tbuckley/cabot-search huggingface dataset:
The role of haemoglobin mass on VO<sub>2</sub>max following normobaric ‘live high–train low’ in endurance-trained athletes
Authors: Paul Robach, Christoph Siebenmann, Robert A Jacobs, Peter Rasmussen, Nikolai Nordsborg, Dominik Pesta, Erich Gnaiger, Víctor Díaz, Andreas Christ, Julia Fiedler, Nadine Crivelli, Niels H Secher, Aurélien Pichon, Marco Maggiorini, Carsten Lundby
Journal: British Journal of Sports Medicine (2012)

It remains unclear by which mechanism ‘live high–train low’ (LHTL) altitude training increases exercise performance. Haematological and skeletal muscle adaptations have both been proposed. To test the hypotheses that (i) LHTL improves maximal oxygen uptake (VO 2 max) and (ii) this improvement is related to hypoxia-induced increases in total haemoglobin mass (Hb mass ) and not to improved maximal oxidative capacity of skeletal muscle, we determined VO 2 max before LHTL and after LHTL, before and after the altitude-induced increases in Hb mass (measured by carbon-monoxide rebreathing) had been abolished by isovolumic haemodilution. We obtained skeletal muscle biopsies to quantify mitochondrial oxidative capacity and efficiency. Sixteen endurance-trained athletes were assigned (double-blinded, placebo controlled) to ≥16 h/day over 4 weeks to normoxia (placebo, n=6) or normobaric hypoxia equivalent to 3000 m altitude (LHTL, n=10). Four-week LHTL did not increase VO 2 max, irrespective of treatment (LHTL: 1.5%; placebo: 2.0%). Hb mass was slightly increased (4.6%) in 5 (of 10) LHTL subjects but this was not accompanied by a concurrent increase in VO 2 max. In the subjects demonstrating an increase in Hb mass , isovolumic haemodilution elicited a 5.8% decrease in VO 2 max. Cycling efficiency was altered neither with time nor by LHTL. Neither maximal capacity of oxidative phosphorylation nor mitochondrial efficiency was modified by time or LHTL. The present results suggest that LHTL has no positive effect on VO 2 max in endurance-trained athletes because (i) muscle maximal oxidative capacity is not improved following LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O 2 transport.
Digital computers versus dynamical systems: A conflation of distinctions
Authors: Gerard O'Brien
Journal: Behavioral and Brain Sciences (1998)

The distinction at the heart of van Gelder's target article is one between digital computers and dynamical systems, but this distinction conflates two more fundamental distinctions in cognitive science that should be kept apart. When this conflation is undone, it becomes apparent that the computational hypothesis is not as dominant in contemporary cognitive science as van Gelder contends; nor has the dynamical hypothesis been neglected.
Myeloperoxidase Is an Early Biomarker of Inflammation and Cardiovascular Risk in Prepubertal Obese Children
Authors: Josune Olza, Concepcion M. Aguilera, Mercedes Gil-Campos, Rosaura Leis, Gloria Bueno, Maria D. Martínez-Jiménez, Miguel Valle, Ramon Cañete, Rafael Tojo, Luis A. Moreno, Angel Gil
Journal: Diabetes Care (2012)

Obesity is associated with a state of chronic low-grade inflammation. Myeloperoxidase (MPO) plays an important role in the initiation and progression of acute and chronic inflammatory diseases, such as cardiovascular disease (CVD). The objectives of the current study were to evaluate plasma MPO levels in prepubertal obese children and to determine whether MPO could be an early biomarker of inflammation and CVD risk.In a prospective multicenter case-control study paired by age and sex of 446 Caucasian prepubertal children ages 6-12 years, 223 normal-weight and 223 obese children were recruited. Blood pressure, waist circumference, weight, and height were measured. In addition to MPO, glucose, insulin, metabolic lipid parameters, oxidized low-density lipoproteins, adiponectin, leptin, resistin, C-reactive protein (CRP), interleukin 6, tumor necrosis factor α, matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor 1 were determined.We found that MPO was elevated in prepubertal obese children and that this enzyme was associated with such proinflammatory and cardiovascular risk biomarkers as CRP, MMP-9, and resistin. Insulin resistance calculated by the homeostatic assessment model was the best predictor of MPO.MPO is an early biomarker of inflammation associated with CVD risk in obese children at the prepubertal age.
Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction
Authors: Liming Wang, Jun Yin, Hannah T. Nickles, Hannes Ranke, Arata Tabuchi, Julia Hoffmann, Christoph Tabeling, Eduardo Barbosa-Sicard, Marc Chanson, Brenda R. Kwak, Hee-Sup Shin, Songwei Wu, Brant E. Isakson, Martin Witzenrath, Cor de Wit, Ingrid Fleming, Hermann Kuppe, Wolfgang M. Kuebler
Journal: Journal of Clinical Investigation (2012)

Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40–/–). In vivo, hypoxemia was more severe in Cx40–/– mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40–/–, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner.
Molecular Imaging of the Cardiac Extracellular Matrix
Authors: Hans J. de Haas, Eloisa Arbustini, Valentin Fuster, Christopher M. Kramer, Jagat Narula
Journal: Circulation Research (2014)

In almost all cardiac diseases, an increase in extracellular matrix (ECM) deposition or fibrosis occurs, mostly consisting of collagen I. Whereas replacement fibrosis follows cardiomyocyte loss in myocardial infarction, reactive fibrosis is triggered by myocardial stress or inflammatory mediators and often results in ventricular stiffening, functional deterioration, and development of heart failure. Given the importance of ECM deposition in cardiac disease, ECM imaging could be a valuable clinical tool. Molecular imaging of ECM may help understand pathology, evaluate impact of novel therapy, and may eventually find a role in predicting the extent of ECM expansion and development of personalized treatment. In the current review, we provide an overview of ECM imaging including the assessment of ECM volume and molecular targeting of key players involved in ECM deposition and degradation. The targets comprise myofibroblasts, intracardiac renin-angiotensin axis, matrix metalloproteinases, and matricellular proteins.
Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway
Authors: Narasimman Gurusamy, Istvan Lekli, Subhendu Mukherjee, Diptarka Ray, Md. Kaimul Ahsan, Mihaela Gherghiceanu, Lawrence M. Popescu, Dipak K. Das
Journal: Cardiovascular Research (2009)

AimsOn the basis of our previous reports that cardioprotection induced by ischaemic preconditioning induces autophagy and that resveratrol, a polyphenolic antioxidant present in grapes and red wine induces preconditioning-like effects, we sought to determine if resveratrol could induce autophagy.
mRNA Expression of BRCA1, PIAS1, and PIAS4 and Survival After Second-line Docetaxel in Advanced Gastric Cancer
Authors: Jia Wei, Carlota Costa, Yitao Ding, Zhengyun Zou, Lixia Yu, Jose Javier Sanchez, Xiaoping Qian, Hong Chen, Ana Gimenez-Capitan, Fanqing Meng, Teresa Moran, Susana Benlloch, Miquel Taron, Rafael Rosell, Baorui Liu
Journal: JNCI Journal of the National Cancer Institute (2011)

Breast cancer susceptibility gene 1 (BRCA1) has a central role in chemotherapy-induced DNA damage response. The protein inhibitor of activated STAT (PIAS) family of proteins, PIAS1 and PIAS4, are also necessary for adequate DNA damage repair. To further understand the role of BRCA1 in DNA repair, we examined the mRNA expression of these genes in 133 advanced (stage III-IV) gastric cancer patients using quantitative reverse transcription polymerase chain reaction. All P values were two-sided. The median overall survival was 12.5 months (95% confidence interval [CI] = 9.8 to 13.4 months). Among 59 patients receiving second-line docetaxel, the median overall survival was 25.8 months (95% CI = 9.2 to 42.4 months) for patients with high BRCA1 expression, 19.1 months (95% CI = 3.4 to 34.8 months) for those with intermediate expression, and 9.5 months (95% CI = 8.7 to 10.2 months) for those with low expression (P = .0062). The risk of mortality was higher in patients with low BRCA1 levels compared with high BRCA1 levels (hazard ratio of death = 2.49, 95% CI = 1.03 to 5.97, P = .037). Survival in patients receiving second-line docetaxel-based chemotherapy showed a similar trend with PIAS1 and PIAS4 mRNA expression levels, although the associations for PIAS4 were not statistically significant.
Effect of Common <i>CYP3A4</i> and <i>CYP3A5</i> Variants on the Pharmacokinetics of the Cytochrome <i>P</i>450 3A Phenotyping Probe Midazolam in Cancer Patients
Authors: Erin R. Lepper, Sharyn D. Baker, Matt Permenter, Nicole Ries, Ron H.N. van Schaik, Paul W. Schenk, Douglas K. Price, Danielle Ahn, Nicola F. Smith, George Cusatis, Roxann G. Ingersoll, Susan E. Bates, Ron H.J. Mathijssen, Jaap Verweij, William D. Figg, Alex Sparreboom
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe. Experimental Design: Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using noncompartmental analysis. Genomic DNA was characterized for the variants by PCR-RFLP, and all genotypes were confirmed by direct nucleotide sequencing. Results: The mean clearance of midazolam was 24.4 ± 9.12 L/h, and phenotypic CYP3A activity varied about 4-fold in this population (range, 10.8-44.3 L/h). There were six carriers of the CYP3A4*1B allele (allele frequency, 0.061). No variant alleles for CYP3A4*17, CYP3A4*18A, or CYP3A5*6 were identified. Forty-eight of the 58 patients were homozygous variant for CYP3A5*3C, eight were heterozygous, and two were homozygous wild type (allele frequency, 0.897). No associations were noted between any of the studied genotypes and the phenotypic measures (P ≥ 0.16). Likewise, a common variant in exon 26 in the gene encoding P-glycoprotein [i.e., ABCB1 (MDR1) 3435C&amp;gt;T] that was previously reported to be linked to CYP3A4 mRNA levels was unrelated to any of the studied phenotypic measures (P ≥ 0.49). Conclusions. The studied genetic variants in CYP3A4 and CYP3A5 are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer.
Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding
Authors: Thomas Gevaert, Joris Vriens, Andrei Segal, Wouter Everaerts, Tania Roskams, Karel Talavera, Grzegorz Owsianik, Wolfgang Liedtke, Dirk Daelemans, Ilse Dewachter, Fred Van Leuven, Thomas Voets, Dirk De Ridder, Bernd Nilius
Journal: Journal of Clinical Investigation (2007)

Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4-/- mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4-/- mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4-/- mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4-/- mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure.
Apoptosis in primary cutaneous amyloidosis
Authors: Y.T. CHANG, C.K. WONG, K.C. CHOW, C.H. TSAI
Journal: British Journal of Dermatology (1999)

Amyloid deposits in primary cutaneous amyloidosis (PCA) may be initially derived from cytokeratin. possibly after keratinocyte death. However, the mechanism of keratinocyte death remains obscure. To investigate the potential role of apoptosis in the pathogenesis of PCA, a retrospective study was conducted on the skin tissues from 20 Chinese patients with PCA. We used a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) method for detecting the apoptotic cells. Immunohistochemical staining was performed to examine the expression of the B-cell leukemia/lymphoma-2 gene (bcl-2) and Fas. Apoptotic cells were shown in 11 of 20 cases (55%) by TUNEL. Histological sections showed that dyskeratotic cells and vacuolar alteration of the basal cells were more commonly observed in the TUNEL-positive group. In all cases of PCA, epidermal expression of bcl-2 was minimal, while expression of Fas was observed on keratinocytes in the basal to granular layers: however, these findings were not different from those in normal skin. Our results suggest that the keratinocyte destruction in PCA may occur as an initial result of apoptosis, which in turn leads to the amyloid formation.
Neurotrophin p75 Receptor (p75 <sup>NTR</sup> ) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis
Authors: Andrea Caporali, Elisabetta Pani, Anton J.G. Horrevoets, Nicolle Kraenkel, Atsuhiko Oikawa, Graciela B. Sala-Newby, Marco Meloni, Brunella Cristofaro, Gallia Graiani, Aurelie S. Leroyer, Chantal M. Boulanger, Gaia Spinetti, Sung Ok Yoon, Paolo Madeddu, Costanza Emanueli
Journal: Circulation Research (2008)

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75 NTR ), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75 NTR expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75 NTR gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75 NTR depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin] , BIRC5 (survivin ), PTTG 1 ( securin ) and VEZF1 . Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75 NTR . Collectively, our data newly demonstrate the antiangiogenic action of p75 NTR and open new avenues for the therapeutic use of p75 NTR inhibition to combat diabetes-induced microvascular liabilities.
The hypthalamo-tectoperiaqueductal system: Unconscious underpinnings of conscious behaviour
Authors: Ralf-Peter Behrendt
Journal: Behavioral and Brain Sciences (2007)

The insight that, in terms of behaviour control, the mesodiencephalic system is superordinate to the cortex should have profound implications for behavioural sciences. Nevertheless, the thalamocortical system could still be deemed an “organ of consciousness” if we came to accept that consciousness is not central to purposeful behaviour, in accordance with instinct theory. Philosophically, Merker's concepts of basic consciousness and ego-centre warrant critical discussion.
Mechanisms of NO/cGMP-Dependent Vasorelaxation
Authors: Matthias Sausbier, Rudolf Schubert, Viktor Voigt, Christoph Hirneiss, Alexander Pfeifer, Michael Korth, Thomas Kleppisch, Peter Ruth, Franz Hofmann
Journal: Circulation Research (2000)

Abstract —Both cGMP-dependent and -independent mechanisms have been implicated in the regulation of vascular tone by NO. We analyzed acetylcholine (ACh)- and NO-induced relaxation in pressurized small arteries and aortic rings from wild-type (wt) and cGMP kinase I–deficient (cGKI –/– ) mice. Low concentrations of NO and ACh decreased the spontaneous myogenic tone in wt but not in cGKI –/– arteries. However, contractions of cGKI –/– arteries and aortic rings were reduced by high concentrations (10 μmol/L) of 2-( N , N -diethylamino)-diazenolate-2-oxide (DEA-NO). Iberiotoxin, a specific blocker of Ca 2+ -activated K + (BK Ca ) channels, only partially prevented the relaxation induced by DEA-NO or ACh in pressurized vessels and aortic rings. DEA-NO increased the activity of BK Ca channels only in vascular smooth muscle cells isolated from wt cGKI +/+ mice. These results suggest that low physiological concentrations of NO decrease vascular tone through activation of cGKI, whereas high concentrations of DEA-NO relax vascular smooth muscle independent of cGKI and BK Ca . NO-stimulated, cGKI-independent relaxation was antagonized by the inhibition of soluble guanylyl cyclase or cAMP kinase (cAK). DEA-NO increased cGMP to levels that are sufficient to activate cAK. cAMP-dependent relaxation was unperturbed in cGKI –/– vessels. In conclusion, low concentrations of NO relax vessels by activation of cGKI, whereas in the absence of cGKI, NO can relax small and large vessels by cGMP-dependent activation of cAK.
Nutrition in Pediatrics—Basic Science and Clinical Application
Authors: S C LING, L T WEAVER
Journal: Gut (1998)

Nutrition in Pediatrics—Basic Science and Clinical Application. 2nd edn. Edited by Walker WA, Watkins JB. (Pp 850; illustrated; price not given.) Hamilton: BC Decker Inc, 1996. ISBN 1-55009-026-7.

Readers of Gut might feel that paediatric nutrition is not among their main interests, but for those who seek to know what is happening in this closely allied field, through scientific curiosity or a desire to expand their clinical horizons, this book is a good starting point. Edited by two American paediatricians who have been energetic and influential in establishing paediatric gastroenterology as a distinct subspecialty, this book aims to do the same for paediatric nutrition. We believe …
Retrovirus-mediated IL-7 expression in leukemic dendritic cells generated from primary acute myelogenous leukemias enhances their functional properties
Authors: Concha Bello-Fernández, Jana Stasakova, Alexander Renner, Nicole Carballido-Perrig, Margit Koening, Martina Waclavicek, Otto Madjic, Leopold Oehler, Oskar Haas, José M. Carballido, Michael Buschle, Walter Knapp
Journal: Blood (2003)
Primary pulmonary lymphangiectasia in infancy and childhood
Authors: P.M. Barker, C.R. Esther, L.A. Fordham, S.J. Maygarden, W.K. Funkhouser
Journal: European Respiratory Journal (2004)

Primary pulmonary lymphangiectasia (PPL) is a rare disorder of unknown aetiology characterised by dilatation of the pulmonary lymphatics. PPL is widely reported to have a poor prognosis in the neonatal period and little is known about the clinical features of patients who survive the newborn period. The current authors report the outcome in nine patients diagnosed in infancy with PPL over a 15-yr period at a single university-based hospital clinic and followed for a median of 6 yrs. Although all of the patients initially experienced respiratory distress, respiratory symptoms improved in most patients after infancy and were notably better by the age of 6 yrs. Many patients had poor weight gain in the first years of life, which eventually improved. Radiological scans showed progressive resolution of neonatal infiltrates, but were characterised by hyperinflation and increased interstitial markings in older children. Most patients had evidence of bronchitis and grew pathogenic organisms from quantitative bronchoalveolar lavage culture. Pulmonary function tests showed predominantly obstructive disease that did not deteriorate over time. In conclusion, these results suggest that primary pulmonary lymphangiectasia does not have as dismal a prognosis as previously described and symptoms and clinical findings improve after the first year of life.
TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets
Authors: Libing Song, Liping Liu, Zhiqiang Wu, Yun Li, Zhe Ying, Chuyong Lin, Jueheng Wu, Bo Hu, Shi-Yuan Cheng, Mengfeng Li, Jun Li
Journal: Journal of Clinical Investigation (2012)

The strength and duration of NF-κB signaling are tightly controlled by multiple negative feedback mechanisms. However, in cancer cells, these feedback loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses IκBα expression and leads to hyperactivation of NF-κB. Here, we report that miR-182 was overexpressed in a different set of gliomas with relatively lower miR-30e* expression and that miR-182 directly suppressed cylindromatosis (CYLD), an NF-κB negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-κB signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo. Furthermore, we found that TGF-β induced miR-182 expression, leading to prolonged NF-κB activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-β hyperactivation and activated NF-κB in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained NF-κB activation in malignant gliomas and may suggest a new target for clinical intervention in human cancer.
Upper Extremity Venous Thrombosis With Pulmonary Embolism
Authors: G. Patrick Clagett
Journal: JAMA (1974)

A patient with a hypercoagulable state developed axillary-subclavian vein thrombosis with pulmonary embolism following excretory urography. Venous stasis, thrombocytosis, and endothelial injury from intravenous contrast media are incriminated in the pathogenesis of this complication. The effect of iothalamate sodium and diatrizoate meglumine-sodium (Renografin 76), on platelet aggregation was investigated and found not to induce platelet aggregation. Heparin sodium therapy should be considered prior to intravenous injection of contrast media in patients who have thrombocytosis.