quite small for most questionnaires (MDC952.2–7.3, 95% CI 1.6 to 11).ConclusionsThe majority of the questionnaires were reliable and precise enough for use at the group level. Samples of only 23–30 individuals were required to achieve acceptable measurement variation at the group level. Further direct comparisons of these questionnaires are required to assess other measurement properties such as validity, responsiveness and meaningful change in young people with FAI.
A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair
Authors: Barkan Shiri , Breitbart Rachelle , Brenner-Zada Galit , Feldon Michal , Assa Amit , Toledano Michal , Berkovitch Sofia , Shavit Itai , Kozer Eran 
Published: May 2013

ObjectivesTo compare the efficacy of oral midazolam alone with a combination of oral midazolam and ketamine in children requiring laceration repair.DesignA randomised, double-blind, placebo-controlled study.SettingPaediatric emergency department.ParticipantsChildren 1–10 years of age with lacerations requiring sedation.InterventionsUsing a computer-generated sequence, children were randomly assigned in blocks of four to one of two groups: oral midazolam (0.5 mg/kg) plus oral placebo and oral midazolam (0.5 mg/kg) plus oral ketamine (5 mg/kg). The allocation sequence was kept by the pharmacy staff, and the investigators were blinded to randomisation until statistical analysis of the study was completed.Main outcome measuresVisual Analogue Scale (VAS) assessment by a parent and Sedation Score assessment by an investigator.Results60 children were recruited; 29 were assigned for treatment with midazolam and 31 for the combination of midazolam and ketamine. There were no differences in basic demographics and wound characteristics between the groups. VAS assessment by a parent was 4.5±3.3 mm in the midazolam+ketamine group versus 4.4±2.7 mm in the midazolam alone group (mean difference 0.1, CI −1.9 to 1.71). Sedation Score during procedure was lower in the midazolam+ketamine group (mean difference 1.14, 95% CI 0.67 to 1.6). Intravenous sedation was required in two (6%) of the children in the midazolam+ketamine group, and in eight (27%) in the midazolam alone group. p=0.039. No clinically significant adverse effects were documented in either group.ConclusionsNo difference was found in pain assessment during local anaesthetic injection between the group treated with midazolam and ketamine, and the group treated with midazolam alone. The combination of oral midazolam and ketamine led to deeper sedation than midazolam alone, with less children requiring intravenous sedation.Clinical trial registrationThe trial was registered in www.clinicaltrials.gov asNCT01470157.
Parental anxiety and affecting factors in acute paediatric blunt head injury
Authors: Serinken M , Kocyigit A , Karcioglu O , Sengül C , Hatipoğlu C , Elicabuk H 
Published: May 2013

ObjectiveThis study is designed to investigate the factors affecting parental anxiety regarding their children with head injury in the emergency department (ED).Materials and methodsThis prospective observational study enrolled all consecutive paediatric patients admitted to the university-based ED with the presenting chief complaint of paediatric blunt head injury (PBHI). The parents were asked to respond to the 10-item questionnaire during both presentation and discharge. Anxiety and persuasion scores of the parents were calculated and magnitudes of the decreases in anxiety and persuasion scores were analysed with respect to sociodemographic and clinical variables.ResultsThe study sample included 341 patients admitted to the ED. The anxiety and persuasion scores of mothers and fathers were not significantly different from each other on presentation while the extent of decrease in anxiety scores of mothers were significantly smaller than that of the fathers (p=0.003). The parents’ education levels had significant impact on anxiety and persuasion scores recorded on presentation. The anxiety and persuasion scores were inversely related to education levels of the parents on presentation (p=0.002 and p=0.000, respectively). In addition, lower education levels were found to be associated with a greater decrease in anxiety and persuasion scores. Neurosurgical consultation also affected the magnitude of the decrease in anxiety and persuasion scores of the parents. The changes in the scores were affected negatively by the parents’ age.ConclusionsRadiological investigations had no significant impact on the decrease in anxiety and persuasion scores of the parents by themselves, while neurosurgical consultation had significant impact on them. Emergency physicians should tailor their strategy to institute effective communication with the parents of children to cut down unnecessary investigations in PBHI.
Systemic antibiotics after incision and drainage of simple abscesses: a meta-analysis
Authors: Singer Adam J , Thode Henry C 
Published: May 2013

BackgroundOver the last decade, there has been a significant increase in the number of cutaneous abscesses. While there is general agreement that abscesses should be treated with incision and drainage, it is unclear whether systemic antibiotics should be routinely prescribed.ObjectiveTo evaluate whether systemic antibiotics, when compared with a placebo, improve cure rates in patients with simple abscesses after incision and drainage.Methods DesignSystematic review and meta-analysis using RevMan5.Patients and settingsChildren and adults with simple abscesses treated in outpatient clinics or emergency departments.Data sourcesCochrane Central, Medline, Embase and bibliographies.Outcome measuresPercentage of patients with complete resolution of abscess without the need for recurrent incision and drainage, additional antibiotics, or hospital admission within 7–10 days of treatment.ResultsWe included four trials, consisting of 589 patients in total (428 adults and 161 children). Patients were randomised to one of three antibiotics (cephridine (27), cephalexin (82), or trimethoprim sulfamethoxazole (161)) or to placebo (285), with 34 lost to follow-up or having incomplete data. When given in addition to incision and drainage, systemic antibiotics did not significantly improve the percentage of patients with complete resolution of their abscesses 7–10 days after treatment (88.1% vs 86.0%; OR 1.17 (95% CI 0.70 to 1.95)).ConclusionsWhen given in addition to incision and drainage, systemic antibiotics do not significantly improve the percentage of patients with complete resolution of their abscesses.
Safety of retained microcatheters: an evaluation of radiofrequency heating in endovascular microcatheters with nitinol, tungsten, and polyetheretherketone braiding at 1.5 T and 3 T
Authors: Losey Aaron D , Lillaney Prasheel , Martin Alastair J , Halbach Van V , Cooke Daniel L , Dowd Christopher F , Higashida Randall T , Saloner David A , Wilson Mark W , Saeed Maythem , Hetts Steven W 
Published: May 2013

BackgroundThe use of ethylene-vinyl alcohol copolymer for liquid embolization of cranial vascular lesions has resulted in microcatheter fragments entrapped in patients following endovascular procedures. Undergoing subsequent diagnostic MRI examinations poses a safety concern due to the possibility of radiofrequency heating of the metallic braid incorporated into the microcatheter. Heating of nitinol, tungsten, and polyetheretherketone (PEEK) braided microcatheters was assessed and compared using a phantom model.MethodsMicrocatheters coupled with fluoroptic temperature probes were embedded in a polyacrylamide gel within a head and torso phantom. Experiments were performed at 1.5 T and 3 T, analyzing the effects of different catheter immersion lengths, specific absorption rate (SAR) levels, short clinical scans, long clinical scans, and microcatheter fragment lengths.ResultsThe maximal increase in temperature for the nitinol braided microcatheter during a 15 min scan was 3.06°C using the T1 fast spin echo sequence at 1.5 T and 0.45°C using the balanced steady state free precession sequence at 3 T. The same scans for fragment lengths of 9, 18, 36, and 72 cm produced maximal temperature rises of 0.68, 0.80, 1.70, and 1.07°C at 1.5 T, respectively. The temperature changes at 3 T for these fragment lengths were 0.66, 0.83, 1.07, and 0.72°C, respectively. The tungsten and PEEK braided microcatheters did not demonstrate heating.ConclusionsSubstantial heating of nitinol braided microcatheters occurred and was a function of SAR level and geometric considerations. SAR and time limitations on MR scanning are proposed for patients with this microcatheter entrapped in their vasculature. In contrast, tungsten and PEEK braided microcatheters showed potential safe use in MRI.
Immunosuppressive therapy in adults with aplastic anaemia: single-institution experience from India
Authors: Nair Velu , Sharma Ajay , Das Satyaranjan , Sondhi Vishal , Sharma Sanjeevan 
Published: May 2013

Abstract

Objective
To determine overall survival and factors predicting survival after immunosuppressive therapy in patients with acquired aplastic anaemia.

Design
Retrospective.

Setting
Tertiary care hospital.

Patients
120 adults diagnosed as having acquired aplastic anaemia between 1 January 1996 and 31 December 2009.

Interventions
Anti-thymocyte globulin (ATG) followed by ciclosporin was administered to all patients for 15–18 months as the initial treatment. Haematological response was assessed 6 months after ATG administration and 6-monthly thereafter. Platelets were transfused if levels were &lt;10 × 103/l and for symptomatic bleeding. Transfusions of red blood cells were given for haemoglobin levels &lt;70 g/l or symptomatic anaemia. Febrile neutropenia was managed with antibiotics, with the addition of antifungal agents after 3–4 days of unresponsive fever. Granulocyte colony-stimulating factor was administered at a dose of 5 µg/kg/day (maximum 300 µg/day) subcutaneously for infective episodes.

Main outcome measures
Primary outcome: overall survival. Secondary outcome: response to immunosuppressive therapy, failure-free survival, relapse and clonal evolutions. The response and relapse criteria were defined in accordance with the British Council for Standards in Haematology guidelines.

Results
Overall response at 6 months after initiation of treatment was 85.8% (103/120). Overall survival at 76 months was 83.4%. Overall survival correlated with presence of response (complete response or partial response) at 6 months after ATG administration (HR=0.021, 95% CI 0.006 to 0.079, p&lt;0.001). The occurrence of infectious complications adversely affected the overall survival (HR=5.71, 95% CI 1.22 to 26.77, p=0.027). Six patients relapsed. There were no deaths or adverse events 12 months after treatment among responders.

Conclusions
In our study, overall survival was 83.4% at a median follow-up of 76 months. The two variables that significantly affected overall survival were response to therapy at 6 months and occurrence of infectious complications.
Eradication of BVDV in cattle: the Norwegian project
Authors: Løken T. , Nyberg O. 
Published: May 2013

The intention of this collaborative project was eradication of pestivirus from the Norwegian cattle population of about 30,000 dairy and beef herds, primarily by identification and culling of persistently infected (PI) animals. Testing was performed in four tiers, with examination for pestivirus antibodies by indirect ELISA in (1) bulk milk, (2) pooled milk from primiparous dairy cows and (3) pooled blood from young stock. The herds positive in the third tier were examined for pestivirus antigen in blood from all antibody‐negative individuals by ­antigen‐capture ELISA, and these animal composed tier (4). Following culling of the PI animals, a herd was considered free from pestivirus when pooled blood from young stock was antibody‐negative on two sampling occasions three months apart. Number of herds with PI animals peaked at about 3000 (10 per cent) in the 2nd project year, then decreased steadily; only three herds (0.01 per cent) contained PI animals 10 years later. Solid, continuous information flow to all relevant partners was crucial to project success. The project saved losses of between 50 million and 200 million Norwegian crowns (NOK) annually (approximately 4.5 million to 18 million GBP). Project running costs for 10 years were 52.4 million NOK. Following project completion, surveillance of the Norwegian cattle population for pestivirus has continued.
Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies
Authors: Brauer Matthew J. , Zhuang Guanglei , Schmidt Maike , Yao Jenny , Wu Xiumin , Kaminker Joshua S. , Jurinka Stefanie S. , Kolumam Ganesh , Chung Alicia S. , Jubb Adrian , Modrusan Zora , Ozawa Tomoko , James C. David , Phillips Heidi , Haley Benjamin , Tam Rachel N.W. , Clermont Anne C. , Cheng Jason H. , Yang Sherry X. , Swain Sandra M. , Chen Daniel , Scherer Stefan J. , Koeppen Hartmut , Yeh Ru-Fang , Yue Peng , Stephan Jean-Philippe , Hegde Priti , Ferrara Napoleone , Singh Mallika , Bais Carlos 
Published: May 2013

Abstract
Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients.
Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy.
Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies.
Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. Clin Cancer Res; 19(13); 3681–92. ©2013 AACR.
Vaccination with Dendritic Cell/Tumor Fusions following Autologous Stem Cell Transplant Induces Immunologic and Clinical Responses in Multiple Myeloma Patients
Authors: Rosenblatt Jacalyn , Avivi Irit , Vasir Baldev , Uhl Lynne , Munshi Nikhil C. , Katz Tami , Dey Bimalangshu R. , Somaiya Poorvi , Mills Heidi , Campigotto Federico , Weller Edie , Joyce Robin , Levine James D. , Tzachanis Dimitrios , Richardson Paul , Laubach Jacob , Raje Noopur , Boussiotis Vassiliki , Yuan Yan Emily , Bisharat Lina , Held Viki , Rowe Jacob , Anderson Kenneth , Kufe Donald , Avigan David 
Published: May 2013

Abstract
Purpose: A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease.
Experimental Design: Twenty-four patients received serial vaccinations with dendritic cell/myeloma fusion cells following posttransplant hematopoietic recovery. A second cohort of 12 patients received a pretransplant vaccine followed by posttransplant vaccinations. Dendritic cells generated from adherent mononuclear cells cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and TNF-α were fused with autologous bone marrow–derived myeloma fusion cells using polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that coexpress dendritic cell and myeloma fusion antigens.
Results: The posttransplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8+ myeloma-specific T cells was observed after ASCT that was significantly expanded following posttransplant vaccination. Seventy-eight percent of patients achieved a best response of complete response (CR)+very good partial response (VGPR) and 47% achieved a CR/near CR (nCR). Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at more than 3 months posttransplant, consistent with a vaccine-mediated effect on residual disease.
Conclusions: The posttransplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with dendritic cell/myeloma fusion fusions resulted in the marked expansion of myeloma-specific T cells and cytoreduction of minimal residual disease. Clin Cancer Res; 19(13); 3640–8. ©2013 AACR.
Src Mediates Cigarette Smoke–Induced Resistance to Tyrosine Kinase Inhibitors in NSCLC Cells
Authors: Filosto Simone , Baston David S. , Chung Samuel , Becker Cathleen R. , Goldkorn Tzipora 
Published: May 2013

Abstract
The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non–small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke–induced resistance to TKIs in both WT EGFR- and L858R MT EGFR–expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke–exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke–exposed L858R EGFR–expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers. Mol Cancer Ther; 12(8); 1579–90. ©2013 AACR.