tbuckley/cabot-search huggingface dataset:
Assessment of coronary artery bypass graft flow by intraoperative Doppler ultrasound technique
Authors: I A SIMPSON, T J SPYT. D J WHEATLEY, S M COBBE
Journal: Cardiovascular Research (1988)

A high frequency (10 MHz) Doppler ultrasound pencil probe was used to estimate flow in coronary artery bypass grafts in vitro and during cardiac surgery. In vitro, increasing the angle of the Doppler transducer in relation to flow caused underestimation of the Doppler derived flow, and using the external rather than internal vessel diameter to calculate cross sectional area caused significant overestimation. This overestimation was considerably greater for the internal mammary artery. Accurate flow estimation was obtained in vitro by the Doppler technique, but considerable variation occurred in patients studied during coronary artery bypass surgery. In conclusion, intraoperative Doppler ultrasound provides a qualitative assessment of phasic flow in coronary artery bypass grafts but is less accurate in quantifying absolute flow in these patients.
Predictors of Long‐Term Renal Outcome in Lupus Nephritis Trials: Lessons Learned from the Euro‐Lupus Nephritis Cohort
Authors: Maria Dall'Era, Miriam G. Cisternas, Dawn E. Smilek, Laura Straub, Frédéric A. Houssiau, Ricard Cervera, Brad H. Rovin, Meggan Mackay
Journal: Arthritis & Rheumatology (2015)

There is a need to determine which response measures in lupus nephritis trials are most predictive of good long-term renal function. We used data from the Euro-Lupus Nephritis Trial to evaluate the performance of proteinuria, serum creatinine (Cr), and urinary red blood cells (RBCs) as predictors of good long-term renal outcome.Patients from the Euro-Lupus Nephritis Trial with proteinuria, serum Cr, and urinary RBC measurements at 3, 6, or 12 months and with a minimum of 7 years of followup were included (n = 76). We assessed the ability of these clinical biomarkers at 3, 6, and 12 months after randomization to predict good long-term renal outcome (defined as a serum Cr value ≤1.0 mg/dl) at 7 years. Receiver operating characteristic curves were generated to assess parameter performance at these time points and to select the best cutoff for individual parameters. Sensitivity and specificity were calculated for the parameters alone and in combination.A proteinuria value of <0.8 gm/day at 12 months after randomization was the single best predictor of good long-term renal function (sensitivity 81% and specificity 78%). The addition of serum Cr to proteinuria as a composite predictor did not improve the performance of the outcome measure; addition of urinary RBCs as a predictor significantly decreased the sensitivity to 47%.This study demonstrates that the level of proteinuria at 12 months is the individual best predictor of long-term renal outcome in patients with lupus nephritis. Inclusion of urinary RBCs as part of a composite outcome measure actually undermined the predictive value of the trial data. We therefore suggest that urinary RBCs should not be included as a component of clinical trial response criteria in lupus nephritis.
Decreased Presynaptic Dopamine Function in the Left Caudate of Depressed Patients With Affective Flattening and Psychomotor Retardation
Authors: Marie-Laure Paillère Martinot, Véronique Bragulat, Eric Artiges, Frédéric Dollé, Françoise Hinnen, Roland Jouvent, Jean-Luc Martinot
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The study assessed striatal presynaptic dopamine function in patients with different subtypes of depression. METHOD: Magnetic resonance imaging and positron emission tomography with [18F]fluorodopa ([18F]DOPA) were used to compare six depressed patients with marked affective flattening and psychomotor retardation, six depressed patients with marked impulsivity and anxiety, and 10 healthy comparison subjects. Depressed patient groups were matched for severity of depression. RESULTS: [18F]DOPA uptake Ki values in the left caudate were significantly lower in patients with psychomotor retardation than in patients with high impulsivity and in comparison subjects. CONCLUSIONS: These results suggest that left caudate dopamine function differs between depressed patients with psychomotor retardation and those with impulsivity and provide direct evidence of a link between dopamine hypofunction and psychomotor retardation in depression.
Oxidized Low-Density Lipoprotein–Dependent Endothelial Arginase II Activation Contributes to Impaired Nitric Oxide Signaling
Authors: Sungwoo Ryoo, Christopher A. Lemmon, Kevin G. Soucy, Gaurav Gupta, Anthony R. White, Daniel Nyhan, Artin Shoukas, Lewis H. Romer, Dan E. Berkowitz
Journal: Circulation Research (2006)

Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, and contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates NO levels in endothelial cells by competing with NO synthase for the substrate l-arginine. In human aortic endothelial cells, OxLDL stimulation increased arginase enzyme activity in a time- and dose-dependent manner. Arginase activity reached its maximum as early as 5 minutes, was maintained for a period of more than 48 hours, and was associated with a reciprocal decrease in NO metabolite (NOx [nitrite and nitrate]) production. Furthermore, OxLDL induced arginase II mRNA expression after 4 hours. Small interfering RNA targeted to arginase II decreased both the quantity and the activity of arginase from baseline, prevented OxLDL-dependent increases in arginase activity, and induced an increase in NOx production. Immunofluorescence analysis revealed an association of arginase II with the microtubule cytoskeleton. Microtubule disruption with nocodazole caused a dramatic redistribution of arginase II to a diffuse cytosolic pattern, increased arginase activity, and decreased NOx production, which was restored in the presence of the specific arginase inhibitor (S)-(2-boronoethyl)-l-cysteine (BEC). On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx. Preincubation of rat aortic rings with OxLDL resulted in an increase in arginase activity and a decrease in NOx production. This was reversed by arginase inhibition with the BEC. Thus, OxLDLs increase arginase activity by a sequence of regulatory events that involve early activation through decreased association with microtubules and a later increase in transcription. Furthermore, increased arginase activity contributes to OxLDL-dependent impairment of NOx production. Arginase, therefore, represents a novel target for therapy in atherosclerosis.
UK urges more flexibility in criteria for flu pandemic alerts
Authors: A. O'Dowd
Journal: BMJ (2009)

Greater flexibility and additional information are needed when deciding whether to declare a flu pandemic, a delegation of countries have told the World Health Organization.

The United Kingdom proposed at this week’s World Health Assembly in Geneva that a phase 6 alert—the top level—should reflect the severity of a new virus and not just its geographical spread.

Speaking at the assembly the health secretary, Alan Johnson, said that WHO should not just be driven by a purely “mechanistic approach” but should also be able to use emerging knowledge about the severity of the disease and other considerations before taking the decision to move a flu pandemic alert to phase 6.

Mr Johnson told WHO’s general secretary, Margaret Chan: “It is my belief we need to give you and your team more flexibility as to whether we move to phase 6.”

Dr …
Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli
Authors: William Renthal, Ian Maze, Vaishnav Krishnan, Herbert E. Covington, Guanghua Xiao, Arvind Kumar, Scott J. Russo, Ami Graham, Nadia Tsankova, Tod E. Kippin, Kerry A. Kerstetter, Rachael L. Neve, Stephen J. Haggarty, Timothy A. McKinsey, Rhonda Bassel-Duby, Eric N. Olson, Eric J. Nestler
Journal: Neuron (2007)
Discovery and biochemical characterisation of four novel biomarkers for osteoarthritis
Authors: Dominique de Seny, Mohammed Sharif, Marianne Fillet, Gaël Cobraiville, Marie-Alice Meuwis, Raphaël Marée, Jean-Philippe Hauzeur, Louis Wehenkel, Edouard Louis, Marie-Paule Merville, John Kirwan, Clio Ribbens, Michel Malaise
Journal: Annals of the Rheumatic Diseases (2011)

Objective Knee osteoarthritis (OA) is a heterogeneous, complex joint pathology of unknown aetiology. Biomarkers have been widely used to investigate OA but currently available biomarkers lack specificity and sensitivity. Therefore, novel biomarkers are needed to better understand the pathophysiological processes of OA initiation and progression. Methods Surface enhanced laser desorption/ionisation-time of flight-mass spectrometry proteomic technique was used to analyse protein expression levels in 284 serum samples from patients with knee OA classified according to Kellgren and Lawrence (K&amp;L) score (0–4). OA serum samples were also compared to serum samples provided by healthy individuals (negative control subjects; NC; n=36) and rheumatoid arthritis (RA) patients (n=25). Proteins that gave similar signal in all K&amp;L groups of OA patients were ignored, whereas proteins with increased or decreased levels of expression were selected for further studies. Results Two proteins were found to be expressed at higher levels in sera of OA patients at all four K&amp;L scores compared to NC and RA, and were identified as V65 vitronectin fragment and C3fpeptide. Of the two remaining proteins, one showed increased expression (unknown protein at m/z of 3762) and the other (identified as connective tissue-activating peptide III protein) was decreased in K&amp;L scores &gt;2 subsets compared to NC, RA and K&amp;L scores 0 or 1 subsets. Conclusion The authors detected four unexpected biomarkers (V65 vitronectin fragment, C3f peptide, CTAP-III and m/z 3762 protein) that could be relevant in the pathophysiological process of OA as having significant correlation with parameters reflecting local inflammation and bone remodelling, as well as decrease in cartilage turnover.
Slow Viral Infections
Authors: B R Brooks, B Jubelt, J R Swarz, R T Johnson
Journal: Annual Review of Neuroscience (1979)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Expression Pattern Shifts Following Duplication Indicative of Subfunctionalization and Neofunctionalization in Regulatory Genes of Arabidopsis
Authors: Jill M. Duarte, Liying Cui, P. Kerr Wall, Qing Zhang, Xiaohong Zhang, Jim Leebens-Mack, Hong Ma, Naomi Altman, Claude W. dePamphilis
Journal: Molecular Biology and Evolution (2005)

Gene duplication plays an important role in the evolution of diversity and novel function and is especially prevalent in the nuclear genomes of flowering plants. Duplicate genes may be maintained through subfunctionalization and neofunctionalization at the level of expression or coding sequence. In order to test the hypothesis that duplicated regulatory genes will be differentially expressed in a specific manner indicative of regulatory subfunctionalization and/or neofunctionalization, we examined expression pattern shifts in duplicated regulatory genes in Arabidopsis. A two-way analysis of variance was performed on expression data for 280 phylogenetically identified paralogous pairs. Expression data were extracted from global expression profiles for wild-type root, stem, leaf, developing inflorescence, nearly mature flower buds, and seedpod. Gene, organ, and gene by organ interaction (G x O) effects were examined. Results indicate that 85% of the paralogous pairs exhibited a significant G x O effect indicative of regulatory subfunctionalization and/or neofunctionalization. A significant G x O effect was associated with complementary expression patterns in 45% of pairwise comparisons. No association was detected between a G x O effect and a relaxed evolutionary constraint as detected by the ratio of nonsynonymous to synonymous substitutions. Ancestral gene expression patterns inferred across a Type II MADS-box gene phylogeny suggest several cases of regulatory neofunctionalization and organ-specific nonfunctionalization. Complete linkage clustering of gene expression levels across organs suggests that regulatory modules for each organ are independent or ancestral genes had limited expression. We propose a new classification, regulatory hypofunctionalization, for an overall decrease in expression level in one member of a paralogous pair while still having a significant G x O effect. We conclude that expression divergence specifically indicative of subfunctionalization and/or neofunctionalization contributes to the maintenance of most if not all duplicated regulatory genes in Arabidopsis and hypothesize that this results in increasing expression diversity or specificity of regulatory genes after each round of duplication.
Phase I and Pharmacologic Study of PKI166, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients with Advanced Solid Malignancies
Authors: Ronald Hoekstra, Herlinde Dumez, Ferry A.L.M. Eskens, Ate van der Gaast, Andre S.T. Planting, Gerda de Heus, Kurt C. Sizer, Christina Ravera, Sujata Vaidyanathan, Corazon Bucana, Isaiah J. Fidler, Allan T. van Oosterom, Jaap Verweij
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies. Experimental Design: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after single and multiple doses at all dose levels. Results: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166 once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed. Stable disease for more than two cycles was observed in 11 patients. Conclusions: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once daily for 2 weeks every 4 weeks.
Intravascular survival of red cells coated with a mutated human anti-D antibody engineered to lack destructive activity
Authors: Kathryn L. Armour, David R. Parry-Jones, Nigel Beharry, James R. Ballinger, Rosey Mushens, R. Keith Williams, Cynthia Beatty, Simon Stanworth, Paul Lloyd-Evans, Marion Scott, Michael R. Clark, A. Michael Peters, Lorna M. Williamson
Journal: Blood (2005)
Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes
Authors: Lalantha Leelarathna, Stuart A. Little, Emma Walkinshaw, Horng Kai Tan, Alexandra Lubina-Solomon, Kavita Kumareswaran, Annette P. Lane, Thomas Chadwick, Sally M. Marshall, Jane Speight, Daniel Flanagan, Simon R. Heller, James A.M. Shaw, Mark L. Evans
Journal: Diabetes Care (2013)

Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial.
Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D4 and methacholine in mild asthma
Authors: R I Ketchell, M D'Amato, M W Jensen, Brian O'Connor
Journal: Thorax (2002)

<b>Background:</b> Cysteinyl leukotrienes (cysteinyl-LTs) have been implicated in the pathogenesis of allergen induced airway responses. Airway responsiveness (AR) to inhaled cysteinyl-LTs is dramatically increased following allergen challenge in animal studies. The effect in man has not been evaluated. <b>Methods:</b> Ten mild steroid-naïve asthmatic subjects with an isolated early asthmatic response (EAR) and 21 with an additional late asthmatic response (LAR) took part in a randomised controlled crossover study to assess AR to inhaled methacholine (MCh) and cysteinyl-LT D<sub>4</sub> (LTD<sub>4</sub>) 22 and 24 hours, respectively, after allergen challenge. Eight subjects had two further LTD<sub>4</sub> challenges separated by a 2 week washout period to assess the reproducibility of inhaled LTD<sub>4</sub> challenge. <b>Results:</b> In subjects with an isolated EAR, non-significant mean (SE) increases in AR of 0.4 (0.4) doubling doses (DD) for MCh and 0.4 (0.5) DD for LTD<sub>4</sub> followed allergen challenge compared with control. A significant correlation between AR to MCh and LTD<sub>4</sub> followed both control (<i>r</i>=0.91, 95% CI 0.67 to 0.98; p=0.0002) and allergen challenge (<i>r</i>=0.79, 95% CI 0.32 to 0.95; p=0.0063). In subjects with an additional LAR there was a significant increase in AR to MCh (1.2 (0.3) DD, p=0.0005) following allergen challenge but no overall effect on AR to LTD<sub>4</sub> (0.69 (0.4) DD, p=0.11). A significant correlation between AR to MCh and LTD<sub>4</sub> was again observed (<i>r</i>=0.70; 95% CI 0.38 to 0.87; p=0.0004) following control, although it was reduced following allergen challenge (<i>r</i>=0.48; 95% CI 0.063 to 0.76; p=0.027). LTD<sub>4</sub> challenge was highly reproducible with a mean difference of 0.2 (0.3) DD between challenges. <b>Conclusions:</b> Allergen challenge significantly increases AR to inhaled MCh but not to LTD<sub>4</sub> in subjects with LAR. The lack of a comparable increase in AR to LTD<sub>4</sub> is surprising. Endogenous cysteinyl-LTs are produced in abundance following allergen challenge and may enhance AR to MCh or induce a degree of tachyphylaxis to LTD<sub>4</sub>.
Preparing raw clinical data for publication: guidance for journal editors, authors, and peer reviewers
Authors: I. Hrynaszkiewicz, M. L Norton, A. J Vickers, D. G Altman
Journal: BMJ (2010)

Many peer reviewed journals now require authors to be prepared to share their raw, unprocessed data with other scientists or state the availability of raw data in published articles, but little information on how such data should be prepared for sharing has emerged. <b>Iain Hrynaszkiewicz and colleagues</b> propose a minimum standard for de-identifying datasets to ensure patient privacy when sharing clinical research data
Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis
Authors: Frédéric R. Santer, Nicole Bacher, Barbara Moser, Dieter Morandell, Sigrun Ressler, Sue M. Firth, Gilles A. Spoden, Consolato Sergi, Robert C. Baxter, Pidder Jansen-Dürr, Werner Zwerschke
Journal: Cancer Research (2006)

Abstract Insulin-like growth factor binding protein-3 (IGFBP-3), the product of a tumor suppressor target gene, can modulate cell proliferation and apoptosis by IGF-I-dependent and IGF-I-independent mechanisms. IGFBP-3 controls the bioavailability of IGFs in the extracellular environment and is known to be subject to degradation by various extracellular proteases. Although nuclear localization and functions of IGFBP-3 have been described in the past, we show as the novel features of this study that the abundance of nuclear IGFBP-3 is directly regulated by ubiquitin/proteasome–dependent proteolysis. We show that IGFBP-3 degradation depends on an active ubiquitin-E1 ligase, specific 26S proteasome inhibitors can efficiently stabilize nuclear IGFBP-3, and the metabolic half-life of nuclear IGFBP-3 is strongly reduced relative to cytoplasmic IGFBP-3. Nuclear IGFBP-3 is highly polyubiquitinated at multiple lysine residues in its conserved COOH-terminal domain and stabilized through mutation of two COOH-terminal lysine residues. Moreover, we show that IGFBP-3, if ectopically expressed in the nucleus, can induce apoptotic cell death. These results suggest that ubiquitin/proteasome–mediated proteolysis of IGFBP-3 may contribute to down-regulation of apoptosis. (Cancer Res 2006; 66(6): 3024-33)
High-Resolution Magnetic Resonance Imaging of Disparities in the Transcapillary Transfer Rates in Orthotopically Inoculated Invasive Breast Tumors
Authors: Maya Dadiani, Raanan Margalit, Noa Sela, Hadassa Degani
Journal: Cancer Research (2004)

Abstract In vivo mapping of the transcapillary fluxes in tumors can help predict the efficacy of delivery of blood-borne anticancer drugs. These fluxes are primarily affected by the vascular permeability and the pressure gradients across the blood vessels’ walls. We describe herein high-resolution dynamic contrast-enhanced magnetic resonance imaging of the influx and outflux transcapillary transfer rates in vivo in invasive MDA-MB-231 tumors orthotopically inoculated in severe combined immunodeficient mice. The tumors were noted for rapid growth, impaired drainage of fluid, and subsequent formation of cysts. Consequently, the time evolution of the contrast enhancement, induced by i.v. injection of Gadolinium diethylene-triamine-penta-acetate, exhibited two distinct patterns: transcapillary transfer in the cellular regions and simple diffusion in the cyst fluid. Both processes were analyzed at pixel resolution applying to each a physiological model and a corresponding algorithm. In the cellular region, the influx and outflux transcapillary transfer rates decreased during tumor growth; however, an increased disparity between the transfer constants was observed, with the outflux rate exceeding the influx rate. This quantitative spatial and temporal mapping of this disparity can provide a means to assess the physiological barriers to tracer delivery. It is hypothesized that both the increased disparity in transcapillary transfer rates and impaired fluid drainage in these tumors could arise from the development of interstitial hypertension.