bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity to musical structure in the human brain
Authors: Fedorenko Evelina , McDermott Josh H. , Norman-Haignere Sam , Kanwisher Nancy
Published: September 2012

Evidence from brain-damaged patients suggests that regions in the temporal lobes, distinct from those engaged in lower-level auditory analysis, process the pitch and rhythmic structure in music. In contrast, neuroimaging studies targeting the representation of music structure have primarily implicated regions in the inferior frontal cortices. Combining individual-subject fMRI analyses with a scrambling method that manipulated musical structure, we provide evidence of brain regions sensitive to musical structure bilaterally in the temporal lobes, thus reconciling the neuroimaging and patient findings. We further show that these regions are sensitive to the scrambling of both pitch and rhythmic structure but are insensitive to high-level linguistic structure. Our results suggest the existence of brain regions with representations of musical structure that are distinct from high-level linguistic representations and lower-level acoustic representations. These regions provide targets for future research investigating possible neural specialization for music or its associated mental processes.
Is saccade averaging determined by visual processing or movement planning?
Authors: Bhutani Neha , Ray Supriya , Murthy Aditya
Published: September 2012

Saccadic averaging that causes subjects' gaze to land between the location of two targets when faced with simultaneously or sequentially presented stimuli has been often used as a probe to investigate the nature of computations that transform sensory representations into an oculomotor plan. Since saccadic movements involve at least two processing stages—a visual stage that selects a target and a movement stage that prepares the response—saccade averaging can either occur due to interference in visual processing or movement planning. By having human subjects perform two versions of a saccadic double-step task, in which the stimuli remained the same, but different instructions were provided (REDIRECT gaze to the later-appearing target vs. FOLLOW the sequence of targets in their order of appearance), we tested two alternative hypotheses. If saccade averaging were due to visual processing alone, the pattern of saccade averaging is expected to remain the same across task conditions. However, whereas subjects produced averaged saccades between two targets in the FOLLOW condition, they produced hypometric saccades in the direction of the initial target in the REDIRECT condition, suggesting that the interaction between competing movement plans produces saccade averaging.
Virtual biomechanics: a new method for online reconstruction of force from EMG recordings
Authors: de Rugy Aymar , Loeb Gerald E. , Carroll Timothy J.
Published: September 2012

Current methods to reconstruct muscle contributions to joint torque usually combine electromyograms (EMGs) with cadaver-based estimates of biomechanics, but both are imperfect representations of reality. Here, we describe a new method that enables online force reconstruction in which we optimize a “virtual” representation of muscle biomechanics. We first obtain tuning curves for the five major wrist muscles from the mean rectified EMG during the hold phase of an isometric aiming task when a cursor is driven by actual force recordings. We then apply a custom, gradient-descent algorithm to determine the set of “virtual pulling vectors” that best reach the target forces when combined with the observed muscle activity. When these pulling vectors are multiplied by the rectified and low-pass-filtered (1.3 Hz) EMG of the five muscles online, the reconstructed force provides a close spatiotemporal match to the true force exerted at the wrist. In three separate experiments, we demonstrate that the technique works equally well for surface and fine-wire recordings and is sensitive to biomechanical changes elicited by a modification of the forearm posture. In all conditions tested, muscle tuning curves obtained when the task was performed with feedback of reconstructed force were similar to those obtained when the task was performed with real force feedback. This online force reconstruction technique provides new avenues to study the relationship between neural control and limb biomechanics since the “virtual biomechanics” can be systematically altered at will.
Short-term synchrony in diverse motor nuclei presumed to receive different extents of direct cortical input
Authors: Keen Douglas A. , Chou Li-Wei , Nordstrom Michael A. , Fuglevand Andrew J.
Published: September 2012

Motor units within human muscles usually exhibit a significant degree of short-term synchronization. Such coincident spiking typically has been attributed to last-order projections that provide common synaptic input across motor neurons. The extent of branched input arising directly from cortical neurons has often been suggested as a critical factor determining the magnitude of short-term synchrony. The purpose of this study, therefore, was to quantify motor unit synchrony in a variety of human muscles differing in the presumed extent of cortical input to their respective motor nuclei. Cross-correlation histograms were generated from the firing times of 551 pairs of motor units in 16 human muscles. Motor unit synchrony tended to be weakest for proximal muscles and strongest for more distal muscles. Previous work in monkeys and humans has shown that the strength of cortical inputs to motor neurons also exhibits a similar proximal-to-distal gradient. However, in the present study, proximal-distal location was not an exclusive predictor of synchrony magnitude. The muscle that exhibited the least synchrony was an elbow flexor, whereas the greatest synchrony was most often found in intrinsic foot muscles. Furthermore, the strength of corticospinal inputs to the abductor hallucis muscle, an intrinsic foot muscle, as assessed through transcranial magnetic stimulation, was weaker than that projecting to the tibialis anterior muscle, even though the abductor hallucis muscle had higher synchrony values compared with the tibialis anterior muscle. We argue, therefore, that factors other than the potency of cortical inputs to motor neurons, such as the number of motor neurons innervating a muscle, significantly affects motor unit synchrony.
On Stable Perturbations of the Generalized Drazin Inverses of Closed Linear Operators in Banach Spaces
Authors: Huang Qianglian , Zhu Lanping , Chen Xiaoru , Zhang Chang
Published: September 2012

We investigate the stable perturbation of the generalized Drazin inverses of closed linear operators in Banach spaces and obtain some new characterizations for the generalized Drazin inverses to have prescribed range and null space. As special cases of our results, we recover the perturbation theorems of Wei and Wang, Castro and Koliha, Rakocevic and Wei, Castro and Koliha and Wei.
Uniplanar Nystagmus Associated with Perceptual and Cognitive Visual Dysfunction due to Presumed Focal Ischemic Occipital Cortical Atrophy: A Missed Diagnosis and New Observation
Authors: Philip Swetha Sara , Dutton Gordon N. , Dorris Liam
Published: September 2012

Uniplanar nystagmus has been described in relation to pathology of the brain stem, retina, optic nerve, sensory visual deprivation, periventricular leucomalacia, and drug toxicity. This paper describes a case of uniplanar nystagmus associated with features of higher visual dysfunction and a presumed focal insult to the occipital lobes following an episode of neonatal apnea.
Figures of Merit for High‐Performance Transparent Electrodes Using Dip‐Coated Silver Nanowire Networks
Authors: Sepulveda-Mora Sergio B. , Cloutier Sylvain G.
Published: September 2012

Homogeneous, highly conductive, and transparent silver nanowire thin films were fabricated using a simple dip‐coating technique and a subsequent annealing step. Silver nanowires with two different average lengths (11 μm and 19 μm) were used in the sample preparation to analyze the dependence of the sheet resistance on the length of the one‐dimensional nanostructures. The best sample had a sheet resistance of 10.2 Ω/□ with optical transmittance of 89.9%. Two figures of merit, the electrical to optical conductivity ratio (σDC/σOP) and ϕTC, were obtained for all the samples in order to measure their performance as
transparent conductive materials.
Assessment of Genotoxic and Cytotoxic Hazards in Brain and Bone Marrow Cells of Newborn Rats Exposed to Extremely Low-Frequency Magnetic Field
Authors: Rageh Monira M. , EL-Gebaly Reem H. , El-Bialy Nihal S.
Published: October 2012

The present study aimed to evaluate the association between whole body exposure to extremely low frequency magnetic field (ELF-MF) and genotoxic , cytotoxic hazards in brain and bone marrow cells of newborn rats. Newborn rats (10 days after delivery) were exposed continuously to 50 Hz, 0.5 mT for 30 days. The control group was treated as the exposed one with the sole difference that the rats were not exposed to magnetic field. Comet assay was used to quantify the level of DNA damage in isolated brain cells. Also bone marrow cells were flushed out to assess micronucleus induction and mitotic index. Spectrophotometric methods were used to measure the level of malondialdehyde (MDA) and the activity of glutathione (GSH) and superoxide dismutase (SOD). The results showed a significant increase in the mean tail moment indicating DNA damage in exposed group (P<0.01,0.001,0.0001). Moreover ELF-MF exposure induced a significant (P<0.01,0.001) four folds increase in the induction of micronucleus and about three folds increase in mitotic index (P<0.0001). Additionally newborn rats exposed to ELF-MF showed significant higher levels of MDA and SOD (P<0.05). Meanwhile ELF-MF failed to alter the activity of GSH. In conclusion, the present study suggests an association between DNA damage and ELF-MF exposure in newborn rats.
Parent Ratings of Executive Functioning in Children with Shunted Hydrocephalus
Authors: Lacy Maureen , Baldassarre Megan , Nader Todd , Frim David
Published: September 2012

Objectives: The present study examined the executive functioning of a group of children with a history of communicating hydrocephalus and how their level of functioning was correlated with parent ratings of executive functioning. Methods: The study examined the executive functioning of 39 shunted children with a history of hydrocephalus and 20 healthy peers. Additionally, parents of both groups of children completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess the parents’ perceptions of their children’s executive functioning. Finally, the study investigated the relationship between the shunted hydrocephalus children’s executive functioning and the parent ratings of their executive functioning. Results: Overall, the children with a history of shunted hydrocephalus displayed more executive dysfunction than their healthy peers. These children were rated by their parents as having more executive dysfunction than their healthy peers and displaying working memory, initiation, mental flexibility and self-monitoring difficulties, which appear to increase with age among the shunted hydrocephalus group. While parent ratings as measured by the BRIEF indices did not correlate with all executive tasks within the shunted hydrocephalus group, the cognitive tests assessing mental flexibility may be sensitive to the problems noted by parents at home. Conclusions: The children with a history of shunted hydrocephalus displayed executive functioning deficits on formal examination. The parents of children with a history of shunted hydrocephalus report ongoing executive difficulties which may increase with age.
Axonal Transport and Mitochondrial Dysfunction in Alzheimer's Disease
Authors: Riemer Jan , Kins Stefan
Published: September 2012

Alzheimer's disease (AD) is the most common form of dementia. It is characterized by pathological hallmarks such as extracellular deposits of amyloid plaques as well as intracellular neurofibrillary tangles and a progressive loss of neurons. Additional early pathological features of AD also include a decline in synapse number, axonal dystrophies, mitochondrial hypometabolism and increased oxidative stress. It is assumed that the aggregates of amyloid-β and tau are not the major pathogenic players in AD, but that nonaggregated oligomeric forms of amyloid-β and specific phosphorylated forms of tau cause neurodegeneration. It is tempting to speculate that oligomeric amyloid-β and phosphorylated tau might trigger mitochondrial dysfunction associated with oxidative stress as well as dysfunctions of axonal transport, leading to the loss of spines and neurodegeneration. Here, we summarize the actual data supporting this hypothesis and provide a model how these different mechanisms might be intertwined with each other.
An Infant with Heart Failure due to Ventricular Dyssynchrony and Refractory Tachycardia Caused by a Right Anterolateral Accessory Pathway
Authors: Suzuki Yukako , Suzuki Takeki , Imai Yasushi , Inuzuka Ryo , Suzuki Tsugutoshi , Nakamura Yoshihide , Ono Hiroshi
Published: September 2012

Wolff-Parkinson-White syndrome is associated with heart failure (HF) mainly via tachycardia. Several case report series have suggested dyssynchrony due to an accessory pathway as a possible cause of HF even in the absence of tachyarrhythmias. The role of cardiac resynchronization in the suppression of anterograde conduction of accessory pathways by catheter ablation or pharmacotherapy in such patients remains unclear, especially in the pediatric population. We describe an infant case with HF due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway. Cardiac resynchronization either by catheter ablation or amiodarone appears to be of value in such cases.
Exercise Training with Weight Loss and either a High- or Low-Glycemic Index Diet Reduces Metabolic Syndrome Severity in Older Adults
Authors: Malin Steven K. , Niemi Nicole , Solomon Thomas P.J. , Haus Jacob M. , Kelly Karen R. , Filion Julianne , Rocco Michael , Kashyap Sangeeta R. , Barkoukis Hope , Kirwan John P.
Published: September 2012

Background: The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low (LoGIx)- or high (HiGIx)-glycemic index diet on the severity of the metabolic syndrome (Z-score). Methods: Twenty-one adults (66.2 ± 1.1 years; BMI = 35.3 ± 0.9 kg/m2) with the metabolic syndrome were randomized to 12 weeks of exercise (60 min/day for 5 days/week at about 85% HRmax) and provided a LoGIx (n = 11) or HiGIx (n = 10) diet. Z-scores were determined from: blood pressure, triglycerides (TGs), high-density lipoproteins (HDLs), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and nonesterfied fatty acid (NEFA) suppression were also assessed. Results: LoGIx and HiGIx diets decreased body mass and insulin resistance and increased aerobic fitness comparably (p < 0.05). LoGIx and HiGIx diets decreased the Z-score similarly as each intervention decreased blood pressure, TGs, FPG and WC (p < 0.05). The HiGIx diet tended to suppress NEFA during insulin stimulation compared with the LoGIx diet (p = 0.06). Conclusions: Our findings highlight that exercise with weight loss reduces the severity of the metabolic syndrome whether individuals were randomized to a HiGIx or a LoGIx diet.
Granulocyte Macrophage Colony-Stimulating Factor in 66 Patients with Myeloid or Lymphoid Neoplasms and Recipients of Hematopoietic Stem Cell Transplantation with Invasive Fungal Disease
Authors: Safdar Amar , Rodriguez Gilhen , Zuniga Jorge , Al Akhrass Fadi , Georgescu Georgia , Pande Anupam
Published: October 2012

Background/Aims: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). Methods: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. Results: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21–264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66–63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27–16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1–16.2; p ≤ 0.05) predicted antifungal treatment failure. Conclusions: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.
German Oldenburg Sentence Test for Children: A Useful Speech Audiometry Tool for Hearing-Impaired Children at Kindergarten and School Age
Authors: Weißgerber Tobias , Baumann Uwe , Brand Thomas , Neumann Katrin
Published: September 2012

Background/Aims: In speech audiometry, sentence tests have the advantage of assessing more words within a given period of time than single-word tests do. Consequently, greater accuracy (steeper discrimination function) is achieved. The recently developed German Oldenburg Sentence Test for Children (OlKiSa) has been evaluated thus far for school-aged children in noise, and normative data for younger children in a quiet environment have been established. In this study, the focus is on its applicability in hearing-impaired children fitted with hearing aids or cochlear implants. Methods: The use of the OlKiSa in a quiet environment in hearing-impaired children aged 4 years or older was evaluated. One hundred and nineteen hearing-impaired children aged between 4 and 10 years performed the OlKiSa in a quiet environment. Individual speech reception thresholds (SRT) were measured aided and unaided and the slopes of the discrimination functions were calculated. Results: Independent of age, the mean slope of the discrimination function for SRT was about 7%/dB in both conditions, which is a high value of steepness for a speech audiometric test in a quiet environment. Conclusion: The OlKiSa in quiet is a reliable test procedure for hearing-impaired children aged 4 years and older.
Posthemorrhagic Hydrocephalus in Preterm Neonates: Socioeconomic Characteristics in a Single-Institution Experience
Authors: Pendleton Courtney , Cristofalo Elizabeth A. , Biondo Gabriella N. , Jallo George I. , Quiñones-Hinojosa Alfredo , Ahn Edward S.
Published: September 2012

Patients with posthemorrhagic hydrocephalus (PHH) from germinal matrix hemorrhage of prematurity often require numerous early interventions, as well as long-term follow-up care from pediatric neurosurgeons, which continues to place high demands on the existing workforce and pediatric health care system. There are established correlations between premature birth and low socioeconomic status. The aim of this study is to characterize the demographic profile and follow-up patterns in this subpopulation of surgically treated infants with PHH from prematurity. Methods: A retrospective analysis of the electronic patient records for a single institution, from 2007 to 2010, was performed. All patients who underwent neurosurgical intervention for the treatment of PHH were selected for further analysis. Data elements available within the records included patient demographic features, inpatient treatments and procedures, inpatient mortality rates, length of stay, and postoperative follow-up at the institution. Socioeconomic status was assessed using the median household income for the patient’s zip code, as reported in the United States Census for the year 2000. Results: A total of 40 patients who underwent neurosurgical intervention for PHH at a single institution were identified. More patients were female (52.5%); the majority of patients were Black (57.5%). No patients were uninsured; most patients had public insurance (62.5%), and 65% were below the Maryland State median household income (USD 52,868). There were trends toward more frequent emergency room visits among those covered by public insurance and those below the state and national median house income, although differences were not statistically significant. Conclusions: Our data indicate that the majority of patients fall within lower household income brackets, are born into households earning less than the statewide median household income, and are covered by public insurance. In light of the socioeconomic profile of the patient population reported here, these data may prove to be useful in preventative strategies aimed toward prematurity, PHH, and the ongoing treatment of hydrocephalus by pediatric neurosurgeons and other pediatric subspecialists.
Association of Genes on Chromosome 6, GRIK2, TMEM217 and TMEM63B (Linked to MRPL14) with Diabetic Retinopathy
Authors: Lin Hui-Ju , Huang Yu-Chuen , Lin Jane-Ming , Wu Jer-Yuarn , Chen Liuh-An , Tsai Fuu-Jen
Published: September 2012

Purpose: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM). The susceptibility genes responsible for increasing the risk for DR in type 2 diabetes (T2D) were sought in this study. Methods: A case-control study was carried out, comprising 749 unrelated T2D individuals with (n = 174) and without (n = 575) DR. Genotypic distributions of single nucleotide polymorphisms (SNPs) were determined for subjects with and without DR. Results: Eight chromosome 6 SNPs, having the most significant differences, were delineated: rs10499298, rs10499299, rs17827966, rs1224329, rs1150790, rs713050, rs2518344 and rs487083; all were associated with genes TMEM217, MRPL14 and GRIK2. After adjusting for the duration of DM and levels of hemoglobin A1c, the TT genotype of rs713050, and the AG + AA genotypes of rs2518344 and rs10499298, differed significantly between those with and without DR. Haplotype analysis revealed haplotype C-A-C, residing in rs10499299, rs10499298 and rs17827966, to have significant linkage disequilibrium. Conclusions: We identified new loci on chromosome 6 associated to DR; all loci showed high levels of linkage disequilibrium.
Complete Testis-Epididymis Nonfusion Anomaly: A Typical Association with Cryptorchid Testis
Authors: Rachmani E. , Zachariou Z. , Snyder H. , Hadziselimovic F.
Published: September 2012

Introduction: Fusion anomalies of the testis and epididymis are associated with cryptorchidism. We present an analysis of the fusion anomalies of the epididymis in cryptorchid boys. Patients and Methods: We performed a retrospective review of patients presenting with undescended testes between 1986 and 1993. Patients were stratified among four groups based on the degree of testis-epididymis nonfusion. Results: A total of 880 testes were eligible for review, of which 93% (815/880) had normal fusion, 3.6% (32/880) had epididymal head nonfusion, 2% (19/880) had epididymal tail nonfusion, and 1.6% (14/880) had complete nonfusion. Increasing degree of nonfusion was associated with higher perioperative testes position. Head and tail nonfusion were observed together with a contralateral descended testis, but less frequently than in bilateral undescended testes (p = 3.89×E–10). Complete nonfusion was not observed in the contralateral descended testes in unilateral cryptorchid boys. Conclusions: Different degrees of fusion anomalies of the epididymis are associated with unilateral and bilateral undescended testis, indicating that nonfusion anomalies interact with epididymal-testicular descent because of impaired epididymal function.
Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery
Authors: Rohatagi Shashank , Kastrissios Helen , Green Michelle , Green Michelle , Shi Minggao , Patel Indravadan , Salazar Daniel , Mendell Jeanne
Published: September 2012

Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.
Fractalkine is an independent predictor of mortality in patients with advanced heart failure
Authors: Koller Lorenz , Hohensinner Philipp , Rychli Kathrin , Zorn Gerlinde , Goliasch Georg , Berger Rudolf , Mörtl Deddo , Maurer Gerald , Huber Kurt , Pacher Richard , Wojta Johann , Hülsmann Martin , Niessner Alexander , Richter Bernhard
Published: September 2012

Immunological processes are implicated in the multifactorial pathophysiology of heart failure (HF). The multifunctional chemokine fractalkine (CX3CL1) promotes the extravasation of cytotoxic lymphocytes into tissues. We aimed to assess the prognostic value of fractalkine in HF. Fractalkine plasma levels were determined in 349 patients with advanced systolic HF (median 75 years, 66% male). During a median follow-up of 4.9 years (interquartile range: 4.6–5.2), 55.9% of patients died. Fractalkine was a significant predictor of all-cause mortality (p <0.001) with a hazard ratio of 2.78 (95% confidence interval: 1.95–3.95) for the third compared to the first tertile. This association remained significant after multivariable adjustment for demographics, clinical predictive variables and N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.008). The predictive value of fractalkine did not significantly differ between patients with ischaemic and non-ischaemic HF aetiology (p=0.79). The predictive value of fractalkine tertiles was not significantly modified by tertiles of NT-proBNP (p=0.18) but was more pronounced in the first and third tertile of NT-proBNP. Fractalkine was also an independent predictor of cardiovascular mortality (p=0.015). Fractalkine levels were significantly lower in patients on angiotensin-converting enzyme inhibitor therapy (p <0.001). In conclusion, circulating fractalkine with its pro-inflammatory and immunomodulatory effects is an independent predictor of mortality in advanced HF patients. Fractalkine improves risk prediction beyond NTproBNP and might therefore help to identify high risk patients who need special care. Our data indicate the implication of immune modulation in HF pathology.
Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1
Authors: Weitnauer Michael , Petry Andreas , BelAiba Rachida , Görlach Agnes
Published: September 2012

Disruption of endothelial homeostasis results in endothelial dysfunction, characterised by a dysbalance between nitric oxide (NO) and reactive oxygen species (ROS) levels often accompanied by a prothrombotic and proproliferative state. The serine protease thrombin not only is instrumental in formation of the fibrin clot, but also exerts direct effects on the vessel wall by activating proliferative and angiogenic responses. In endothelial cells, thrombin can induce NO as well as ROS levels. However, the relative contribution of these reactive species to the angiogenic response towards thrombin is not completely clear. Since plasminogen activator inhibitor-1 (PAI-1), a direct target of the proangiogenic transcription factors hypoxia-inducible factors (HIFs), exerts prothrombotic and proangiogenic activities we investigated the role of ROS and NO in the regulation of HIF-1α, PAI-1 and capillary formation in response to thrombin. Thrombin enhanced the formation of NO as well as ROS generation involving the GTPase Rac1 in endothelial cells. Rac1-dependent ROS formation promoted induction of HIF-1α, PAI-1 and capillary formation by thrombin, while NO reduced ROS bioavailability and subsequently limited induction of HIF-1α, PAI-1 and the angiogenic response. Importantly, thrombin activation of Rac1 was diminished by NO, but enhanced by ROS. Thus, our findings show that capillary formation induced by thrombin via Rac1-dependent activation of HIF-1 and PAI-1 is limited by the concomitant release of NO which reduced ROS bioavailability. Rac1 activity is sensitive to ROS and NO, thereby playing an essential role in fine tuning the endothelial response to thrombin.
A novel flow cytometry single tube bead assay for quantitation of von Willebrand factor antigen and collagen-binding
Authors: Favaloro Emmanuel , Koutts Jerry , Mina Ashraf
Published: September 2012

Deficiency of or defects in the plasma protein von Willebrand factor (VWF) lead to bleeding and von Willebrand disease (VWD), which may be congenital or acquired. VWD is considered the most common inherited bleeding disorder and laboratory testing for VWF level and activity is critical for appropriate diagnosis and management. We have designed and established a novel Flow Cytometry (FC) based method for measuring VWF antigen (VWF:Ag) and collagen binding (VWF:CB), together in the same tube and at the same time. The results of the novel FC method have been compared against existing reference methods using a range of normal and pathological material. Methods correlated well (VWF:Ag, r=0.866; VWF:CB, r=0.888) and generally permitted similar discrimination of quantitative versus qualitative VWD types (e.g. type 1 vs type 2A or 2B VWD). The novel procedure is expected to permit future streamlined performance of VWD screening, either using stand-alone FC systems or potentially incorporated into FC-capable automated blood cell and particle counters to allow for improved, automated and faster identification or exclusion of VWD.
Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism
Authors: Dahm Anders , Jacobsen Anne Flem , Sandvik Leiv , Sandset Per Morten , Bergrem Astrid
Published: September 2012

Limited data exist on thrombophilia and the risk of venous thrombosis (VT) during pregnancy and postpartum. The objectives of the present study were to investigate the role of haemostatic risk factors for pregnancy-related VT and their phenotypic expression in deep-vein thrombosis (DVT) and pulmonary embolism (PE). Total 313 cases with objectively verified first time VT and 353 controls were selected from a source population of 377,155 women with 613,232 pregnancies. The adjusted odds ratio (aOR) for pregnancy-related VT was 1.7 (95% confidence interval [CI] 1.1–2.8) for women with factor VIII >90th percentile. The aOR for VT for endogenous thrombin potential and D-dimer values >90thpercentiles were 1.8 (95% CI 1.1–3.0) and 2.1 (95% CI 1.3–3.3), respectively. Factor IX >90thpercentile or free protein S ≤the 5th percentile increased the risk for PE, and the aORs were 2.4 (95% CI 1.1–5.0) and 3.1 (95% CI 1.3–7.2), respectively. Women carrying the factor V Leiden (F5 rs6025) polymorphism, or who had reduced sensitivity to activated protein C (aPC) in the absence of F5 rs6025, had increased risk for DVT, with unadjusted ORs 7.7 (95% CI 4.7–12.7) and 3.5 (95% CI 2.2–5.4), respectively. Women with a history of pregnancy-related VT showed activation of coagulation and had elevated factor VIII. Furthermore, high levels of factor IX and low levels of free protein S were associated with increased risk for PE, whereas aPC resistance and F5 rs6025 were risk factors for DVT and not PE.
Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy
Authors: Hubers Lowiek , Spyropoulos Alex , Eikelboom John , Connolly Benjamin , Van Spall Harriette , Schulze Karleen , Cuddy Spencer , Stehouwer Alexander , Schulman Sam , Connolly Stuart , Nieuwlaat Robby
Published: September 2012

Excellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0–3.0 (TTR), with a one-sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: –1.4% to 4.1%];p-value for noninferiority=0.002;p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system.
The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition
Authors: Vinnikov Ilya , Shahzad Khurrum , Bock Fabian , Ranjan Satish , Wolter Juliane , Kashif Muhammed , Oh Jun , Bierhaus Angelika , Nawroth Peter , Kirschfink Michael , Conway Edward , Madhusudhan Thati , Isermann Berend , Wang Hongjie
Published: September 2012

Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anticoagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeDmice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeDmice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p <0.001). In vitroTM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and –notably –on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeDmice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.
Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery
Authors: Marx Svetlana , Dahl Ola , Marder Victor , Schulze Astrid , Wehling Martin , Weiss Christel , Harenberg Job
Published: September 2012

New oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 ± 5 and 34 ± 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 ± 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 ± 5 and 34 ± 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery.
The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors
Authors: Zaane Bregje van , Romualdi Erica , Brandjes Dees , Gerdes Victor , Squizzato Alessandro , Stuijver Danka
Published: September 2012

Several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess;however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo. Data sources included MEDLINE (2006–2012), EMBASE (2006–2012), and reference lists. The sources were combined with our previous search containing studies from 1980–2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random-effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross-sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis.
Biomarkers of platelet activation in acute coronary syndromes
Authors: Ferroni Patrizia , Riondino Silvia , Vazzana Natale , Santoro Nicole , Guadagni Fiorella , Davì Giovanni
Published: September 2012

The most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of antiplatelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of in vivoplatelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of in vivoplatelet activation should be specific, unaltered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet ac- tivation in the setting of ACS.
Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure
Authors: Caplin Ben , Wang Zhen , Slaviero Anna , Tomlinson James , Dowsett Laura , Delahaye Mathew , Salama Alan ,   The International Consortium for Blood Pressure Genome-Wide Association Studies, Wheeler David C. , Leiper James
Published: September 2012

Objective—

Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure.

Methods and Results—

In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (
P
=0.0052).

Conclusion—

Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.
Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein
Authors: Bojic Lazar A. , Sawyez Cynthia G. , Telford Dawn E. , Edwards Jane Y. , Hegele Robert A. , Huff Murray W.
Published: September 2012

Objective—

Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression.

Methods and Results—

THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced β-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1β, macrophage inflammatory protein 1α, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)
erk
and AKT/forkhead box protein O1 signaling.

Conclusion—

The combined PPARδ-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.
Rivaroxaban Delivery and Reversal at a Venous Flow Rate
Authors: Haynes Laura M. , Orfeo Thomas , Mann Kenneth G.
Published: September 2012

Objective—

Rivaroxaban is an oral anticoagulant that directly targets both free factor Xa and factor Xa in complex with its protein cofactor, factor Va, in the prothrombinase complex. It is approved in the United States for the prophylaxis of deep vein thrombosis and stroke in patients with atrial fibrillation; however, it also carries a black box warning regarding the risk of thrombosis after discontinuation of treatment. The purpose of this study was to determine the degree to which rivaroxaban, over a range of physiologically relevant free plasma concentrations, inhibits preassembled prothrombinase at a typical venous shear rate (100 s
−1
) and to determine the dynamics of rivaroxaban washout.

Methods and Results—

Prothrombinase was assembled on phospholipid-coated glass capillaries. Its activity was characterized with respect to the activation of prothrombin (mean plasma concentration, 1.4 μmol/L) in the absence and presence of rivaroxaban (2, 5, and 10 nmol/L). The degree of inactivation of preassembled prothrombinase is sensitive to the solution-phase rivaroxaban concentration; however, prothrombinase unmasking upon removal of rivaroxaban is concentration independent.

Conclusion—

The model system presented suggests that when rivaroxaban plasma concentrations decrease after cessation of therapy, there will be an unmasking of thrombus-associated prothrombinase that may be related to the reported rebound phenomena.