bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia
Authors: Kennedy Glen A. , Morris Kirk L. , Subramonpillai Elango , Curley Cameron , Butler Jason , Durrant Simon 
Published: April 2013

SummaryThis prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre‐, mid‐ and post‐ each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19–130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment‐related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.
The effect of hydroxcarbamide therapy on survival of children with sickle cell disease
Authors: Lopes de Castro Lobo Clarisse , Pinto Jorge F. C. , Nascimento Emilia M. , Moura Patricia G. , Cardoso Gilberto P. , Hankins Jane S. 
Published: April 2013

SummaryAlthough evidence is accumulating that hydroxycarbamide decreases mortality among adults with sickle cell disease (SCD), there are no published data regarding the effect of hydroxycarbamide on mortality among children. The Paediatric Hydroxycarbamide Program was established to treat children with SCD aged 3–18 years if they met disease severity criteria. Mortality data and clinical/laboratorial effects of hydroxycarbamide were retrospectively collected for the first 9 years of the Program. Mortality among those who received hydroxycarbamide was compared to that of untreated children. Among 1760 subjects, 267 received hydroxycarbamide at a median dose of 20·8 mg/kg/d (range 10–32) for a median of 2 years (range 0·1–6·5). Survival among hydroxycarbamide‐treated children was significantly greater than that among untreated ones (99·5% vs. 94·5%, P = 0·01), due primarily to fewer deaths from acute chest syndrome and infection. Hydroxycarbamide therapy was significantly associated with increases in haemoglobin concentration, fetal haemoglobin, mean corpuscular volume, and reduction in platelet counts, reticulocytes and neutrophils. Toxicity was minimal and predominantly mild reversible neutropenia. Significantly fewer hospitalizations and emergency room visits, and shorter admissions were observed among hydroxycarbamide‐treated subjects, when compared to the 12‐month period prior to treatment initiation. Hydroxycarbamide therapy reduces disease severity and is probably associated with decreased mortality among children with SCD.
Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease
Authors: Wang Hui , Luo Wei , Wang Jintao , Guo Chiao , Wolffe Stephanie L. , Wang Julia , Sun Eddy B. , Bradley Kori N. , Campbell Andrew D. , Eitzman Daniel T. 
Published: April 2013

SummarySickle cell disease (SCD) is associated with vascular complications including premature stroke. The role of atherothrombosis in these vascular complications is unclear. To determine the effect of SCD on atherosclerosis and thrombosis, mice with SCD along with controls were generated by transplantation of bone marrow from mice carrying the homozygous sickle cell mutation (Hbbhβs/hβs) or wild‐type mice (Hbb+/+) into C57BL6/J or apolipoprotein E deficient (Apoe−/−) recipient mice. At the time of sacrifice, 23–28 weeks following bone marrow transplantation, anaemia, reticulocytosis, and splenomegaly were present in mice receiving Hbbhβs/hβs bone marrow compared with control mice. Analysis of atherosclerosis involving the aortic root revealed reduced atherosclerotic lesion area with reduced macrophage content and increased collagen content in Apoe−/−, Hbbhβs/hβs mice compared to Apoe−/−, Hbb+/+ mice. In a carotid thrombosis model, the time to thrombosis was prolonged in Hbbhβs/hβs mice compared to Hbb+/+ mice. This apparent protective effect of SCD on atherosclerosis and thrombosis was diminished by inhibition of heme oxygenase‐1 (HMOX1) using zinc protoporphyrin IX.We conclude that SCD in mice is paradoxically protective against atherosclerosis and thrombosis, highlighting the complexity of vascular events in SCD. This protective effect is at least partially mediated by induction of HMOX1.
Influence of the hippocampus on amino acid utilizing and cholinergic neurons within the nucleus accumbens is promoted by histamine viaH1receptors
Authors: Kraus M M , Prast H , Philippu A 
Published: April 2013

Background and PurposeThe influence of the neurotransmitter histamine on spontaneous and stimulation‐evoked release of glutamate, aspartate,GABAandAChin the nucleus accumbens (NAc) was investigatedin vivo.Experimental ApproachUsing the push–pull superfusion technique, histaminergic compounds were applied to theNAcand neurotransmitter release was assessed. In some experiments, the fornix/fimbria of the hippocampus was electrically stimulated by a microelectrode and evoked potentials were monitored in theNAc.Key ResultsSuperfusion of theNAcwith theH1receptor antagonist triprolidine (50 μM) decreased spontaneous outflow of glutamate, aspartate andACh, while release ofGABAremained unaffected. Superfusion with histamine elevated release ofACh, without influencing that of the amino acids. Electrical stimulation of the fornix/fimbria enhanced the output of amino acids andAChwithin theNAc. The evoked outflow of glutamate andAChwas diminished on superfusion with triprolidine, while release of aspartate andGABAwas not affected. Superfusion of theNAcwith histamine intensified the stimulation‐evoked release of glutamate andAch. Histamine also elevated the stimulation‐induced release of aspartate, without influencing that ofGABA. Presuperfusion with triprolidine abolished the reinforced effect of histamine on stimulation‐evoked transmitter release within theNAc.Conclusion and ImplicationsNeuronal histamine activatesH1receptors and increases spontaneous release of glutamate, aspartate andAChwithin theNAc. Stimulation of the hippocampal fornix/fimbria tract also enhances release of glutamate andAChwithin theNAcand this effect is intensified byH1receptor stimulation within theNAc. The latter effects, which are mediated by hippocampal afferences, might play an important role in mnemonic performance and in emotional processes such as anxiety and stress disorders.Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visithttp://dx.doi.org/ 10.1111/bph.2013.170.issue‐1
5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor
Authors: Newman Amy S , Batis Nikolaos , Grafton Gillian , Caputo Francesca , Brady Catherine A , Lambert Jeremy J , Peters John A , Gordon John , Brain Keith L , Powell Andrew D , Barnes Nicholas M 
Published: April 2013

Background and PurposeThe 5‐HT3 receptor is a ligand‐gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non‐selective effects at pharmacologically active concentrations. The present study identifies 5‐chloroindole (Cl‐indole) as a potent PAM of the 5‐HT3 receptor.Experimental Approach5‐HT3 receptor function was assessed by the increase in intracellular calcium and single‐cell electrophysiological recordings in HEK293 cells stably expressing the h5‐HT3A receptor and also the mouse native 5‐HT3 receptor that increases neuronal contraction of bladder smooth muscle.Key ResultsCl‐indole (1–100 μM) potentiated agonist (5‐HT) and particularly partial agonist [(S)‐zacopride, DDP733, RR210, quipazine, dopamine, 2‐methyl‐5‐HT, SR57227A, meta chlorophenyl biguanide] induced h5‐HT3A receptor‐mediated responses. This effect of Cl‐indole was also apparent at the mouse native 5‐HT3 receptor. Radioligand‐binding studies identified that Cl‐indole induced a small (∼twofold) increase in the apparent affinity of 5‐HT for the h5‐HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl‐indole was able to reactivate desensitized 5‐HT3 receptors. In contrast to its effect on the 5‐HT3 receptor, Cl‐indole did not alter human nicotinic α7 receptor responses.Conclusions and ImplicationsThe present study identifies Cl‐indole as a relatively potent and selective PAM of the 5‐HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5‐HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.Linked ArticlesRecent reviews on allosteric modulation can be found at:Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476‐5381.2012.02223.xRoche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231
Role of theKCa3.1 K+channel in auricular lymph nodeCD4+T‐lymphocyte function of the delayed‐type hypersensitivity model
Authors: Ohya Susumu , Nakamura Erina , Horiba Sayuri , Kito Hiroaki , Matsui Miki , Yamamura Hisao , Imaizumi Yuji 
Published: April 2013

Background and PurposeThe intermediate‐conductanceCa2+‐activatedK+channel (KCa3.1) modulates theCa2+response through the control of the membrane potential in the immune system. We investigated the role ofKCa3.1 on the pathogenesis of delayed‐type hypersensitivity (DTH) in auricular lymph node (ALN)CD4+T‐lymphocytes of oxazolone (Ox)‐inducedDTHmodel mice.Experimental ApproachThe expression patterns ofKCa3.1 and its possible transcriptional regulators were compared amongALN T‐lymphocytes of three groups [non‐sensitized (Ox–/–),Ox‐sensitized, but non‐challenged (Ox+/–) and Ox‐sensitized and ‐challenged (Ox+/+)] using real‐time polymerase chain reaction, Western blotting and flow cytometry.KCa3.1 activity was measured by whole‐cell patch clamp and the voltage‐sensitive dye imaging. The effects ofKCa3.1 blockade were examined by the administration of selectiveKCa3.1 blockers.Key ResultsSignificant up‐regulation ofKCa3.1a was observed inCD4+T‐lymphocytes ofOx+/– andOx+/+, without any evident changes in the expression of the dominant‐negative form,KCa3.1b. Negatively correlated with this, the repressor element‐1 silencing transcription factor (REST) was significantly down‐regulated. Pharmacological blockade ofKCa3.1 resulted in an accumulation of theCD4+T‐lymphocytes ofOx+/+ at theG0/G1phase of the cell cycle, and also significantly recovered not only the pathogenesis ofDTH, but also the changes in theKCa3.1 expression and activity in theCD4+T‐lymphocytes ofOx+/– andOx+/+.Conclusions and ImplicationsThe up‐regulation ofKCa3.1a in conjunction with the down‐regulation ofRESTmay be involved inCD4+T‐lymphocyte proliferation in theALNsofDTHmodel mice; andKCa3.1 may be an important target for therapeutic intervention in allergy diseases such asDTH.
The single C‐terminal helix of human phospholipid scramblase 1 is required for membrane insertion and scrambling activity
Authors: Francis Vincent G. , Mohammed Abdul M. , Aradhyam Gopala K. , Gummadi Sathyanarayana N. 
Published: April 2013

Human phospholipid scramblase 1 (hPLSCR1) belongs to the ATP‐independent class of phospholipid translocators which possess a single EF‐hand‐like Ca2+‐binding motif and also a C‐terminal helix (CTH). The CTH domain of hPLSCR1 was believed to be a putative single transmembrane helix at the C‐terminus. Recent homology modeling studies by Bateman et al. predicted that the hydrophobic nature of this helix is due to its packing in the core of the protein domain and proposed that this is not a true transmembrane helix [Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A & Johannes S. Bioinformatics 2008, 25, 159]. To determine the exact function of the CTH of hPLSCR1, we deleted the CTH domain and determined: (a) whether CTH plays any role beyond membrane anchorage, (b) the functional consequences of CTH deletion, and (c) any conformational changes associated with CTH in a lipid environment. In vitro reconstitution studies confirm that the predicted CTH is required for membrane insertion and scrambling activity. CTH deletion caused a 50% decrease in binding affinity of Ca2+ for ∆CTH‐hPLSCR1 (Ka = 115 μm) compared with hPLSCR1 (Ka = 249 μm). Far UV‐CD studies revealed that the CTH peptide adopts α‐helicity only in the presence of SDS micelles and negatively charged vesicles, indicating that electrostatic interactions are required for insertion of the peptide. CTH peptide‐quenching studies confirm that the predicted CTH inserts into the membrane and its ability to interact with the membrane depends on the presence of charge interactions. TOXCAT assay revealed that CTH of hPLSCR1 does not oligomerize in the membrane. We conclude that CTH is required for membrane insertion and Ca2+ coordination and also plays an important role in the functional conformation of hPLSCR1.
Childhood and Adolescent Migraine Prevention (CHAMP) Study: A Double‐Blinded, Placebo‐Controlled, Comparative Effectiveness Study of Amitriptyline, Topiramate, and Placebo in the Prevention of Childhood and Adolescent Migraine
Authors: Hershey Andrew D. , Powers Scott W. , Coffey Christopher S. , Eklund Dixie D. , Chamberlin Leigh Ann , Korbee Leslie L. ,   CHAMP Study Group
Published: April 2013

BackgroundMigraine is one of the most common health problems for children and adolescents. If not successfully treated, it can impact patients and families with significant disability due to loss of school, work, and social function. When headaches become frequent, it is essential to try to prevent the headaches. For children and adolescents, this is guided by extrapolation from adult studies, a limited number of small studies in children and adolescents and practitioner preference. The aim of the Childhood and Adolescent Migraine Prevention (CHAMP) study is to determine the most effective preventive agent to use in children and adolescents.MethodsCHAMP is a double‐blinded, placebo‐controlled, multicenter, comparative effectiveness study of amitriptyline and topiramate for the prevention of episodic and chronic migraine, designed to mirror real‐world practice, sponsored by the US National Institute of Neurological Disorders and Stroke/National Institutes of Health (U01NS076788). The study will recruit 675 subjects between the ages of 8 and 17 years old, inclusive, who have migraine with or without aura or chronic migraine as defined by the International Classification of Headache Disorders, 2nd Edition, with at least 4 headaches in the 28 days prior to randomization. The subjects will be randomized in a 2:2:1 (amitriptyline: topiramate: placebo) ratio. Doses are weight based and will be slowly titrated over an 8‐week period to a target dose of 1 mg/kg of amitriptyline and 2 mg/kg of topiramate. The primary outcome will be a 50% reduction in headache frequency between the 28‐day baseline and the final 28 days of treatment (weeks 20‐24).ConclusionsThe goal of the CHAMP study is to obtain level 1 evidence for the effectiveness of amitriptyline and topiramate in the prevention of migraine in children and adolescents. If this study proves to be positive, it will provide information to the practicing physician as how to best prevent migraine in children and adolescents and subsequently improve the disability and outcomes.
An analysis of benefits and risk information on pharmaceutical web sites for the treatment of menopause
Authors: Charbonneau Deborah H. 
Published: April 2013

AbstractBackgroundAs the Internet is a source of information for many health consumers, there is a need to evaluate the information about prescription drugs provided on pharmaceutical manufacturers' web sites.ObjectivesUsing a sample of pharmaceutical manufacturers' web sites for the treatment of menopause, the main objective of this study was to evaluate consumer‐oriented information about benefits and risks of prescription drugs for the treatment of menopause provided on pharmaceutical web sites.MethodsPharmaceutical manufacturers' web sites for analysis were identified using a list of U.S. FDA‐approved hormone therapies for the treatment of menopause.ResultsThis study revealed substantial gaps in how benefits and risk information were presented on the web sites. Specifically, information about the benefits was prominent while risk information was incomplete and challenging to find. Further, references to the scientific literature to support claims advertised about prescription drug benefits were not provided.ConclusionsGiven the lack of scientific evidence to support claims of benefits and limited disclosure about risks, more information is needed for consumers to be able to weigh the benefits and risks of these treatments for menopause. Overall, these findings provide guidance for evaluating drug information provided on pharmaceutical web sites.
Integrating information literacy in health sciences curricula: a case study from Québec
Authors: Clairoux Natalie , Desbiens Sylvie , Clar Monique , Dupont Patrice , St‐Jean Monique 
Published: April 2013

AbstractObjectiveTo portray an information literacy programme demonstrating a high level of integration in health sciences curricula and a teaching orientation aiming towards the development of lifelong learning skills. The setting is a French‐speaking North American university.MethodsThe offering includes standard workshops such asMEDLINEsearching and specialised sessions such as pharmaceutical patents searching. A contribution to an international teaching collaboration in Haiti where workshops had to be thoroughly adapted to the clientele is also presented. Online guides addressing information literacy topics complement the programme.Results and evaluationA small team of librarians and technicians taught 276 hours of library instruction (LI) during the 2011–2012 academic year. Methods used for evaluating information skills include scoring features of literature searches and user satisfaction surveys.DiscussionPrivileged contacts between librarians and faculty resulting from embedded LI as well as from active participation in library committees result in a growing reputation of library services across academic departments and bring forth collaboration opportunities. Sustainability and evolution of the LI programme is warranted by frequent communication with partners in the clinical field, active involvement in academic networks and health library associations, and reflective professional strategies.
Influence of several root canal disinfection methods on pushout bond strength of self‐etch post and core systems
Authors: Katalinić I. , Glockner K. , Anić I. 
Published: April 2013

AbstractAimTo determine the effect of four root canal disinfection protocols (2.5% sodium hypochlorite, 0.2% chlorhexidine gluconate, gaseous ozone and Nd : YAG laser) on the pushout bond strength of a self‐etch post and core system.MethodologySixty anterior single‐rooted permanent human teeth were used. Root canals were instrumented with ProTaper instruments (Dentsply Maillefer; Ballaigues, Switzerland). Roots were divided into four groups (n = 15 each) according to the final disinfection protocol: sodium hypochlorite, chlorhexidine gluconate, gaseous ozone and Nd:YAG laser. Fibre‐reinforced composite post preparations were created in previously filled root canals, and posts cemented according to the manufacturer's instructions. Roots were then uniformly sectioned and prepared for the pushout bond strength testing in a universal testing machine. One‐way anova with post hoc Scheffe test was used for statistical analysis. SEM imaging of one sample from each group was made.ResultsThe only significant difference (P = 0.004) was observed between sodium hypochlorite irrigation, which was associated with the lowest bond strength, and Nd:YAG laser irradiation, which provided the highest bond strength. There was no difference between root canal pre‐treatment with sodium hypochlorite, gaseous ozone and chlorhexidine, nor between gaseous ozone, chlorhexidine and Nd : YAG laser.ConclusionSodium hypochlorite irrigation was associated with the lowest bond strength values and Nd : YAG laser irradiation with the highest bond strength values for a self‐etch post and core system bonded to root canal dentine.
Novel anticoagulants and laboratory testing
Authors: Eby C. 
Published: April 2013

SummaryThe introduction of several oral direct anticoagulants within the past 2–3 years has dramatically changed clinical practice and has also impacted on utilization and interpretation of coagulation laboratory testing. This article reviews the effects of the oral thrombin inhibitor, dabigatran, and the oral factor Xa inhibitors, rivaroxaban and apixaban, on screening and diagnostic coagulation tests, and describes methods for measuring the their anticoagulant activity in plasma. Currently, there are evidence gaps regarding the role of laboratory testing for surveillance and management of adverse events associated with these new anticoagulants which do not require routine therapeutic drug monitoring. This is a rapidly changing field, and coagulation laboratory experts have a major role in ensuring patients receive appropriate testing and accurate interpretations of results.
Bone marrow evaluation for pediatric patients
Authors: Proytcheva M. 
Published: April 2013

SummaryDue to the immaturity of the hematopoietic system at birth and different oxygenation and immune response needs of the growing organism, the bone marrow composition at birth and early infancy differs as compared to older children and adults. These age‐related differences, while generally recognized, are not well known to the world of hematopathology. The purpose of this article is to address the current limitation of the literature by reviewing the bone marrow ontology, its composition at birth, and the changes occurring during early infancy, and to compare these findings to adults. The review also provides a useful framework for bone marrow examination in children.