bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infusion of clinical‐grade enriched regulatory T cells delays experimental xenogeneic graft‐versus‐host disease
Authors: Hannon Muriel , Lechanteur Chantal , Lucas Sophie , Somja Joan , Seidel Laurence , Belle Ludovic , Bruck France , Baudoux Etienne , Giet Olivier , Chantillon Anne‐Marie , Delvenne Philippe , Drion Pierre , Beguin Yves , Humblet‐Baron Stéphanie , Baron Frédéric 
Published: June 2013

BackgroundWe investigated the ability of clinical‐grade enriched human regulatory T cells (Treg) to attenuate experimental xenogeneic graft‐versus‐host disease (GVHD) induced by peripheral blood mononuclear cells (PBMNCs; autologous to Treg) infusion in NSG mice, as well as verified their inability to induce xenogeneic GVHD when infused alone.Study Design and MethodsHuman Treg were isolated from peripheral blood apheresis products with a cell separation system (CliniMACS, Miltenyi Biotec GmbH) using a two‐step procedure (simultaneous CD8 and CD19 depletion followed by CD25‐positive selection) in six independent experiments with six different healthy volunteer donors. Sublethally (2.5 Gy) irradiated NSG mice were given 2 × 106 cytapheresis (PBMNC) product cells intravenously (IV) without (PBMNC group) or with 1 × 106 Treg (PBMNC + Treg group), while other NSG mice received 2 × 106 enriched Treg alone (also in IV; Treg group).ResultsThe first five procedures were successful at obtaining a relatively pure Treg population (defined as >50%), while the sixth procedure, due to a technical problem, was not (Treg purity, 42%). Treg cotransfusion significantly delayed death from xenogeneic GVHD in the first five experiments, (p < 0.0001) but not in the sixth experiment. Importantly, none of the mice given enriched Treg alone (Treg group) experienced clinical signs of GVHD, while, interestingly, the CD4+ cells found in these mice 26 days after transplantation were mainly conventional T cells (median CD25+FoxP3+ cells among human CD4+ total cells were only 2.1, 3.1, and 12.2% in spleen, marrow, and blood, respectively).ConclusionsInfusion of clinical‐grade enriched Treg delayed the occurrence of xenogeneic GVHD without inducing toxicity in this murine model.
Deep Integration and Production Networks: An Empirical Analysis
Authors: Orefice Gianluca , Rocha Nadia 
Published: June 2013

AbstractThis paper investigates the two‐way relationship between deep integration and production networks trade. We capture deep integration with a set of indices constructed in terms of policy areas covered in preferential trade agreements. We estimate an augmented gravity equation to investigate the impact of deep integration on production networks trade. The results show that on average, signing deeper agreements increases production networks trade between member countries by almost 12 percentage points. In addition, the impact of deep integration is higher for trade in automobile parts and information and technology products compared with textile products. To analyse whether higher levels of network trade increase the likelihood of signing deeper agreements, we follow the literature on the determinants of preferential trade agreements. The estimation results show that, after taking into account other PTA determinants, a ten percentage increase in the share of production network trade over total trade increases the depth of an agreement by approximately 6 percentage points. In addition, the probability of signing deeper agreements is higher for country pairs involved in North–South production sharing and for countries belonging to the Asia region.
In vitro efficacy of the essential oil from Leptospermum scoparium (manuka) on antimicrobial susceptibility and biofilm formation in Staphylococcus pseudintermedius isolates from dogs
Authors: Song Chi‐Youn , Nam Eui‐Hwa , Park Seol‐Hee , Hwang Cheol‐Yong 
Published: June 2013

BackgroundStaphylococcus pseudintermedius is a common pathogen of skin and ear infections in dogs. The widespread and rapid emergence of meticillin‐resistant S. pseudintermedius (MRSP) has created therapeutic challenges in veterinary medicine and the need for alternative treatments.Hypothesis/ObjectivesWe aimed to evaluate the in vitro antimicrobial activity of the essential oil manuka (Leptospermum scoparium) against S. pseudintermedius.MethodsThis study was performed using S. pseudintermedius strains isolated from dogs with skin and ear infections collected throughout Korea between 2009 and 2011. The in vitro antimicrobial activity of manuka oil against 39 MRSP and 11 meticillin‐susceptible S. pseudintermedius (MSSP) strains was analysed by measuring minimal inhibitory concentrations (MICs) using the agar dilution method and biofilm inhibition activity as assessed by the colorimetric microtitre plate assay.ResultsOur results indicated that manuka oil had excellent activity against all bacterial isolates. The MICs for MRSP and MSSP to manuka oil were in the range of 2−9 to 2−6 and 2−9 to 2−7% (v/v), respectively. Manuka oil was a potent inhibitor of S. pseudintermedius biofilm formation, and the majority of bacteria decreased by >50%. No significant differences were observed in the MICs or biofilm formation between the MRSP and MSSP strains.Conclusions and clinical importanceThese results suggest that manuka oil has the potential to be a useful therapeutic option for treating superficial infections caused by MRSP and MSSP; further clinical investigations are required.
Specificity in monosynaptic and disynaptic bulbospinal connections to thoracic motoneurones in the rat
Authors: de Almeida Anoushka T. R. , Kirkwood Peter A. 
Published: June 2013

Key points
In the rat, unlike in other species, motoneurones of both the internal intercostal nerve and the external intercostal nerve show a phase of excitation in expiration.
This study investigated the pathways transmitting this excitation from the medulla.
Direct (monosynaptic) excitation was found from individual expiratory neurones in the medulla to internal intercostal nerve motoneurones, but only indirect (disynaptic) excitation was found from the same neurones to the motoneurones of the external intercostal nerve.
This is the first demonstration of two separate pathways from individual long descending fibres specific to two different sets of motoneurones.
This specificity could be useful in studying plasticity or regeneration in thoracic segments in investigations of mechanisms involved in spinal cord injury and repair.
Abstract  The respiratory activity in the intercostal nerves of the rat is unusual, in that motoneurones of both branches of the intercostal nerves, internal and external, are activated during expiration. Here, the pathways involved in that activation were investigated in anaesthetised and in decerebrate rats by cross‐correlation and by intracellular spike‐triggered averaging from expiratory bulbospinal neurones (EBSNs), with a view to revealing specific connections that could be used in studies of experimental spinal cord injury. Decerebrate preparations, which showed the strongest expiratory activity, were found to be the most suitable for these measurements. Cross‐correlations in these preparations showed monosynaptic connections from 16/19 (84%) of EBSNs, but only to internal intercostal nerve motoneurones (24/37, 65% of EBSN/nerve pairs), whereas disynaptic connections were seen for external intercostal nerve motoneurones (4/19, 21% of EBSNs or 7/25, 28% of EBSN/nerve pairs). There was evidence for additional disynaptic connections to internal intercostal nerve motoneurones. Intracellular spike‐triggered averaging revealed excitatory postsynaptic potentials, which confirmed these connections. This is believed to be the first report of single descending fibres that participate in two different pathways to two different groups of motoneurones. It is of interest compared with the cat, where only one group of motoneurones is activated during expiration and only one of the pathways has been detected. The specificity of the connections could be valuable in studies of plasticity in pathological situations, but care will be needed in studying connections in such situations, because their strength was found here to be relatively weak.
Monte Carlo simulation of photon buildup factors for shielding materials in radiotherapy x‐ray facilities
Authors: Karim Karoui Mohamed , Kharrati Hedi 
Published: June 2013

Purpose:This paper presents the results of a series of calculations to determine buildup factors for ordinary concrete, baryte concrete, lead, steel, and iron in broad beam geometry for photons energies from 0.125 to 25.125 MeV at 0.250 MeV intervals.Methods:Monte CarloN‐particle radiation transport computer code has been used to determine the buildup factors for the studied shielding materials.Results:The computation of the primary broad beams using buildup factors data was done for nine published megavoltage photon beam spectra ranging from 4 to 25 MV in nominal energies, representing linacs made by the three major manufacturers. The first tenth value layer and the equilibrium tenth value layer are calculated from the broad beam transmission for these nine primary megavoltage photon beam spectra.Conclusions:The results, compared with published data, show the ability of these buildup factor data to predict shielding transmission curves for the primary radiation beam. Therefore, the buildup factor data can be combined with primary, scatter, and leakage x‐ray spectra to perform computation of broad beam transmission for barriers in radiotherapy shielding x‐ray facilities.
Phase I, Open-Label, Single-Dose Study To Evaluate the Pharmacokinetics and Safety of Telbivudine in Children and Adolescents with Chronic Hepatitis B
Authors: Stein Daniel S. , Ke June , Uy Grace , Bosheva Miroslava , Qi Yin , Praestgaard Jens 
Published: June 2013

ABSTRACTTelbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to <6 and 6 to 12 years receiving a single 15-mg/kg dose showed similar plasma exposures. To predict the steady-state exposure, plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.)
In Vitro
Activity of CEM-102 (Fusidic Acid) against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus
Authors: Sahm D. F. , Deane J. , Pillar C. M. , Fernandes P. 
Published: June 2013

ABSTRACT

Clinical development of CEM-102 (fusidic acid) has recently begun in the United States for chronic oral treatment of prosthetic joint infections. To support this development, the
in vitro
activity of fusidic acid against important
Staphylococcus aureus
clones and resistance phenotypes was determined. Against 51 such isolates, the modal fusidic acid MIC was 0.12 μg/ml (range, 0.06 to 0.25 μg/ml for 49 isolates). This level of
in vitro
fusidic acid activity underscores the potential clinical utility of this compound in the United States.
Adaptation-Based Resistance to Siderophore-Conjugated Antibacterial Agents by Pseudomonas aeruginosa
Authors: Tomaras Andrew P. , Crandon Jared L. , McPherson Craig J. , Banevicius Mary Anne , Finegan Steven M. , Irvine Rebecca L. , Brown Matthew F. , O'Donnell John P. , Nicolau David P. 
Published: June 2013

ABSTRACT

Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard
in vitro
MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent
in vitro
activity against
Pseudomonas aeruginosa
when tested using standard assay conditions. Unfortunately, the
in vitro
findings did not correlate with the
in vivo
results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new
in vitro
assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some
P. aeruginosa
isolates
in vivo
.
Unique and Highly Selective Anticytomegalovirus Activities of Artemisinin-Derived Dimer Diphenyl Phosphate Stem from Combination of Dimer Unit and a Diphenyl Phosphate Moiety
Authors: He Ran , Forman Michael , Mott Bryan T. , Venkatadri Rajkumar , Posner Gary H. , Arav-Boger Ravit 
Published: June 2013

ABSTRACT
We report that the artemisinin-derived dimer diphenyl phosphate (DPP; dimer 838) is the most selective inhibitor of human cytomegalovirus (CMV) replication among a series of artemisinin-derived monomers and dimers. Dimer 838 was also unique in being an irreversible CMV inhibitor. The peroxide unit within artemisinins' chemical structures is critical to their activities, and its absence results in loss of anti-CMV activities. Surprisingly, the deoxy dimer of 838 retained modest anti-CMV activity, suggesting that the DPP moiety of dimer 838 contributes to its anti-CMV activities. DPP alone did not inhibit CMV replication, but triphenyl phosphate (TPP) had modest CMV inhibition, although its selectivity index was low. Artemisinin DPP derivatives dimer 838 and monomer diphenyl phosphate (compound 558) showed stronger CMV inhibition and a higher selectivity index than their analogs lacking the DPP unit. An add-on and removal assay revealed that removing DPP derivatives (compounds 558 and 838) but not the non-DPP backbones (artesunate and compound 606) at 24 h postinfection (hpi) already resulted in dominant CMV inhibition. CMV inhibition was fully irreversible with 838 and partially irreversible with 558, while non-DPP artemisinins were reversible inhibitors. While all artemisinin derivatives and TPP reduced the expression of the CMV immediate early 2 (IE2), UL44, and pp65 proteins at or after 48 hpi, only TPP inhibited the expression of both IE1 and IE2. Combination of a non-DPP dimer (compound 606) with TPP was synergistic in CMV inhibition, while ganciclovir and TPP were additive. Although TPP shared structural similarity with monomer DPP (compound 558) and dimer DPP (compound 838), its pattern of CMV inhibition was significantly different from the patterns of the artemisinins. These findings demonstrate that the DPP group contributes to the unique activities of compound 838.
Small-Molecule Inhibitors of Lethal Factor Protease Activity Protect against Anthrax Infection
Authors: Moayeri Mahtab , Crown Devorah , Jiao Guan-Sheng , Kim Seongjin , Johnson Alan , Leysath Clinton , Leppla Stephen H. 
Published: June 2013

ABSTRACT

Bacillus anthracis
, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated their
in vivo
efficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins.
A Colanic Acid Operon Deletion Mutation Enhances Induction of Early Antibody Responses by Live Attenuated Salmonella Vaccine Strains
Authors: Wang Shifeng , Shi Huoying , Li Yuhua , Shi Zhaoxing , Zhang Xin , Baek Chang-Ho , Mothershead Tabor , Curtiss Roy 
Published: June 2013

ABSTRACTColanic acid (CA) is a common exopolysaccharide produced by many genera in theEnterobacteriaceae. It is critical for biofilm formation on HEp-2 cells and on chicken intestinal tissue bySalmonella. In this study, we generated different CA synthesis gene mutants and evaluated the immune responses induced by these mutants. One of these mutations, Δ(wza-wcaM)8, which deleted the whole operon for CA synthesis, was introduced into twoSalmonellavaccine strains attenuated by auxotrophic traits or by the regulated delayed attenuation strategy (RDAS). The mice immunized with the auxotrophicSalmonellavaccine strain with the deletion mutation Δ(wza-wcaM)8developed higher vaginal IgA titers against the heterologous protective antigen and higher levels of antigen-specific IgA secretion cells in lungs. InSalmonellavaccine strains with RDAS, the strain with the Δ(wza-wcaM)8mutation resulted in higher levels of protective antigen production duringin vitrogrowth. Mice immunized with this strain developed higher serum IgG and mucosal IgA antibody responses at 2 weeks. This strain also resulted in better gamma interferon (IFN-γ) responses than the strain without this deletion at doses of 108and 109CFU. Thus, the mutation Δ(wza-wcaM)8will be included in various recombinant attenuatedSalmonellavaccine (RASV) strains with RDAS derived fromSalmonella entericaserovar Paratyphi A andSalmonella entericaserovar Typhi to induce protective immunity against bacterial pathogens.
Cryptococcus neoformans Promotes Its Transmigration into the Central Nervous System by Inducing Molecular and Cellular Changes in Brain Endothelial Cells
Authors: Vu Kiem , Eigenheer Richard A. , Phinney Brett S. , Gelli Angie 
Published: June 2013

ABSTRACT

Cryptococcus
spp. cause fungal meningitis, a life-threatening infection that occurs predominately in immunocompromised individuals. In order for
Cryptococcus neoformans
to invade the central nervous system (CNS), it must first penetrate the brain endothelium, also known as the blood-brain barrier (BBB). Despite the importance of the interrelation between
C. neoformans
and the brain endothelium in establishing CNS infection, very little is known about this microenvironment. Here we sought to resolve the cellular and molecular basis that defines the fungal-BBB interface during cryptococcal attachment to, and internalization by, the human brain endothelium. In order to accomplish this by a systems-wide approach, the proteomic profile of human brain endothelial cells challenged with
C. neoformans
was resolved using a label-free differential quantitative mass spectrometry method known as spectral counting (SC). Here, we demonstrate that as brain endothelial cells associate with, and internalize, cryptococci, they upregulate the expression of several proteins involved with cytoskeleton, metabolism, signaling, and inflammation, suggesting that they are actively signaling and undergoing cytoskeleton remodeling via annexin A2, S100A10, transgelin, and myosin. Transmission electronic microscopy (TEM) analysis demonstrates dramatic structural changes in nuclei, mitochondria, the endoplasmic reticulum (ER), and the plasma membrane that are indicative of cell stress and cell damage. The translocation of HMGB1, a marker of cell injury, the downregulation of proteins that function in transcription, energy production, protein processing, and the upregulation of cyclophilin A further support the notion that
C. neoformans
elicits changes in brain endothelial cells that facilitate the migration of cryptococci across the BBB and ultimately induce endothelial cell necrosis.
Diagnostic utility of androgen receptor expression in discriminating poorly differentiated urothelial and prostate carcinoma
Authors: Downes Michelle R , Torlakovic Emina E , Aldaoud Najla , Zlotta Alexandre R , Evans Andrew J , van der Kwast Theodorus H 
Published: June 2013

AimsPathological separation of poorly differentiated urothelial and prostate carcinoma is difficult, but imperative because of the impact on patient management. Tumour morphology, in conjunction with a panel of immunohistochemistry (IHC), such as prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), CK7, CK20, p63 and high molecular weight keratins (HMWKs) are usually employed to resolve this issue. Androgen receptor (AR) expression is maintained in high-grade, undifferentiated prostate carcinoma, and thus, could be considered as a potentially useful adjunct to the conventional panel of markers.MethodsWe performed an institutional review of all cases from 2006 to 2012 in which AR IHC had been performed to determine its diagnostic utility in discriminating between poorly differentiated urothelial and prostate carcinoma. Of the eligible cases (n=40), there were 9 high-grade urothelial carcinomas, 27 prostate carcinomas and 4 with both prostate and bladder tumours. All diagnoses were made by integrating the clinical, radiological, morphological and IHC results.ResultsIn all the prostate carcinomas, there was diffuse, intense nuclear staining for AR. The urothelial tumours were either negative, had cytoplasmic staining or showed occasionally weak nuclear staining. The difference was highly significant with p<0.0001 (Mann–Whitney U test).ConclusionsWe conclude that AR is an important marker as it is best able to distinguish between poorly differentiated urothelial and prostate carcinoma. AR appears superior to PSA and PSAP, which are not consistently expressed in high-grade prostate carcinoma. Also, high-grade urothelial carcinoma may be negative for CK20, p63/HMWK and occasionally CK7. We advocate the inclusion of AR in the panel of markers to differentiate these tumours.