tbuckley/cabot-search huggingface dataset:
FGF10 promotes regional foetal cardiomyocyte proliferation and adult cardiomyocyte cell-cycle re-entry
Authors: Francesca Rochais, Rachel Sturny, Cho-Ming Chao, Karim Mesbah, Michael Bennett, Tim J. Mohun, Saverio Bellusci, Robert G. Kelly
Journal: Cardiovascular Research (2014)

Cardiomyocyte proliferation gradually declines during embryogenesis resulting in severely limited regenerative capacities in the adult heart. Understanding the developmental processes controlling cardiomyocyte proliferation may thus identify new therapeutic targets to modulate the cell-cycle activity of cardiomyocytes in the adult heart. This study aims to determine the mechanism by which fibroblast growth factor 10 (FGF10) controls foetal cardiomyocyte proliferation and to test the hypothesis that FGF10 promotes the proliferative capacity of adult cardiomyocytes.Analysis of Fgf10(-/-) hearts and primary cardiomyocyte cultures reveals that altered ventricular morphology is associated with impaired proliferation of right but not left-ventricular myocytes. Decreased FOXO3 phosphorylation associated with up-regulated p27(kip) (1) levels was observed specifically in the right ventricle of Fgf10(-/-) hearts. In addition, cell-type-specific expression analysis revealed that Fgf10 and its receptor, Fgfr2b, are expressed in cardiomyocytes and not cardiac fibroblasts, consistent with a cell-type autonomous role of FGF10 in regulating regional specific myocyte proliferation in the foetal heart. Furthermore, we demonstrate that in vivo overexpression of Fgf10 in adult mice promotes cardiomyocyte but not cardiac fibroblast cell-cycle re-entry.FGF10 regulates regional cardiomyocyte proliferation in the foetal heart through a FOXO3/p27(kip1) pathway. In addition, FGF10 triggers cell-cycle re-entry of adult cardiomyocytes and is thus a potential target for cardiac repair.
Azithromycin for Prevention of Exacerbations of COPD
Authors: Richard K. Albert, John Connett, William C. Bailey, Richard Casaburi, J. Allen D. Cooper, Gerard J. Criner, Jeffrey L. Curtis, Mark T. Dransfield, MeiLan K. Han, Stephen C. Lazarus, Barry Make, Nathaniel Marchetti, Fernando J. Martinez, Nancy E. Madinger, Charlene McEvoy, Dennis E. Niewoehner, Janos Porsasz, Connie S. Price, John Reilly, Paul D. Scanlon, Frank C. Sciurba, Steven M. Scharf, George R. Washko, Prescott G. Woodruff, Nicholas R. Anthonisen
Journal: New England Journal of Medicine (2011)

Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).
NOMENCLATURE OF THYROID-STIMULATING ANTIBODIES
Authors: D.D. Adams, S. Dirmikis, Deborah Doniach, D.J. El Kabir, R. Hall, H.K. Ibbertson, W.J. Irvine, P. Kendall-Taylor, S.W. Manley, S.Q. Mehdi, D.S. Munro, H.D. Purves, B.R. Smith, R.D.H. Stewart
Journal: The Lancet (1975)
Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia
Authors: R Mani, Y Mao, F W Frissora, C-L Chiang, J Wang, Y Zhao, Y Wu, B Yu, R Yan, X Mo, L Yu, J Flynn, J Jones, L Andritsos, S Baskar, C Rader, M A Phelps, C-S Chen, R J Lee, J C Byrd, L J Lee, N Muthusamy
Journal: Leukemia (2014)
Trimetrexate in Relapsed T-Cell Lymphoma With Skin Involvement
Authors: A. H. Sarris, A. Phan, M. Duvic, J. Romaguera, P. McLaughlin, O. Mesina, K. King, L. J. Medeiros, G. Z. Rassidakis, B. Samuels, F. Cabanillas
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated. PATIENTS AND METHODS: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus. TMTX (200 mg/m 2 ) was given intravenously every 14 days without topical or systemic corticosteroids. Patients who responded received up to 12 doses. RESULTS: Twenty patients were assessable for response. Median age was 59 years (range, 45 to 87 years); 13 patients were men. Three patients had anaplastic large-cell lymphoma, 15 had mycosis fungoides or Sézary syndrome (14 with large-cell transformation), and two had peripheral T-cell lymphoma. Serum lactate dehydrogenase was high in 35%, and beta-2 microglobulin was more than 3.0 mg/L in 35% of patients. The median number of previous regimens was three (range, two to 15) and included MTX in five patients. Disease was refractory to the regimen immediately preceding TMTX in 85% of patients. Responses were complete in one and partial in eight patients (overall response rate, 45%). Two of five patients previously treated with MTX responded. Grade 3 or 4 mucositis was observed after 4%, infection after 3%, neutropenic fever after 6%, neutrophils less than 100/μL after 4%, and platelets less than 10,000/μL after 3% of TMTX doses. CONCLUSION: TMTX is active with acceptable toxicity in this population and merits further investigation.
The utility of tiotropium among patients with chronic obstructive pulmonary disease (COPD): An updated meta-analysis of randomized controlled trials
Authors: Johann Paolo Augusto Almazar, Hazel Delfin, Joel Santiaguel
Journal: European Respiratory Journal (2013)

Tiotropium, an inhaled anticholinergic used in the management of COPD, exhibits an effective bronchodilator response at once-daily dosing. In 2010, the US-FDA issued a statement indicating its cardiovascular safety based on the UPLIFT trial, the largest and longest placebo-controlled trial on Tiotropium. However, there is still question on the drug’s cardiovascular safety, especially in comparison to inhaled LABAs. We determined the efficacy of long-term tiotropium use on mortality, exacerbations, and hospitalizations compared to inhaled LABAs. RCTs among patients with COPD comparing Tiotropium monotherapy with inhaled LABAs with at least 6 months follow-up were identified from different electronic databases and thru handsearching. Data on all-cause mortality, mortality from pulmonary and cardiovascular causes, and rates of hospitalizations and exacerbations were identified. The date of last search is September 7, 2012. Two independent investigators evaluated and extracted relevant data. From 495 studies, 5 trials with a total of 10,759 patients met inclusion criteria. Tiotropium did not reduce all-cause mortality (RR 0.83 95%CI 0.40-1.70), mortality from respiratory causes (RR 0.70 95%CI 0.40-1.25), and mortality from cardiovascular causes (RR 1.57 95%CI 0.86-2.85). Tiotropium significantly decreased the risk for exacerbations (RR 0.91 95%CI 0.85-0.98), and exhibited a trend towards decreased hospitalizations (RR 0.78 95%CI 0.61-1.00).  Tiotropium did not reduce mortality compared to inhaled LABAs. Tiotropium significantly decreased the risk for exacerbations, and showed a trend towards possible decreased hospitalizations.
Tinea Incognito Misdiagnosed as Erythema Migrans
Authors: Henry M. Feder
Journal: New England Journal of Medicine (2000)

To the Editor: A 12-year-old girl presented to her primary care physician with a 6-cm circle of erythema with central clearing on the side of her neck. The patient lived in an area of Connecticut where Lyme disease is endemic. Her physician diagnosed erythema migrans and prescribed amoxicillin (500 mg three times a day for 20 days). After 20 days of antibiotic therapy, the rash had enlarged and contained multiple rings (Figure 1). Her physician thought she had erythema migrans that was unresponsive to amoxicillin therapy. The eruption was mildly pruritic, and the patient had no constitutional symptoms. At this . . .
Divergent expression of delayed rectifier K+ channel subunits during mouse heart development
Authors: D Franco
Journal: Cardiovascular Research (2001)

The repolarization phase of the cardiac action potential is dependent on transmembrane K+ currents. The slow (IKs) and fast (IKr) components of the delayed-rectifier cardiac K+ current are generated by pore-forming α subunits KCNQ1 and KCNH2, respectively, in association with regulatory β-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the β-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that α subunits are homogeneously distributed within the myocardium, whereas the β subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K+ currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential β-subunit distribution.
Homocysteine Induces Endothelial Cell Detachment and Vessel Wall Thickening During Chick Embryonic Development
Authors: Marit J. Boot, Régine P.M. Steegers-Theunissen, Robert E. Poelmann, Liesbeth van Iperen, Adriana C. Gittenberger-de Groot
Journal: Circulation Research (2003)

Homocysteine affects the migration and differentiation of neural crest cells in vitro and can result in neural tube defects in vivo. Furthermore, homocysteine has been described as an important determinant in vascular disease in human adults. However, little is known about the effects of homocysteine on the development of embryonic vessels. In this study, we injected homocysteine (30 micromol/L) into the neural tube lumen of chick embryos at the time point of neural crest cell emigration, and analyzed the effects on the neural crest-derived pharyngeal arch arteries, like the brachiocephalic arteries, and the mesoderm-derived arteries, such as the dorsal aorta. By stage HH35, we observed detachment of the endothelium, decreased expression of the extracellular matrix proteins fibrillin-2, and fibronectin in the pharyngeal arch arteries, whereas the dorsal aorta was identical in homocysteine-neural tube-injected and control embryos. No effect of homocysteine on endothelin-1 mRNA expression was observed. By stage HH40, the brachiocephalic arteries of homocysteine-neural tube-injected embryos displayed a decreased lumen diameter, an increased intima- and media-thickness, and an increased number of actin layers compared with the brachiocephalic arteries in control embryos. We propose that homocysteine affects the neural crest-derived smooth muscle cells and their extracellular matrix proteins in the pharyngeal arch arteries, resulting in an abnormal smooth muscle to endothelial cell interaction, leading to endothelial cell detachment. We suggest that, as in adult life, increased homocysteine concentrations lead to vascular damage in the embryo. This prenatal damage might increase the susceptibility to develop vessel pathology later in life.
Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less
Authors: S-M Lin
Journal: Gut (2005)

<b>Aims:</b> The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC). <b>Patients and methods:</b> A total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed. <b>Results:</b> One, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA <i>v</i> PEI, p = 0.012; RFTA <i>v</i> PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA <i>v</i> PEI, p = 0.031; RFTA <i>v</i> PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA <i>v</i> PEI, p = 0.038; RFTA <i>v</i> PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA <i>v</i> PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA <i>v</i> PEI and PAI, p = 0.035). <b>Conclusions:</b> RFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.
Identification and properties of ATP-sensitive potassium channels in myocytes from rabbit Purkinje fibres
Authors: P Light
Journal: Cardiovascular Research (1999)

Objective: Our goal was to identify the ATP-sensitive potassium (KATP) channels in cardiac Purkinje cells and to document the functional properties that might distinguish them from KATP channels in other parts of the heart. Methods: Single Purkinje cells and ventricular myocytes were isolated from rabbit heart. Standard patch-clamp techniques were used to record action potential waveforms, and whole-cell and single-channel currents. Results: The KATP channel opener levcromakalim (10 μM) caused marked shortening of the Purkinje cell action potential. Under whole-cell voltage-clamp, levcromakalim induced an outward current, which was blocked by glibenclamide (5 μM), in both Purkinje cells and ventricular myocytes. Metabolic poisoning of Purkinje cells with NaCN and 2-deoxyglucose caused a significant shortening of the action potential (control 376±51 ms; 6 min NaCN/2-deoxyglucose 153±21 ms). This effect was reversed with the application of glibenclamide. Inside-out membrane patches from Purkinje cells showed unitary current fluctuations which were inhibited by cytoplasmic ATP with an IC50 of 119 μM and a Hill coefficient of 2.1. This reflects ∼five-fold lower sensitivity to ATP inhibition than for KATP channels from ventricular myocytes under the same conditions. The slope conductance of Purkinje cell KATP channels, with symmetric, 140 mM K+, was 60.1±2.0 pS (mean±SEM). Single-channel fluctuations showed mean open and closed times of 3.6±1.5 ms and 0.41±0.2 ms, respectively, at −60 mV and ∼21°C. At positive potentials, KATP channels exhibited weak inward rectification that was dependent on the concentration of internal Mg2+. Computer simulations, based on the above results, predict significant shortening of the Purkinje cell action potential via activation of KATP channels in the range 1–5 mM cytoplasmic ATP. Conclusions: Purkinje cell KATP channels may represent a molecular isoform distinct from that present in ventricular myocytes. The presence of KATP channels in the Purkinje network suggests that they may have an important influence on cardiac rhythm and conduction during periods of ischemia.
The SH3–SAM Adaptor HACS1 is Up-regulated in B Cell Activation Signaling Cascades
Authors: Yuan Xiao Zhu, Sally Benn, Zhi Hua Li, Ellen Wei, Esther Masih-Khan, Young Trieu, Meenakshi Bali, C. Jane McGlade, Jaime O. Claudio, A. Keith Stewart
Journal: The Journal of Experimental Medicine (2004)

HACS1 is a Src homology 3 and sterile alpha motif domain–containing adaptor that is preferentially expressed in normal hematopoietic tissues and malignancies including myeloid leukemia, lymphoma, and myeloma. Microarray data showed HACS1 expression is up-regulated in activated human B cells treated with interleukin (IL)-4, CD40L, and anti–immunoglobulin (Ig)M and clustered with genes involved in signaling, including TNF receptor–associated protein 1, signaling lymphocytic activation molecule, IL-6, and DEC205. Immunoblot analysis demonstrated that HACS1 is up-regulated by IL-4, IL-13, anti-IgM, and anti-CD40 in human peripheral blood B cells. In murine spleen B cells, Hacs1 can also be up-regulated by lipopolysaccharide but not IL-13. Induction of Hacs1 by IL-4 is dependent on Stat6 signaling and can also be impaired by inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and nuclear factor κB. HACS1 associates with tyrosine-phosphorylated proteins after B cell activation and binds in vitro to the inhibitory molecule paired Ig-like receptor B. Overexpression of HACS1 in murine spleen B cells resulted in a down-regulation of the activation marker CD23 and enhancement of CD138 expression, IgM secretion, and Xbp-1 expression. Knock down of HACS1 in a human B lymphoma cell line by small interfering ribonucleic acid did not significantly change IL-4–stimulated B cell proliferation. Our study demonstrates that HACS1 is up-regulated by B cell activation signals and is a participant in B cell activation and differentiation.
Matrix Embedding Alters the Immune Response Against Endothelial Cells In Vitro and In Vivo
Authors: Heiko Methe, Helen M. Nugent, Adam Groothuis, Philip Seifert, Mohamed H. Sayegh, Elazer R. Edelman
Journal: Circulation (2005)

Background— Endothelial cell (EC) dysfunction represents the first manifestation of atherosclerotic disease. Restoration of endothelium via seeding or transfection is hampered by local alterations in flow, inflammation, and metabolic activation. Perivascular EC matrix implants are shielded from these forces and still control vascular repair. The host immune response to such implants, however, remains largely unknown. We investigated the effect of embedding of ECs within 3-dimensional matrices on host immune responses in vitro and in vivo. Methods and Results— We compared expression of major histocompatibility complex (MHC), costimulatory, and adhesion molecules by free aortic ECs or ECs embedded in Gelfoam matrices by flow-cytometry. T-cell proliferation was assessed by [ 3 H] thymidine incorporation. Humoral immune response (ELISA and FACS analysis) and cellular (histopathology) infiltration were investigated after subcutaneous injection of free porcine aortic ECs (PAEs) or of a Gelfoam/EC block, or after concomitant injection of PAEs adjacent to Gelfoam in rats. Aortic ECs embedded in Gelfoam expressed lower levels of MHC class II, costimulatory, and adhesion molecules compared with free ECs ( P &lt;0.001), and induced 3-fold less proliferation of human CD4 + T-cells ( P &lt;0.0005). Implantation of a Gelfoam/EC block in rats nearly abrogated the immune response with 1.75- to 9.0-fold downregulation in tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1, and PAE-specific immunoglobulin G ( P &lt;0.005) and 3.3- to 4.5-fold reduction in leukocytic tissue infiltration. Injecting PAEs adjacent to Gelfoam induced a significant response comparable to that of free implanted PAEs. Conclusions— Embedding ECs within 3-dimensional matrices alters the host immune response by inhibiting expression of MHC class II, costimulatory, and adhesion molecules, offering the rationale to develop novel therapies for vascular diseases.
Effects of Combination Therapy With Glyburide and Insulin on Serum Lipid Levels in NIDDM Patients With Secondary Sulfonylurea Failure
Authors: Sven G Karlander, Mark KM Gutniak, Suad Efendic
Journal: Diabetes Care (1991)

To compare the long-term effect of combined treatment with insulin and glyburide versus insulin alone on serum lipid levels in non-insulin-dependent diabetic (NIDDM) patients with secondary failure to sulfonylurea therapy.The study was a randomized double-blind placebo-controlled parallel trial with a duration of 325 days. The study was conducted at a referral-based endocrinology clinic. Subjects were a sequential sample of 20 patients with NIDDM with failure to respond to glyburide treatment after at least 1 yr of adequate glucose control with this therapy. The patients were randomized to treatment with insulin and glyburide (IG) or insulin and placebo (IP). Insulin was given twice daily to all patients as a mixture of NPH and regular insulins in dosages aiming at optimal glucose control. Glyburide or placebo was taken before breakfast (7 mg) and dinner (3.5 mg).Mean HbA1c decreased from 11.1% (range 9.8-12.9%) before insulin to 9.1% (range 6.8-11.4%) on day 325 (P less than 0.001) in IG patients and from 10.3% (range 8.4-13.3%) to 9.0% (range 6.3-11.8%) (P less than 0.05) in IP patients. In both groups, there was an increase in high-density lipoprotein cholesterol of approximately 20% lasting throughout the study (P less than 0.01). During the first 83 days of the study, there was a decrease in serum cholesterol (P less than 0.01) and serum triglycerides (P less than 0.05) in both groups. All changes in lipid variables were comparable in magnitude and duration in both treatment with insulin and glyburide in NIDDM patients with secondary sulfonylurea failure improves lipid metabolism to a similar degree as insulin therapy alone.