tbuckley/cabot-search huggingface dataset:
Effects of verapamil on the extracellular K+rise during myocardial ischaemia in dogs
Authors: J F LOPEZ, R C ORCHARD
Journal: Cardiovascular Research (1985)

The effects of verapamil on the [K+]o rise produced by myocardial ischaemia were assessed in 26 open chest mongrel dogs. Ischaemia was produced by intermittent occlusion of the LAD artery (15 dogs) or by reduction of flow of the cannulated LAD (11 dogs). Specially constructed valinomycin K+ sensitive electrodes were inserted into the mid myocardium in the central zone of ischaemia (CZ); in the margin (MZ) and in the nonischaemic zone (NZ). Occlusion of the coronary artery under controlled conditions produced significant [K+]o rise, greater in the CZ than in the MZ. During the infusion of verapamil the ischaemic [K+]o rise was substantially reduced in both zones. During controlled 75% reduction of coronary flow the [K+]o reached a plateau that remained stable until reperfusion was re-established. During verapamil infusion, the plateau showed a steady decline, both in the CZ and in the MZ. The changes in [K+]o produced by verapamil, during myocardial ischaemia are probably due to: coronary dilatation of the marginal arteries and+or to a reduction of the late cellular K+ conductance due to a decrease in the intracellular Ca2+, produced by verapamil.
Expression of Mutant p53 Proteins Implicates a Lineage Relationship between Neural Stem Cells and Malignant Astrocytic Glioma in a Murine Model
Authors: Yuan Wang, Jiong Yang, Huarui Zheng, Gerald J. Tomasek, Peng Zhang, Paul E. McKeever, Eva Y.-H.P. Lee, Yuan Zhu
Journal: Cancer Cell (2009)
Similar anti-Proteus mirabilis titres in P1 positive and P1 negative individuals with rheumatoid arthritis.
Authors: J Kjeldsen-Kragh, T Rashid, A Ebringer
Journal: Annals of the Rheumatic Diseases (1995)

Similar anti-Proteus mirabilis titres in P1 positive and P1 negative individuals with rheumatoid arthritis During recent years there have been several reports showing increased antibody levels against Proteus mirabilis in patients with rheumatoid arthritis (RA).`Pmirabilis is a
Phase I/II Study of the Src Inhibitor Dasatinib in Combination With Erlotinib in Advanced Non–Small-Cell Lung Cancer
Authors: Eric B. Haura, Tawee Tanvetyanon, Alberto Chiappori, Charles Williams, George Simon, Scott Antonia, Jhanelle Gray, Sharon Litschauer, Leticia Tetteh, Anthony Neuger, Lanxi Song, Bhupendra Rawal, Michael J. Schell, Gerold Bepler
Journal: Journal of Clinical Oncology (2010)

Purpose Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non–small-cell lung cancer. Patients and Methods Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment. Results Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control. Conclusion The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Current status of rabies and prospects for elimination
Authors: Anthony R Fooks, Ashley C Banyard, Daniel L Horton, Nicholas Johnson, Lorraine M McElhinney, Alan C Jackson
Journal: The Lancet (2014)

Rabies is one of the most deadly infectious diseases, with a case-fatality rate approaching 100%. The disease is established on all continents apart from Antarctica; most cases are reported in Africa and Asia, with thousands of deaths recorded annually. However, the estimated annual figure of almost 60 000 human rabies fatalities is probably an underestimate. Almost all cases of human rabies result from bites from infected dogs. Therefore, the most cost-effective approach to elimination of the global burden of human rabies is to control canine rabies rather than expansion of the availability of human prophylaxis. Mass vaccination campaigns with parenteral vaccines, and advances in oral vaccines for wildlife, have allowed the elimination of rabies in terrestrial carnivores in several countries worldwide. The subsequent reduction in cases of human rabies in such regions advocates the multidisciplinary One Health approach to rabies control through the mass vaccination of dogs and control of canine populations.
Lung eosinophilic inflammation and airway hyperreactivity are enhanced by murine anaphylactic, but not nonanaphylactic, IgG1 antibodies
Authors: Maria Fernanda Macedo-Soares, Denise M Itami, Carla Lima, Adenir Perini, Eliana L Faquim-Mauro, Milton A Martins, Mahasti S Macedo
Journal: Journal of Allergy and Clinical Immunology (2004)
Targeted Deletion of Hepatic <i>Igf1</i> in TRAMP Mice Leads to Dramatic Alterations in the Circulating Insulin-Like Growth Factor Axis but Does Not Reduce Tumor Progression
Authors: Makoto Anzo, Laura J. Cobb, David L. Hwang, Hemal Mehta, Jonathan W. Said, Shoshana Yakar, Derek LeRoith, Pinchas Cohen
Journal: Cancer Research (2008)

The role of systemic and local insulin-like growth factor I (IGF-I) in the development of prostate cancer is still controversial. Transgenic adenocarcinoma mouse prostate (TRAMP) mice express the SV40 T-antigen under the control of the probasin promoter, and spontaneously develop prostate cancer. We crossed TRAMP mice with liver IGF-deficient (LID) mice to produce LID-TRAMP mice, a mouse model of prostate cancer with low serum IGF-I, to allow us to study the effect of circulatory IGF-I levels on the development of prostate cancer. LID mice have a targeted deletion of the hepatic Igf1 gene but retain normal expression of Igf1 in extrahepatic tissues. Serum IGF-I and IGFBP-3 levels in LID and LID-TRAMP mice were measured using novel assays, which showed that they are approximately 10% and 60% of control L/L- mice, respectively. Serum growth hormone (GH) levels of LID-TRAMP mice were 3.5-fold elevated relative to L/L-TRAMP mice (P < 0.001), but IGFBP-2 levels were not different. Surprisingly, rates of survival, metastasis, and the ratio of genitourinary tissue weight to body weight were not significantly different between LID-TRAMP and L/L-TRAMP mice. There was also no difference in the pathologic stage of the prostate cancer between the two groups at 9 to 19 weeks of age. LID-TRAMP tumors displayed increased levels of GH receptors and increased Akt phosphorylation. These results are in striking contrast with the published model of the GH-deficient lit/lit-TRAMP, which has smaller tumors and improved survival, and indicate that the reduction in systemic IGF-I is not sufficient to inhibit prostate cancer tumor progression in the TRAMP model, which may require a reduction of GH levels as well.
The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance
Authors: Hsi-Hsien Lin, Douglas E. Faunce, Martin Stacey, Ania Terajewicz, Takahiko Nakamura, Jie Zhang-Hoover, Marilyn Kerley, Michael L. Mucenski, Siamon Gordon, Joan Stein-Streilein
Journal: The Journal of Experimental Medicine (2005)

We show that the mouse macrophage-restricted F4/80 protein is not required for the development and distribution of tissue macrophages but is involved in the generation of antigen-specific efferent regulatory T (T reg) cells that suppress antigen-specific immunity. In the in vivo anterior chamber (a.c.)–associated immune deviation (ACAID) model of peripheral tolerance, a.c. inoculation of antigen into F4/80−/− mice was unable to induce efferent T reg cells and suppress delayed-type hypersensitivity (DTH) responses. Moreover, the use of anti-F4/80 mAb and F4/80−/− APCs in an in vitro ACAID model showed that all APC cells in the culture must be able to express F4/80 protein if efferent T reg cells were to be generated. In a low-dose oral tolerance model, WT but not F4/80−/− mice generated an efferent CD8+ T reg cell population that suppressed an antigen-specific DTH response. Peripheral tolerance was restored in F4/80−/− mice by adoptive transfer of F4/80+ APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8+ T reg cells.
Early, active rehabilitation following mini-open repair of Achilles tendon rupture: a prospective study
Authors: J D F Calder, T S Saxby
Journal: British Journal of Sports Medicine (2005)

To assess the use of a supervised active rehabilitation program following repair of acute Achilles tendon ruptures using a minimally invasive suture system.We performed a prospective study on 46 patients undergoing surgical repair of acute Achilles tendon ruptures using the Achillon suture system. All patients began a supervised active rehabilitation program from 2 weeks postoperatively. Patients were placed in a range of motion brace fixed at 20 degrees equinus for 2 weeks to allow wound healing followed by active movement from neutral to full plantar flexion for 4 weeks.At a minimum follow up of 12 months there were no re-ruptures. All patients were able to return to their previous sporting activities by 6 months post operation. The average American Orthopaedic Foot and Ankle Society (AOFAS) score at 6 months was 98, with 42 patients having excellent and four patients good Leppilahti scores. The average time to return to work was 22 days. One patient had a superficial wound infection which settled with 5 days of oral antibiotics. Two patients had altered sensation in the distribution of the sural nerve which settled spontaneously within 3 months.The Achillon suture system appears to allow a safe early active rehabilitation program and achieves a high rate of success. Further evaluation is necessary with regard to potential damage to the sural nerve.
Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Interferes with Extracellular Signal-regulated Kinase (ERK) and Jun NH2-terminal Kinase (JNK) Activation, but Does Not Affect Phosphorylation of T Cell Receptor ζ and ZAP70
Authors: Concepcion Revilla Calvo, Derk Amsen, Ada M. Kruisbeek
Journal: The Journal of Experimental Medicine (1997)

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-ζ chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
Increased Activity of Constitutive Nitric Oxide Synthase in Cardiac Endothelium in Spontaneous Hypertension
Authors: Eduardo Nava, Georg Noll, Thomas F. Lüscher
Journal: Circulation (1995)

We analyzed the activity of nitric oxide synthase in the rat heart to study whether this activity is affected by high blood pressure. Hearts from young (3 to 4 weeks old) and adult (15 to 25 weeks old) Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were excised and frozen in liquid nitrogen. The activities of Ca(2+)-dependent (cNOS) and Ca(2+)-independent (iNOS) were determined in homogenized tissues by measuring the conversion of [14C]-L-arginine to [14C]-L-citrulline in the presence or absence of either EGTA (1 mmol/L) or EGTA plus NG-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L each).Arterial pressure was higher in adult SHR than in young SHR and WKY rats of both ages (P < .01). The cNOS activity was two to three times higher in hypertensive than in normotensive hearts (P = .01 to P = .04). No significant activity of iNOS was detected in any tissue. Studies of the right and left ventricles demonstrated a higher cNOS activity in the left sides of the hearts of adult SHR (P < .05). No differences were found in hearts from WKY rats. Selective removal of endocardial or coronary endothelial cells in hearts of SHR and WKY rats substantially reduced cNOS activity (P < .01).The cNOS activity is upregulated in cardiac endothelial cells of genetically hypertensive rats. The high activity of cardiac cNOS is related to increased arterial pressure of these animals. We propose that in the heart, endothelial cells respond with a higher production of nitric oxide as a compensatory mechanism against high blood pressure and its damaging effects in this organ.
A breathless female
Authors: R.K. Kedia, A. Sullivan, M. Stephens, M.B. Allen
Journal: European Respiratory Journal (1999)

The career paths of 544 UK medical school graduates were followed for 10 years. Although general practice was not attractive to graduates initially, it became popular in subsequent years, mainly because it was seen as offering a superior quality of life. Once in general practice both men and women chose to work reduced hours and/or in non-principal posts. The findings suggest the need to look more closely at the nature of these trends and the implications for patient care and service provision.
p53 Negatively Regulates Transcription of the Pyruvate Dehydrogenase Kinase Pdk2
Authors: Tanupriya Contractor, Chris R. Harris
Journal: Cancer Research (2011)

In cancer cells, the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as the Warburg effect. The consequences and mechanisms of this metabolic peculiarity are incompletely understood. Here we report that p53 status is a key determinant of the Warburg effect. Wild-type p53 expression decreased levels of pyruvate dehydrogenase kinase-2 (Pdk2) and the product of its activity, the inactive form of the pyruvate dehydrogenase complex (P-Pdc), both of which are key regulators of pyruvate metabolism. Decreased levels of Pdk2 and P-Pdc in turn promoted conversion of pyruvate into acetyl-CoA instead of lactate. Thus, wild-type p53 limited lactate production in cancer cells unless Pdk2 could be elevated. Together, our results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2. These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism.
Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure.
Authors: R L Duerr, S Huang, H R Miraliakbar, R Clark, K R Chien, J Ross
Journal: Journal of Clinical Investigation (1995)

To determine whether additional hypertrophy would be beneficial or maladaptive in cardiac failure, the effects of insulin-like growth factor (IGF-1) were investigated in rats with left ventricular (LV) dysfunction. In normal rats, 3 mg/kg per d of recombinant human IGF-1 for 14 d augmented LV wt (32%) and increased LV/body wt ratio (P < 0.01). 2 d after coronary occlusion, rats were randomized to IGF-1 (3 mg/kg per d) or placebo. After 2 wk, IGF-1-treated rats showed significant increases in LV wt (13%) and LV wt/tibial length ratio, but LV/body wt ratio was unchanged. By microangiography, compared with controls (n = 12) IGF-1-treated rats (n = 16) showed increased LV end-diastolic volume (19%) and stroke volume (31%) (both significant normalized to tibial length, but not to body wt). Average infarct size did not differ between groups. The LV ejection fraction (EF) was not significantly different between groups, but estimated cardiac output was higher in treated rats; there was a significant interaction for the EF between infarct size and treatment (P = 0.029) and a trend for EF to be higher in treated rats with large infarctions (EF 33.4 vs 25.1% in controls). Myocyte cross-sectional areas in noninfarcted LV zones tended to be larger in treated rats (232.1 vs 205.4 microns 2; P = 0.10), but there was no difference in capillary density and collagen content did not differ between groups. In conclusion, IGF-1 administration caused hypertrophy of the normal heart in vivo. When stimulated by IGF-1, the severely dysfunctional heart in evolving myocardial infarction is capable of undergoing additional hypertrophy with evidence of improved function, suggesting a beneficial effect. Further investigation of the potential role of growth factor therapy in heart failure appears warranted.
PTH Pulsatility but Not Calcium Sensitivity Is Restored after Total Parathyroidectomy with Heterotopic Autotransplantation
Authors: Claus P. Schmitt, Swee Löcken, Otto Mehls, Johannes D. Veldhuis, Thomas Lehnert, Eberhard Ritz, Franz Schaefer
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. In healthy humans, parathyroid hormone (PTH) is secreted via basal mode with superimposed oscillatory bursts every 8 to 12 min. Amplitude and frequency changes mediate the instantaneous response of the parathyroids to changes in ambient Ca2+ concentrations. The parathyroid gland tetrad may be synchronized by autonomic innervation. This study investigated the effect of total parathyroidectomy and heterotopic autotransplantation of parathyroid tissue (PTX) on PTH secretion patterns in nine patients with end-stage renal disease. Intact-PTH versus time concentration profiles were obtained early (1 to 8 wk, n = 4) or late (15 to 33 mo, n = 5) after PTX. In four patients late after PTX, Ca2+ responsiveness of PTH secretion was additionally investigated by citrate and calcium clamp studies. The nonrandomness of plasma PTH fluctuations was assessed by the approximate entropy (ApEn) statistic, and secretion characteristics by multiparametric deconvolution analysis. Results were compared with those of matched normal subjects and chronic renal failure (CRF) patients without PTX. PTH burst frequency was 2.9 ± 0.1 h−1 early and 7 ± 0.4 h−1 late after PTX as compared with 8.1 ± 0.4 h−1 in CRF and 7 ± 0.3 h−1 in healthy controls. Fractional pulsatile PTH secretion was diminished after PTX (18 ± 2%) compared with healthy controls (32 ± 5%, P < 0.05) and CRF patients (25 ± 4%, P = 0.05). The orderliness of PTH release was significantly reduced after PTX (ApEn: 1.59 ± 0.03 versus 1.41 ± 0.09 in healthy and 1.46 ± 0.03 in CRF controls, P < 0.01). Acute hypocalcemia elicited a lesser increase in pulsatile PTH secretion in PTX patients (147 ± 134%) than in the CRF (500 ± 92%, P = 0.05) and healthy controls (1410 ± 290%, P < 0.05), mainly due to a diminished mass of PTH secreted per burst. Pulsatile PTH secretion was also resistant to hypercalcemia, wherein the suppression of burst mass was significantly reduced compared with that in healthy controls. In conclusion, pulsatile PTH secretion is partially restored within 2 yr of PTX. However, the capacity of the autotransplanted tissue to adapt to changes in ionized calcium remains profoundly disturbed. E-Mail: [email protected]
Lymphotoxin Beta Receptor Signaling in Intestinal Epithelial Cells Orchestrates Innate Immune Responses against Mucosal Bacterial Infection
Authors: Yugang Wang, Ekaterina P. Koroleva, Andrei A. Kruglov, Dmitry V. Kuprash, Sergei A. Nedospasov, Yang-Xin Fu, Alexei V. Tumanov
Journal: Immunity (2010)
CELL TO CELL INTERACTION IN THE IMMUNE RESPONSE
Authors: J. F. A. P. Miller, G. F. Mitchell
Journal: The Journal of Experimental Medicine (1968)

An injection of viable thymus or thoracic duct lymphocytes was absolutely essential to enable a normal or near-normal 19S liemolysin-forming cell response in the spleens of neonatally thymectomized mice challenged with sheep erythrocytes. Syngeneic thymus lymphocytes were as effective as thoracic duct lymphocytes in this system and allogeneic or semiallogeneic cells could also reconstitute their hosts. No significant elevation of the response was achieved by giving either bone marrow cells, irradiated thymus or thoracic duct cells, thymus extracts or yeast. Spleen cells from reconstituted mice were exposed to anti-H2 sera directed against either the donor of the thymus or thoracic duct cells, or against the neonatally thymectomized host. Only isoantisera directed against the host could significantly reduce the number of hemolysin-forming cells present in the spleen cell suspensions. It is concluded that these antibody-forming cells are derived, not from the inoculated thymus or thoracic duct lymphocytes, but from the host. Thoracic duct cells from donors specifically immunologically tolerant of sheep erythrocytes had a markedly reduced restorative capacity in neonatally thymectomized recipients challenged with sheep erythrocytes. These results have suggested that there are cell types, in thymus or thoracic duct lymph, with capacities to react specifically with antigen and to induce the differentiation, to antibody-forming cells, of hemolysin-forming cell precursors derived from a separate cell line present in the neonatally thymectomized hosts.
Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process
Authors: Jae Young Choi, Monal Khansaheb, Nam Soo Joo, Mauri E. Krouse, Robert C. Robbins, David Weill, Jeffrey J. Wine
Journal: Journal of Clinical Investigation (2009)

Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections.
Characterization of Antigen Presenting Cells in a Murine Subchronic Fungal Exposure Model
Authors: Ajay P. Nayak, Brett J. Green, Tara L. Croston, Angela R. Lemons, Nikki B. Marshall, W.Travis Goldsmith, Michael Kashon, Brandon F. Law, Lauren M. Wagner, Carrie M. Long, Dori M. Germolec, Donald H. Beezhold
Journal: Journal of Allergy and Clinical Immunology (2015)