bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single amino acid substitution in the R3 domain of GLABRA1 leads to inhibition of trichome formation in Arabidopsis without affecting its interaction with GLABRA3
Authors: Dai Xuemei , Zhou Limei , Zhang Wei , Cai Ling , Guo Hongyan , Tian Hainan , Schiefelbein John , Wang Shucai 
Published: December 2015

AbstractGLABRA1 (GL1) is an R2R3 MYB transcription factor that regulates trichome formation in Arabidopsis by interacting with the bHLH transcription factor GLABRA3 (GL3) or ENHANCER OF GL3 (EGL3). The conserved [D/E]L×2 [R/K]×3L×6L×3R amino acid signature in the R3 domain of MYB proteins has been shown to be required for the interaction of MYBs with R/B‐like bHLH transcription factors. By using genetic and molecular analyses, we show that the glabrous phenotype in the nph4‐1 mutant is caused by a single nucleotide mutation in the GL1 gene, generating a Ser to Phe substitution (S92F) in the conserved [D/E]L×2[R/K]×3L×6L×3R amino acid signature of GL1. Activation of the integrated GL2p:GUS reporter gene in protoplasts by cotransfection of GL1 and GL3 or EGL3 was abolished by this GL1‐S92F substitution. However, GL1‐S92F interacted successfully with GL3 or EGL3 in protoplast transfection assays. Unlike VPGL1GL3, the fusion protein VPGL1‐S92FGL3 failed to activate the integrated GL2p:GUS reporter gene in transfected protoplasts. These results suggested that the S92 in the conserved [D/E]L×2 [R/K]×3L×6L×3R amino acid signature of GL1 is not essential for the interaction of GL1 and GL3, but may play a role in the binding of GL1 to the promoters of its target genes.
Energy expenditure and growth failure after intestinal transplantation: A case report
Authors: Matthé Stefanie , Pirenne Jacques , Knops Noël 
Published: December 2015

AbstractWe present a 12‐yr‐old boy who received a combined liver–pancreas small bowel transplantation at the age of two. The post‐operative period was complicated by wound closure problems resulting in a large asymptomatic abdominal wall defect. Further follow‐up was uneventful, with the exception of new onset growth failure not explained by extensive routine investigations. An indirect calorimetry was performed. The resting energy expenditure (REE) was significantly increased (126% of predicted), demanding a daily caloric intake of 123 kcal/kg body weight (normal for age: 80 kcal/kg). In the absence of classic reasons for increased REE, a thermal camera revealed increased dermal heat loss at the abdominal wall defect (estimated surplus in energy loss of at least 29 kcal/day: 10.4% of the elevated REE). In addition, we found lower total lung capacity due to impaired abdominal breathing. In the exploration of growth failure in children after (ITx), increased REE must be taken into account. Indirect calorimetry can serve as a valuable diagnostic tool for evaluating individual energy requirements and nutritional support. In this child, exaggerated heat loss through an aberrant abdominal wall could be a potential important contributor to the patient's increased energy requirements.
Dem Measurements of A Gravel‐Bed Surface Using Two Scales of Images
Authors: Wang Chi‐Kuei , Chung Jui‐Teng , Lin Yu‐Li 
Published: December 2015

AbstractDetermining the geometry of an exposed gravel‐bed surface is important in understanding river flow characteristics. This study presents a method of generating a digital elevation model (DEM) of exposed gravel‐bed surfaces using two different scales of images of a riverine environment. The small scale DEM covers an area of 4·5 m × 4·5 m and serves as the reference base, whereas several large scale DEMs provide highly detailed elevation information along the site diagonals. The equipment includes a consumer‐grade camera and is light and easy to set up in the field. Highly automated procedures using several off‐the‐shelf packages ease the burden of generating DEMs of the gravel‐bed surface, reducing the technological obstacles for other disciplines. This study evaluates the accuracy of the proposed method at three study sites with different grain sizes along the Hou‐Jue River in southern Taiwan. The elevation accuracy obtained by the proposed method was validated by a total station and achieved a root mean square error of 2·9 to 4·3 mm.
Emergence of OXA-162 Carbapenemase- and DHA-1 AmpC Cephalosporinase-Producing Sequence Type 11 Klebsiella pneumoniae Causing Community-Onset Infection in Greece
Authors: Voulgari Evangelia , Poulou Aggeliki , Dimitroulia Evangelia , Politi Lida , Ranellou Kyriaki , Gennimata Vassiliki , Markou Fani , Pournaras Spyros , Tsakris Athanassios 
Published: December 2015

ABSTRACT

OXA-48-like carbapenemases have only recently emerged in Europe. OXA-162 is a rare OXA-48 variant usually coexpressed with extended-spectrum β-lactamases. Here, we report the identification of the first OXA-162 carbapenemase-producing
Klebsiella pneumoniae
isolates, which coexpressed an AmpC cephalosporinase (DHA-1), retrieved from a patient in Greece. They belonged to a single sequence type (ST11) and caused the first documented community-onset urinary tract infections attributable to an OXA-48-like-producing
Enterobacteriaceae
strain.
Artemether-Lumefantrine Pharmacokinetics and Clinical Response Are Minimally Altered in Pregnant Ugandan Women Treated for Uncomplicated Falciparum Malaria
Authors: Nyunt Myaing M. , Nguyen Vy K. , Kajubi Richard , Huang Liusheng , Ssebuliba Joshua , Kiconco Sylvia , Mwima Moses W. , Achan Jane , Aweeka Francesca , Parikh Sunil , Mwebaza Norah 
Published: December 2015

ABSTRACT

Artemether-lumefantrine is a first-line regimen for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy. Previous studies have reported changes in the pharmacokinetics and clinical outcomes following treatment with artemether-lumefantrine in pregnant women compared to nonpregnant adults; however, the results are inconclusive. We conducted a study in rural Uganda to compare the pharmacokinetics of artemether-lumefantrine and the treatment responses between 30 pregnant women and 30 nonpregnant adults with uncomplicated
Plasmodium falciparum
malaria. All participants were uninfected with HIV, treated with a six-dose regimen of artemether-lumefantrine, and monitored clinically for 42 days. The pharmacokinetics of artemether, its metabolite dihydroartemisinin, and lumefantrine were evaluated for 21 days following treatment. We found no significant differences in the overall pharmacokinetics of artemether, dihydroartemisinin, or lumefantrine in a direct comparison of pregnant women to nonpregnant adults, except for a statistically significant but small difference in the terminal elimination half-lives of both dihydroartemisinin and lumefantrine. There were seven PCR-confirmed reinfections (5 pregnant and 2 nonpregnant participants). The observation of a shorter terminal half-life for lumefantrine may have contributed to a higher frequency of reinfection or a shorter posttreatment prophylactic period in pregnant women than in nonpregnant adults. While the comparable overall pharmacokinetic exposure is reassuring, studies are needed to further optimize antimalarial efficacy in pregnant women, particularly in high-transmission settings and because of emerging drug resistance. (This study is registered at ClinicalTrials.gov under registration no. NCT01717885.)
Virulence Genes in Expanded-Spectrum-Cephalosporin-Resistant and -Susceptible Escherichia coli Isolates from Treated and Untreated Chickens
Authors: Baron S. , Delannoy S. , Bougeard S. , Larvor E. , Jouy E. , Balan O. , Fach P. , Kempf I. 
Published: December 2015

ABSTRACT

This study investigated antimicrobial resistance, screened for the presence of virulence genes involved in intestinal infections, and determined phylogenetic groups of
Escherichia coli
isolates from untreated poultry and poultry treated with ceftiofur, an expanded-spectrum cephalosporin. Results show that none of the 76 isolates appeared to be Shiga toxin-producing
E. coli
or enteropathogenic
E. coli
. All isolates were negative for the major virulence factors/toxins tested (
ehxA
,
cdt
, heat-stable enterotoxin [ST], and heat-labile enterotoxin [LT]). The few virulence genes harbored in isolates generally did not correlate with isolate antimicrobial resistance or treatment status. However, some of the virulence genes were significantly associated with certain phylogenetic groups.
Risk Factors and Outcomes for Intestinal Carriage of AmpC-Hyperproducing Enterobacteriaceae in Intensive Care Unit Patients
Authors: Poignant Simon , Guinard Jérôme , Guigon Aurélie , Bret Laurent , Poisson Didier-Marc , Boulain Thierry , Barbier François 
Published: December 2015

ABSTRACT

In a cohort of 1,209 intensive care unit (ICU) patients, the prevalence of intestinal colonization with high-level expressed AmpC cephalosporinase-producing
Enterobacteriaceae
(HLAC-PE) rose steadily from 2% at admission to 30% in patients with lengths of stay (LOS) exceeding 4 weeks. In multivariate analysis, LOS was the main predictor of carriage acquisition after adjustment on antimicrobial exposure. HLAC-PE infection occurred in 15% of carriers. Carriage and infection were associated with a marked increase in carbapenem consumption.
Antimicrobial Susceptibilities of Abiotrophia defectiva, Granulicatella adiacens, and Granulicatella elegans
Authors: Alberti Michael O. , Hindler Janet A. , Humphries Romney M. 
Published: December 2015

ABSTRACT

Nutritionally variant streptococci (NVS) are fastidious Gram-positive cocci comprised of the species
Abiotrophia defectiva
,
Granulicatella adiacens
, and
Granulicatella elegans
. NVS are an important cause of bacteremia and infective endocarditis (IE) associated with significant morbidity and mortality. Antimicrobial susceptibility testing (AST) was performed for 14 antimicrobials using the broth microdilution MIC method described in the Clinical and Laboratory Standards Institute (CLSI) M45 guideline. A total of 132 clinical NVS blood isolates collected from 2008 to 2014 were tested. Species level identification of NVS isolates was achieved by 16S rRNA gene sequencing and/or matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Ninety isolates were identified as
G. adiacens
, 37 as
A. defectiva
, and 5 as
G. elegans
. All isolates were susceptible to vancomycin (MIC
90
= 1 μg/ml), and none displayed high-level resistance to aminoglycosides.
G. adiacens
was considerably more susceptible to penicillin than
A. defectiva
(38.9% versus 10.8% of isolates susceptible) but was less susceptible to cephalosporins than was
A. defectiva
(43.3% versus 100% of isolates susceptible to ceftriaxone). Several isolates were resistant to levofloxacin (6%), erythromycin (51%), and clindamycin (10%). The MIC
90
for daptomycin was ≥4 μg/ml for
G. adiacens
and
A. defectiva
.
G. elegans
isolates were 100% susceptible to all antimicrobials tested, with the exception of erythromycin, to which only 20% were susceptible. This study provides antimicrobial susceptibility data for a recent collection of NVS and demonstrates important NVS species-related differences with respect to susceptibility to penicillin, cephalosporins, carbapenems, and daptomycin. Species-level identification of NVS organisms when susceptibility testing is not readily available may aid in treatment decisions.
AVAILABILITY OF PEDIATRIC FORMULATIONS FOR THE 100 MOST PRESCRIBED DRUGS IN PEDIATRIC AMBULATORY CARE – 2002 VS. 2010
Authors: Ziesenitz Victoria C. , Anker Johannes N. van den , Amirshahi Maryann 
Published: December 2015

IntroductionUS legislative efforts over the past two decades have attempted to promote therapeutic equity for the pediatric population. The objective of this study was to explore trends in the availability of pediatric formulations for the most commonly prescribed drugs in US pediatric ambulatory care.MethodsA retrospective review of the CDC's National Ambulatory Care Survey (NAMCS) from 2002–10 was performed focusing on visits involving children<6 years. The top 100 medications prescribed for which an oral dosage form was available were identified. The availability of a pediatric specific formulation was determined from FDA labeling data. Trends were compared between 2002 and 2010.ResultsIn total, 94,152,217 prescriptions in 2002 and 2010 were analyzed. The most often prescribed drugs were anti-infectives (52.8 vs. 41.6%), respiratory agents (19.2 vs. 21.7%) and antipyretics/ analgesics (14.6 vs. 21.1%). In 2002, a pediatric formulation was available for 94.4% of prescriptions in comparison 95.5% in 2010 (p<0.05). Pediatric formulations were more commonly available for anti-infectives (95.3 vs. 95.9%), antipyretics/ analgesics (99.8 vs. 99.4%) as well as for respiratory (99.5 vs. 98.7%), endocrinologic (80.2 vs. 95.7%), and gastrointestinal (92.6 vs. 97.9%) agents, whereas pediatric formulations were lacking for cardiovascular (68.0 vs. 52.1%), neurologic (46.6 vs. 55.2%) and psychotherapeutic drugs (76.3 vs. 66.1%, all p<0.05).ConclusionSince the US Best Pharmaceuticals for Children Act 2002, more pediatric specific formulations have become available. Anti-infective agents, respiratory agents and antipyretics/analgesics have been the most commonly prescribed drugs in children <6 years.
A SYSTEMS PHARMACOLOGY MODEL TO EXPLAIN DEVELOPMENTAL DIFFERENCES IN SENSITIVITY TO DRUG-INDUCED QT PROLONGATION
Authors: Gotta Verena , Pfister Marc , Anker John van den , Graaf Piet van der 
Published: December 2015

BackgroundNeonates have been reported to be more sensitive to drugs prolonging the QT-interval than adults. As explanation a developmental change in myocardial ion-channel density has been proposed. Here we explore changes in ion-channel density using a mechanistic pharmacodynamic model and clinical sotalol literature data.Materials and MethodsThe applied model relates in vitro and in vivo drug potency (regarding IKr-receptor occupancy and QTc-prolongation, respectively) by a system-specific transducer function. We characterized this function first for preclinical dog and in vitro data (moxifloxacin, sotalol, dofetilide). From a corresponding dofetilide model in adults we derived scaling factors for the system-specific parameters (maximal in vivo QTc-effect Em,dog/Em,adults, transducer ratio τ,dog/τ,adults; τ is proportional to the receptor density in vivo). The derived relationship was used to predict clinical sotalol pharmacodynamics in adults. Literature data was used to evaluate this scaling approach. Simulations of different τ values were performed to explore pharmacodynamic differences in neonates.ResultsIn adults, the agonistic activity of dofetilide was higher than in dogs (τ,adults≈2x τ,dogs), while the estimated maximal in vivo QTc-prolongation was similar (Em≈27% from baseline). This relationship could also predict clinical sotalol pharmacodynamics in adults and children. The steeper PD profile in neonates could be explained by a higher IKr-receptor density (τ, neonates≈2x τ, adults).ConclusionThis model-based approach allowed to integrate and scale in vitro and in vivo (preclinical, clinical adult and neonate) drug effects on the QTc-interval. The preliminary results confirm the hypothesis that IKr-receptor density is higher (≈2 times) in neonates than in adults and children.
INNOVATIVE REGULATORY-CONFORMING BIOANALYTICAL APPROACHES ENABLING SYSTEMATIC INVESTIGATIONS OF PHARMACOKINETICS AND PHARMACODYNAMICS BY PAEDIATRIC CLINICAL STUDIES IN ALL AGE GROUPS
Authors: Burckhardt Björn B , Tins Jutta , Läer Stephanie 
Published: December 2015

BackgroundClinical investigations on pharmacokinetics and pharmacodynamics are highly required to improve paediatric pharmacotherapy. Especially in neonates and infants the conduct is challenging due to e.g. high ethical and analytical burdens. The trial-related blood lost should not exceed 3% of the total blood volume within 4 weeks (1). Appropriate assays are lacking which leads to the fact that many drugs are not sufficiently investigated in small children.ObjectiveDevelopment of a tailored comprehensive bioanalytical setting for pharmacokinetic and pharmacodynamic investigations of drugs acting on the RAA system in neonates up to adolescents.MethodsBioanalytical HPLC-MS/MS methods for invasive and non-invasive determination of pharmacokinetics of aliskiren and enalapril in 50–100 µL serum, urine, and saliva were developed. Changes of humoral parameters of the RAA system were measured by five immunological assays in a total volume of 2.1 mL. All assays were scaled up to a high throughput approaches to meeting clinical demands. The applicability of the low-volume assays was assessed by a proof-of-concept study in 22 healthy volunteers and a regulatory-compliant Phase I study.ResultsThe conducted studies using the low-volume assays revealed comparable pharmacokinetic results of aliskiren and enalapril in serum and urine when compared to literature. Changes in the humoral parameters are also similar and prove the applicability of the bioanalytical platform. Very dense and reliable individual concentration-time profiles of the drugs and the humoral parameters over 192 h were obtained in 45 mL blood only. Saliva appeared inappropriate to replace invasive pharmacokinetic sampling.ConclusionThe child-appropriate bioanalytical platform can be applied in upcoming paediatric Phase II and Phase III studies of the LENA (Labeling of Enalapril from Neonates up to Adolescents) project. Meaningful concentration-time profiles with 6–7 sampling points can be obtained even in neonates without infringing ethical recommendations on trial-related blood lost.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
SAFE-PEDRUG: A NEW STRATEGY FOR PAEDIATRIC DRUG RESEARCH
Authors: Bruyne Pauline De , Meesters Kevin , Walle Johan Vande 
Published: December 2015

BackgroundDrug evaluation in children is stimulated by initiatives of the Regulatory Authorities; in Europe by the ‘Paediatric Regulation'. As stated in this Regulation, Paediatric Investigational Plans must be submitted to the Paediatric Committee around the end of Phase I adult trials. However, the proposed paediatric trials tend to be amended frequently and postponed to the end of the drug evaluation process, as they are largely based on extrapolations of results of adult trials.Materials and methodsExperts in paediatrics, pharmaceutical sciences, veterinary medicine and ethics (of three Belgian universities) collaborated to develop a research consortium that will focus mainly on generating paediatric pharmacokinetic and pharmacodynamic (PK/PD) knowledge before the actual human trials are performed. National and international stakeholders (including Industry, Regulatory Authorities, and Patient Organisations) support this consortium in the valorisation of results.ResultsThe above-mentioned networking resulted in the SAFE-PEDRUG project, funded by the Agency for Innovation by Science and Technology (Flanders). This program will explore the value of the porcine juvenile animal model and PK modelling (physiologically-based pharmacokinetic modelling) in providing prior paediatric PK/PD-knowledge. For the evaluation of this approach, three case compounds were selected: desmopressin, lisinopril, and fluoroquinolones. The results of the models are plotted against human paediatric data. Furthermore, PK/PD in neonates and critically ill children will also be explored.ConclusionA close collaboration of experts and stakeholders is mandatory for the future of paediatric pharmacology. Exchange of ideas and knowledge can help to tailor paediatric clinical trials to the PK/PD-characteristics and needs of children.
GLATIRAMER ACETATE AND PREGNANCY IN WOMEN WITH MULTIPLE SCLEROSIS – RESULTS FROM THE GERMAN MULTIPLE SCLEROSIS AND PREGNANCY REGISTRY
Authors: Herbstritt Sandra , Gold Ralf , Hellwig Kerstin 
Published: December 2015

ObjectiveTo determine the effect of glatiramer acetate (GLAT) exposure during pregnancy on perinatal outcome in women with multiple sclerosis (MS).BackgroundMS is one of the most common neurological diseases of the central nervous system, which mainly affects young women of reproductive age.Only limited data are available on whether GLAT exposure during pregnancy has an effect on perinatal outcome.MethodsWe compared the outcome of pregnancies of patients with MS exposed to GLAT with pregnancies of unexposed controls. Women with MS were enrolled into the German Multiple Sklerosis and pregnancy registry. Data were assessed with a standardized questionnaire during pregnancy and the postpartum year. Detailed information on course of MS, concomitant medication, pregnancy course and outcome was obtained.ResultsWe collected data on 230 pregnancies: 135 with exposure to GLAT and 95 MS controls unexposed to disease-modifying therapies (DMTs) during pregnancy.While 25 of the exposed pregnancies are still ongoing we did not document any malformation in the first 110 GLAT exposed pregnancies with at least 6 months postpartum follow up. The rate of spontaneous abortions did not differ compared to unexposed controls. 3 (3.15%) infants of the DMT unexposed women were born with malformations of non-genetic origin and 1 (0.95%) newborn was diagnosed with Wolf Hirschhorn syndrome.ConclusionsGLAT exposure does not constitute a major human teratogen or influence outcome of pregnancy negatively compared to untreated women with MS. Final data including the outcome of ongoing pregnancies will be presented at the time of the meeting.
ANTIEPILEPTIC DRUG PRESCRIBING FOR CHILDREN IN ITALY
Authors: Putignano Daria , Clavenna Antonio , Campi Rita , Bonati Maurizio 
Published: December 2015

The aim of the study was to evaluate prescription profile of antiepileptic drugs (AEDs) in pediatric population.Prescriptions reimbursed by the National Health System, involving 1,669,370 children and adolescents, dispensed between 2003–2012 by the retail pharmacies in the Lombardy Region, were analysed.AEDs classified according to International Anatomic-Therapeutical-Chemical Classification system (ATC subgroup: N03A).Prevalence was defined as the number of patients received at least one AED prescription per 1000 inhabitants and incidence was defined as the number of patients received an AED prescription for the first time (no AED prescriptions in the previous 12 months) per 1000 inhabitants. The first prescription dispensed to incident cases was analyzed.During 2012, 6,088 children and adolescents (3.6‰ of the population) received at least one AED prescription. The incident cases were 1,465 (incidence 0.86‰). Prevalence and incidence showed significant differences across time.In 2012 about 96% of incident cases was treated with only one AED and of these approximately 78% was treated with an older, while 22% with a newer AED. Valproic acid was the most used at the first prescription (56.2%), followed by carbamazepine (11.5%) and levetiracetam (9.2%). The use of newer AEDs increased across time (χ2t=23.75 P<0.005): in particular the prescriptions of carbamazepine decreased accross time (CAGR: −5.3%), while those of levetiracetam increased (CAGR: +35.4%).Despite conventional AEDs were still the main treatment for epileptic children, there was a decrease of carbamazepine and an increase of levetiracetam. These findings are consistent with results from drug utilization studies performed in other countries.