tbuckley/cabot-search huggingface dataset:
Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction
Authors: Yasushi Sakata, Kazuhiro Yamamoto, Toshiaki Mano, Nagahiro Nishikawa, Junichi Yoshida, Takeshi Miwa, Masatsugu Hori, Tohru Masuyama
Journal: Cardiovascular Research (2003)

Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident.Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks.Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings' upregulation.This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.
Variants in Nicotinic Receptors and Risk for Nicotine Dependence
Authors: Laura Jean Bierut, Jerry A. Stitzel, Jen C. Wang, Anthony L. Hinrichs, Richard A. Grucza, Xiaoling Xuei, Nancy L. Saccone, Scott F. Saccone, Sarah Bertelsen, Louis Fox, William J. Horton, Naomi Breslau, John Budde, C. Robert Cloninger, Danielle M. Dick, Tatiana Foroud, Dorothy Hatsukami, Victor Hesselbrock, Eric O. Johnson, John Kramer, Samuel Kuperman, Pamela A.F. Madden, Kevin Mayo, John Nurnberger, Ovide Pomerleau, Bernice Porjesz, Oliver Reyes, Marc Schuckit, Gary Swan, Jay A. Tischfield, Howard J. Edenberg, John P. Rice, Alison M. Goate
Journal: American Journal of Psychiatry (2008)

Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor ( CHRNA5 ). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4 , and the risk of smoking. Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.
Heparin‐like anticoagulants in asthma
Authors: E. C. Lasser, R. A. Simon, S. G. Lyon, A. E. Hamblin, R. Stein
Journal: Allergy (1987)

In a previous study, and in the present study, we have found that the baseline plasma samples of patients with asthma contain average levels of an endogenous heparin‐like material (EHM) that is significantly higher than that noted in non‐allergic, non‐asthmatic controls. This material appears to have properties of both heparin and heparan sulfate. Three out of six patients responding to inhalational antigen challenge displayed an acute increment in EHM concentration that coincided with a fall in FEV 1 values. The relation of EHM concentration to provoked asthma, or to asthma in general, remains to be determined.
A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)
Authors: Edgar R. Wood, Anne T. Truesdale, Octerloney B. McDonald, Derek Yuan, Anne Hassell, Scott H. Dickerson, Byron Ellis, Christopher Pennisi, Earnest Horne, Karen Lackey, Krystal J. Alligood, David W. Rusnak, Tona M. Gilmer, Lisa Shewchuk
Journal: Cancer Research (2004)

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.
Nimesulide: clinical and histological evidences of severe hepatotoxicity
Authors: F. Bessone, L. Colombato, M.E. Passamonti, J. Ferrer, A. Godoy, H. Bagnulo, J. Grignola, M. Rondan, F. Villamil, C. Guma, I. Gierer, J. Vorobioff, N. Domínguez, E. Fassio, H. Tanno
Journal: Journal of Hepatology (2001)
Characterization of 46 patient-specific BCR-ABL1 fusions and detection of SNPs upstream and downstream the breakpoints in chronic myeloid leukemia using next generation sequencing
Authors: Jana Linhartova, Lenka Hovorkova, Simona Soverini, Adela Benesova, Monika Jaruskova, Hana Klamova, Jan Zuna, Katerina Machova Polakova
Journal: Molecular Cancer (2015)

In chronic myeloid leukemia, the identification of individual BCR-ABL1 fusions is required for the development of personalized medicine approach for minimal residual disease monitoring at the DNA level. Next generation sequencing (NGS) of amplicons larger than 1000 bp simplified and accelerated a process of characterization of patient-specific BCR-ABL1 genomic fusions. NGS of large regions upstream and downstream the individual breakpoints in BCR and ABL1 genes, respectively, also provided information about the sequence variants such are single nucleotide polymorphisms.
Inhibition of Nitrobenzylthioinosine-Sensitive Adenosine Transport by Elevated <scp>d</scp> -Glucose Involves Activation of P <sub>2Y2</sub> Purinoceptors in Human Umbilical Vein Endothelial Cells
Authors: Jorge Parodi, Carlos Flores, Claudio Aguayo, M. Isolde Rudolph, Paola Casanello, Luis Sobrevia
Journal: Circulation Research (2002)

Chronic incubation with elevated d -glucose reduces adenosine transport in endothelial cells. In this study, exposure of human umbilical vein endothelial cells to 25 mmol/L d -glucose or 100 μmol/L ATP, ATP-γ-S, or UTP, but not ADP or α,β-methylene ATP, reduced adenosine transport with no change in transport affinity. Inhibition of transport by d -glucose, ATP, and ATP-γ-S was associated with reduced maximal binding, with no changes in the apparent dissociation constant for nitrobenzylthioinosine (NBMPR). A significant reduction (≈60±10%, P &lt;0.05; n=6) in the number of human equilibrative NBMPR-sensitive nucleoside transporters (hENT1s) per cell (1.8±0.1×10 6 in 5 mmol/L d -glucose) and in hENT1 mRNA levels was observed in cells exposed to d -glucose or ATP-γ-S. Incubation with elevated d -glucose, but not with d -mannitol, increased the ATP release by 3±0.2-fold . The effects of d -glucose and nucleotides on the number and activity of hENT1 and hENT1 mRNA were blocked by reactive blue 2 (nonspecific P 2Y purinoceptor antagonist), suramin (Gα s protein inhibitor), or hexokinase but not by pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (nonselective P 2 purinoceptor antagonist). Our findings demonstrate that inhibition of adenosine transport via hENT1 in endothelial cells cultured in 25 mmol/L d -glucose could be due to stimulation of P 2Y2 purinoceptors by ATP, which is released from these cells in response to d -glucose. This could be a mechanism to explain in part the vasodilatation observed in the early stages of diabetes mellitus or in response to d -glucose infusion.
The relationship between variable region determinants and antigen specificity on mitogen reactive B cell subsets.
Authors: D Primi, F Mami, C Le Guern, P A Cazenave
Journal: The Journal of Experimental Medicine (1982)

On the basis of previous frequency determinations we could set up large numbers of cultures, each containing less than one competent precursor B cell specific for beta-galactosidase or for each of three idiotopes previously found on a monoclonal anti-beta-galactosidase antibody. Cultures were polyclonally activated by either lipopolysaccharide or Nocardia-delipidated cell mitogen. Each culture supernatant was individually tested for hemagglutination activity against sheep erythrocytes coupled with beta-galactosidase or with each of the three purified monoclonal anti-idiotypic antibodies. The results showed that only a minority of those clones positive for only one or two idiotopes recognized antigen. However, all those clones simultaneously positive for the three V region determinants recognized beta-galactosidase. The implications of these results for our understanding of the relationship between the antigen-binding site and idiotope expression are discussed.
Response to Open Peer Commentaries on “Trans Fat Bans and Human Freedom”
Authors: David Resnik
Journal: The American Journal of Bioethics (2010)

Click to increase image sizeClick to decrease image size Acknowledgments This article is not subject to US copyright law. This research was supported by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). The views expressed in this article are solely the views of the author. They do not represent the opinions of the NIEHS, NIH, or the U.S. government. I am grateful to Chris Portier and Bill Schrader for helpful comments.
Making cycle helmets compulsory: ethical arguments for legislation
Authors: A. Sheikh, A. Cook, R. Ashcroft
Journal: Journal of the Royal Society of Medicine (2004)

For both medical and social reasons, there is strong interest in promoting the use of the pedal cycle in Britain. First, regular cycling is beneficial to health; second, cycling is one of the most ecologically friendly modes of transportation.1,2 An important obstacle to wider use of bicycles, however, is public concern about safety3—especially the risk of death and disability from head injury. An increasing body of research suggests that the risk of serious head injury can be substantially lessened by use of a cycle helmet,4 and for the past decade cyclists have been urged to adopt this protective measure; yet rates of usage in Britain remain disappointingly poor.5 Thus, some authorities suggest that the British Government should follow several other countries and make the use of cycle helmets mandatory.6 In this paper, we consider the ethical and moral arguments for and against helmet legislation.
Sucessful treatment of severe bone pain and acute arthritis in chronic myelomonocytic leukaemia by cytosine arabinoside.
Authors: D Douer, A Weinberger, M Djaldetti, J Pinkhas, None De Vries
Journal: Annals of the Rheumatic Diseases (1977)

An elderly patient with chronic myelomonocytic leukaemia developed severe bone pains and acute gonarthritis. Intravenously administered cytosine arabinoside brought dramatic relief of the bone pains and led to a rapid subsidence of the arthritis, without achieving haematological remission.
Altered expression of genes involved in hepatic morphogenesis and fibrogenesis are identified by cDNA microarray analysis in biliary atresia
Authors: Limin Chen, Andrew Goryachev, Jin Sun, Peter Kim, Hui Zhang, James M. Phillips, Pascale Macgregor, Sylvie Lebel, Aled M. Edwards, Qiongfang Cao, Katryn N. Furuya
Journal: Hepatology (2003)

Biliary atresia (BA) is characterized by a progressive, sclerosing, inflammatory process that leads to cirrhosis in infancy. Although it is the most common indication for liver transplantation in early childhood, little is known about its etiopathogenesis. To elucidate factors involved in this process, we performed comprehensive genome–wide gene expression analysis using complementary DNA (cDNA) microarrays. We compared messenger RNA expression levels of approximately 18,000 human genes from normal, diseased control, and end–stage BA livers. Reverse–transcription polymerase chain reaction (RT–PCR) and Northern blot analysis were performed to confirm changes in gene expression. Cluster and principal component analysis showed that all BA samples clustered together, forming a distinct group well separated from normal and diseased controls. We further identified 35 genes and ESTs whose expression differentiated BA from normal and diseased controls. Most of these genes are known to be associated with cell signaling, transcription regulation, hepatic development, morphogenesis, and fibrogenesis. In conclusion, this study serves to delineate processes that are involved in the pathogenesis of BA.
A Living Fossil in the Genome of a Living Fossil: Harbinger Transposons in the Coelacanth Genome
Authors: J. J. Smith, K. Sumiyama, C. T. Amemiya
Journal: Molecular Biology and Evolution (2011)

Emerging data from the coelacanth genome are beginning to shed light on the origin and evolution of tetrapod genes and noncoding elements. Of particular relevance is the realization that coelacanth retains active copies of transposable elements that once served as raw material for the evolution of new functional sequences in the vertebrate lineage. Recognizing the evolutionary significance of coelacanth genome in this regard, we employed an ab initio search strategy to further classify its repetitive complement. This analysis uncovered a class of interspersed elements (Latimeria Harbinger 1—LatiHarb1) that is a major contributor to coelacanth genome structure and gene content (∼1% to 4% or the genome). Sequence analyses indicate that 1) each ∼8.7 kb LatiHarb1 element contains two coding regions, a transposase gene and a gene whose function is as yet unknown (MYB-like) and 2) copies of LatiHarb1 retain biological activity in the coelacanth genome. Functional analyses verify transcriptional and enhancer activities of LatiHarb1 in vivo and reveal transcriptional decoupling that could permit MYB-like genes to play functional roles not directly linked to transposition. Thus, LatiHarb1 represents the first known instance of a harbinger-superfamily transposon with contemporary activity in a vertebrate genome. Analyses of LatiHarb1 further corroborate the notion that exaptation of anciently active harbinger elements gave rise to at least two vertebrate genes (harbi1 and naif1) and indicate that the vertebrate gene tsnare1 also traces its ancestry to this transposon superfamily. Based on our analyses of LatiHarb1, we speculate that several functional features of harbinger elements may predispose the transposon superfamily toward recurrent exaptive evolution of cellular coding genes. In addition, these analyses further reinforce the broad utility of the coelacanth genome and other "outgroup" genomes in understanding the ancestry and evolution of vertebrate genes and genomes.
Platelets Play an Essential Role in Separating the Blood and Lymphatic Vasculatures During Embryonic Angiogenesis
Authors: Laura Carramolino, Joana Fuentes, Clara García-Andrés, Valeria Azcoitia, Dieter Riethmacher, Miguel Torres
Journal: Circulation Research (2010)

Rationale : Several mutations that impair the development of blood lineages in the mouse also impair the formation of the lymphatic vasculature and its separation from the blood vasculature. However, the basis for these defects has remained unknown because the mutations characterized affect more than one blood lineage. Objective : We tested the hypothesis that megakaryocytes/platelets are required for the formation of the lymphatic vasculature and its separation from the blood vascular system. Methods and Results : We characterized the vascular patterning defects of mice deficient for the homeodomain transcription factor Meis1 (myeloid ecotropic viral integration site 1), which completely lack megakaryocyte/platelets. Meis1 null embryos fail to separate the blood and lymphatic vasculature, showing blood-filled primary lymphatic sacs and superficial lymphatic vessels. To test the involvement of megakaryocytes/platelets in this phenotype, we generated megakaryocyte/platelet-specific deficient mice by targeted lineage ablation, without affecting other blood lineages. This model reproduces the lymphatic/blood vasculature separation defects observed in Meis1 mutants. A similar phenotype was induced by antibody-mediated ablation of circulating platelets in wild type mice. Strong association of platelets with vascular endothelium at regions of contact between lymphatic sacs and veins confirmed a direct role of platelets in the separation of the 2 vasculatures. Conclusions : In addition to their known protective function in the response accidental vascular injury, platelets are also required during embryonic lymphangiogenesis for the separation of the nascent lymphatic vasculature from blood vessels.
Body mass index and asthma incidence among USA adults
Authors: E.S. Ford
Journal: European Respiratory Journal (2004)

The aim of this study was to examine the association between body mass index (BMI) and asthma incidence. Data from the baseline examination conducted during 1971-1975, and the first follow-up conducted during 1982-1984, of the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (a cohort study) was used. Asthma was self-reported or reported by proxies. BMI was calculated from measured height and weight obtained during the baseline examination. Among 9,456 participants aged 25-74 yrs who were free of asthma at baseline, 317 participants reported a diagnosis of asthma during the follow-up interview. Compared with participants with a BMI of 18.5-<25.0 kg.m(-2), the odds ratio (OR) for those with a BMI of > or =35 kg x m(-2) was 1.87 (95% confidence interval (CI) 1.12-3.13). ORs were similar for males and females. However, only 125 of the 298 participants who recalled a date of onset reported a diagnosis that occurred after their baseline examination. Among this group of participants, BMI was not significantly associated with asthma incidence (OR 1.52, 95% CI 0.62-3.77). In conclusion, although obese people reported more "incident" asthma during follow-up, it remains unclear whether this represents reactivation of previously diagnosed asthma or the onset of new cases, and whether these new cases actually represent true asthma or respiratory symptoms misdiagnosed as asthma.
Pulmonary hypertension in COPD: results from the ASPIRE registry
Authors: Judith Hurdman, Robin Condliffe, Charlie A. Elliot, Andrew Swift, Smitha Rajaram, Christine Davies, Catherine Hill, Neil Hamilton, Iain J. Armstrong, Catherine Billings, Lauren Pollard, Jim M. Wild, Allan Lawrie, Rod Lawson, Ian Sabroe, David G. Kiely
Journal: European Respiratory Journal (2012)

The phenotype and outcome of severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is described in small numbers, and predictors of survival are unknown. Data was retrieved for 101 consecutive, treatment-naïve cases of pulmonary hypertension in COPD. Mean ± SD follow-up was 2.3 ± 1.9 years. 59 patients with COPD and severe pulmonary hypertension, defined by catheter mean pulmonary artery pressure ≥40 mmHg, had significantly lower carbon monoxide diffusion, less severe airflow obstruction but not significantly different emphysema scores on computed tomography compared to 42 patients with mild-moderate pulmonary hypertension. 1- and 3-year survival for severe pulmonary hypertension, at 70% and 33%, respectively, was inferior to 83% and 55%, respectively, for mild-moderate pulmonary hypertension. Mixed venous oxygen saturation, carbon monoxide diffusion, World Health Organization functional class and age, but not severity of airflow obstruction, were independent predictors of outcome. Compassionate treatment with targeted therapies in 43 patients with severe pulmonary hypertension was not associated with a survival benefit, although improvement in functional class and/or fall in pulmonary vascular resistance >20% following treatment identified patients with improved survival. Standard prognostic markers in COPD have limited value in patients with pulmonary hypertension. This study identifies variables that predict outcome in this phenotype. Despite poor prognosis, our data suggest that further evaluation of targeted therapies is warranted.
The intramural coronary artery: another cause for sudden death with exercise?
Authors: M D Cheitlin
Journal: Circulation (1980)

SUDDEN DEATH, the ultimate complication, is generally thought of in the context of coronary artery disease.Most studies of the total experience with death that occurs suddenly and unexpectedly and is not associated with trauma conclude that about 90% are associated with pathologically significant coronary atherosclerosis.1Sudden death in young people, especially while engaging in strenuous physical activity, is a rare and always shocking, tragic event.The causes of sudden unexpected death in young people are more varied and appear to be increasing.In this issue of Circulation, Morales, Romanelli and Boucek report three cases of sudden death that occurred during severe exercise.Autopsy revealed evidence of previous myocardial fibrosis and necrosis, which they attributed to myocardial bridging of the left anterior descending coronary artery and, in the third case, also of the right coronary artery.So we add to the short list of known causes of sudden death in young people the myocardial muscle bridge, sometimes referred to as an intramural cor- onary artery.The evidence presented to support this explanation, with the exception of the first case, is based entirely on the pathologic findings at autopsy.Unequivocally, all three patients had a portion of their left anterior descending coronary artery pass in-