tbuckley/cabot-search huggingface dataset:
Electrophysiological Properties of Cardiac Muscle in the Anterior Mitral Valve Leaflet and the Adjacent Atrium in the Dog
Authors: ANDREW L. WIT, JOHN J. FENOGLIO, BERNARD M. WAGNER, ARTHUR L. BASSETT
Journal: Circulation Research (1973)

Transmembrane action potentials were recorded from multiple sites in isolated canine anteromedial left atrial wall preparations with the anterior mitral valve leaflet attached. The preparations were superfused with Tyrode's solution. When the left atrial wall was electrically stimulated, activity propagated into the mitral valve leaflet. Typical atrial action potentials occurred in atrial wall fibers. However, maximum diastolic potential, total action potential amplitude, and rate of depolarization decreased markedly in the atrium overlying the fibrous annulus (junctional region), and repolarization characteristics were altered in this region. Mitral valve muscle fibers demonstrated still lower maximum diastolic potential, action potential amplitude, and rate of depolarization. Electrical excitation of single discrete regions in the mitral valve leaflet did not result in conduction to the atrium; conduction block occurred in the junctional region. However, simultaneous excitation of several mitral valve sites did cause an impulse to propagate to the atrium, but transmembrane action potentials of junctional fibers were characteristically different from those recorded from the same junctional fibers during activation from the atrium. Muscle fibers in the mitral valve leaflet were capable of developing spontaneous diastolic depolarization, which resulted in automatic impulse initiation, when they were exposed to epinephrine or norepinephrine (1 x 10 -7 to 1 x 10 -5 M) or when they were stretched. Spontaneous diastolic depolarization and automaticity also occurred occasionally without pharmacological or other experimental interventions; moreover, spontaneous activity originating in the mitral valve leaflet could propagate into and activate the atrial wall. Acetylcholine abolished spontaneous activity. These data suggest that the mitral valve could act as a site of ectopic impulse initiation in the left atrium.
Radioembolization of Liver Metastases From Colorectal Cancer Using Yttrium-90 Microspheres With Concomitant Systemic Oxaliplatin, Fluorouracil, and Leucovorin Chemotherapy
Authors: Ricky A. Sharma, Guy A. Van Hazel, Bruno Morgan, David P. Berry, Keith Blanshard, David Price, Geoffrey Bower, Jennifer A. Shannon, Peter Gibbs, William P. Steward
Journal: Journal of Clinical Oncology (2007)

Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)--containing the beta-emitter, yttrium-90--into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX).A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity.Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months.The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.
Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis
Authors: Charlotte JJ van Asch, Merel JA Luitse, Gabriël JE Rinkel, Ingeborg van der Tweel, Ale Algra, Catharina JM Klijn
Journal: The Lancet Neurology (2010)
Association of Sleep-disordered Breathing and the Occurrence of Stroke
Authors: Michael Arzt, Terry Young, Laurel Finn, James B. Skatrud, T. Douglas Bradley
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Sleep-disordered breathing has been linked to stroke in previous studies. However, these studies either used surrogate markers of sleep-disordered breathing or could not, due to cross-sectional design, address the temporal relationship between sleep-disordered breathing and stroke.Objectives: To determine whether sleep-disordered breathing increases the risk for stroke.Methods: We performed cross-sectional and longitudinal analyses on 1,475 and 1,189 subjects, respectively, from the general population. Sleep-disordered breathing was defined by the apnea–hypopnea index (frequency of apneas and hypopneas per hour of sleep) obtained by attended polysomnography. The protocol, including polysomnography, risk factors for stroke, and a history of physician-diagnosed stroke, was repeated at 4-yr intervals.Measurements and Main Results: In the cross-sectional analysis, subjects with an apnea–hypopnea index of 20 or greater had increased odds for stroke (odds ratio, 4.33; 95% confidence interval, 1.32–14.24; p = 0.02) compared with those without sleep-disordered breathing (apnea–hypopnea index, <5) after adjustment for known confounding factors. In the prospective analysis, sleep-disordered breathing with an apnea–hypopnea index of 20 or greater was associated with an increased risk of suffering a first-ever stroke over the next 4 yr (unadjusted odds ratio, 4.31; 95% confidence interval, 1.31–14.15; p = 0.02). However, after adjustment for age, sex, and body mass index, the odds ratio was still elevated, but was no longer significant (3.08; 95% confidence interval, 0.74–12.81; p = 0.12).Conclusions: These data demonstrate a strong association between moderate to severe sleep-disordered breathing and prevalent stroke, independent of confounding factors. They also provide the first prospective evidence that sleep-disordered breathing precedes stroke and may contribute to the development of stroke.
Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy
Authors: Dushyant V Sahani, Tao Jiang, Koichi Hayano, Dan G Duda, Onofrio A Catalano, Marek Ancukiewicz, Rakesh K Jain, Andrew X Zhu
Journal: Journal of Hematology & Oncology (2013)

To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC). In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm2, and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated. After 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 2.15 min−1 to 0.94 min−1 (P = 0.0001) with increases in median apparent diffusion coefficient (ADC) from 0.88 × 10-3 mm2/s to 0.98 × 10-3 mm2/s (P = 0.0001). Tumor size remained unchanged by RECIST and mRECIST (both P > 0.05). Patients who showed larger drop in Ktrans and Kep at 2 weeks correlated with favorable clinical outcome, and higher baseline Ktrans and larger drop in EVF correlated with longer PFS (all P < 0.05). There was a significant association between a decrease in sVEGFR2 and the drop in Ktrans and Kep (P = 0.044, P = 0.030), and a significant and borderline association between decrease in TNF-α and the drop in Ktrans and Kep, respectively (P = 0.051, P = 0.035). In HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST. ClinicalTrials.gov: NCT00361309
SR2 elements, non-long terminal repeat retrotransposons of the RTE-1 lineage from the human blood fluke Schistosoma mansoni
Authors: A. C. Drew, D. J. Minchella, L. T. King, D. Rollinson, P. J. Brindley
Journal: Molecular Biology and Evolution (1999)

As in other eukaryotes, a substantial portion of the genome of the human blood flukes belonging to the genus Schistosoma appears to be composed of mobile genetic elements and other repetitive sequences. The constitutent elements and their relative organization are not well understood, although retroposons (the SM alpha elements) and a family of non-long terminal repeat (LTR) retrotransposons (the SR1 elements) have been reported from the genome of Schistosoma mansoni. Here, we report the presence of a second family of non-LTR retrotransposons from S. mansoni which we have termed the SR2 elements. SR2 elements are members of a recently described lineage of non-LTR retrotransposons typified by the RTE-1 non-LTR retrotransposon of Caenorhabditis elegans. We determined the sequence for approximately 3.9 kb of a consensus full-length SR2 element, which included a long 5' untranslated region (UTR), potential first and second open reading frames (ORFs) of 78 and 1,018 amino acid residues, respectively, a short 3' UTR, and an A-rich 3' terminus. SR2 elements were bound by target site duplications. The putative first and second ORFs did not overlap. The second ORF was homologous to retroviral pol and encoded an apurinic/apyrimidinic endonuclease and a reverse transcriptase. A number of extremely short SR2 elements of less than 0.5 kb, reminiscent of SINEs, were also characterized. These consisted solely of the 5' and 3' UTRs of full-length SR2 elements, having both ORFs deleted. Analysis indicated that these SINE-like SR2 elements were produced by replication of a SINE-like SR2 element, rather than by repeated deletions within larger SR2 elements.
Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis
Authors: T. G. Pavey, A. H. Taylor, K. R. Fox, M. Hillsdon, N. Anokye, J. L. Campbell, C. Foster, C. Green, T. Moxham, N. Mutrie, J. Searle, P. Trueman, R. S. Taylor
Journal: BMJ (2011)

<b>Objective</b> To assess the impact of exercise referral schemes on physical activity and health outcomes. <b>Design </b>Systematic review and meta-analysis. <b>Data sources</b> Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. <b>Study selection </b>Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. Population: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes. <b>Results</b> Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference −0.82, −1.28 to −0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses.<b></b>Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. <b>Conclusions </b>Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.
DESIGN OF THERAPEUTIC STUDIES IN HERPES SIMPLEX ENCEPHALITIS
Authors: R.J. Whitley, S.J. Soong, C.A. Alford, M.S. Hirsch, R. Schooley, M.N. Oxman, J.D. Connor, R. Betts, R. Dolin, R.C. Reichman, B. Skoldenberg, M. Forsgren, K. Alestig, A. Frydén, K. Norlin, R. Norrby, E. Olding-Stenkvist
Journal: The Lancet (1985)
Cell cycle control of c-kit+IL-7R+ B precursor cells by two distinct signals derived from IL-7 receptor and c-kit in a fully defined medium.
Authors: M Yasunaga, F Wang, T Kunisada, S Nishikawa, S Nishikawa
Journal: The Journal of Experimental Medicine (1995)

An important goal for the investigation of the proliferation of mammalian cells is to establish a fully defined condition for culturing them in vitro. Here, we report establishment of a fully defined culture condition that supports the primary culture of normal c-kit+IL-7 receptor (IL-7R)+ B precursor cells without the aid of stromal cell lines. This defined culture condition contains IL-7, the ligand for c-kit, transferrin, insulin, and bovine serum albumin as protein components. By using the cell lines derived from RAG2(-/-) mice, which do not differentiate into c-kit- stage, we have evaluated the role of each protein in the cell cycle progression of c-kit+IL-7R+ B precursor cells. Since B precursor cells can grow without insulin, c-kit remains a sole functional receptor tyrosine kinase for their growth. While both c-kit ligand (KL) and IL-7 are the requisite molecules for sustained proliferation of B precursor cells, each molecule plays distinct roles. IL-7 starvation results in prompt arrest of the cells at G1. An accumulation of the cells in the mitotic phase was also detected. Thus, the major role of IL-7 is to regulate the G1/S transition and the process of cytokinesis of B precursor cells. Although prolonged KL starvation over 48 h resulted in accumulation of G1 cells, its effect could not be detected within 24 h, which is long enough for all the cells to complete one cell cycle. This suggests that KL might be involved in the cell cycle progression of B precursor cells in a manner that its signal could still be effective in the one or two cell cycles that follow. Although molecular nature of the signals underlying the present observation awaits future investigation, the method described in this report would provide a useful model system for investigating the signaling pathways that are involved in the cell cycle progression of B precursor cells.
Deficient Attentional Modulation of the Startle Response in Patients With Schizotypal Personality Disorder
Authors: Erin A. Hazlett, Jill Levine, Monte S. Buchsbaum, Jeremy M. Silverman, Antonia New, Elizabeth M. Sevin, Liza A. Maldari, Larry J. Siever
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Attentional deficits have been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. The purpose of this study was to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated subjects with schizotypal personality disorder. METHOD: Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed in an acoustic attention-to-prepulse paradigm. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval. RESULTS: The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response. In contrast, the subjects with schizotypal personality disorder failed to show this pattern. CONCLUSIONS: Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.
The Cell Surface Receptor SLAM Controls T Cell and Macrophage Functions
Authors: Ninghai Wang, Abhay Satoskar, William Faubion, Duncan Howie, Susumu Okamoto, Stefan Feske, Charles Gullo, Kareem Clarke, Miriam Rodriguez Sosa, Arlene H. Sharpe, Cox Terhorst
Journal: The Journal of Experimental Medicine (2004)

Signaling lymphocyte activation molecule (SLAM), a glycoprotein expressed on activated lymphocytes and antigen-presenting cells, has been shown to be a coregulator of antigen-driven T cell responses and is one of the two receptors for measles virus. Here we show that T cell receptor–induced interleukin (IL)-4 secretion by SLAM−/− CD4+ cells is down-regulated, whereas interferon γ production by CD4+ T cells is only slightly up-regulated. Although SLAM controls production of IL-12, tumor necrosis factor, and nitric oxide in response to lipopolysaccharide (LPS) by macrophages, SLAM does not regulate phagocytosis and responses to peptidoglycan or CpG. Thus, SLAM acts as a coreceptor that regulates signals transduced by the major LPS receptor Toll-like receptor 4 on the surface of mouse macrophages. A defective macrophage function resulted in an inability of SLAM−/− C57Bl/6 mice to remove the parasite Leishmania major. We conclude that the coreceptor SLAM plays a central role at the interface of acquired and innate immune responses.
The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease
Authors: Niels Vande Casteele, Reena Khanna, Barrett G Levesque, Larry Stitt, G Y Zou, Sharat Singh, Steve Lockton, Scott Hauenstein, Linda Ohrmund, Gordon R Greenberg, Paul J Rutgeerts, Ann Gils, William J Sandborn, Séverine Vermeire, Brian G Feagan
Journal: Gut (2014)

Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab.In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission.Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 μg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission.The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.
Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system.
Authors: R A Clark, S J Klebanoff
Journal: The Journal of Experimental Medicine (1975)

A cytotoxic effect of human neutrophils on mammalian tumor cells is demonstrated. Cytotoxicity depends on the presence of intact neutrophils, phagocytosable particles, and a halide cofactor and is inhibited by azide, cyanide, and catalase. Neutrophils from patients with myeloperoxidase (MPO) deficiency or defective H1O2 production are not cytotoxic, but activity is resotred by addition of purified MPO or H2O2 respectively. The findings support a mechanism involving the phagocytosis-induced extracellular release of MPO and H2O2 and their reation with a halide cofactor to damage the target cells.
Procontractile G protein–mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling
Authors: Till F. Althoff, Julián Albarrán Juárez, Kerstin Troidl, Cong Tang, Shengpeng Wang, Angela Wirth, Mikito Takefuji, Nina Wettschureck, Stefan Offermanns
Journal: The Journal of Experimental Medicine (2012)

Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G12/G13 and Gq/G11 antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα12/Gα13 or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gαq/Gα11 deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein–mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.