tbuckley/cabot-search huggingface dataset:
Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness
Authors: L M Schachter
Journal: Thorax (2001)

<h3>BACKGROUND</h3> A study was undertaken to assess whether the recent increases in prevalence of both asthma and obesity are linked and to determine if obesity is a risk factor for diagnosed asthma, symptoms, use of asthma medication, or airway hyperresponsiveness. <h3>METHODS</h3> Data from 1971 white adults aged 17–73 years from three large epidemiological studies performed in NSW were pooled. Doctor diagnosis of asthma ever, history of wheeze, and medication use in the previous 12 months were obtained by questionnaire. Body mass index (BMI) in kg/m<sup>2</sup> was used as a measure of obesity. Airway hyperresponsiveness (AHR) was defined as dose of &lt;3.9 μmol histamine required to provoke a fall in forced expiratory volume in one second (FEV<sub>1</sub>) of 20% or more (PD<sub>20</sub>FEV<sub>1</sub>). Adjusted odds ratios (OR) were obtained by logistic regression. <h3>RESULTS</h3> After adjusting for atopy, age, sex, smoking history, and family history, severe obesity was a significant risk factor for recent asthma (OR 2.04, p=0.048), wheeze in the previous 12 months (OR 2.6, p=0.001), and medication use in the previous 12 months (OR 2.83, p=0.005), but not for AHR (OR 0.87, p=0.78). FEV<sub>1</sub> and forced vital capacity (FVC) were significantly reduced in the group with severe obesity, but FEV<sub>1</sub>/FVC ratio, peak expiratory flow (PEF), and mid forced expiratory flow (FEF<sub>25–75</sub>) were not different from the group with normal BMI. The underweight group (BMI &lt;18.5 kg/m<sup>2</sup>) had increased symptoms of shortness of breath, increased airway responsiveness, and reduced FEV<sub>1</sub>, FVC, PEF, and FEF<sub>25–75</sub> with similar use of asthma medication as subjects in the normal weight range. <h3>CONCLUSIONS</h3> Although subjects with severe obesity reported more wheeze and shortness of breath which may suggest a diagnosis of asthma, their levels of atopy, airway hyperresponsiveness, and airway obstruction did not support the suggestion of a higher prevalence of asthma in this group. The underweight group appears to have more significant respiratory problems with a higher prevalence of symptoms, reduced lung function, and increased airway responsiveness without an increase in medication usage. This group needs further investigation.
Rapid Three-Dimensional Echocardiography
Authors: Marek Belohlavek, Kazuaki Tanabe, Decho Jakrapanichakul, Jerome F. Breen, James B. Seward
Journal: Circulation (2001)

Background —Clinical applicability of conventional ultrasonographic systems using mechanical adapters for 3D echocardiographic imaging has been limited by long acquisition and processing times. We developed a rapid (6-s) acquisition technique that collects apical tomograms using a continuously internally rotating transthoracic transducer. This study was performed to examine the clinical feasibility of rapid-acquisition 3D echocardiography to estimate left ventricular end-diastolic and end-systolic volumes using electron-beam computed tomography as the reference standard. Methods and Results —We collected a series of 6 to 11 apical echocardiographic tomograms, depending on heart rate, in 11 patients. There was good correlation, low variability, and low bias between rapid 3D echocardiography and electron-beam computed tomography for measuring left ventricular end-diastolic volume ( r =0.96; standard error of the estimate, 21.34 mL; bias, −4.93 mL) and left ventricular end-systolic volume ( r =0.96; standard error of the estimate, 14.78 mL; bias, −6.97 mL). Conclusions —The rapid-acquisition 3D echocardiography extends the use of a multiplane, internally rotating handheld transducer so that it becomes a precise and clinically feasible tool for assessing left ventricular volumes and function. A rapid-image acquisition time of 6 s would allow repeated image collection during the course of a clinical echocardiographic examination. Additional work must address rapid and automated data processing.
Symptom Experience After Discontinuing Use of Estrogen Plus Progestin
Authors: Judith K Ockene, David H Barad, Barbara B Cochrane, Joseph C Larson, Margery Gass, Sylvia Wassertheil-Smoller, JoAnn E Manson, Vanessa M Barnabei, Dorothy S Lane, Robert G Brzyski, Milagros C Rosal, Judy Wylie-Rosett, Jennifer Hays
Journal: JAMA (2005)

ContextLittle is known about women's experiences after stopping menopausal hormone therapy.ObjectiveTo describe women's symptoms and management strategies after stopping the intervention in a large estrogen plus progestin trial.Design, Setting, and ParticipantsCross-sectional survey of 8405 women (89.9%; N = 9351) at 40 clinical centers who were still taking study pills (conjugated equine estrogens plus medroxyprogesterone [CEE + MPA] or placebo) when the estrogen plus progestin intervention (Women's Health Initiative) was stopped. Surveys were mailed 8 to 12 months after the stop date. Logistic regression was used to model vasomotor symptoms and pain or stiffness symptoms as functions of former treatment and baseline symptoms, adjusted for appropriate covariates.Main Outcome MeasuresSymptoms (vasomotor or pain and stiffness) and management strategies.ResultsRespondents' mean (SD) age at trial stop date was 69.1 (6.7) years. They averaged 5.7 years of taking study pills. Moderate or severe vasomotor symptoms after discontinuing study pill use were reported by 21.2% of former CEE + MPA and 4.8% of placebo group respondents overall and by 55.5% and 21.3%, respectively, with these symptoms at baseline (randomization). Compared with respondents in the former placebo group, moderate or severe vasomotor symptoms (adjusted odds ratio [AOR] 5.82; 95% confidence interval [CI], 4.92-6.89) and pain or stiffness symptoms (AOR, 2.16; 95% CI, 1.95-2.40) were more likely in respondents in the former CEE + MPA group. Both vasomotor symptoms (AOR, 5.36; 95% CI, 4.51-6.38) and pain or stiffness symptoms (AOR, 3.21; 95% CI, 2.90-3.56) also were more likely in women with these symptoms at baseline. Women reported a wide range of strategies to manage symptoms.ConclusionsMore than half of the women with vasomotor symptoms at randomization to active CEE + MPA also reported these symptoms after discontinuing use of the study pills. However, these participants did not include women who were unwilling to be randomized or who had stopped taking the study pills earlier. These findings should be considered when advising women to treat menopausal symptoms with hormone therapy for as short duration as possible. Investigation of alternative strategies to manage menopausal symptoms is warranted.
Thrombospondin-4 Is Required for Stretch-Mediated Contractility Augmentation in Cardiac Muscle
Authors: Oscar H. Cingolani, Jonathan A. Kirk, Kinya Seo, Norimichi Koitabashi, Dong-ik Lee, Genaro Ramirez-Correa, Djahida Bedja, Andreas S. Barth, An L. Moens, David A. Kass
Journal: Circulation Research (2011)

One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism.
Molecular cloning of the major surface antigen of leishmania.
Authors: L L Button, W R McMaster
Journal: The Journal of Experimental Medicine (1988)

The gene encoding gp63, the major surface glycoprotein of Leishmania promastigotes, was isolated from Leishmania major using a synthetic oligonucleotide probe based on the NH2-terminal protein sequence of purified gp63. DNA sequence analysis and the translated amino acid sequence indicate that gp63 is synthesized as precursor molecule having both an NH2-terminal preregion (signal peptide) and an adjacent proregion. This structure is consistent with the protease activity of gp63 since many other proteases are synthesized as precursor forms requiring processing for enzymatic activity. Hybridization studies demonstrated that there are multiple copies of the gp63 gene in the genome of L. major and other Leishmania species. The conservation of the coding sequence of gp63 amongst diverse species of Leishmania provides further support for the importance of gp63 during the life cycle of Leishmania.
Spatial control of the βAR system in heart failure: the transverse tubule and beyond
Authors: Julia Gorelik, Peter T. Wright, Alexander R. Lyon, Sian E. Harding
Journal: Cardiovascular Research (2013)

The beta1-adrenoceptors (β1AR) and beta-2 (β2AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the βAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bio-imaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the βAR. The β2AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of β2AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac βARs. Loss of cellular structure has proved key to the observed loss of confined β2AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal β2AR signalling. At the level of the organ, the expression of the two βAR subtypes varies between regions with the β2AR forming a greater proportion of the βAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated β2AR can signal via Gi protein to produce negatively inotropic effects.
The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance
Authors: Karisa C. Schreck, Pete Taylor, Luigi Marchionni, Vidya Gopalakrishnan, Eli E. Bar, Nicholas Gaiano, Charles G. Eberhart
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one. We investigated whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy. Experimental Design: We used GBM neurosphere lines to investigate the effects of a gamma-secretase inhibitor (MRK-003) on tumor growth, and chromatin immunoprecipitation to study the regulation of other genes by Notch targets. We also evaluated the effect of combined therapy with a Hedgehog inhibitor (cyclopamine) in GBM and medulloblastoma lines, and in primary human GBM cultures. Results: GBM cells are at least partially resistant to long-term MRK-003 treatment, despite ongoing Notch pathway suppression, and show concomitant upregulation of Wnt and Hedgehog activity. The Notch target Hes1, a repressive transcription factor, bound the Gli1 first intron, and may inhibit its expression. Similar results were observed in a melanoma-derived cell line. Targeting Notch and Hedgehog simultaneously induced apoptosis, decreased cell growth, and inhibited colony-forming ability more dramatically than monotherapy. Low-passage neurospheres isolated from freshly resected human GBMs were also highly susceptible to coinhibition of the two pathways, indicating that targeting multiple developmental pathways can be more effective than monotherapy at eliminating GBM-derived cells. Conclusions: Notch may directly suppress Hedgehog via Hes1 mediated inhibition of Gli1 transcription, and targeting both pathways simultaneously may be more effective at eliminating GBMs cells. Clin Cancer Res; 16(24); 6060–70. ©2010 AACR.
Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients
Authors: M.J. BOFFA, A. SMITH, R.J.G. CHALMERS, D.M. MITCHELL, B. ROWAN, T.W. WARNES, M. SHOMAF, N.Y. HABOUBI
Journal: British Journal of Dermatology (1996)

This study was designed to establish whether measurement of a serological marker of fibrosis might reduce the need for liver biopsy in psoriatic patients receiving methotrexate (MTX). Levels of type III procollagen aminopeptide (PIIINP-O and PIIINP-B) and laminin P1 (LamP1-B) were measured in 147 serum samples taken at the time of liver biopsy in 87 patients receiving long-term MTX treatment for severe psoriasis. Biopsies were classified as: (1) normal, (2) steatosis, (3) inflammation, (4) fibrosis, or (5) cirrhosis. Groups 3-5 were considered to show clinically relevant abnormality. Compared with controls, PIIINP-O was significantly raised in the group of MTX-treated psoriatics (P < 0.001). Within this group, levels were significantly higher in patients with inflammation, fibrosis or cirrhosis compared with those with normal histology or steatosis alone (P < 0.0001). In contrast, PIIINP-B and LamP1-B did not distinguish between controls and MTX-treated patients or between histological groups. Forty-two patients had two or more biopsies with simultaneous PIIINP-O measurement. PIIINP-O levels at the time of the first biopsy were normal in six of the seven patients whose histology was initially normal and subsequently became abnormal. A single measurement of PIIINP-O thus did not predict which patients might develop abnormal histology following further MTX. In a group of 17 patients, PIIINP-O was measured 3-monthly for up to 6 years during MTX treatment. PIIINP-O was elevated at some time during follow-up in all three patients who developed abnormal histology but was consistently normal in eight of the 11 patients whose histology remained or became normal. Our findings indicate that PIIINP-O is of value in detecting liver damage and, particularly if measured serially, may reduce the need for liver biopsy in MTX-treated patients. Although the test does not detect all patients with fibrosis, it would appear that the risk of missing significant liver damage in patients with persistently normal PIIINP-O is low.
In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor
Authors: Greta Maria Paola Giordano Attianese, Virna Marin, Valentina Hoyos, Barbara Savoldo, Irene Pizzitola, Sarah Tettamanti, Valentina Agostoni, Matteo Parma, Maurilio Ponzoni, Maria T. S. Bertilaccio, Paolo Ghia, Andrea Biondi, Gianpietro Dotti, Ettore Biagi
Journal: Blood (2011)
Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes
Authors: Siddhartha Jaiswal, Pierre Fontanillas, Jason Flannick, Alisa Manning, Peter V. Grauman, Brenton G. Mar, R. Coleman Lindsley, Craig H. Mermel, Noel Burtt, Alejandro Chavez, John M. Higgins, Vladislav Moltchanov, Frank C. Kuo, Michael J. Kluk, Brian Henderson, Leena Kinnunen, Heikki A. Koistinen, Claes Ladenvall, Gad Getz, Adolfo Correa, Benjamin F. Banahan, Stacey Gabriel, Sekar Kathiresan, Heather M. Stringham, Mark I. McCarthy, Michael Boehnke, Jaakko Tuomilehto, Christopher Haiman, Leif Groop, Gil Atzmon, James G. Wilson, Donna Neuberg, David Altshuler, Benjamin L. Ebert
Journal: New England Journal of Medicine (2014)

The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.
Epidermal growth factor acts as a corticotropin-releasing factor in chronically catheterized fetal lambs.
Authors: D H Polk, M G Ervin, J F Padbury, R W Lam, A L Reviczky, D A Fisher
Journal: Journal of Clinical Investigation (1987)

Epidermal growth factor (EGF) has been reported to stimulate adrenocorticotropin hormone (ACTH), growth hormone and prolactin secretion from pituitary tissue in vitro, and in large doses evokes ACTH secretion in adult sheep in vivo. In order to assess a possible role for EGF in the pituitary hyperfunction characteristic of the in utero fetus, we measured changes in plasma immunoreactive ACTH concentrations after acute administration of saline, purified mouse EGF or synthetic ovine corticotropin releasing factor (CRF) to chronically catheterized fetal sheep. Both CRF and EGF were associated with increases in plasma immunoreactive ACTH concentrations. Peak values 60 min after 10-micrograms injections of either EGF or CRF increased from baseline ACTH values of 61 +/- 11 pg/ml to 191 +/- 37 and 178 +/- 25 pg/ml, respectively. Dose-response studies indicate that at low doses (less than 20 micrograms) EGF is as potent a stimulus for ACTH release as CRF. EGF infusion was not associated with detectable changes in circulating CRF, catecholamines, arginine vasopressin levels, or plasma growth hormone concentrations. We speculate that EGF may be important in the regulation of pituitary function in the developing mammalian fetus.
Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice
Authors: Marine Baptissart, Aurélie Vega, Emmanuelle Martinot, Aurélien J. Pommier, Sander M. Houten, Geoffroy Marceau, Angélique de Haze, Silvère Baron, Kristina Schoonjans, Jean-Marc A. Lobaccaro, David H. Volle
Journal: Hepatology (2014)

Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-α) and TGR5 (G-protein-coupled bile acid receptor 1; GPBAR1). Although both receptors are expressed within the testes, the potential effect of BAs on testis physiology and male fertility has not been explored thus far. Here, we demonstrate that mice fed a diet supplemented with cholic acid have reduced fertility subsequent to testicular defects. Initially, germ cell sloughing and rupture of the blood-testis barrier occur and are correlated with decreased protein accumulation of connexin-43 (Cx43) and N-cadherin, whereas at later stages, apoptosis of spermatids is observed. These abnormalities are associated with increased intratesticular BA levels in general and deoxycholic acid, a TGR5 agonist, in particular. We demonstrate here that Tgr5 is expressed within the germ cell lineage, where it represses Cx43 expression through regulation of the transcriptional repressor, T-box transcription factor 2 gene. Consistent with this finding, mice deficient for Tgr5 are protected against the deleterious testicular effects of BA exposure. Conclusions : These data identify the testis as a new target of BAs and emphasize TGR5 as a critical element in testicular pathophysiology. This work may open new perspectives on the potential effect of BAs on testis physiology during liver dysfunction. (Hepatology 2014;60:1054-1065)
Evaluation of the atrophogenic potential of different glucocorticoids using optical coherence tomography, 20-MHz ultrasound and profilometry; a double-blind, placebo-controlled trial
Authors: M. Coßmann, J. Welzel
Journal: British Journal of Dermatology (2006)

Background Skin atrophy is one of the main side-effects of topical corticosteroid therapy. Although the use of high-frequency ultrasound is an established method that has been studied previously, it allows measurements of the slow-reacting dermal thickness only. Objectives To investigate the decreasing epidermal thickness, which occurs earlier, we used optical coherence tomography (OCT), a high-resolution noninvasive imaging technique, and compared it with 20-MHz ultrasound and profilometry. Patients/methods In this double-blind placebo-controlled trial 20 healthy volunteers applied four different corticosteroids and the cream base formulation as placebo to the volar part of both arms once a day over a 4-week period. The epidermal thickness, the dermal thickness and the skin surface roughness were assessed using OCT, high-frequency ultrasound and profilometry. Results Each of the three methods allowed the detection and monitoring of significant corticosteroid-induced skin atrophy and its reversibility. The changes correlated with the potency of the steroids. The epidermal thickness decreased significantly in all test areas, even in the placebo and the untreated fields. As expected, the reduction in epidermal thickness was more pronounced and could be detected earlier by OCT than the reduction of dermal thickness using ultrasound. The epidermal surface roughness investigated using profilometry showed a slight smoothing. Conclusions OCT allows a simple, fast and noninvasive in vivo measurement of the epidermal thickness. To evaluate the atrophogenic potential of corticosteroids it is more suitable than high-frequency ultrasound as epidermal thickness decreases earlier. In addition, epidermal thickness is a more sensitive indicator of steroid atrophy as the degree of thinning is much higher compared with the dermal atrophy. Profilometry might give further information; however, it would not be suitable for clinical use as the results were generally less pronounced. In the future, OCT might be useful to detect corticosteroid-induced side-effects at the beginning for monitoring the therapy.
Antibody-Based Delivery of Interleukin-2 to Neovasculature Has Potent Activity Against Acute Myeloid Leukemia
Authors: Katrin L. Gutbrodt, Christoph Schliemann, Leonardo Giovannoni, Katharina Frey, Thomas Pabst, Wolfram Klapper, Wolfgang E. Berdel, Dario Neri
Journal: Science Translational Medicine (2013)

Neovascular structures in acute myeloid leukemia can be targeted using a cognate antibody fused to human interleukin-2.