tbuckley/cabot-search huggingface dataset:
Diminished inotropic response of aged myocardium to catecholamines.
Authors: E G Lakatta, G Gerstenblith, C S Angell, N W Shock, M L Weisfeldt
Journal: Circulation Research (1975)

The effect of advanced age on the response of active tension, maximal rate of tension development (dT/dt), and contraction duration to catecholamines and to calcium was evaluated in isometric trabeculae carneae from young adult (6-month-old), middle-aged (12-month-old), and aged (25-month-old) rats. Control values were not age dependent except for that for contraction duration which was prolonged in the aged group. At a norepinephrine concentration of 8 times 10-5M, dT/dt increased to 163.8 plus or minus 5.3% of control in the young adult group and to 125.9 plus or minus 6.3% of control in the aged group (P smaller than 0.001). Active tension increased to 121.3 plus or minus 4.0% of control in the young adult muscles but did not increase in the aged muscles (P smaller than 0.01). Contraction duration shortened proportionately in both age groups. Similar results were obtained with isoproterenol. In contrast to the response to catecholamines, there was no age difference in the response of active tension and dT/dt to increasing concentrations of calcium. It is concluded that the intrinsic inotropic response to catecholamines is diminished in the aged myocardium. This finding does not appear to result from differences in tachyphylaxis, tissue uptake of catecholamines, or the ability of the contractile proteins to respond to increasing concentrations of calcium but instead may result from a decreased ability of catecholamines to increase the intracellular calcium available for contraction.
Comparison of initial lymphoma staging using computed tomography (CT) and magnetic resonance (MR) imaging
Authors: B. Richard Hoane, Anthony F. Shields, Bruce A. Porter, James W. Borrow
Journal: American Journal of Hematology (1994)

While MR is known to be superior to other imaging methods for detecting marrow involvement by lymphoma, MR is also capable of detecting abnormal lymph nodes. Our objective was to determine whether MR employing short TI inversion recovery (STIR) was comparable to CT in the initial staging of 23 patients with Hodgkin's disease (12 patients) and non-Hodgkin's lymphoma (11 patients). MR images of chest, abdomen, pelvis, and femoral marrow were obtained using the STIR and T1-weighted spin-echo (T1-SE) techniques, employing a protocol initially designed for marrow assessment. In all cases, CT-detected adenopathy was also found by MR. Four patients had marrow involvement by MR, undetected by CT. We conclude that MR and CT may be equivalent imaging modalities in the detection of nodal involvement, and that MR has an advantage in its ability to diagnose marrow involvement. Given the high frequency of focal marrow abnormalities detected by MR in patients with Hodgkin's disease and high-grade non-Hodgkin's lymphoma, MR may be the preferred staging modality for these patients.
Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells
Authors: M. Contoli, K. Ito, A. Padovani, D. Poletti, B. Marku, M. R. Edwards, L. A. Stanciu, G. Gnesini, A. Pastore, A. Spanevello, P. Morelli, S. L. Johnston, G. Caramori, A. Papi
Journal: Allergy (2015)

Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown.We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed.Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3.IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
Sunitinib Inhibition of Stat3 Induces Renal Cell Carcinoma Tumor Cell Apoptosis and Reduces Immunosuppressive Cells
Authors: Hong Xin, Chunyan Zhang, Andreas Herrmann, Yan Du, Robert Figlin, Hua Yu
Journal: Cancer Research (2009)

Abstract The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an antiangiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. To improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with signal transducer and activator of transcription 3 (Stat3) activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances the antitumor effects of sunitinib, whereas expression of a constitutively activated Stat3 mutant rescues tumor cell death. Intravital multiphoton microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor–associated myeloid-derived suppressor cells (MDSC), down-regulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits the direct proapoptotic activity of sunitinib on tumor cells and positive effects on tumor immunologic microenvironment. [Cancer Res 2009;69(6):2506–13]
Perinatal Loss of Nkx2-5 Results in Rapid Conduction and Contraction Defects
Authors: Laura E. Briggs, Morihiko Takeda, Adolfo E. Cuadra, Hiroko Wakimoto, Melissa H. Marks, Alexandra J. Walker, Tsugio Seki, Suk P. Oh, Jonathan T. Lu, Colin Sumners, Mohan K. Raizada, Nobuo Horikoshi, Ellen O. Weinberg, Kenji Yasui, Yasuhiro Ikeda, Kenneth R. Chien, Hideko Kasahara
Journal: Circulation Research (2008)

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na + channel pore-forming α-subunit (Na v 1.5-α), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca 2+ for contraction (conduction–contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca 2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.
Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells
Authors: Hamida Hammad, Mirjam Kool, Thomas Soullié, Shuh Narumiya, François Trottein, Henk C. Hoogsteden, Bart N. Lambrecht
Journal: The Journal of Experimental Medicine (2007)

Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D2 binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3+ CD4+ regulatory T cells that suppressed inflammation in an interleukin 10–dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP–dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.
Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase
Authors: John F. Kurland, William P. Tansey
Journal: Cancer Research (2008)

Myc is a transcription factor that features prominently in cancer. The oncogenicity of Myc stems from its ability to regulate expression of genes required for cell growth and proliferation. Although the mechanisms through which Myc activates transcription have been extensively studied, less is known about how Myc represses transcription. Recently, we reported that a conserved element within Myc-MbIII- is important for transcriptional repression. Here, we investigate the mechanism through which MbIII contributes to repression. We show that Myc represses transcription of target genes Id2 and Gadd153 by a process that involves histone deacetylation. We show that MbIII is important for repression of these genes and present evidence that this element contributes to repression by recruiting the histone deacetylase HDAC3 to the Id2 and Gadd153 promoters. These results describe a mechanistic role for MbIII in transcription, and reveal that recruitment of HDAC3 is a process by which Myc represses gene activity.
Randomized Dose Ranging Study of the Reduction of Fasting and Postprandial Glucose in Type 2 Diabetes by Nateglinide (A-4166)
Authors: Fiona M. Gribble, Susan E. Manley, Jonathan C. Levy
Journal: Diabetes Care (2001)

This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal.A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min.The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide.A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.
ANTIBLASTIC PHENOMENA IN ACTIVE ACQUIRED IMMUNITY AND IN NATURAL IMMUNITY TO PNEUMOCOCCUS
Authors: M. A. Barber
Journal: The Journal of Experimental Medicine (1919)

The paper gives the results of a series of experiments made with a special technique for the purpose of testing whether or not so called antiblastic phenomena or bactericidal phenomena play any part in immunity to pneumococcus. The technique employed is that devised by the writer and consists in the isolation of single bacteria and their growth in hanging drops where growth can be continuously observed. From these experiments it may be concluded that: (1) Whole fresh blood, coagulated plasma, or serum of the immunized horse added directly to pneumococci, has considerable inhibiting action on the growth of pneumococci. The inhibiting effect of the fresh blood, coagulated plasma, or serum of a normal horse, however, is as marked as that of a horse highly immunized to pneumococci of the same type. This property, therefore, does not seem to be of importance in acquired immunity in the horse. No such property has been demonstrated in whole fresh rabbit blood. (2) It has been impossible to demonstrate that antiblastic phenomena play any part in natural immunity to pneumococcus, at least as far as the immunity of the pigeon is concerned. The whole fresh blood of the pigeon under the conditions employed exhibits no inhibiting action on the growth rate of pneumococci.
CRT IN MILD HEART FAILURE: RESPONSE IN RELATION TO HEART FAILURE ETIOLOGY? 24 MONTH RESULTS FROM THE RESYNCHRONISATION REVERSES REMODELLING IN SYSTOLIC LEFT VENTRICULAR DYSFUNCTION (REVERSE) STUDY
Authors: Cecilia Linde, William T. Abraham, Michael R. Gold, Martin St. John Sutton, Stefano Ghio, Jean Claude Daubert
Journal: Journal of the American College of Cardiology (2010)
mTOR as a Molecular Target in HPV-Associated Oral and Cervical Squamous Carcinomas
Authors: Alfredo A. Molinolo, Christina Marsh, Mohamed El Dinali, Nitin Gangane, Kaitlin Jennison, Stephen Hewitt, Vyomesh Patel, Tanguy Y. Seiwert, J. Silvio Gutkind
Journal: Clinical Cancer Research (2012)

The incidence of head and neck squamous cell carcinomas (HNSCC) associated with human papillomavirus (HPV) infection has increased over the past decades in the United States. We aimed at examining the global impact of HPV-associated HNSCC and whether the established key role of mTOR activation in HNSCC is also observed in HPV(+) HNSCC lesions, thereby providing novel treatment options for HPV-associated HNSCC patients.An international HNSCC tissue microarray (TMA) was used to analyze the expression of p16(INK4A), a surrogate for HPV infection, and Akt-mTOR pathway activation. Results were confirmed in a large collection of HPV(-) and HPV(+) HNSCC cases and in a cervical cancer (CCSCC) TMA. Observations were validated in HNSCC and CCSCC-derived cell lines, which were xenografted into immunodeficient mice for tumorigenesis assays.Approximately 20% of all HNSCC lesions could be classified as HPV(+), irrespective of their country of origin. mTOR pathway activation was observed in most HPV(+) HNSCC and CCSCC lesions and cell lines. The preclinical efficacy of mTOR inhibition by rapamycin and RAD001 was explored in HPV(+) HNSCC and CCSCC tumor xenografts. Both mTOR inhibitors effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden. These results emphasize the emerging global impact of HPV-related HNSCCs and indicate that the activation of the mTOR pathway is a widespread event in both HPV(-) and HPV-associated HNSCC and CCSCC lesions.The emerging results may provide a rationale for the clinical evaluation of mTOR inhibitors as a molecular targeted approach for the treatment of HPV-associated malignancies.
ROLE OF THE CLOTTING SYSTEM IN CELL-MEDIATED HYPERSENSITIVITY
Authors: Robert B. Colvin, Richard A. Johnson, Martin C. Mihm, Harold F. Dvorak
Journal: The Journal of Experimental Medicine (1973)

The expression of delayed-type hypersensitivity in animals has been inhibited by a variety of anticoagulants, but direct evidence for activation of clotting in the evolution of these reactions has been lacking. Using the fluorescent antibody technique we here demonstrate that fibrin deposition is a prominent and consistent feature of both allergic contact dermatitis and classic delayed hypersensitivity skin reactions in man. Fib was detected in 55 of 58 delayed reactions studied at the peak of their intensity. The characteristic distribution of Fib-principally in the intervascular portions of the reticular dermis with sparing of vessels and their associated cuffs of mononuclear cells-is unusual and quite different from that described in antibody-mediated lesions in animals or man. Fib was found in vessel walls in only 2 of 94 biopsies studied. With a single exception, deposition of immunoglobulins and complement was not observed. The pathogensis and significance of Fib deposition in these reactions are not yet clear. Fib is ultimately derived from circulating fibrinogen, and its accumulation provides additional evidence for locally increased vascular permeability in delayed hypersensitivity. Polymerization of extravascular fibrinogen could be triggered nonspecifically by dermal elements (e.g., collagen) or by a product of sensitized lymphocytes. The appearance of Fib early in the development of these reactions (4-8 h after epicutaneous test with DNCB) and inhibition studies with anticoagulants together suggest that clotting may have a role in their pathogenesis, possibly by the release of bioactive peptides from fibrinogen/fibrin or by contributing to the induration characteristic of delayed hypersensitivity.
Smoking Affects Response to Inhaled Corticosteroids or Leukotriene Receptor Antagonists in Asthma
Authors: Stephen C. Lazarus, Vernon M. Chinchilli, Nancy J. Rollings, Homer A. Boushey, Reuben Cherniack, Timothy J. Craig, Aaron Deykin, Emily DiMango, James E. Fish, Jean G. Ford, Elliot Israel, James Kiley, Monica Kraft, Robert F. Lemanske, Frank T. Leone, Richard J. Martin, Gene R. Pesola, Stephen P. Peters, Christine A. Sorkness, Stanley J. Szefler, Michael E. Wechsler, John V. Fahy
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control.To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke.In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast.Primary outcome was change in prebronchodilator FEV(1) in smokers versus nonsmokers. Secondary outcomes included peak flow, PC(20) methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV(1), bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV(1) (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers.In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.
Response to a randomized trial of methotrexate vs. azathioprine for severe atopic eczema: a critical appraisal
Authors: M.E. Schram, E. Roekevisch, M.M.G. Leeflang, J.D. Bos, J. Schmitt, P.I. Spuls
Journal: British Journal of Dermatology (2012)

Journal Article Response to a randomized trial of methotrexate vs. azathioprine for severe atopic eczema: a critical appraisal Get access M.E. Schram, M.E. Schram Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar E. Roekevisch, E. Roekevisch Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.M.G. Leeflang, M.M.G. Leeflang Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J.D. Bos, J.D. Bos Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J. Schmitt, J. Schmitt University Allergy Centre, University Hospital Carl Gustav Carus, Dresden, Germany E‐mail: m.e.schram@amc.uva.nl Search for other works by this author on: Oxford Academic Google Scholar P.I. Spuls P.I. Spuls Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 4, 1 April 2012, Page 704, https://doi.org/10.1111/j.1365-2133.2012.10874.x Published: 01 April 2012
Protective effect of gold rings and rheumatoid arthritis
Authors: H. BOLOSI
Journal: Annals of the Rheumatic Diseases (1998)

I found the article of Mulherin and colleagues1regarding a presumably protective effect of gold rings against articular erosions in rheumatoid arthritis (RA) very interesting, but it surely raises more problems than it can solve.

A few years ago we published a similar observation2 that contradicts the hypothesis that the metacarpophalangeal (MCP) joint of the left ring finger would have remained less affected by the disease because of lymphatic drainage of the gold from the ring worn distally to it.

Our case was a …