bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged cerebral circulation time is more associated with symptomatic carotid stenosis than stenosis degree or collateral circulation
Authors: Hu Yong-Sin , Guo Wan-Yuo , Lee I-Hui , Chang Feng-Chi , Lin Chung-Jung , Lin Chun-Jen , Luo Chao-Bao , Wu Chih-Chun , Lee Han-Jui 
Published: August 2017

Background and purposeCurrent practice of revascularization for carotid stenosis (CS) primarily relies on symptoms and degree of stenosis. Other parameters, such as collateral circulation and cerebral circulation time (CCT), might influence the stroke risk in CS. This study was conducted to (1) investigate whether CCT is more associated with symptomatic CS than degree of stenosis and (2) elucidate the associations among the degree of stenosis, collateral status, and CCT.MethodsFrom 2010 to 2016, 82 patients with unilateral CS were enrolled for DSA and divided into symptomatic and asymptomatic groups based on clinical presentation. CCT was defined as the difference between the time taken by the cavernous internal carotid artery and parietal vein to reach the maximal contrast medium intensities on lateral DSA. The degree of stenosis, collateral status, and CCT of the two groups were compared. Logistic regression analysis was performed to estimate the OR for symptomatic CS with the imaging variables.ResultsThe symptomatic group had a significantly higher degree of stenosis and longer CCT. CCT (OR 1.95, p=0.013) was more associated with symptomatic CS than the degree of stenosis (OR 1.03, p=0.229), after adjustment for potential confounders—namely, age, sex, antithrombotic use, and collateral status. Symptomatic high grade CS with collaterals had a non-significantly shorter CCT than those without collaterals.ConclusionsDSA derived CCT is more reflective of the hemodynamic differences between symptomatic and asymptomatic CS than degree of stenosis. Collaterals may not effectively reduce CCT in symptomatic high grade CS.
Impact of time to endovascular reperfusion on outcome differs according to the involvement of the proximal MCA territory
Authors: Hedderich Dennis M , Boeckh-Behrens Tobias , Friedrich Benjamin , Wiestler Benedikt , Wunderlich Silke , Zimmer Claus , Fischer Urs , Kleine Justus F , Kaesmacher Johannes 
Published: August 2017

BackgroundThe time interval between symptom onset and reperfusion is a major determinant of the benefit of endovascular therapy (ET) and patients’ outcome. The impact of time may be attenuated in patients with robust collaterals. However, not all regions in the middle cerebral artery (MCA) territory have access to collaterals.PurposeTo evaluate if the involvement of the poorly collateralized proximal MCA territory has an impact on the degree of time dependency of patients’ outcome.MethodsPatients with MCA occlusions treated with ET and involvement/sparing of the proximal striatocapsular MCA territory (SC+/SC−, each n=97) were matched according to their symptom onset to reperfusion times (SORTs). Correlation and impact of time on outcome was evaluated with strata of SC+/SC− using multivariate logistic regression models (LRMs), including interaction terms. Discharge National Institute of Health Stroke Scale (NIHSS-DIS) score <5 and discharge modified Rankin Scale (mRS-DIS) score ≤2 were prespecified outcome measures.ResultsA stronger correlation between all outcome measures (NIHSS-DIS/ΔNIHSS/mRS-DIS) and SORTs was found for SC+ patients than for SC−patients. SORTs were significant variables in LRMs for mRS-DIS score ≤2 and NIHSS-DIS score <5 in SC+ but not in SC− patients. Interaction of SC+ and SORTs was significant in LRMs for both endpoints.ConclusionTime dependency of outcome after ET is more pronounced if parts of the proximal MCA territory are affected. This may reflect the lack of collateralization in the striatocapsular region and a more stringent cell death with time. If confirmed, this finding may affect the selection of patients based on different time windows according to the territory at risk.
Creatine (methyl-d3) dilution in urine for estimation of total body skeletal muscle mass: accuracy and variability vs. MRI and DXA
Authors: Clark Richard V. , Walker Ann C. , Miller Ram R. , O’Connor-Semmes Robin L. , Ravussin Eric , Cefalu William T. 
Published: August 2017

A noninvasive method to estimate muscle mass based on creatine ( methyl-d3) (D3-creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58–76 yr old) fasted overnight and then received an oral 30-mg dose of D3-creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3–4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography–tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D3-creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = −3.00 ± 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 ± 3.7 kg). However, intraindividual variability was high with the D3-creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D3-creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d3) (D3-creatine) and D3-creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D3-creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less bias than DXA. However, intraindividual variability is high with the D3-creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted.
Single passive leg movement assessment of vascular function: contribution of nitric oxide
Authors: Broxterman Ryan M. , Trinity Joel D. , Gifford Jayson R. , Kwon Oh Sung , Kithas Andrew C. , Hydren Jay R. , Nelson Ashley D. , Morgan David E. , Jessop Jacob E. , Bledsoe Amber D. , Richardson Russell S. 
Published: August 2017

The assessment of passive leg movement (PLM)-induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCAUC). l-NMMA significantly attenuated ΔLBFpeak [492 ± 153 (l-NMMA) vs. 719 ± 238 (control) ml/min], LBFAUC [57 ± 34 (l NMMA) vs. 147 ± 63 (control) ml], ΔLVCpeak [4.7 ± 1.1 (l-NMMA) vs. 8.0 ± 3.0 (control) ml·min−1·mmHg−1], and LVCAUC [0.5 ± 0.3 (l-NMMA) vs. 1.6 ± 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for ΔLBFpeak, r = 0.85 for LBFAUC, r = 0.94 for ΔLVCpeak, and r = 0.95 for LVCAUC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability.
UBC-Nepal Expedition: acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea level and high altitude
Authors: Tymko Michael M. , Tremblay Joshua C. , Steinback Craig D. , Moore Jonathan P. , Hansen Alex B. , Patrician Alexander , Howe Connor A. , Hoiland Ryan L. , Green Daniel J. , Ainslie Philip N. 
Published: August 2017

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g., shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that 1) at rest, SNA would be elevated and FMD would be reduced at HA compared with sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344 m) and HA (5,050 m) in 14 participants during mild lower-body negative pressure (LBNP; −10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants ( n = 5). Our findings were 1) at rest, SNA was elevated ( P < 0.01), and absolute FMD was reduced ( P = 0.024), but relative FMD remained unaltered ( P = 0.061), at HA compared with SL; and 2) despite significantly altering SNA with LBNP (+60.3 ± 25.5%) and LBPP (−37.2 ± 12.7%) ( P < 0.01), FMD was unaltered at SL ( P = 0.448) and HA ( P = 0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA. NEW & NOTEWORTHY The role of the sympathetic nervous system on endothelial function remains unclear. We used lower-body negative and positive pressure to manipulate sympathetic nervous activity at sea level and high altitude and measured brachial endothelial function via flow-mediated dilation. We found that acutely altering sympathetic nervous activity had no effect on endothelial function.
Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i
Authors: Rehwaldt Jordan D. , Rodgers Buel D. , Lin David C. 
Published: August 2017

Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis.
Effect of zileuton on osteoporotic bone and its healing, expression of bone, and brain genes in rats
Authors: Saul D. , Ninkovic M. , Komrakova M. , Wolff L. , Simka P. , Gasimov T. , Menger B. , Hoffmann D. B. , Rohde V. , Sehmisch S. 
Published: August 2017

Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing, and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton (which is an inhibitor of arachidonate 5-lipoxygenase), is known to have a positive effect on bone tissue repair and brain ischemia. We studied the effect of zileuton on osteopenic bone and its healing and on the genes considered to be crucial for the cross talks between bone and brain. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 wk, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10, or 100 mg/kg body wt) for 5 wk. In tibiae, bone volume, callus and cortical volume, and gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 or 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal, decreasing their density. The expression level of brain Sema3a, known to regulate bone mass positively, was downregulated after ovariectomy. In contrast, bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy, whereas zileuton treatment (10 or 100 mg) resulted in reverse effects. Here, we describe for the first time the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in cross talk between bones and brain, and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s). NEW & NOTEWORTHY Zileuton, a 5-lipoxygenase inhibitor, increased bone volume, callus and cortical volume in osteotomized tibia, and trabecular and cortical volume in femur. Although the expression of Sema3a (positively regulating bone mass) in brain was downregulated and Sema4d (negatively regulating bone mass) was upregulated in tibia callus after ovariectomy, zileuton could counteract these effects. Rbbp4 (involved in age-related memory loss) was increased in tibia callus after ovariectomy.
Social experience alters socially induced serotonergic fluctuations in the inferior colliculus
Authors: Keesom Sarah M. , Sloss Brooklyn G. , Erbowor-Becksen Zita , Hurley Laura M. 
Published: August 2017

Past social experience and current social context shape the responses of animals to social signals. The serotonergic system is one potential mechanism by which both experiential and contextual factors could be conveyed to sensory systems, such as the auditory system, for multiple reasons. 1) Many features of the serotonergic system are sensitive to social experience. 2) Elevations in serotonergic activity are triggered by social partners, and variations in socially triggered serotonergic responses reflect behavioral differences among social encounters. 3) Serotonin is an auditory neuromodulator, altering how auditory neurons respond to sounds including conspecific vocalizations. In this study, we tested how social experience influences the socially triggered serotonergic response in the inferior colliculus, an auditory midbrain region with an important role in vocalization processing. We used carbon fiber voltammetry to measure serotonin during social interactions of male mice ( Mus musculus) from different social backgrounds: 4 weeks of grouped or individual housing. When paired with an unfamiliar male, both group-housed and individually housed males demonstrated elevations in serotonin; however, individually housed males exhibited socially triggered serotonergic responses with delayed time courses compared with the group-housed males. Furthermore, group-housed males displayed previously described correlations between the socially triggered serotonergic response and behaviors such as social investigation. In contrast, individually housed males did not show these serotonin-behavior relationships. These results suggest that social experience gained via social housing may shape the ability of the central serotonergic system to encode social context in sensory regions.NEW & NOTEWORTHY We demonstrate that past social experience influences the fidelity with which the serotonergic system represents social context in an auditory region. Social experience altered the time course of socially triggered serotonergic responses and changed how the serotonergic system reflects behavioral variations among social encounters of the same context. These findings are significant to the study of communication, suggesting that centralized neuromodulatory systems potentially convey integrated information regarding past experience and current context to primary sensory regions.
Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma
Authors: Lee Eunjee , Pain Margaret , Wang Huaien , Herman Jacob A. , Toledo Chad M. , DeLuca Jennifer G. , Yong Raymund L. , Paddison Patrick , Zhu Jun 
Published: August 2017

AbstractGlioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore–microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518–29. ©2017 AACR.
Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury
Authors: Heery Christopher R. , Palena Claudia , McMahon Sheri , Donahue Renee N. , Lepone Lauren M. , Grenga Italia , Dirmeier Ulrike , Cordes Lisa , Marté Jenn , Dahut William , Singh Harpreet , Madan Ravi A. , Fernando Romaine I. , Hamilton Duane H. , Schlom Jeffrey , Gulley James L. 
Published: August 2017

Abstract
Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector–based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.
Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.
Results: MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.
Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833–45. ©2017 AACR.