bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of a medium‐throughput approach for the genotyping of RHD variants and report of nine novel rare alleles
Authors: Fichou Yann , Le Maréchal Cédric , Jamet Déborah , Bryckaert Laurence , Ka Chandran , Audrézet Marie‐Pierre , Le Gac Gérald , Dupont Isabelle , Chen Jian‐Min , Férec Claude 
Published: December 2012

BackgroundThe routinely used serologic methods are robust in accurately typing standard D− or D+ blood. However, they result in discrepancy in weak or partial D blood, which requires genetic analysis. We have previously used denaturing high‐performance liquid chromatography (DHPLC) to screen the entire RHD‐coding sequence. However, DHPLC is technically challenging, labor‐intensive, and time‐consuming. To overcome these inconveniences, we sought to develop a new two‐step approach.Study Design and MethodsA total of 430 blood samples with D phenotype ambiguity were recruited for this study. The three most frequent weak D alleles (i.e., weak D, Type 1; weak D, Type 2; and weak D, Type 3), which altogether account for 60% to 90% of the atypical RHD alleles in the Caucasian population, were first identified by Tm‐shift genotyping. The remaining unidentified samples were then subjected to a single‐tube multiplex polymerase chain reaction (PCR) amplification of all 10 RHD exons followed by direct sequencing.ResultsOptimal conditions for efficient and reliable identification of the three most common weak D variants by Tm‐shift genotyping were established. All 10 RHD exons were successfully amplified in a single‐multiplex PCR procedure. Employment of the two‐step analysis identified RHD variants in 91.6% of the 430 studied samples. Two of the nine previously undescribed variants, c.335G>T and c.939G>A, were found to cause aberrant mRNA splicing by means of a splicing minigene assay.ConclusionThe new two‐step analysis proved to be much easier and cheaper than the DHPLC method and therefore is convenient to be used as a routine, medium‐throughput approach for RHD genotyping.
Frequency and risk factors for donor reactions in an anonymous blood donor survey
Authors: Goldman Mindy , Osmond Lori , Yi Qi‐Long , Cameron‐Choi Keltie , O'Brien Sheila F. 
Published: December 2012

BackgroundAdverse donor reactions can result in injury and decrease the likelihood of donor return. Reaction reports captured in the blood center's database provide an incomplete picture of reaction rates and risk factors.Study Design and MethodsWe performed an anonymous survey, mailed to 40,000 donors in 2008, including questions about symptoms, height, weight, sex, and donation status. Reaction rates were compared to those recorded in our database. Possible risk factors were assessed for various reactions.ResultsThe response rate was 45.5%. A total of 32% of first‐time and 14% of repeat donors reported having any adverse symptom, most frequently bruising (84.9 per 1000 donors) or feeling faint or weak (66.2 per 1000). Faint reactions were two to eight times higher than reported in our database, although direct comparison was difficult. Younger age, female sex, and first‐time donation status were risk factors for systemic and arm symptoms. In females, low estimated blood volume (EBV) was a risk factor for systemic symptoms. Only 51% of donors who consulted an outside physician also called Canadian Blood Services. A total of 10% of first‐time donors with reactions found adverse effects information inadequate.ConclusionThis study allowed us to collect more information about adverse reactions, including minor symptoms and delayed reactions. Based on our findings of the risk factors and frequency of adverse reactions, we are implementing more stringent EBV criteria for younger donors and providing more detailed information to donors about possible adverse effects and their management.
China and the World Trading System
Authors: Mattoo Aaditya , Subramanian Arvind 
Published: December 2012

AbstractThe WTO has been until recently an effective framework for cooperation because it has continually adapted to changing economic realities. The current Doha Agenda is an aberration because it does not reflect one of the biggest shifts in the international economic and trading system: the rise of China. Even though China will have a stake in maintaining trade openness, an initiative that builds on but redefines the Doha Agenda would anchor China more fully in the multilateral trading system. Such an initiative would have two pillars. First, a new negotiating agenda that would include the major issues of interest to China and its trading partners and thus unleash the powerful reciprocal liberalisation mechanism that has driven the WTO process to previous successes. Second, new restraints on bilateralism and regionalism that would help preserve incentives for maintaining the current broadly non‐discriminatory trading order.
Rapid Antimicrobial Susceptibility Testing by Sensitive Detection of Precursor rRNA Using a Novel Electrochemical Biosensing Platform
Authors: Halford Colin , Gonzalez Rodrigo , Campuzano Susana , Hu Bo , Babbitt Jane T. , Liu Jun , Wang Joseph , Churchill Bernard M. , Haake David A. 
Published: December 2012

ABSTRACT

Precursor rRNA (pre-rRNA) is an intermediate stage in the formation of mature rRNA and is a useful marker for cellular metabolism and growth rate. We developed an electrochemical sensor assay for
Escherichia coli
pre-rRNA involving hybridization of capture and detector probes with tail sections that are spliced away during rRNA maturation. A ternary self-assembled monolayer (SAM) prepared on gold electrode surfaces by coassembly of thiolated capture probes with hexanedithiol and posttreatment with 6-mercapto-1-hexanol minimized the background signal and maximized the signal-to-noise ratio. Inclusion of internal calibration controls allowed accurate estimation of the pre-rRNA copy number per cell. As expected, the ratio of pre-rRNA to mature rRNA was low during stationary phase and high during log phase. Pre-rRNA levels were highly dynamic, ranging from 2 copies per cell during stationary phase to ∼1,200 copies per cell within 60 min of inoculation into fresh growth medium. Specificity of the assay for pre-rRNA was validated using rifampin and chloramphenicol, which are known inhibitors of pre-rRNA synthesis and processing, respectively. The DNA gyrase inhibitor, ciprofloxacin, was found to act similarly to rifampin; a decline in pre-rRNA was detectable within 15 min in ciprofloxacin-susceptible bacteria. Assays for pre-rRNA provide insight into cellular metabolism and are promising predictors of antibiotic susceptibility.
Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients
Authors: Zeuli John D. , Wilson John W. , Estes Lynn L. 
Published: December 2012

ABSTRACT

QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (
P
= 0.03) and a left-ventricular ejection fraction of <55% (
P
= 0.02). Low magnesium (
P
= 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (
P
= 0.17), and female sex (
P
= 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.
In Vitro
Pharmacodynamics of AZD5206 against Staphylococcus aureus
Authors: Tam Vincent H. , Chang Kai-Tai , Yang Zhen , Newman Joseph , Hu Ming 
Published: December 2012

ABSTRACT

AZD5206 is a novel antimicrobial agent with potent
in vitro
activity against
Staphylococcus aureus
. We evaluated the
in vitro
pharmacodynamics of AZD5206 against a standard wild-type methicillin-susceptible strain (ATCC 29213) and a clinical strain of methicillin-resistant
S. aureus
(SA62). Overall, bacterial killing against a low baseline inoculum was more remarkable. Low dosing exposures and/or high baseline inoculum resulted in early reduction in bacterial burden, followed by regrowth and selective amplification of the resistant population.
STB5
Is a Negative Regulator of Azole Resistance in Candida glabrata
Authors: Noble Jason A. , Tsai Huei-Fung , Suffis Sara D. , Su Qin , Myers Timothy G. , Bennett John E. 
Published: December 2012

ABSTRACT

The opportunistic yeast pathogen
Candida glabrata
is recognized for its ability to acquire resistance during prolonged treatment with azole antifungals (J. E. Bennett, K. Izumikawa, and K. A. Marr. Antimicrob. Agents Chemother. 48:1773–1777, 2004). Resistance to azoles is largely mediated by the transcription factor
PDR1
, resulting in the upregulation of ATP-binding cassette (ABC) transporter proteins and drug efflux. Studies in the related yeast
Saccharomyces cerevisiae
have shown that Pdr1p forms a heterodimer with another transcription factor, Stb5p. In
C. glabrata
, the open reading frame (ORF) designated CAGL0I02552g has 38.8% amino acid identity with
STB5
(YHR178w) and shares an N-terminal Zn
2
Cys
6
binuclear cluster domain and a fungus-specific transcriptional factor domain, prompting us to test for homologous function and a possible role in azole resistance. Complementation of a Δyhr178w (Δ
stb5
) mutant with CAGL0I02552g resolved the increased sensitivity to cold, hydrogen peroxide, and caffeine of the mutant, for which reason we designated CAGl0I02552g
CgSTB5
. Overexpression of
CgSTB5
in
C. glabrata
repressed azole resistance, whereas deletion of
CgSTB5
caused a modest increase in resistance. Expression analysis found that
CgSTB5
shares many transcriptional targets with
CgPDR1
but, unlike the latter, is a negative regulator of pleiotropic drug resistance, including the ABC transporter genes
CDR1
,
PDH1
, and
YOR1
.
Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and
N
-Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania
Authors: Staehli Hodel Eva Maria , Csajka Chantal , Ariey Frédéric , Guidi Monia , Kabanywanyi Abdunoor Mulokozi , Duong Socheat , Decosterd Laurent Arthur , Olliaro Piero , Beck Hans-Peter , Genton Blaise 
Published: December 2012

ABSTRACT

The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (
CYP
, namely,
CYP2A6
,
CYP2B6
,
CYP2C8
,
CYP2C9
,
CYP2C19
,
CYP2D6
,
CYP3A4
, and
CYP3A5
) and the
N
-acetyltransferase 2 gene (
NAT2
) on the pharmacokinetics of artemisinin-based combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for
CYP2C9
*
3
,
CYP2D6
*
10
(100C→T),
CYP3A5
*
3
,
NAT2
*
6
, and
NAT2
*
7
. In contrast, higher frequencies of mutant alleles were found in Tanzanians for
CYP2D6
*
17
(1023C→T and 2850C→T),
CYP3A4
*
1B
,
NAT2
*
5
, and
NAT2
*
14
. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisinin-based combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.
Gentamicin in Hemodialyzed Critical Care Patients: Early Dialysis after Administration of a High Dose Should Be Considered
Authors: Veinstein Anne , Venisse Nicolas , Badin Julie , Pinsard Michel , Robert René , Dupuis Antoine 
Published: December 2012

ABSTRACT

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. We performed Monte Carlo simulations (MCS) to determine the best gentamicin pharmacokinetic profile (high peak and low trough concentrations). Then, 6 mg/kg of gentamicin was infused into 10 ICU patients over a period of 30 min. A 4-h-long hemodialysis session was started 30 min after the end of the infusion. Pharmacokinetic samples were regularly collected over 24 h. A one-compartment model with zero-order input and first-order elimination was developed in Nonmem version VI to analyze patients' measured gentamicin concentration-versus-time profiles. Finally, additional MCS were performed to compare the regimen chosen with the FDA-approved gentamicin regimen. High peak concentrations (
C
max
, 31.8 ± 16.8 mg/liter) were achieved. The estimated
C
24
and
C
48
values (concentrations 24 and 48 h, respectively, after the beginning of the infusion) were 4.1 ± 2.3 and 1.8 ± 1.2 mg/liter, respectively. The volume of distribution was 0.21 ± 0.06 liter/kg. MCS confirmed that the dosing regimen chosen achieved the target
C
max
whereas the FDA-approved regimen did not (31.0 ± 10.9 versus 8.8 ± 3.1 mg · liter
−1
). Moreover, the
C
24
values were similar while the AUC
0-24
values were moderately increased (190.8 ± 65.0 versus 135 ± 42.2 mg · h · liter
−1
). Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high
C
max
and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.
Plasmid Content of a Clinically Relevant Klebsiella pneumoniae Clone from the Czech Republic Producing CTX-M-15 and QnrB1
Authors: Dolejska Monika , Villa Laura , Dobiasova Hana , Fortini Daniela , Feudi Claudia , Carattoli Alessandra 
Published: December 2012

ABSTRACT

The entire plasmid content of a multidrug-resistant, CTX-M-15-producing
Klebsiella pneumoniae
ST416 clone was investigated. Two FII
K
plasmids, pKDO1 (127 kb) and pKPN-CZ (207 kb), were identified and found to carry a formidable set of genes conferring resistance to toxic compounds, metals, and antimicrobial drugs and exhibiting novel features putatively associated with adaptation and fitness of the bacterium in the human host.
Bruton's Tyrosine Kinase Regulates Shigella flexneri Dissemination in HT-29 Intestinal Cells
Authors: Dragoi Ana-Maria , Talman Arthur M. , Agaisse Hervé 
Published: December 2012

ABSTRACT

Shigella flexneri
is a Gram-negative intracellular pathogen that infects the intestinal epithelium and utilizes actin-based motility to spread from cell to cell.
S. flexneri
actin-based motility has been characterized in various cell lines, but studies in intestinal cells are limited. Here we characterized
S. flexneri
actin-based motility in HT-29 intestinal cells. In agreement with studies conducted in various cell lines, we showed that
S. flexneri
relies on neural Wiskott-Aldrich Syndrome protein (N-WASP) in HT-29 cells. We tested the potential role of various tyrosine kinases involved in N-WASP activation and uncovered a previously unappreciated role for Bruton's tyrosine kinase (Btk) in actin tail formation in intestinal cells. We showed that Btk depletion led to a decrease in N-WASP phosphorylation which affected N-WASP recruitment to the bacterial surface, decreased the number of bacteria displaying actin-based motility, and ultimately affected the efficiency of spread from cell to cell. Finally, we showed that the levels of N-WASP phosphorylation and Btk expression were increased in response to infection, which suggests that
S. flexneri
infection not only triggers the production of proinflammatory factors as previously described but also manipulates cellular processes required for dissemination in intestinal cells.
Intracellularly Induced Cyclophilins Play an Important Role in Stress Adaptation and Virulence of Brucella abortus
Authors: Roset Mara S. , García Fernández Lucía , DelVecchio Vito G. , Briones Gabriel 
Published: December 2012

ABSTRACT

Brucella
is an intracellular bacterial pathogen that causes the worldwide zoonotic disease brucellosis.
Brucella
virulence relies on its ability to transition to an intracellular lifestyle within host cells. Thus, this pathogen must sense its intracellular localization and then reprogram gene expression for survival within the host cell. A comparative proteomic investigation was performed to identify differentially expressed proteins potentially relevant for
Brucella
intracellular adaptation. Two proteins identified as cyclophilins (CypA and CypB) were overexpressed in the intracellular environment of the host cell in comparison to laboratory-grown
Brucella
. To define the potential role of cyclophilins in
Brucella
virulence, a double-deletion mutant was constructed and its resulting phenotype was characterized. The
Brucella abortus
Δ
cypAB
mutant displayed increased sensitivity to environmental stressors, such as oxidative stress, pH, and detergents. In addition, the
B. abortus
Δ
cypAB
mutant strain had a reduced growth rate at lower temperature, a phenotype associated with defective expression of cyclophilins in other microorganisms. The
B. abortus
Δ
cypAB
mutant also displays reduced virulence in BALB/c mice and defective intracellular survival in HeLa cells. These findings suggest that cyclophilins are important for
Brucella
virulence and survival in the host cells.
Microbial Modulation of Host Immunity with the Small Molecule Phosphorylcholine
Authors: Clark Sarah E. , Weiser Jeffrey N. 
Published: December 2012

ABSTRACTAll microorganisms dependent on persistence in a host for survival rely on either hiding from or modulating host responses to infection. The small molecule phosphorylcholine, or choline phosphate (ChoP), is used for both of these purposes by a wide array of bacterial and parasitic microbes. While the mechanisms underlying ChoP acquisition and expression are diverse, a unifying theme is the use of ChoP to reduce the immune response to infection, creating an advantage for ChoP-expressing microorganisms. In this minireview, we discuss several benefits of ChoP expression during infection as well as how the immune system fights back against ChoP-expressing pathogens.
Construction and analysis of a SSH cDNA library of Eucalyptus grandis × Eucalyptus urophylla 9224 induced by Cylindrocladium quinqueseptatum
Authors: Feng Li-Zhen , Guo Wen-Shuo , Xie Wan-Feng , Chen Quan-Zhu , Ye Xiao-Zhen 
Published: December 2012

Leaf blight caused by Cylindrocladium quinqueseptatum Boedijn & Reitsma is a major disease occurring in Eucalyptus plantlets and saplings worldwide. Current studies on the resistance to this disease in eucalypti have focused primarily on analyzing the relationship between the disease and the metabolic products from the anatomic structure of Eucalyptus leaves and their physiological responses to pathogen invasion. There have been no reports on the mechanisms of molecular responses. Previous research suggests that Eucalyptus grandis × Eucalyptus urophylla 9224 is the highest resistant cultivar among the 11 ones planted in Fujian Province. Therefore, in this study, the molecular responses of E. grandis × E. urophylla 9224 to C. quinqueseptatum were investigated by means of suppression subtractive hybridization (SSH). In total, 928 clones were obtained from the forward SSH cDNA library of E. grandis × E. urophylla 9224, and 25 up-regulated genes were identified by screening the library using the method of reverse northern hybridization. The results show that among these, 23 up-regulated genes with known functions were involved in signal transduction, plant resistance response, photosynthesis, energy transfer, protein metabolism, and plant growth.
A BCI-based application in music
Authors: Folgieri Raffaella , Zichella Matteo 
Published: December 2012

The relationship between the brain and music represents a fundamental field for investigation in HCI (human-computer interaction), for example, in games, virtual reality, and digital entertainment, due to the impact of music on human experience, emotions, and cognitive processes. For a low cost and the possibility of real-time analysis, the brain computer Interface (BCI) offers the potential for using music in HCI-related applications, as in games and entertainment.
In many studies related to music and the brain, BCI devices have been used both for psychological aims and for neuro-feedback-based therapy. In our work we focus on the possibility of enabling users to consciously play a specific musical note through low-cost BCI devices by reading subjects' brainwaves under a combined paradigm of audio, gesture, and visual stimuli. The results encourage further developments and future research.
Molecular Pathways: Targeted α-Particle Radiation Therapy
Authors: Baidoo Kwamena E. , Yong Kwon , Brechbiel Martin W. 
Published: December 2012

Abstract
An α-particle, a 4He nucleus, is exquisitely cytotoxic and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α-radiation, the result of its high mean energy deposition [high linear energy transfer (LET)] and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells [targeted α-therapy (TAT)] with minimal normal tissue effects. A burgeoning interest in the development of TAT is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematologic cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double-strand DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly affect cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT-induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as 225Ac, 211At, 213Bi, 212Pb, and 223Ra. Clin Cancer Res; 19(3); 530–7. ©2012 AACR.