bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe infections after single umbilical cord blood transplantation in adults with or without the co‐infusion ofCD34+cells from a third‐party donor: results of a multicenter study from the Grupo Español de Trasplante Hematopoyético (GETH)
Authors: Martino R. , Bautista G. , Parody R. , García I. , Esquirol A. , Rovira M. , Cabrera J.R. , Regidor C. , Fores R. , García‐Marco J.A. , Serrano D. , Barba P. , Heras I. , Marquez‐Malaver F.J. , Sánchez‐Ortega I. , Duarte R. , Saavedra S. , Sierra J. , Vazquez L. ,   the Infectious/Non‐infectious Complications Subcommittee of the Grupo Español de Trasplante Hematopoyético (GETH)
Published: February 2015

AbstractBackgroundUmbilical cord blood transplantation (CBT) is an established alternative source of stem cells in the setting of unrelated transplantation. When compared with other sources, single‐unitCBT(sCBT) is associated with a delayed hematologic recovery, which may lead to a higher infection‐related mortality (IRM). Co‐infusion with thesCBTofCD34+peripheral blood stem cells from a third‐party donor (TPD) (sCBT + TPDCD34+) has been shown to markedly accelerate leukocyte recovery, potentially reducing theIRM. However, to our knowledge, no comparative studies have focused on severe infections andIRMwith these 2sCBTstrategies.MethodsA total of 148 consecutivesCBT(2000–2010, median follow‐up 4.5 years) were included in a multicenter retrospective study to analyze the incidence and risk factors ofIRMand severe viral and invasive fungal infections (IFIs). Neutrophil engraftment occurred in 90% ofsCBT(n = 77) and 94%sCBT + TPDCD34+(n = 71) recipients at a median of 23 and 12 days post transplantation, respectively (P < 0.01).ResultsThe 4‐yearIRMwas 24% and 20%, respectively (P = 0.7), with no differences at day +30 (5% and 4%, respectively) and day +100 (10% and 8%, respectively). In multivariate analysis early status of the underlying malignancy, cytomegalovirus (CMV)‐seronegative recipient and highCD34+cell content in the cord blood unit before cryostorage (≥1.4 × 105/kg) were protective ofIRM. Among the causes ofIRM, bacterial infections andIFIs were more common insCBT(15% vs. 4%), whileCMVdisease and parasitic infections were more common in thesCBT + TPDCD34+cohort (5% vs. 16%).ConclusionThese data show thatsCBTsupported withTPDCD34+cells results in much shorter periods of post‐transplant leukopenia, but the short‐ and long‐term rates ofIRMwere comparable to those ofsCBT, presumably because immune recovery is equally delayed in both graft types.
Metabolic and photosynthetic consequences of blocking starch biosynthesis in the green alga Chlamydomonas reinhardtii sta6 mutant
Authors: Krishnan Anagha , Kumaraswamy G. Kenchappa , Vinyard David J. , Gu Huiya , Ananyev Gennady , Posewitz Matthew C. , Dismukes G. Charles 
Published: February 2015

SummaryUpon nutrient deprivation, microalgae partition photosynthate into starch and lipids at the expense of protein synthesis and growth. We investigated the role of starch biosynthesis with respect to photosynthetic growth and carbon partitioning in the Chlamydomonas reinhardtii starchless mutant, sta6, which lacks ADP‐glucose pyrophosphorylase. This mutant is unable to convert glucose‐1–phosphate to ADP‐glucose, the precursor of starch biosynthesis. During nutrient‐replete culturing, sta6 does not re‐direct metabolism to make more proteins or lipids, and accumulates 20% less biomass. The underlying molecular basis for the decreased biomass phenotype was identified using LC–MS metabolomics studies and flux methods. Above a threshold light intensity, photosynthetic electron transport rates (water → CO2) decrease in sta6 due to attenuated rates of NADPH re‐oxidation, without affecting photosystems I or II (no change in isolated photosynthetic electron transport). We observed large accumulations of carbon metabolites that are precursors for the biosynthesis of lipids, amino acids and sugars/starch, indicating system‐wide consequences of slower NADPH re‐oxidation. Attenuated carbon fixation resulted in imbalances in both redox and adenylate energy. The pool sizes of both pyridine and adenylate nucleotides in sta6 increased substantially to compensate for the slower rate of turnover. Mitochondrial respiration partially relieved the reductant stress; however, prolonged high‐light exposure caused accelerated photoinhibition. Thus, starch biosynthesis in Chlamydomonas plays a critical role as a principal carbon sink influencing cellular energy balance however, disrupting starch biosynthesis does not redirect resources to other bioproducts (lipids or proteins) during nutrient‐replete culturing, resulting in cells that are susceptible to photochemical damage caused by redox stress.
Evaluation of the protection of primates transfused with variant Creutzfeldt‐Jakob disease–infected blood products filtered with prion removal devices: a 5‐year update
Authors: Lescoutra‐Etchegaray Nathalie , Jaffré Nina , Sumian Chryslain , Durand Valérie , Correia Evelyne , Mikol Jacqueline , Luccantoni‐Freire Sophie , Culeux Audrey , Deslys Jean‐Philippe , Comoy Emmanuel E. 
Published: February 2015

BACKGROUNDAnalysis of archived appendix samples reveals that one in 2000 individuals in the United Kingdom may carry the infectious prion protein associated with variant Creutzfeldt‐Jakob disease (vCJD), raising questions about the risk of transfusion transmission from apparently healthy carriers. Blood leukoreduction shows limited efficiency against prions. Therefore, in absence of antemortem diagnostic tests, prion removal filters, including the P‐Capt filter were designed to improve blood transfusion safety.STUDY DESIGN AND METHODSWe evaluated the performances of two filters, the P‐Capt and one prototype (PMC#005), with blood‐borne infectivity in two independent experiments. Blood was drawn twice from prion‐infected macaques. Corresponding RBCCs were prepared according to two different procedures: in Study A, the leukoreduction step was followed by the filtration through the P‐Capt. In Study B, the leukoreduction and prion removal were performed simultaneously through the PMC#005. For each study, two groups of three animals were transfused twice with samples before or after filtration.RESULTSAmong the six macaques transfused with nonfiltered samples, five developed neurologic signs but only four exhibited peripheral detectable protease‐resistant prion protein (PrPres) accumulation. In Study A, the three animals transfused with P‐Capt–filtered samples remain asymptomatic and devoid of PrPres in lymph node biopsies 6 years after the transfusion. In Study B, one animal transfused with PMC#005‐filtered samples developed vCJD.CONCLUSIONAfter 5 to 6 years of progress, this ongoing study provides encouraging results on the prion blood removal performances of the P‐Capt filter in macaques, an utmost relevant model for human prion diseases.
Collection of peripheral blood progenitor cells on Day 4 is feasible and effective while reducing granulocyte–colony‐stimulating factor exposure to healthy donors
Authors: Flommersfeld Sabine , Sohlbach Kristina , Jaques Gabriele , Bein Gregor , Hoffmann Jörg , Kostrewa Philippe , Sachs Ulrich J. 
Published: February 2015

BACKGROUNDPeripheral blood progenitor cells (PBPCs) are the most common stem cell source for allogeneic transplantations. Analysis of our collection data obtained with a Spectra Optia device (Terumo) for apheresis demonstrated collection efficacies (CEs) exceeding our internal target levels of 5 × 106 CD34+ cells/kg body weight of the recipient when collected on Day 5. We thus aimed to investigate whether collection on Day 4 would lead to adequate amounts of PBPCs while minimizing granulocyte–colony‐stimulating factor (G‐CSF) exposure in healthy donors.STUDY DESIGN AND METHODSWe compared feasibility and effectiveness of Day 5 versus Day 4 collections with data obtained from 23 and 18 allogeneic procedures, respectively.RESULTSBoth groups were comparable with regard to donor and collection characteristics. Product characteristics as well as platelet loss, CE, throughput, and collection rate did not differ between both protocols. A higher contamination with white blood cells (WBCs; ×109/L) was observed in products collected on Day 5 compared to Day 4 (231 [range, 181‐299] vs. 203 [range, 165‐239]; p = 0.004). A second apheresis procedure was required in three of 23 patients and three of 18 patients, respectively (p = 0.6) to obtain the required PBPC dose.CONCLUSIONSPBPC apheresis on Day 4 seems as feasible and effective as collection on Day 5. Collection on Day 4 produces lower WBC content in the product and allows a reduction in G‐CSF exposure to healthy donors.
Blood utilization at a national referral hospital in sub‐Saharan Africa
Authors: Butler Elissa K. , Hume Heather , Birungi Isaac , Ainomugisha Brenda , Namazzi Ruth , Ddungu Henry , Kajja Isaac , Nabadda Susan , McCullough Jeffrey 
Published: February 2015

BACKGROUNDA safe and adequate supply of blood is critical to improving health care systems in sub‐Saharan Africa, where little is known about the current use of blood. The aim of this study was to comprehensively describe the use of blood at a tertiary care hospital to inform future efforts to strengthen blood programs in resource‐limited settings.STUDY DESIGN AND METHODSData were collected from blood bank documentation for all units issued at Mulago Hospital Complex in Kampala, Uganda, from mid‐January to mid‐April 2014.RESULTSA total of 6330 units (69% whole blood, 32% red blood cells, 6% platelets, 2% plasma) were issued over the 3‐month study period to 3662 unique patients. Transfusion recipients were 58% female and median age was 27 years (interquartile range [IQR], 14–41). Median pretransfusion hemoglobin was 5.6 g/dL (IQR, 4.0–7.2 g/dL, n = 1090). Strikingly, cancer was the top indication for transfusion (33.5%), followed by pregnancy‐related complications (12.4%) and sickle cell disease (6.9%).CONCLUSIONThis study provides a comprehensive picture of blood use at a national referral hospital in sub‐Saharan Africa. Noncommunicable diseases, particularly oncologic conditions, represent a large proportion of demand for transfusion services.
Outcome following treatment of soft tissue and visceral extraskeletal osteosarcoma in 33 dogs: 2008–2013
Authors: Duffy D. , Selmic L. E. , Kendall A. R. , Powers B. E. 
Published: February 2015

AbstractExtraskeletal osteosarcoma (EOS) is a rare, highly malignant mesenchymal neoplasm arising from viscera or soft tissues characterised by the formation of osteoid in the absence of bone involvement. Owing to the rarity of these neoplasms very little information exists on treatment outcomes. The purpose of this study was to describe the outcome following surgical treatment of non‐mammary and non‐thyroidal soft tissue and visceralEOSin dogs. Thirty‐three dogs were identified; the most common primary tumour site was the spleen. Dogs that had wide or radical tumour excision had longer survival times compared with dogs that had only marginal tumour excision performed [median survival time of 90 days (range: 0–458 days) versus median survival time of 13 days (range: 0–20 days)]. The use of surgery should be considered in the management of dogs with non‐mammary and non‐thyroidal soft tissue and visceralEOS.
Thermosensitive and Mucoadhesive Pluronic-Hydroxypropylmethylcellulose Hydrogel Containing the Mini-CD4 M48U1 Is a Promising Efficient Barrier against HIV Diffusion through Macaque Cervicovaginal Mucus
Authors: Bouchemal Kawthar , Aka-Any-Grah Armelle , Dereuddre-Bosquet Nathalie , Martin Loïc , Lievin-Le-Moal Vanessa , Le Grand Roger , Nicolas Valérie , Gibellini Davide , Lembo David , Poüs Christian , Koffi Armand , Ponchel Gilles 
Published: February 2015

ABSTRACT

To be efficient, vaginal microbicide hydrogels should form a barrier against viral infections and prevent virus spreading through mucus. Multiple particle tracking was used to quantify the mobility of 170-nm fluorescently labeled COOH-modified polystyrene particles (COOH-PS) into thermosensitive hydrogels composed of amphiphilic triblock copolymers with block compositions EO

n

-PO

m

-EO

n

(where EO refers to ethylene oxide and PO to propylene oxide) containing mucoadhesive hydroxypropylmethylcellulose (HPMC). COOH-PS were used to mimic the size and the surface charge of HIV-1. Analysis of COOH-PS trajectories showed that particle mobility was decreased by Pluronic hydrogels in comparison with cynomolgus macaque cervicovaginal mucus and hydroxyethylcellulose hydrogel (HEC; 1.5% by weight [wt%]) used as negative controls. Formulation of the peptide mini-CD4 M48U1 used as an anti-HIV-1 molecule into a mixture of Pluronic F127 (20 wt%) and HPMC (1 wt%) did not affect its anti-HIV-1 activity in comparison with HEC hydrogel. The 50% inhibitory concentration (IC
50
) was 0.53 μg/ml (0.17 μM) for M48U1-HEC and 0.58 μg/ml (0.19 μM) for M48U1-F127-HPMC. The present work suggests that hydrogels composed of F127-HPMC (20/1 wt%, respectively) can be used to create an efficient barrier against particle diffusion in comparison to conventional HEC hydrogels.
Quercetin Sensitizes Fluconazole-Resistant Candida albicans To Induce Apoptotic Cell Death by Modulating Quorum Sensing
Authors: Singh B. N. , Upreti D. K. , Singh B. R. , Pandey G. , Verma S. , Roy S. , Naqvi A. H. , Rawat A. K. S. 
Published: February 2015

ABSTRACT

Quorum sensing (QS) regulates group behaviors of
Candida albicans
such as biofilm, hyphal growth, and virulence factors. The sesquiterpene alcohol farnesol, a QS molecule produced by
C. albicans
, is known to regulate the expression of virulence weapons of this fungus. Fluconazole (FCZ) is a broad-spectrum antifungal drug that is used for the treatment of
C. albicans
infections. While FCZ can be cytotoxic at high concentrations, our results show that at much lower concentrations, quercetin (QC), a dietary flavonoid isolated from an edible lichen (
Usnea
longissima
), can be implemented as a sensitizing agent for FCZ-resistant
C. albicans
NBC099, enhancing the efficacy of FCZ. QC enhanced FCZ-mediated cell killing of NBC099 and also induced cell death. These experiments indicated that the combined application of both drugs was FCZ dose dependent rather than QC dose dependent. In addition, we found that QC strongly suppressed the production of virulence weapons—biofilm formation, hyphal development, phospholipase, proteinase, esterase, and hemolytic activity. Treatment with QC also increased FCZ-mediated cell death in NBC099 biofilms. Interestingly, we also found that QC enhances the anticandidal activity of FCZ by inducing apoptotic cell death. We have also established that this sensitization is reliant on the farnesol response generated by QC. Molecular docking studies also support this conclusion and suggest that QC can form hydrogen bonds with Gln969, Thr1105, Ser1108, Arg1109, Asn1110, and Gly1061 in the ATP binding pocket of adenylate cyclase. Thus, this QS-mediated combined sensitizer (QC)-anticandidal agent (FCZ) strategy may be a novel way to enhance the efficacy of FCZ-based therapy of
C. albicans
infections.
Autophagy Regulates Colistin-Induced Apoptosis in PC-12 Cells
Authors: Zhang Ling , Zhao Yonghao , Ding Wenjian , Jiang Guozheng , Lu Ziyin , Li Li , Wang Jinli , Li Jian , Li Jichang 
Published: February 2015

ABSTRACT
Colistin is a cyclic cationic polypeptide antibiotic with activity against multidrug-resistant Gram-negative bacteria. Our recent study demonstrated that colistin induces apoptosis in primary chick cortex neurons and PC-12 cells. Although apoptosis and autophagy have different impacts on cell fate, there is a complex interaction between them. Autophagy plays an important role as a homeostasis regulator by removing excessive or unnecessary proteins and damaged organelles. The aim of the present study was to investigate the modulation of autophagy and apoptosis regulation in PC-12 cells in response to colistin treatment. PC-12 cells were exposed to colistin (125 to 250 μg/ml), and autophagy was detected by visualization of monodansylcadaverine (MDC)-labeled vacuoles, LC3 (microtubule-associated protein 1 light chain 3) immunofluorescence microscopic examination, and Western blotting. Apoptosis was measured by flow cytometry, Hoechst 33258 staining, and Western blotting. Autophagosomes were observed after treatment with colistin for 12 h, and the levels of LC3-II gene expression were determined; observation and protein levels both indicated that colistin induced a high level of autophagy. Colistin treatment also led to apoptosis in PC-12 cells, and the level of caspase-3 expression increased over the 24-h period. Pretreatment of cells with 3-methyladenine (3-MA) increased colistin toxicity in PC-12 cells remarkably. However, rapamycin treatment significantly increased the expression levels of LC3-II and beclin 1 and decreased the rate of apoptosis of PC-12 cells. Our results demonstrate that colistin induced autophagy and apoptosis in PC-12 cells and that the latter was affected by the regulation of autophagy. It is very likely that autophagy plays a protective role in the reduction of colistin-induced cytotoxicity in neurons.
The Mycobacterium tuberculosis Outer Membrane Channel Protein CpnT Confers Susceptibility to Toxic Molecules
Authors: Danilchanka Olga , Pires David , Anes Elsa , Niederweis Michael 
Published: February 2015

ABSTRACT

Mycobacterium tuberculosis
, the causative agent of tuberculosis, is protected from toxic solutes by an effective outer membrane permeability barrier. Recently, we showed that the outer membrane channel protein CpnT is required for efficient nutrient uptake by
M. tuberculosis
and
Mycobacterium bovis
BCG. In this study, we found that the
cpnT
mutant of
M. bovis
BCG is more resistant than the wild type to a large number of drugs and antibiotics, including rifampin, ethambutol, clarithromycin, tetracycline, and ampicillin, by 8- to 32-fold. Furthermore, the
cpnT
mutant of
M. bovis
BCG was 100-fold more resistant to nitric oxide, a major bactericidal agent required to control
M. tuberculosis
infections in mice. Thus, CpnT constitutes the first outer membrane susceptibility factor in slow-growing mycobacteria. The dual functions of CpnT in uptake of nutrients and mediating susceptibility to toxic molecules are reflected in macrophage infection experiments: while loss of CpnT was detrimental for
M. bovis
BCG in macrophages that enable bacterial replication, presumably due to inadequate nutrient uptake, it conferred a survival advantage in macrophages that mount a strong bactericidal response. Importantly, the
cpnT
gene showed a significantly higher density of nonsynonymous mutations in drug-resistant clinical
M. tuberculosis
strains, indicating that CpnT is under selective pressure in human tuberculosis and/or during chemotherapy. Our results indicate that the CpnT channel constitutes an outer membrane gateway controlling the influx of nutrients and toxic molecules into slow-growing mycobacteria. This study revealed that reducing protein-mediated outer membrane permeability might constitute a new drug resistance mechanism in slow-growing mycobacteria.
Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations
Authors: Berg Maya , García-Hernández Raquel , Cuypers Bart , Vanaerschot Manu , Manzano José I. , Poveda José A. , Ferragut José A. , Castanys Santiago , Dujardin Jean-Claude , Gamarro Francisco 
Published: February 2015

ABSTRACT

Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL).
In vitro
,
Leishmania donovani
promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.
Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii
Authors: Yadav Rajbharan , Landersdorfer Cornelia B. , Nation Roger L. , Boyce John D. , Bulitta Jürgen B. 
Published: February 2015

ABSTRACT

Acinetobacter baumannii
is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize β-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant
A. baumannii
. We studied combinations of 10 β-lactams and three aminoglycosides against four
A. baumannii
strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of
A. baumannii
using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (≤2.3 log
10
) of
A. baumannii
ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other β-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/liter combined with an aminoglycoside yielded synergistic killing (>5 log
10
) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant
A. baumannii
(MIC, 32 mg/liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log
10
killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.