tbuckley/cabot-search huggingface dataset:
Voltage- and use-dependent modulation of cardiac calcium channels by the dihydropyridine (+)-202-791.
Authors: T J Kamp, M C Sanguinetti, R J Miller
Journal: Circulation Research (1989)

The modulation of L-type voltage sensitive calcium channels in isolated guinea pig ventricular myocytes by the dihydropyridine (+)-202-791 was examined with the whole-cell voltage-clamp technique with 1.8 mM Ba or Ca as the charge carrier. Striking voltage- and use-dependent effects of the dihydropyridine calcium channel "agonist" (+)-202-791 were revealed. From a holding potential of -60 mV, depolarizing test pulses in the presence of (+)-202-791 demonstrated a concentration-dependent (EC50, 177 nM) increase in the measured peak inward barium current compared to control. In contrast, more depolarized holding potentials (greater than or equal to -30 mV) (+)-202-791 caused a biphasic effect on the peak inward current resulting in a transient enhancement followed by a steady-state block. A saturable, concentration-dependent hyperpolarizing shift in the voltage dependence of current inactivation was observed in the presence of (+)-202-791 with an EC50 of 10.2 nM. The voltage dependence of current activation was also shifted in the hyperpolarizing direction in the presence of (+)-202-791. A use-dependent relative block by (+)-202-791 was observed after repetitive depolarizing test pulses at a frequency of 2 Hz. Thus, the single enantiomer (+)-202-791 can result in either an increase in the whole cell calcium channel current (favored by hyperpolarized holding potentials and low rates of stimulation) or block of calcium channel current (favored by depolarized holding potentials and high rates of stimulation). Various combinations of (-)-202-791, a reported calcium channel antagonist, and (+)-202-791 resulted in intermediate effects on voltage sensitive calcium or barium currents compared with the presence of either enantiomer alone, and no clear cooperative interactions between the enantiomers were observed in contrast to a previous single channel study (Kokuban S, Prod'ham B, Becker C, Porzig H, Reuter H: Studies on Ca channels in intact cardiac cells: Voltage-dependent effects and cooperative interaction of dihydropyridine enantiomers. Mol Pharmacol 1986;30:571-584). The results are discussed in relation to the possible presence of multiple dihydropyridine receptors associated with the voltage sensitive calcium channel.
Long acting beta 2 agonists and theophylline in stable chronic obstructive pulmonary disease
Authors: M. Cazzola, C. F. Donner, M. G. Matera
Journal: Thorax (1999)

The natural history of chronic obstructive pulmonary disease (COPD) is characterised by an accelerated annual decline in forced expiratory volume in one second (FEV1). One of the most crucial factors in COPD is therefore the means by which this annual decline can be delayed. Bronchodilator therapy is usually prescribed to relieve the symptoms, reverse airway obstruction and, hopefully, to slow the rate of disease progression and decelerate the decline in pulmonary function. However, the Lung Health Study, in its five year observation of almost 6000 patients at risk of developing COPD,1 reported that the rate of decline of lung function in smokers with mild to moderate COPD could be significantly slowed by smoking cessation but not by bronchodilator therapy.

Nonetheless, bronchodilators are an important form of treatment to reduce symptoms in COPD. As any improvement in airflow might be extremely important in these patients, the recent BTS guidelines for the management of COPD2 state that bronchodilators are the cornerstone of symptomatic treatment for the reversible component of airway obstruction. Short acting β2 agonists used as required are recommended to be tried first in view of their more rapid relief of symptoms. If β agonists do not control symptoms adequately or if regular maintenance therapy is desired, an anticholinergic agent can be added or substituted. The addition of oral theophylline should only be considered if inhaled treatments have failed to provide enough benefit.

A long acting version of β2 agonists has also been developed. At present, long acting β agonist bronchodilators such as formoterol and salmeterol are an interesting new therapeutic option for COPD, but their role in its treatment is still debated.3Salmeterol and formoterol appear to be more effective than short acting β agonists4 and, in patients with stable COPD, salmeterol is …
Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma
Authors: Atsushi Otsuka, Jil Dreier, Phil F. Cheng, Mirjam Nägeli, Holger Lehmann, Lea Felderer, Ian J. Frew, Shigeto Matsushita, Mitchell P. Levesque, Reinhard Dummer
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. Experimental Design: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. Results: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4+, HLA-DR-class II+, and CD8+ cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. Conclusions: We show that Hh pathway inhibitor–induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network. Clin Cancer Res; 21(6); 1289–97. ©2015 AACR.
Maturational regulation of globotriaosylceramide, the Shiga-like toxin 1 receptor, in cultured human gut epithelial cells.
Authors: M S Jacewicz, D W Acheson, M Mobassaleh, A Donohue-Rolfe, K A Balasubramanian, G T Keusch
Journal: Journal of Clinical Investigation (1995)

Differentiated villus intestinal epithelial cells express globotriaosylceramide, the Shiga-like toxin 1 (SLT-1) receptor, and are sensitive to toxin-mediated cytotoxicity, whereas undifferentiated crypt cells neither express Gb3 nor respond to toxin. To investigate if SLT-1 receptors are maturationally regulated in human intestinal cells, we examined the effect of butyrate, a known transcriptional regulator of differentiation genes in many cell types, using cultured colonic cancer-derived epithelial cell lines. Exposure to butyrate increased villus cell marker enzymes such as alkaline phosphatase, sucrase, and lactase, expression of toxin receptors, and sensitivity to SLT-1 in villus-like CaCo-2A and HT-29 cells. These effects were reversibly inhibited by preincubation of CaCo-2A cells with actinomycin D or cycloheximide. Butyrate-treated CaCo-2A cells unable to bind fluoresceinated SLT-1 B subunit were undifferentiated as assessed by alkaline phosphatase activity. HT-29 cells induced to differentiate by another signal, glucose deprivation, upregulated receptor content and response to toxin. Crypt-like T-84 cells responded to butyrate with a modest increase in alkaline phosphatase and toxin binding, but no induction of sucrase or lactase, and no change in sensitivity to toxin. The results demonstrate that expression of SLT-1 toxin receptors and toxin sensitivity are coregulated with cellular differentiation in cultured intestinal cells.
Distribution of histamine, 5-hydroxytryptamine, and other pharmacologically active substances in the human stomach
Authors: J. G. Murray, J. H. Wyllie
Journal: Gut (1964)

tion of the substance under suitable conditions must mimic the physiological function.4 In addition, one expects to find that physiological function and function induced by injection of the substance are affected similarly by inhibitory drugs.5 After denervation the effector cells become hypersensitive to the substance.This first paper is concerned with the distribution of histamine within the human stomach.The mechanism of secretion is discussed in the following article (Clark, Curnow, Murray, Stephens, and Wyllie, 1964).METHODS MATERIAL Human stomachs were obtained in the operating theatre as soon as they were removed from the patients.A specimen usually consisted of about two- thirds of the stomach.It was opened along the greater curvature and rinsed under cold tap water.After removing small pieces for routine pathology, the specimen was placed in the deep freeze at -15°C.This was usually about 10 minutes after removal from the body.PREPARATIONS Two methods of preparing the material were used.
Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog.
Authors: G I Shulman, W W Lacy, J E Liljenquist, U Keller, P E Williams, A D Cherrington
Journal: Journal of Clinical Investigation (1980)

To study the effects of hyperglycemia on the metabolism of alanine and lactate independent of changes in plasma insulin and glucagon, glucose was infused into five 36-h-fasted dogs along with somatostatin and constant replacement amounts of both insulin and glucagon. Hepatic uptakes of alanine and lactate were calculated using the arteriovenous difference technique. [14C]Alanine was infused to measure the conversion of alanine and lactate into glucose. Hyperglycemia (delta 115 mg/dl) of 2 h duration caused the plasma alanine level to increase by over 50%. This change was caused by an increase in the inflow of alanine into plasma since the net hepatic uptake of the amino acid did not change. Taken together, the above findings indicate that glucose per se can significantly impair the fractional extraction of alanine by the liver. Hepatic extraction of lactate was also affected by hyperglycemia and had fallen to zero within 90 min of starting the glucose infusion. This fall was associated with a doubling of arterial lactate level. Conversion of [14C]-alanine and [14C]lactate into [14C]glucose was suppressed by 60 +/- 11% after 2 h of hyperglycemia, and because this fall could not be entirely accounted for by decreased lactate extraction an inhibitory effect of glucose on gluconeogenesis within the liver is suggested. These studies indicate that the plasma glucose level per se can be an important determinant of the level of alanine and lactate in plasma as well as the rate at which they are converted to glucose.
Required Role of Apoptotic Myogenic Precursors and Toll-like Receptor Stimulation for the Establishment of Autoimmune Myositis in Experimental Murine Models
Authors: Clara Sciorati, Antonella Monno, Dana P. Ascherman, Elena Seletti, Angelo A. Manfredi, Patrizia Rovere‐Querini
Journal: Arthritis & Rheumatology (2014)

Objective Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models. Methods Expression of the autoantigen histidyl–transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti‐HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll‐like receptor 7 (TLR‐7) agonist R848. Results Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the α‐sarcoglycan/dystrophin complex in mice were uniformly associated with up‐regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti‐HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B–irradiated, HisRS‐expressing apoptotic myoblasts in the presence of R848 triggered the production of anti‐HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype. Conclusion In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM.
Respiratory motion correction in dynamic MRI using robust data decomposition registration – Application to DCE-MRI
Authors: Valentin Hamy, Nikolaos Dikaios, Shonit Punwani, Andrew Melbourne, Arash Latifoltojar, Jesica Makanyanga, Manil Chouhan, Emma Helbren, Alex Menys, Stuart Taylor, David Atkinson
Journal: Medical Image Analysis (2013)

Motion correction in Dynamic Contrast Enhanced (DCE-) MRI is challenging because rapid intensity changes can compromise common (intensity based) registration algorithms. In this study we introduce a novel registration technique based on robust principal component analysis (RPCA) to decompose a given time-series into a low rank and a sparse component. This allows robust separation of motion components that can be registered, from intensity variations that are left unchanged. This Robust Data Decomposition Registration (RDDR) is demonstrated on both simulated and a wide range of clinical data. Robustness to different types of motion and breathing choices during acquisition is demonstrated for a variety of imaged organs including liver, small bowel and prostate. The analysis of clinically relevant regions of interest showed both a decrease of error (15–62% reduction following registration) in tissue time–intensity curves and improved areas under the curve (AUC60) at early enhancement.
Interactions of granulocytes with the lungs.
Authors: K L Brigham, B Meyrick
Journal: Circulation Research (1984)

Under normal conditions, there is a sizeable pool of marginated granulocytes in the lung circulation which is in dynamic equilibrium with the circulating granulocyte pool. The number of granulocytes in the lungs' microcirculation may depend on pulmonary blood flow or biochemical interactions between granulocytes and pulmonary vascular endothelium, or both. There is some evidence that normal lung function may be affected by granulocytes. Several acute and chronic diseases may result, at least in part, from interactions of granulocytes with the lungs. Acute diffuse lung injury (adult respiratory distress syndrome) is characterized by diffuse pulmonary inflammation, and, in animal models, some of the lung dysfunction depends on the presence of granulocytes. Bronchoconstriction and airway hyperreactivity, characteristic of asthma, may be influenced by granulocyte-generated products of arachidonic acid. Granulocyte-derived proteases and oxidants may contribute to the pathogenesis of pulmonary emphysema and may affect connective tissue synthesis in interstitial pulmonary fibrosis. There is some evidence suggesting a connection between granulocytes and chronic pulmonary hypertension. The fact that some interventions which cause pulmonary leukostasis do not cause severe, persistent lung injury indicates that as yet unknown factors may determine whether interactions of granulocytes with the lungs are benign or pathological. Such factors could include the generation of humoral substances, and metabolites of arachidonic acid are particularly interesting in this regard. Research related to interactions of granulocytes with the lungs suggests strongly that such interactions are integral to the pathogenesis of several lung diseases. Understanding those diseases will require further basic studies of granulocyte behavior and the modes of communication between cells intrinsic to the lung and granulocytes.
Suppressive Role of B Cells in Chronic Colitis of T Cell Receptor α Mutant Mice
Authors: Atsushi Mizoguchi, Emiko Mizoguchi, R. Neal Smith, Frederic I. Preffer, Atul K. Bhan
Journal: The Journal of Experimental Medicine (1997)

The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-α−/− mice was explored by creating double mutant mice (TCR-α−/− × immunoglobulin (Ig)μ−/−), which lack B cells. TCR-α−/− × Igμ−/− mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-α−/− mice. Colitis was induced in recombination-activating gene-1 (RAG-1−/−) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-α−/− × Igμ−/− mice. When purified B cells from TCR-α−/− mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1−/− mice. Administration of the purified Ig from TCR-α−/− mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-α−/− × Igμ−/− mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-α−/− × Igμ−/− mice as compared to Igμ−/− mice and TCR-α−/− mice. Administration of the purified Ig from TCR-α−/− mice into TCR-α−/− × Igμ−/− mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.
Static Relationship of Cycle Length to Reentrant Circuit Geometry
Authors: Edward J. Ciaccio, Constantino Costeas, James Coromilas, Andrew L. Wit
Journal: Circulation (2001)

Background Knowledge of the pathway common to both wave fronts in figure-8 reentrant circuits (ie, the isthmus) is of importance for catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that quantitative measures of reentry isthmus geometry were interrelated and could be correlated with tachycardia cycle length. Methods and Results A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure-8 pattern of conduction was used for initial analysis (experiments in 20 canine hearts with monomorphic reentry). Sinus-rhythm and reentry activation maps were constructed, and quantitative (skeletonized) geometric parameters of the isthmus and border zone were measured from the maps. Regression equations were used to determine significant correlation relationships between skeletonized variables, which can be described as follows. Tachycardia cycle length, measured from the ECG R-R interval, increases with increasing isthmus length, width, narrowest width, angle with respect to muscle fibers, and circuit path length determined by use of sinus-rhythm measurements. After this procedure, in 5 test-set experiments, tachycardia cycle length measured from the R-R interval, in combination with regression coefficients calculated from initial experiments, correctly predicted isthmus geometry (mean estimated/actual isthmus overlap 70.5%). Also, the circuit path length determined with sinus-rhythm measurements correctly estimated the tachycardia cycle length (mean error 6.2±2.5 ms). Conclusions Correlation relationships derived from measurements using reentry and sinus-rhythm activation maps are useful to assess isthmus geometry on the basis of tachycardia cycle length. Such estimates may improve catheter ablation site targeting during clinical electrophysiological study.
Effect of stretching duration on active and passive range of motion in the lower extremity.
Authors: J M Roberts, K Wilson
Journal: British Journal of Sports Medicine (1999)

OBJECTIVES: To investigate the effect of different durations of stretching (five or 15 seconds) on active and passive range of motion (ROM) in the lower extremity during a five week flexibility training programme. METHOD: Twenty four university sport club members (19 men, five women), with a mean (SD) age of 20.5 (1.35) years, were randomly assigned to one of three groups (two treatment and one control). The two treatment groups participated in a static active stretching programme three times a week for a five week period, holding each stretch for a duration of either five or 15 seconds. The total amount of time spent in a stretched position was controlled. The five second group performed each stretch nine times and the 15 second group three times resulting in a total stretching time of 45 seconds for both groups for each exercise. The control group did not stretch. Active and passive ROM were determined during left hip flexion, left knee flexion, and left knee extension before and after the training programme using an inclinometer. RESULTS: Two factor within subject analysis of variance indicated no significant difference in ROM before and after the training programme for the control group. However, significant improvements in active and passive ROM (p &lt; 0.05) were shown in both treatment groups after the five week training programme. Two factor analysis of variance with repeated measures and post hoc analysis showed significant differences between the treatment groups and the control group for the improvements observed in active (p &lt; 0.05) and passive (p &lt; 0.05) ROM. The five and 15 second treatment groups did not differ from one another when ROM was assessed passively, but significant differences were apparent for active ROM, with the 15 second group showing significantly greater improvements (p &lt; 0.05) than the five second group. CONCLUSION: These findings suggest that holding stretches for 15 seconds, as opposed to five seconds, may result in greater improvements in active ROM. However, sustaining a stretch may not significantly affect the improvements gained in passive ROM.
Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions
Authors: Jason A Roberts, Mohd H Abdul-Aziz, Jeffrey Lipman, Johan W Mouton, Alexander A Vinks, Timothy W Felton, William W Hope, Andras Farkas, Michael N Neely, Jerome J Schentag, George Drusano, Otto R Frey, Ursula Theuretzbacher, Joseph L Kuti
Journal: The Lancet Infectious Diseases (2014)