bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of infections during interferon‐based treatment in patients with chronic hepatitis C virus infection and advanced hepatic fibrosis
Authors: Maan Raoel , van der Meer Adriaan J , Hansen Bettina E , Feld Jordan J , Wedemeyer Heiner , Dufour Jean‐François , Lammert Frank , Manns Michael P , Zeuzem Stefan , Janssen Harry L A , de Knegt Robert J , Veldt Bart J
Published: February 2015

Background & Aim

Pegylated interferon‐based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon‐based treatment among patients with chronic hepatitis C virus (HCV) infection and advanced hepatic fibrosis and its relation to treatment‐induced neutropenia.

Methods

This cohort study included all consecutive patients with chronic HCV infection and biopsy‐proven bridging fibrosis or cirrhosis (Ishak 4–6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500–749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively.

Results

This study included 723 interferon‐based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.38–5.90, P = 0.005) and severe neutropenia at the previous visit (OR 5.42, 95% CI 1.34–22.0, P = 0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with pegylated interferon, severe neutropenia was not significantly associated (OR 1.63, 95% CI 0.19–14.2, P = 0.660).

Conclusions

In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon‐based therapy were generally mild. Severe interferon‐induced neutropenia rarely occurred, but was associated with on‐treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.
Sonic Hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma
Authors: Tsai Chiao‐Ling , Hsu Feng‐Ming , Tzen Kai‐Yuan , Liu Wei‐Lin , Cheng Ann‐Lii , Cheng Jason Chia‐Hsien
Published: February 2015

Background and Aim

Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation‐induced SHH signaling occurs in HCC and whether SHH inhibitor acts as a radiosensitizer.

Methods

The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh‐7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin‐V staining, and poly (ADP‐ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor.

Results

Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either modality alone. The antiproliferative activity of cyclopamine was attributable to apoptosis induction. Radiation dose‐dependently upregulated the expression of Gli‐1 (a transcription factor induced by SHH), and this effect was observed mainly in the nucleus. When combined with cyclopamine, irradiation inhibited Gli‐1 and increased DNA double‐strand breakage. Radiotherapy increased SHH and Gli‐1 expression in allogeneic tumor. When compared with radiotherapy alone, cyclopamine with radiotherapy reduced the mean tumor size of orthotopic tumors by 67% (P < 0.05).

Conclusion

Combining an SHH inhibitor with radiotherapy may enhance HCC cell and orthotopic tumor radiosensitivity.
Syn‐metamorphic folding in the Tauern Window, Austria dated by Th–Pb ages from individual allanite porphyroblasts
Authors: Cliff R. A. , Oberli F. , Meier M. , Droop G. T. R. , Kelly M.
Published: February 2015

High‐precision 232Th–208Pb dates have been obtained from allanite porphyroblasts that show unambiguous microstructural relationships to fabrics in a major syn‐metamorphic fold in the SE Tauern Window, Austria. Three porphyroblasts were analysed from a single garnet mica schist from the Peripheral Schieferhülle in the core of the Ankogel Synform, one of a series of folds which developed shortly before the thermal peak of Alpine epidote–amphibolite facies metamorphism: allanite grain 1 provided two analyses with a combined age of 27.7 ± 0.7 Ma; grain 2, which was slightly bent and fractured during crenulation, provided two analyses with a combined age of 27.7 ± 0.4 Ma; a single analysis from grain 3, which overgrew an already crenulated fabric, gave an age of 28.0 ± 1.4 Ma. The five 232Th–208Pb ages agree within error and define an isochron with an age of 27.71 ± 0.36 Ma (95% confidence level; MSWD = 0.46). The results imply that the crenulation event was in progress in a short interval (<1 Ma) c. 28 Ma, and that the Ankogel Synform was forming at this time. The thermal peak of regional metamorphism in the SE Tauern Window was probably attained shortly after 28 Ma, only c. 5 Ma after eclogite facies metamorphism in the central Tauern Window. Metasediment may contain allanite porphyroblasts with clear‐cut microstructural relationships to fabric development and metamorphic crystallization; for such rocks, 232Th–208Pb dating on microsamples offers a powerful geochronological tool.
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

Background

ATX‐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.

Objectives

This phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamic effects of ATX‐101 (100‐mg total dose).

Methods

Following 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.

Results

After 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.

Conclusions

This 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

Background

Type 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.

Objective

The 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.

Methods

Cellular 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).

Results

IFN‐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.

Conclusion

β‐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

Voxel‐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

Isolated 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

Objective

This study describes processes used to develop and test pediatric oral healthcare quality measures and provides recommendations for implementation.

Methods

At 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.

Results

Of 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.

Conclusions

Broad 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

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

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

Background/Aims

Transient 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).

Methods

From 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.

Results

The 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.

Conclusions

TE 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

Peptidoglycan 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

Background

Electrostimulation 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 concept

Our 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.

Results

The 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.

Conclusions

Our 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

Background

Response 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.

Methods

A 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.

Results

Echocardiographic 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.

Conclusion

Of 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

Background

Determining 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.

Methods

Data 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.

Results

The 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).

Conclusion

In 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.
Which Hemodynamic Parameter Predicts Nitroglycerin‐Potentiated Head‐Up Tilt Test Response?
Authors: RUSSO VINCENZO , PAPA ANDREA ANTONIO , CIARDIELLO CARMINE , RAGO ANNA , PROIETTI RICCARDO , CALABRÒ PAOLO , RUSSO MARIA GIOVANNA , NIGRO GERARDO
Published: February 2015

Background

The aim of our study was to identify the early hemodynamic predictors of head‐up tilt test (HUTT) outcome in healthy patients with recurrent unexplained syncope.

Methods and Results

The study involved 95 patients (mean age 38 ± 15; 42 male) who were referred for the evaluation of the syncopal episodes from October 2012 to May 2013. According to the nitroglycerin‐potentiated diagnostic tilt test response, the study population was divided into two groups: HUTT+ Group (61 patients, mean age 37 ± 10; 27 male) and HUTT– Group (34 patients, mean age 38 ± 11; 15 male) with no tilt‐induced syncope. Finger arterial blood pressure (BP) was recorded during tilt testing. Left ventricular stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were computed from the pressure pulsations. After nitroglycerin administration, the HUTT+ Group showed a significant increase in heart rate (92.0 ± 7.3 beats/min vs 68.9 ± 8.7 beats/min, P < 0.0001), with well‐maintained systolic BP (111.6 ± 14.1 mm Hg vs 108.8 ± 11.5 mm Hg; P = 0.332) and diastolic BP (66.1 ± 8.5 mm Hg vs 63.1 ± 6.9 mm Hg; P = 0.0913); a significant decrease in SV (53.9 ± 8.0 mL vs 78.6 ± 8.2 mL; P < 0.0001) and CO (4.0 ± 0.5 L/min vs 5.8 ± 1.0 L/min; P < 0.001), and a significant increase in TPR (1.3 ± 0.3 U vs 0.9 ± 0.2 U, P < 0.0011). We tested three hemodynamic parameters (SV, CO, and TPR) as predictors of positive tilt test response with receiver‐operating characteristic curve analysis.

Conclusions

Our results show that, 2 minutes after nitroglycerin administration, a statistically significant decrease of SV values (<67 mL) strongly predicts (area under the curve, 0.985; P < 0.0001) the HUTT‐positive response in healthy patients with recurrent unexplained syncope.
Impact of a Novel Catheter Tracking System on Radiation Exposure during the Procedural Phases of Atrial Fibrillation and Flutter Ablation
Authors: MALLIET NICOLAS , ANDRADE JASON G. , KHAIRY PAUL , NGUYEN THANH HIEN KIEM , VENIER SANDRINE , DUBUC MARC , DYRDA KATIA , GUERRA PETER , MONDÉSERT BLANDINE , RIVARD LÉNA , TADROS RAFIK , TALAJIC MARIO , THIBAULT BERNARD , ROY DENIS , MACLE LAURENT
Published: February 2015

Background

Fluoroscopic guidance is used to position catheters during cardiac ablation. We evaluated the impact of a novel nonfluoroscopic sensor‐guided electromagnetic navigation system (MG) on radiation exposure during catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL).

Methods

A total of 134 consecutive patients referred for ablation of AF (n = 44) or AFL (n = 90) ablation were prospectively enrolled. In one group the MG system was used for nonfluoroscopic catheter positioning, whereas in the conventional group standard fluoroscopy was utilized. Fluoroscopy times were assessed for each stage of procedure and total radiation exposure was quantified.

Results

Patient characteristics were similar between the groups. The procedural end point was achieved in all. Median (interquartile range [IQR]) fluoroscopy times were 12.5 minutes (7.6, 17.4) MG group versus 21.5 minutes (15.3, 23.0) conventional group (P < 0.0001) for AF ablation, and 0.8 minutes (0.4, 2.5) MG group versus 9.9 minutes (5.1, 22.5) conventional group (P < 0.0001) for AFL ablation. Median (IQR) total radiation exposure (μGy·m2) was 1,107 (906, 2,033) MG group versus 2,835 (1,688, 3,855) conventional group (P = 0.0001) for AF ablation, and 161 (65, 537) MG group versus 1,651 (796, 4,569) conventional group (P < 0.0001) for AFL ablation. No difference in total procedural time was seen.

Conclusions

The use of a novel nonfluoroscopic catheter tracking system is associated with a significant reduction in radiation exposure during AF and AFL ablation (61% and 90% reduction, respectively). In the era of heightened awareness of the importance of radiation reduction, this system represents a safe and efficient tool to decrease radiation exposure during electrophysiological ablation procedures.
Systematic Implantation of Pacemaker/ICDs under Active Oral Anticoagulation Irrespective of Patient's Individual Preoperative Thromboembolic Risk
Authors: CANO ÓSCAR , ANDRÉS ANA , JIMÉNEZ REBECA , OSCA JOAQUÍN , ALONSO PAU , RODRÍGUEZ YDELISE , SANCHO‐TELLO MARÍA‐JOSÉ , OLAGÜE JOSÉ , CASTRO JOSÉ E. , SALVADOR ANTONIO , MARTÍNEZ‐DOLZ LUIS
Published: February 2015

Background

A wide variability in the perioperative management of oral anticoagulation (OAC) has been documented in patients receiving cardiac rhythm management devices (CRMDs). We sought to evaluate the safety and feasibility of a new perioperative strategy consisting in systematically continuing OAC in all patients irrespective of their individual thromboembolic (TE) risk.

Methods

A total of 278 consecutive patients on chronic OAC receiving CRMDs were prospectively included. Patients were classified in high and low TE risk according to current guidelines for the perioperative management of antithrombotic therapy, but underwent implantation under active OAC (international normalized ratio 2–4) irrespective of their preoperative TE risk. Bleeding and TE complications were evaluated as well as other procedure‐related complications, hospital stays, and the feasibility of outpatient implantations.

Results

A total of 117 patients were considered at high TE risk and 161 at low TE risk. Overall, the incidence of pocket hematoma was 2.9% with only three patients requiring pocket revision. Low TE risk patients had a very low incidence of pocket hematoma (1.9%) without needing pocket revision. The mean hospital stay was 1.17 ± 1.8 days and 169 patients (61%) received their CRMD in an outpatient basis, including 77 patients who were implanted with an implantable cardioverter defibrillator. No TE events were detected during the 30‐day postimplant observation period in any patient. No other significant complications related with the implant (pneumothorax, hemothorax, cardiac tamponade) were registered.

Conclusions

Systematic continuation of OAC in all patients undergoing implantation of CRMDs is safe and feasible, thus simplifying and standardizing the perioperative management in this setting.
Defibrillator Deactivation against a Patient's Wishes: Perspectives of Electrophysiology Practitioners
Authors: DAESCHLER MARGARET , VERDINO RALPH J. , CAPLAN ARTHUR L. , KIRKPATRICK JAMES N.
Published: February 2015

Background

Unilateral do‐not‐resuscitate (DNR) orders (against patient/family wishes) have been ethically justified in cases of medical futility. We investigated whether electrophysiology practitioners believe medical futility justifies unilateral implantable cardioverter defibrillator (ICD) deactivation.

Methods and Results

Email invitations to take an online survey were sent to 1,894 electrophysiology practitioners. A total of 384 responses were collected (response rate 20.6%). Though the sample included respondents from Europe, Asia, Australia, South America, and Africa, the majority were from North America (78%), were academically affiliated (64%), and practiced in an urban setting (67.8%). Deactivation of ICD shock function in agreement with patient wishes and a preexisting DNR were not considered physician‐assisted suicide (93.2%, 358/384). However, a majority of the sample responded that it was not ethical/moral for doctors to deactivate ICDs against patients’ wishes (77.1%, 296/384) or against family/surrogates’ wishes (72.4%, 278/384), even in the context of medical futility. A majority indicated that deactivating ICD shock function is not ethically/morally different than withholding cardiopulmonary resuscitation or external defibrillation in a code (72.7%, 277/381), but was different than deactivating pacing in a pacemaker‐dependent patient (82.8%, 318/384). In the classification of interventions, a plurality (43.0%, 165/383) regarded ICDs to be unlike any other intervention. Concerning pacemakers, 50% (191/382) considered them to be like dialysis (a therapy that keeps patients alive).

Conclusions

This international sample of electrophysiology practitioners considered ICD and pacemaker deactivation to be ethically distinct. While ICD deactivation was considered appropriate in the setting of patient/family agreement, unilateral deactivation was not.
Protein carbonylation during natural leaf senescence in winter wheat, as probed by fluorescein‐5‐thiosemicarbazide
Authors: Havé M. , Leitao L. , Bagard M. , Castell J.‐F. , Repellin A.
Published: February 2015

Leaf senescence is characterised by a massive degradation of proteins in order to recycle nitrogen to other parts of the plant, such as younger leaves or developing grain/seed. Protein degradation during leaf senescence is a highly regulated process and it is suggested that proteins to be degraded are marked by an oxidative modification (carbonylation) that makes them more susceptible to proteolysis. However, there is as yet no evidence of an increase in protein carbonylation level during natural leaf senescence. The aim of our study was thus to monitor protein carbonylation level during the process of natural senescence in the flag leaf of field‐grown winter wheat plants. For this purpose, we adapted a fluorescence‐based method using fluorescein‐5‐thiosemicarbazide (FTC) as a probe for detecting protein carbonyl derivatives. As used for the first time on plant material, this method allowed the detection of both quantitative and qualitative modifications in protein carbonyl levels during the last stages of wheat flag leaf development. The method described herein represents a convenient, sensitive and reproducible alternative to the commonly used 2,4‐dinitrophenylhydrazine (DNPH)‐based method. In addition, our analysis revealed changes in protein carbonylation level during leaf development that were associated with qualitative changes in protein abundance and carbonylation profiles. In the senescing flag leaf, protein carbonylation increased concomitantly with a stimulation of endoproteolytic activity and a decrease in protein content, which supports the suggested relationship between protein oxidation and proteolysis during natural leaf senescence.
Clade classification of monolignol biosynthesis gene family members reveals target genes to decrease lignin in Lolium perenne
Authors: van Parijs F. R. D. , Ruttink T. , Boerjan W. , Haesaert G. , Byrne S. L. , Asp T. , Roldán‐Ruiz I. , Muylle H.
Published: February 2015

In monocots, lignin content has a strong impact on the digestibility of the cell wall fraction. Engineering lignin biosynthesis requires a profound knowledge of the role of paralogues in the multigene families that constitute the monolignol biosynthesis pathway. We applied a bioinformatics approach for genome‐wide identification of candidate genes in Lolium perenne that are likely to be involved in the biosynthesis of monolignols. More specifically, we performed functional subtyping of phylogenetic clades in four multigene families: 4CL, COMT, CAD and CCR. Essential residues were considered for functional clade delineation within these families. This classification was complemented with previously published experimental evidence on gene expression, gene function and enzymatic activity in closely related crops and model species. This allowed us to assign functions to novel identified L. perenne genes, and to assess functional redundancy among paralogues. We found that two 4CL paralogues, two COMT paralogues, three CCR paralogues and one CAD gene are prime targets for genetic studies to engineer developmentally regulated lignin in this species. Based on the delineation of sequence conservation between paralogues and a first analysis of allelic diversity, we discuss possibilities to further study the roles of these paralogues in lignin biosynthesis, including expression analysis, reverse genetics and forward genetics, such as association mapping. We propose criteria to prioritise paralogues within multigene families and certain SNPs within these genes for developing genotyping assays or increasing power in association mapping studies. Although L. perenne was the target of the analyses presented here, this functional subtyping of phylogenetic clades represents a valuable tool for studies investigating monolignol biosynthesis genes in other monocot species.
Genome size shifts: karyotype evolution in Crepis section Neglectoides (Asteraceae)
Authors: Enke N. , Kunze R. , Pustahija F. , Glöckner G. , Zimmermann J. , Oberländer J. , Kamari G. , Siljak‐Yakovlev S.
Published: February 2015

Plant genome size evolution is a very dynamic process: the ancestral genome of angiosperms was initially most likely small, which led to a tendency towards genome increase during evolution. However, findings in several angiosperm lineages demonstrate mechanisms that also led to genome size contraction. Recent molecular investigations on the Asteraceae genus Crepis suggest that several genomic reduction events have occurred during the evolution of the genus. This study focuses on the Mediterranean Crepis sect. Neglectoides, which includes three species with some of the smallest genomes within the whole genus. Crepis neglecta has the largest genome in sect. Neglectoides, approximately twice the size of the two species Crepis cretica and Crepis hellenica. Whereas C. cretica and C. hellencia are more closely related to each other than to C. neglecta the karyotypes of the latter species and C. cretica are similar, while that of C. hellenica differs considerably. Here, the karyotypic organisation of the three species is investigated with fluorescence in‐situ hybridisation and studied in a molecular phylogenetic framework based on the nuclear markers Actin, CHR12, CPN60B, GPCR1 and XTH23. Our findings further corroborate the occurrence of genome size contraction in Crepis, and suggest that the difference in genome size between C. neglecta and C. cretica is mostly due to elimination of dispersed repetitive elements, whereas chromosomal reorganisation was involved in the karyotype formation of C. hellenica.
The Association of Stillbirth with Depressive Symptoms 6–36 Months Post‐Delivery
Authors: Hogue Carol J. R. , Parker Corette B. , Willinger Marian , Temple Jeff R. , Bann Carla M. , Silver Robert M. , Dudley Donald J. , Moore Janet L. , Coustan Donald R. , Stoll Barbara J. , Reddy Uma M. , Varner Michael W. , Saade George R. , Conway Deborah , Goldenberg Robert L. ,   Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network Writing Group
Published: February 2015

Background

Stillbirths (>20 weeks’ gestation), which account for about 1 in 200 US pregnancies, may grieve parents deeply. Unresolved grief may lead to persistent depression.

Methods

We compared depressive symptoms in 2009 (6–36 months after index delivery) among consenting women in the Stillbirth Collaborative Research Network's population‐based case–control study conducted 2006–08 (n = 275 who delivered a stillbirth and n = 522 who delivered a healthy livebirth (excluding livebirths <37 weeks, infants who had been admitted to a neonatal intensive care unit or who died). Women scoring >12 on the Edinburgh Depression Scale were classified as currently depressed. Crude (cOR) and adjusted (aOR) odds ratios and 95% confidence intervals [CI] were computed from univariate and multivariable logistic models, with weighting for study design and differential consent. Marginal structural models examined potential selection bias due to low follow‐up.

Results

Current depression was more likely in women with stillbirth (14.8%) vs. healthy livebirth (8.3%, cOR 1.90 [95% CI 1.20, 3.02]). However, after control for history of depression and factors associated with both depression and stillbirth, the stillbirth association was no longer significant (aOR 1.35 [95% CI 0.79, 2.30]). Conversely, for the 76% of women with no history of depression, a significant association remained after adjustment for confounders (aOR 1.98 [95% CI 1.02, 3.82]).

Conclusions

Improved screening for depression and referral may be needed for women's health care. Research should focus on defining optimal methods for support of women suffering stillbirth so as to lower the risk of subsequent depression.
Recruitment for Longitudinal, Randomised Pregnancy Trials Initiated Preconception: Lessons from the Effects of Aspirin in Gestation and Reproduction Trial
Authors: Lesher Laurie L. , Matyas Rebecca A. , Sjaarda Lindsey A. , Newman Sarah L. , Silver Robert M. , Galai Noya , Hovey Kathleen M. , Wactawski‐Wende Jean , Emerick Leah , Lynch Anne M. , Mead Betsy , Townsend Janet M. , Perkins Neil J. , Mumford Sunni L. , Stanford Joseph , Schisterman Enrique F.
Published: February 2015

Background

Recruitment into large, preconception randomised clinical trials (RCT) is challenging. We describe clinic and community‐based preconception recruitment strategies for the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and highlight approaches that were and were not successful. This longitudinal RCT was conducted at four major sites in the US. Eligible women had one to two prior pregnancy losses and were actively trying to become pregnant.

Methods

Provider/clinic and community‐based outreach strategies were utilised, and the recruitment rate and costs of methods were assessed.

Results

A screening questionnaire was completed by 5485 women; 42.4% (n = 2323) screened were initially eligible, of whom 50.7% (n = 1228) were randomised. Provider/clinic‐based recruitment yielded the highest number eligible of those screened (30.1%) and also the most randomised participants overall (40.3%). The next highest yield came from direct mail and brochures/flyers at 13.1% and 12.5% of women randomised, respectively. However, direct mailings cost $720 per participant randomised. Other than word of mouth, provider/clinic‐based recruitment was the most cost effective method, costing an average of $60 per randomised participant. Web‐based recruitment yielded 4.7% of participants at a cost of $278 per randomised participant.

Conclusions

Provider and clinic‐based recruitment was the most effective and cost‐efficient method of recruitment in a preconception intervention study of reproduction among women.