bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1 pharmacokinetic study of ATX‐101: serum lipids and adipokines following synthetic deoxycholic acid injections
Authors: Walker Patricia , Lee Daniel 
Published: February 2015

SummaryBackgroundATX‐101 (deoxycholic acid injection, Kythera Biopharmaceuticals, Inc.) is a proprietary formulation of pure synthetic deoxycholic acid (DCA). It is undergoing clinical investigation as an injectable drug for contouring the submental area by reducing submental fat (SMF). When injected into subcutaneous fat, ATX‐101 causes focal adipocytolysis, the targeted destruction of fat cells.ObjectivesThis phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamic effects of ATX‐101 (100‐mg total dose).MethodsFollowing PK evaluation of baseline endogenous DCA, lipids, and adipokines in the initial stage of the study (samples collected at hours 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, 15.5, and 24.5), 10 subjects received subcutaneous injections of ATX‐101 into abdominal fat. PK evaluation of DCA, lipids, and adipokines was repeated in the second phase of the study.ResultsAfter ATX‐101 injections, plasma concentration of DCA increased transiently, reached a maximum plasma concentration rapidly, and returned to endogenous concentrations within 12 h postdose. ATX‐101 injection was not associated with any clinically meaningful changes in systemic concentrations of total cholesterol, total triglycerides, free fatty acids, C‐reactive protein, or interleukin‐6. Adverse events were mild in severity, transient, and showed a temporal relationship to dosing.ConclusionsThis study demonstrated favorable safety and PK profiles, and no clinically meaningful changes in DCA, lipids, and proinflammatory cytokines following subcutaneous injection of ATX‐101. Our results support continued clinical investigation of ATX‐101 as an injectable drug to reduce SMF.
Increased β‐haemolytic group A streptococcal M6 serotype and streptodornase B‐specific cellular immune responses in Swedish narcolepsy cases
Authors: Ambati A. , Poiret T. , Svahn B.‐M. , Valentini D. , Khademi M. , Kockum I. , Lima I. , Arnheim‐Dahlström L. , Lamb F. , Fink K. , Meng Q. , Kumar A. , Rane L. , Olsson T. , Maeurer M. 
Published: February 2015

AbstractBackgroundType 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin‐positive neurons.ObjectiveThe aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon‐gamma (IFNγ) production from immune cells in response to molecularly defined targets.MethodsCellular reactivity defined by IFNγ production was examined in blood from 38 (HLA‐DQB1*06:02+) Pandemrix‐vaccinated narcolepsy cases and 76 (23 HLA‐DQB1*06:02+ and 53 HLA‐DQB1*06:02−) control subjects, matched for age, sex and exposure, using a variety of different antigens: β‐haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X‐179A and A/H1N1/California/7/09 NYMC X‐181 vaccine antigens, previous Flu‐A and ‐B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA‐1 and EBNA‐3) and auto‐antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue).ResultsIFN‐γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T‐cell recognition of M6 and streptodornase B was confirmed at the single‐cell level by intracellular cytokine (IL‐2, IFNγ, tumour necrosis factor‐alpha and IL‐17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls.Conclusionβ‐haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M‐type‐specific IFN‐γ cellular immune response.
Statistical Instability of TBSS Analysis Based on DTI Fitting Algorithm
Authors: Maximov Ivan I. , Thönneßen Heike , Konrad Kerstin , Amort Laura , Neuner Irene , Shah N. Jon 
Published: February 2015

ABSTRACTVoxel‐based DTI analysis is an important approach in the comparison of subject groups by detecting and localizing gray and white matter changes in the brain. One of the principal problems for intersubject comparison is the absence of a “gold standard” processing pipeline. As a result, contradictory results may be obtained from identical data using different data processing pipelines, for example, in the data normalization or smoothing procedures. Tract‐based spatial statistics (TBSS) shows potential to overcome this problem by automatic detection of white matter changes and decreasing variation in the performed analysis. However, skeleton projection approaches, such as TBSS, critically depend on the accuracy of the diffusion scalar metric estimations. In this work, we demonstrate that the agreement and reliability of TBSS results depend on the applied DTI data processing algorithm. Statistical tests have been performed using two in vivo measured datasets and compared with different implementations of the least squares algorithm. As a result, we recommend repeating TBSS analysis using different fitting algorithms, in particular, using on iteratively‐assessed robust estimators, as accurate and more reliable approach in voxel‐based analysis, particularly, for TBSS. Repeating TBSS analysis allows one to detect and localize suspicious regions in white matter which were estimated as the regions with significant difference. Finally, we did not find a favorite fitting algorithm (or class of them) which can be marked as more reliable for group comparison.
Reversible Splenial Lesion Syndrome (RESLES) Following Glufosinate Ammonium Poisoning
Authors: Jeong Tae Oh , Yoon Jae Chol , Lee Jae Baek , Jin Young Ho , Hwang Seung Bae 
Published: February 2015

ABSTRACTIsolated and reversible lesion restricted to the splenium of the corpus callosum, known as reversible splenial lesion syndrome, have been reported in patients with infection, high‐altitude cerebral edema, seizures, antiepileptic drug withdrawal, or metabolic disturbances. Here, we report a 39‐year‐old female patient with glufosinate ammonium (GLA) poisoning who presented with confusion and amnesia. Diffusion‐weighted magnetic resonance imaging of the brain revealed cytotoxic edema of the splenium of the corpus callosum. The lesion was not present on follow‐up MR imaging performed 9 months later. We postulate that a GLA‐induced excitotoxic mechanism was the cause of this reversible splenial lesion.
Developing and testing pediatric oral healthcare quality measures
Authors: Herndon Jill Boylston , Crall James J. , Aravamudhan Krishna , Catalanotto Frank A. , Huang I‐Chan , Rudner Nancy , Tomar Scott L. , Shenkman Elizabeth A. 
Published: February 2015

AbstractObjectiveThis study describes processes used to develop and test pediatric oral healthcare quality measures and provides recommendations for implementation.MethodsAt the request of the Centers for Medicare and Medicaid Services, the Dental Quality Alliance (DQA) was formed in 2008 as a multi‐stakeholder group to develop oral healthcare quality measures. For its initial focus on pediatric care, measure development processes included a literature review and environmental scan to identify relevant measure concepts, which were rated on importance, feasibility, and validity using the RAND/UCLA modified Delphi approach. These measure concepts and a gap assessment led to the development of a proposed set of measures that were tested for feasibility, reliability, and validity.ResultsOf 112 measure concepts identified, 59 met inclusion criteria to undergo formal rating. Twenty‐one of 59 measure concepts were rated as “high scoring.” Subsequently, 11 quality and related care delivery measures comprising a proposed pediatric starter set were developed and tested; 10 measures met feasibility, reliability, and validity criteria and were approved by the DQA stakeholder membership. These measures are currently being incorporated into Medicaid, Children's Health Insurance Program, and commercial quality improvement programs.ConclusionsBroad stakeholder engagement, rigorous measure development and testing processes, and regular opportunities for public input contributed to the development and validation of the first set of fully specified and tested pediatric oral healthcare quality measures, which have high feasibility for implementation in both public and private sectors. This achievement marks an important essential step toward improving oral healthcare and oral health outcomes for children.
Alpinumisoflavone and abyssinone V 4′-methylether derived from E
rythrina lysistemon (Fabaceae) promote HDL-cholesterol synthesis and prevent cholesterol gallstone formation in ovariectomized rats
Authors: Mvondo Marie A , Njamen Dieudonné , Kretzschmar Georg , Imma Bader Manuela , Tanee Fomum Stephen , Wandji Jean , Vollmer Günter 
Published: February 2015

Abstract

Objectives
E rythrina lysistemon was found to improve lipid profile in ovariectomized rats. Alpinumisoflavone (AIF) and abyssinone V 4′-methylether (AME) derived from this plant induced analogous effects on lipid profile and decreased atherogenic risks. To highlight the molecular mechanism of action of these natural products, we evaluated their effects on the expression of some estrogen-sensitive genes associated with cholesterol synthesis (Esr1 and Apoa1) and cholesterol clearance (Ldlr, Scarb1 and Cyp7a1).

Methods
Ovariectomized rats were subcutaneously treated for three consecutive days with either compound at the daily dose of 0.1, 1 and 10 mg/kg body weight (BW). Animals were sacrificed thereafter and their liver was collected. The mRNA of genes of interest was analysed by quantitative real-time polymerase chain reaction.

Key findings
Both compounds downregulated the mRNA expression of Esr1, a gene associated with cholesterogenesis and cholesterol gallstone formation. AME leaned the Apoa1/Scarb1 balance in favour of Apoa1, an effect promoting high-density lipoprotein (HDL)-cholesterol formation. It also upregulated the mRNA expression of Ldlr at 1 mg/kg/BW per day (25%) and 10 mg/kg/BW per day (133.17%), an effect favouring the clearance of low-density lipoprotein (LDL)-cholesterol. Both compounds may also promote the conversion of cholesterol into bile acids as they upregulated Cyp7a1 mRNA expression.

Conclusion
AIF and AME atheroprotective effects may result from their ability to upregulate mechanisms promoting HDL-cholesterol and bile acid formation.
Genotyping of CYP2C19 polymorphisms and its clinical validation in the ethnic Arab population
Authors: Tayeb Hamsa T , Bakheet Dana H , Zaza Khaled , Wakil Salma M , Dzimiri Nduna 
Published: February 2015

Abstract

Objectives
The drug-metabolizing enzymes and transporters (DMET) Plus microarray and x-Tag assays have recently been developed for genotyping individuals in personalized medicine. Furthermore, the cytochrome 450-2C19 (CYP2C19) is a key metabolic enzyme encoded by a polymorphic gene commonly associated with diminished metabolism and variable clinical responses to several drugs in an ethnicity-dependent fashion. Therefore, validation of these clinical procedures as well as knowledge of the ethnic-specific incidences of these gene variants is prerequisite for determining their clinical relevance in any given population.

Methods
We determined the distribution of familiar CYP2C19 variants by the DMET Plus chip in 600 candidates and replicated the findings by the Affymetrix Axiom Genome-Wide Asian Structure Identification Array in 5413 individuals, all Saudis of ethic Arab origin. We then tested the robustness of employing the Luminex xMAP system clinically by comparing the results of genotyping 500 Saudi individuals visiting the Blood Bank of our institution with the findings of the two platforms.

Key findings
The DMET Plus genotyping revealed that eight of the CYP2C19 variants showed some changes. Thereby, the CYP2C19*17 exhibited the highest minor allele frequency (MAF) of 0.256, followed by the CYP2C19_801 (frequency = 0.055). Six other variants, including the CYP2C19*3, showed MAF in the range of 0.001–0.002. We replicated the frequencies of the CYP2C19*17 and CYP2C19*3, and additionally established that of the CYP2C19*2 (0.099) using the Axiom platform. The xTag genotyping also indicated that 0.834 of the 500 Saudi individuals were extensive metabolizers (*1/*1), 0.158 carried the *1/*2 genotype, 0.01% carried *2/*2 (poor metabolizers) and one each (0.2%) harboured the *1/*8, *2/*3 (intermediate metabolizers) and *8/*8 (poor metabolizers) genotypes.

Conclusions
The results showed reproducible genotyping of the CYP2C19 variants in the Saudi Arab population using two Affymetrix platforms and phenotyping using the Luminex xTag assay. The prevalence of two clinically relevant genotypes (CYP2C19*2 and CYP2C19*3) were similar to other ethnic groups, while that of the CYP2C19*17 was comparably higher.
Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study
Authors: Seo Yeon Seok , Kim Moon Young , Kim Seung Up , Hyun Bae Si , Jang Jae Young , Lee Jin Woo , Lee Jung Il , Suh Sang Jun , Park Soo Young , Park Hana , Jung Eun Uk , Kim Byung Seok , Kim In Hee , Lee Tae Hee , Um Soon Ho , Han Kwang‐Hyub , Kim Sang Gyune , Paik Soon Koo , Choi Jong Young , Jeong Soung Won , Jin Young Joo , Lee Kwan Sik , Yim Hyung Joon , Tak Won Young , Hwang Seong Gyu , Lee Youn Jae , Lee Chang Hyeong , Kim Dae‐Ghon , Kang Young Woo , Kim Young Seok ,   The Korean Transient Elastography Study Group
Published: February 2015

AbstractBackground/AimsTransient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC).MethodsFrom April 2006 to June 2014, 916 patients (567 CHB and 349 CHC) who underwent LB and TE at 15 centres were analyzed. The Batts and Ludwig scoring system was used for histologic assessment. Aspartate aminotransferase (AST)–to–platelet ratio indexes (APRI) were calculated. Area under the receiver operating characteristic curve (AUROC) was used.ResultsThe median age, LS value, and APRI score were 45 years, 8.8 kPa, and 0.61, respectively, in CHB patients vs. 51 years, 6.8 kPa and 0.55, respectively, in CHC patients. TE was significantly superior to APRI in CHB patients (AUROC 0.774 vs. 0.72 for ≥F2, 0.849 vs. 0.812 for ≥F3, and 0.902 vs. 0.707 for F4, respectively; all P < 0.05). Furthermore, TE was significantly superior for predicting ≥ F3 stage (AUROC 0.865 vs. 0.840, P = 0.009) whereas it was similar for predicting ≥ F2 and F4 stage (AUROC 0.822 vs. 0.796; 0.910 vs. 0.884; all P > 0.05) in CHC patients. In CHB patients, optimal cut‐off LS values were 7.8 kPa for ≥F2, 8.2 kPa for ≥ F3, and 11.6 kPa for F4, vs. 6.8 kPa, 8.6 kPa, and 14.5 kPa, respectively, in CHC patients.ConclusionsTE can accurately assess the degree of liver fibrosis in Korean patients with CVH. TE was superior to APRI for predicting each fibrosis stage.
Nucleotide Second Messenger‐Mediated Regulation of a Muralytic Enzyme in Streptomyces
Authors: St‐Onge Renée J. , Haiser Henry J. , Yousef Mary R. , Sherwood Emma , Tschowri Natalia , Al‐Bassam Mahmoud , Elliot Marie A. 
Published: February 2015

SummaryPeptidoglycan degradative enzymes have important roles at many stages during the bacterial life cycle, and it is critical that these enzymes be stringently regulated to avoid compromising the integrity of the cell wall. How this regulation is exerted is of considerable interest: promoter‐based control and protein‐protein interactions are known to be employed; however, other regulatory mechanisms are almost certainly involved. In the actinobacteria, a class of muralytic enzymes – the ‘resuscitation‐promoting factors’ (Rpfs) – orchestrates the resuscitation of dormant cells. In this study, we have taken a holistic approach to exploring the mechanisms governing RpfA function using the model bacterium Streptomyces coelicolor and have uncovered unprecedented multilevel regulation that is coordinated by three second messengers. Our studies show that RpfA is subject to transcriptional control by the cyclic AMP receptor protein, riboswitch‐mediated transcription attenuation in response to cyclic di‐AMP, and growth stage‐dependent proteolysis in response to ppGpp accumulation. Furthermore, our results suggest that these control mechanisms are likely applicable to cell wall lytic enzymes in other bacteria.
A Model of Electrostimulation Based on the Membrane Capacitance as Electromechanical Transducer for Pore Gating
Authors: IRNICH WERNER , KROLL MARK W. 
Published: February 2015

BackgroundElectrostimulation has gained enormous importance in modern medicine, for example, in implantable pacemakers and defibrillators, pain stimulators, and cochlear implants. Most electrostimulation macromodels use the electrical current as the primary parameter to describe the conventional strength‐duration relationship of the output of a generator. These models normally assume that the stimulation pulse charges up the passive cell membrane capacitance, and then the increased (less‐negative) transmembrane potential activates voltage‐gated sodium channels. However, this model has mechanistic and accuracy limitations.Novel conceptOur model assumes that the membrane capacitance is an electromechanical transducer and that the membrane is compressed by the endogenous electric field. The pressure is quadratically correlated with the transmembrane voltage. If the pressure is reduced by an exogenous field, the compression is released and, thus, opening the pores for Na+ influx initiates excitation.ResultsThe exogenous electric field must always be equal to or greater than the rheobase field strength (rheobase condition). This concept yields a final result that the voltage‐pulse‐content produced by the exogenous field between the two ends of a cell is a linear function of the pulse duration at threshold level. Thus, the model yields mathematical formulations that can describe and explain the characteristic features of electrostimulation.ConclusionsOur model of electrostimulation can describe and explain electrostimulation at cellular level. The model's predictions are consistent with published experimental studies. Practical applications in cardiology are discussed in the light of this model of electrostimulation.
Response to Cardiac Resynchronization Therapy as Assessed by Time‐Based Speckle Tracking Imaging
Authors: GHANI ABDUL , DELNOY PETER PAUL H.M. , ADIYAMAN AHMET , OTTERVANGER JAN PAUL , RAMDAT MISIER ANAND R. , SMIT JAAP JAN J. , ELVAN ARIF 
Published: February 2015

BackgroundResponse to cardiac resynchronization therapy (CRT) is still difficult to predict with previously investigated dyssynchrony indices. The predictive value of speckle tracking strain analysis has not been fully delineated yet. The objective of this study was to assess the predictive value of longitudinal strain (LS) and radial strain (RS) speckle tracking measurements on echocardiographic and clinical response to CRT.MethodsA total of 138 consecutive patients with functional class II–IV heart failure who underwent CRT were studied. Echocardiography was performed at baseline and during follow‐up. Six different time‐based left ventricular (LV)‐dyssynchrony indices were measured with LS and RS. Echocardiographic response to CRT was defined as a reduction in LV end‐systolic volume ≥15% and clinical response as survival without heart failure hospitalization. Multivariable analyses were performed to adjust for potential confounding factors.ResultsEchocardiographic and clinical follow‐up was 22 ± 8 and 42 ± 8 months, respectively. Ninety‐six patients (70%) were classified as echocardiographic responders and 114 patients (83%) survived without heart failure hospitalization. QRS duration and nonischemic etiology predicted echocardiographic response to CRT. None of the speckle tracking indices was different between echocardiographic responders and nonresponders to CRT. Regarding clinical response, only maximal delay between six segments in four‐chamber view measured with LS was different between responders and nonresponders, with 154‐ms delay as the optimal cut‐off value. Neither stratified analyses in patients with sinus rhythm nor multivariable analyses did change these findings.ConclusionOf all time‐based measured speckle tracking indices, only maximal delay between six segments in four‐chamber view as assessed with LS was associated with clinical response to CRT.
Predicting Interatrial Septum Rotation: Is the Position of the Heart or the Direction of the Coronary Sinus Reliable?
Authors: SUN HUAN , WANG YANJING , ZHANG ZHENMING , LIU LIN , YANG PING 
Published: February 2015

BackgroundDetermining the location of the interatrial septum (IAS) is crucial for cardiac electrophysiology procedures. Empirical methods of predicting IAS orientation depend on anatomical landmarks, including determining it from the direction of the coronary sinus (CS) and the position of the heart (e.g., vertical or transverse). However, the reliability of these methods for predicting IAS rotation warrants further study. The purpose of this study was to assess the clinical utility of the relationship between IAS orientation, CS direction, and heart position.MethodsData from 115 patients undergoing coronary computed tomography (CT) angiography with no evidence of cardiac structural disease were collected and analyzed. Angulations describing IAS orientation, CS direction, and heart position were measured. The relationships between IAS orientation and each of the other two parameters were subsequently analyzed.ResultsThe mean angulations for IAS orientation, CS direction, and heart position were 36.8 ± 7.3° (range 19.1–53.6), 37.7 ± 6.6° (range 21.3–50.1), and 37.1 ± 8.3° (range 19.2–61.0), respectively. We found a significant correlation between IAS orientation and CS direction (r = 0.928; P < 0.01), and the linear regression equation was drawn: IAS orientation = 2.01 + 1.03 × CS direction (r2 = 0.86). No correlation was observed between IAS orientation and heart position (P = 0.86).ConclusionIn patients without structural heart disease, CS direction may be a reliable predictor of IAS orientation, and may serve as a helpful reference for clinicians during invasive electrophysiological procedures. Further study is warranted to clarify the relationship between IAS orientation and heart position.