bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type II Secretion Substrates ofLegionella pneumophilaTranslocate Out of the Pathogen-Occupied Vacuole via a Semipermeable Membrane
Authors: Truchan Hilary K. , Christman Harry D. , White Richard C. , Rutledge Nakisha S. , Cianciotto Nicholas P. 
Published: June 2017

ABSTRACTLegionella pneumophilareplicates in macrophages in a host-derived phagosome, termed theLegionella-containing vacuole (LCV). While the translocation of type IV secretion (T4S) effectors into the macrophage cytosol is well established, the location of type II secretion (T2S) substrates in the infected host cell is unknown. Here, we show that the T2S substrate ProA, a metalloprotease, translocates into the cytosol of human macrophages, where it associates with the LCV membrane (LCVM). Translocation is detected as early as 10 h postinoculation (p.i.), which is approximately the midpoint of the intracellular life cycle. However, it is detected as early as 6 h p.i. if ProA is hyperexpressed, indicating that translocation depends on the timing of ProA expression and that any other factors necessary for translocation are in place by that time point. Translocation occurs with allL. pneumophilastrains tested and in amoebae, natural hosts forL. pneumophila. It was absent in murine bone marrow-derived macrophages and murine macrophage cell lines. The ChiA chitinase also associated with the cytoplasmic face of the LCVM at 6 h p.i. and in a T2S-dependent manner. Galectin-3 and galectin-8, eukaryotic proteins whose localization is influenced by damage to host membranes, appeared within the LCV of infected human but not murine macrophages beginning at 6 h p.i. Thus, we hypothesize that ProA and ChiA are first secreted into the vacuolar lumen by the activity of the T2S and subsequently traffic into the macrophage cytosol via a novel mechanism that involves a semipermeable LCVM.IMPORTANCEInfection of macrophages and amoebae plays a central role in the pathogenesis ofL. pneumophila, the agent of Legionnaires’ disease. We have previously demonstrated that the T2S system ofL. pneumophilagreatly contributes to intracellular infection. However, the location of T2S substrates within the infected host cell is unknown. This report presents the first evidence of aL. pneumophilaT2S substrate in the host cell cytosol and, therefore, the first evidence of a non-T4S effector trafficking out of the LCV. We also provide the first indication that the LCV is not completely intact but is instead semipermeable and that this occurs in human but not murine macrophages. Given this permeability, we hypothesize that other T2S substrates and LCV lumenal contents can escape into the host cell cytosol. Thus, these substrates may represent a battery of previously unidentified effectors that can interact with host factors and contribute to intracellular infection byL. pneumophila.
Effectiveness of an online SUpport PRogramme (SUPR) for older hearing aid users: study protocol for a cluster randomised controlled trial
Authors: Meijerink Janine FJ , Pronk Marieke , Paulissen Bernadette , Witte Birgit I , Wouden Bregje van der , Jansen Vera , Kramer Sophia E 
Published: June 2017

BackgroundAn educational SUpport PRogramme called SUPR has been developed for hearing aid users (HAUs) and their communication partners (CPs) offering care beyond hearing aid fitting. SUPR teaches its users communication strategies, hearing aid handling skills and personal adjustment to hearing impairment.Methods/designUsing a cluster randomised controlled trial design, 70 Dutch hearing aid dispenser practices were randomised into hearing aid fitting (care as usual, 34 practices) and hearing aid fitting including SUPR (36 practices). The aim was to recruit a total of 569 older (aged 50+ years) first-time (n=258) and experienced (n=311) HAUs and their CPs. SUPR consists of a Practical Support Booklet and online material offered via email over a period of 6–7 months. The booklet provides practical information on hearing aids, advice on communication strategies and home exercises. The online material consists of educational videos on hearing aid functionality and usage, communication strategies and peer testimonials. Finally, noncommittal email contact with the dispenser is offered. Every HAU is asked to assign a CP who is advised to be involved intensively. Effect measurements for HAUs and their CPs will occur at baseline and at 6, 12 and 18 months follow-up via online questionnaires. The primary outcomes for HAUs will be the use of communication strategies as measured by the subscales of the Communication Profile for the Hearing Impaired. A process evaluation will be performed.Ethics and disseminationThe study was approved by the Dutch Institutional Review Board of the VU Medical University Center Amsterdam. This intervention could contribute to lowering the hearing impairment burden in our ageing society. The results will be disseminated through peer-reviewed publications and scientific conferences.Trial registration numberISRCTN77340339; Pre-results.
The proinflammatory cytokine tumor necrosis factor-α excites subfornical organ neurons
Authors: Simpson Nick J. , Ferguson Alastair V. 
Published: June 2017

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNF-α−/− mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNF-α into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNF-α, while direct administration of TNF-α into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNF-α. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNF-α on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNF-α depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration dependent. Interestingly, following 24-h incubation with TNF-α, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNF-α elevates SFO neuron excitability. This effect was likely mediated by the transient sodium current, as TNF-α increased the magnitude of the current and lowered its threshold of activation. In contrast, TNF-α did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNF-α exposure elevates SFO neuron activity, providing a basis for TNF-α hypertensive and sympathetic effects. NEW & NOTEWORTHY Considerable recent evidence has suggested important links between inflammation and the pathological mechanisms underlying hypertension. The present study describes cellular mechanisms through which acute and long-term exposure of tumor necrosis factor-α (TNF-α) influences the activity of subfornical organ neurons by modulating the voltage-gated transient Na+ current. This provides critical new information regarding the specific pathological mechanisms through which inflammation and TNF-α in particular may result in the development of hypertension.
Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors
Authors: Tolcher Anthony W. , Sznol Mario , Hu-Lieskovan Siwen , Papadopoulos Kyriakos P. , Patnaik Amita , Rasco Drew W. , Di Gravio Donna , Huang Bo , Gambhire Dhiraj , Chen Ying , Thall Aron D. , Pathan Nuzhat , Schmidt Emmett V. , Chow Laura Q.M. 
Published: June 2017

Abstract
Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.
Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.
Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders.
Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.
See related commentary by Pérez-Ruiz et al., p. 5326
Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
Authors: Hassani Zahra , Saleh Ali , Turpault Soumaya , Khiati Salim , Morelle Willy , Vignon Jacques , Hugnot Jean-Philippe , Uro-Coste Emmanuelle , Legrand Philippe , Delaforge Marcel , Loiseau Séverine , Clarion Ludovic , Lecouvey Marc , Volle Jean-Noël , Virieux David , Pirat Jean-Luc , Duffau Hugues , Bakalara Norbert 
Published: June 2017

Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.
Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment–Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction])
Authors: Pasupathy Sivabaskari , Tavella Rosanna , Grover Suchi , Raman Betty , Procter Nathan E.K. , Du Yang Timothy , Mahadavan Gnanadevan , Stafford Irene , Heresztyn Tamila , Holmes Andrew , Zeitz Christopher , Arstall Margaret , Selvanayagam Joseph , Horowitz John D. , Beltrame John F. 
Published: June 2017

Background:
Contemporary ST-segment–elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention.

Methods:
This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging–assessed infarct size. Secondary end points included cardiac magnetic resonance–determined myocardial salvage and creatine kinase kinetics.

Results:

Of 112 randomized patients with ST-segment–elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance–assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2];
P
=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37–79) compared with placebo (27%; interquartile range, 14–42;
P
<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (
P
=0.08).

Conclusions:
High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes.

Clinical Trial Registration:

Australian New Zealand Clinical Trials Registry. URL:
http://www.anzctr.org.au/
. Unique identifier: 12610000280000.
Hiving off the non-essential: analysing which public organizations outsource administrative overhead
Authors: Boon Jan , Verhoest Koen , De Borger Bruno 
Published: June 2017

This study contributes to our understanding of the characteristics of public organizations that are more likely to outsource administrative overhead. Despite the climate of ongoing crisis that urges public organizations to focus their resources on core tasks, little is known about the characteristics of organizations that hive off the delivery of non-essential administrative overhead processes to the private sector. This study runs a panel data Tobit model to test whether different effect sizes of structural, institutional and political characteristics are found regarding the probability of outsourcing and the degree of outsourcing of administrative overhead. We find that organizational size, formal autonomy, inertia and time matter for understanding the outsourcing of public organizations. Points for practitioners Across the globe, governments have turned to a rationalization of administrative overhead in response to austerity demands posed by the global financial crisis. The present study shows that large differences exist between organizations in terms of their propensity to turn to the private sector – one of the classic recipes for achieving efficiency gains – for the delivery of administrative overhead, and helps practitioners gain insight into the determinants of administrative overhead outsourcing.
Neuromuscular electrical stimulation improves exercise tolerance in patients with advanced heart failure on continuous intravenous inotropic support use—randomized controlled trial
Authors: Forestieri Patrícia , Bolzan Douglas W , Santos Vinícius B , Moreira Rita Simone Lopes , de Almeida Dirceu Rodrigues , Trimer Renata , de Souza Brito Flávio , Borghi-Silva Audrey , de Camargo Carvalho Antonio Carlos , Arena Ross , Gomes Walter J , Guizilini Solange 
Published: June 2017

Objective: To evaluate the impact of a short-term neuromuscular electrical stimulation program on exercise tolerance in hospitalized patients with advanced heart failure who have suffered an acute decompensation and are under continuous intravenous inotropic support. Design: A randomized controlled study. Subjects: Initially, 195 patients hospitalized for decompensated heart failure were recruited, but 70 were randomized. Intervention: Patients were randomized into two groups: control group subject to the usual care ( n = 35); neuromuscular electrical stimulation group ( n = 35) received daily training sessions to both lower extremities for around two weeks. Main measures: The baseline 6-minute walk test to determine functional capacity was performed 24 hours after hospital admission, and intravenous inotropic support dose was daily checked in all patients. The outcomes were measured in two weeks or at the discharge if the patients were sent back home earlier than two weeks. Results: After losses of follow-up, a total of 49 patients were included and considered for final analysis (control group, n = 25 and neuromuscular electrical stimulation group, n = 24). The neuromuscular electrical stimulation group presented with a higher 6-minute walk test distance compared to the control group after the study protocol (293 ± 34.78 m vs. 265.8 ± 48.53 m, P < 0.001, respectively). Neuromuscular electrical stimulation group also demonstrated a significantly higher dose reduction of dobutamine compared to control group after the study protocol (2.72 ± 1.72 µg/kg/min vs. 3.86 ± 1.61 µg/kg/min, P = 0.001, respectively). Conclusion: A short-term inpatient neuromuscular electrical stimulation rehabilitation protocol improved exercise tolerance and reduced intravenous inotropic support necessity in patients with advanced heart failure suffering a decompensation episode.
Thoracic paravertebral block versus intravenous patient-controlled analgesia for pain treatment in patients with multiple rib fractures
Authors: Yeying Ge , Liyong Yuan , Yuebo Chen , Yu Zhang , Guangao Ye , Weihu Ma , Liujun Zhao 
Published: June 2017

Objectives To assess the effect of thoracic paravertebral block (PVB) on pain management and preservation of pulmonary function compared with intravenous, patient-controlled analgesia (IVPCA) in patients with multiple rib fractures (MRFs). Methods Ninety patients with unilateral MRFs were included in this prospective study and randomly assigned to the TPVB or IVPCA group. The visual analogue scale (VAS) pain score, blood gas analysis, and bedside spirometry were measured and recorded at different time points after analgesia. Results TPVB and IVPCA provided good pain relief. VAS scores were significantly lower in the TPVB group than in the IVPCA group at rest and during coughing ( P < 0.05). Patients in the TPVB group had a higher PaO2 and PaO2/FiO2 and lower P(A–a)O2 compared with the IVPCA group ( P < 0.05). Moreover, patients in the TPVB group showed higher FVC, FEV1/FVC, and PEFR, and fewer complications than did the IVPCA group ( P < 0.05). Conclusion TPVB is superior to IVPCA in pain relief and preservation of pulmonary function in patients with MRFs.
Do Ligamentum Teres Tears Portend Inferior Outcomes in Patients With Borderline Dysplasia Undergoing Hip Arthroscopic Surgery? A Match-Controlled Study With a Minimum 2-Year Follow-up
Authors: Chaharbakhshi Edwin O. , Perets Itay , Ashberg Lyall , Mu Brian , Lenkeit Christopher , Domb Benjamin G. 
Published: June 2017

Background: Arthroscopic surgery in borderline dysplastic hips remains controversial, but the role of the ligamentum teres (LT) has not been studied in this setting. Hypothesis: Borderline dysplastic patients with LT tears have worse short-term outcomes than those without LT tears. Study Design: Cohort study; Level of evidence, 3. Methods: Data were prospectively collected on patients who underwent arthroscopic surgery between February 2008 and April 2014. The inclusion criteria were borderline dysplasia (lateral center-edge angle [LCEA], 18°-25°) and labral tears; arthroscopic treatments including labral preservation and capsular plication; and preoperative patient-reported outcome scores including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score–Sport-Specific Subscale, and visual analog scale for pain. Patients were excluded for preoperative Tönnis osteoarthritis grade >0, workers’ compensation claims, previous ipsilateral hip surgery and conditions, or frank dysplasia (LCEA <18°). Patients with LT tears were pair-matched to patients without tears for sex, age at surgery ±10 years, body mass index (<30 kg/m2 vs ≥30 kg/m2), labral treatment type, and microfracture. Results: Of 68 eligible patients, 63 (93%) had a minimum 2-year follow-up, and 30 (48%) had LT tears. Twenty patients in each group were pair-matched. The mean follow-up time was 54.3 months (range, 24.2-83.8 months) for the LT tear group and 38.6 months (range, 24.6-70.6 months) for the control group ( P = .002). Ninety percent were female. There were no significant differences regarding demographics or intra-operative procedures. The LT tear group trended toward lower postoperative mHHS ( P = .09) and NAHS ( P = .09) values. Mean satisfaction was 8.1 for the LT tear group and 7.9 for the control group. Preoperative and follow-up scores were not significantly different between the groups. The LT tear group had 5 revisions, with 1 revision in the control group. Three patients (15%) in the LT tear group underwent total hip arthroplasty (THA); no patients in the control group required THA. Conclusion: In borderline dysplastic patients undergoing hip arthroscopic surgery with labral treatment and capsular plication, LT tears may indicate advanced instability and portend slightly inferior outcomes when compared with a match-controlled group. Borderline dysplastic patients with LT tears may have increased propensities toward revision arthroscopic surgery and conversion to THA. LT tears in these patients may warrant consideration for additional procedures including periacetabular osteotomy and LT reconstruction.