We characterized the tachykinin receptor(s) mediating ‘sensory‐efferent’ neural control of release of 35 S0 4 ‐labelled macromolecules (mucus) from ferret trachea in vitro in Ussing chambers using selective tachykinin antagonists. Secretion was induced by substance P (SP), neurokinin A (NKA), capsaicin, the NK 1 tachykinin receptor agonist [Sar 9 , Met(O 2 )) 11 ] substance P ([Sar 9 SP), or acetylcholine (ACh), or by electrical stimulation of nerves. Antagonists used were FK888 and L‐668,169, selective for the NK, receptor, SR 48968, selective for the NK 2 receptor, and FK224, a dual antagonist at NK 1 and NK 2 receptors. The selectivity of FK888 and SR 48968 was examined on NKA‐induced contraction of ferret tracheal smooth muscle in vitro . SP (1 μ m ) increased mucus secretion by 695% above vehicle controls. FK888 (0.1 μ m ‐30μ m ) inhibited SP‐induced secretion in a dose‐dependent manner, with complete inhibition at IOJXM and an IC50 of 1 μ m . L‐668,169 (1 μ m ) also completely inhibited SP‐induced secretion. NKA (1 μ m ) significantly increased mucus secretion by 271% above baseline, a response which was completely inhibited by FK888 (10 μ m ) or L‐668,169 (μ m ). Secretion induced by ACh (10 μ m : 317% above baseline) was not inhibited by FK888 but was inhibited by atropine. Capsaicin (10μ m )‐induced secretion (456% above vehicle controls) was significantly inhibited by FK888 and by L‐668,169 (111% and 103% inhibition respectively). Electrical stimulation (50 V, 10 Hz, 0.5 ms, 5 min) increased mucus output above baseline (increased by 12 to 26 fold), a response blocked by tetrodotoxin (0.1 μ m ). FK888 (10μ m ) inhibited the increase in secretion due to electrical stimulation by 47%. Atropine, propranolol and phentolamine in combination (APP) inhibited the response to electrical stimulation by 48%. The remaining NANC response, i.e. in the presence of APP, was further reduced by 66% with FK888. FK224 (10μ m ) inhibited neurally‐evoked secretion by 73%. SR 48968 (0.1 μ m ) had no effect on electrically‐stimulated or [Sar 9 ]SP‐induced secretion. NKA (10μ m ‐10μ m : in the presence of DMSO control vehicle) induced tracheal smooth muscle contraction in a concentration‐dependent manner with a maximal contraction of 30% of the maximal response to ACh (10 μ m ) and an EC50 of 0.3 JIM. SR 48968 (0.1 μ in DMSO) inhibited the NKA‐induced contraction whereas FK888 did not. Neither antagonist had any inhibitory effect on ACh‐induced contraction. We conclude that ‘sensory‐efferent’ neurogenic mucus secretion in ferret trachea in vitro is mediated via tachykinin NK 1 receptors with no involvement of NK 2 receptors. Potent and selective tachykinin antagonists may have therapeutic potential in bronchial diseases such as asthma and chronic bronchitis in which neurogenic mucus hypersecretion may be aetiologically important.
Introduction and objectives The development of second-generation optical coherence tomography (i.e. Fourier domain optical coherence tomography, FD-OCT) has made it possible to perform high speed pull-backs during image acquisition without the need for transient occlusion of the coronary artery. The objective of this study was to assess the reproducibility of FD-OCT systems for characterizing plaque and evaluating stent implantation in patients undergoing a percutaneous coronary intervention. Methods The study included 45 patients scheduled for percutaneous coronary intervention who were enrolled between May and December 2008. Image acquisition was performed by FD-OCT using a non-occlusive technique and employing pull-back speeds ranging from 5 to 20 mm/s. Interstudy, interobserver and intraobserver reproducibility of plaque characterization and stent analysis were assessed. Results Fourier domain imaging was successfully performed in all patients (n=45). The average flush rate was 3±0.4 mL/s and the contrast volume per pull-back was 16.1±3.5 mL. The mean pull-back duration and length were 3.2±1.2 s and 53.3±12.4 mm, respectively. The interstudy reproducibility for visualizing edge dissection, tissue prolapse, intrastent dissection and malapposition was excellent (κ=1). The kappa values for interstudy, interobserver and intraobserver agreement on plaque characterization were 0.92, 0.82 and 0.95, respectively. Conclusions A second-generation OCT system (i.e. FD-OCT) involving high-speed data acquisition demonstrated good interstudy, interobserver and intraobserver reproducibility for characterizing plaque and evaluating stent implantation in patients undergoing a percutaneous coronary intervention. Introducción y objetivos Se ha desarrollado una segunda generación de sistemas de tomografía de coherencia óptica (OCT) (dominio de Fourier, OCT-DF) que permiten las retiradas a alta velocidad sin necesidad de ocluir transitoriamente la arteria coronaria durante la obtención de imágenes. El objetivo de este estudio es evaluar la reproducibilidad de los sistemas de OCT-DF para la caracterización de la placa y la evaluación de la implantación del stent en pacientes a los que se practican intervenciones coronarias percutáneas. Métodos Entre mayo y diciembre de 2008, se incluyó en el estudio a 45 pacientes para los que se había programado una intervención coronaria percutánea. La adquisición de la OCT-DF se realizó con una técnica no oclusiva con velocidades de retirada de entre 5 y 20 mm/s. Se evaluó la reproducibilidad entre estudios, entre observadores y en el observador para la caracterización de la placa y el análisis de los stents. Resultados La obtención de imágenes de dominio de Fourier se realizó satisfactoriamente en todos los pacientes (n = 45). El ritmo de infusión medio fue de 3 ± 0,4 ml/s y el volumen de contraste por retirada, 16,1 ± 3,5 ml. La media de duración y longitud de la retirada fue de 3,2 ± 1,2 s y 53,3 ± 12,4 mm. La reproducibilidad entre estudios, en cuanto a la visualización de la disección del borde, el prolapso tisular, la disección en el stent y la mala aposición, fue excelente (κ = 1). Los valores de kappa para la coincidencia entre estudios, entre observadores y en el observador en la caracterización de la placa fueron 0,92, 0,82 y 0,95 respectivamente. Conclusiones La tecnología de OCT de segunda generación, que obtiene datos a alta velocidad, muestra buena reproducibilidad entre estudios, entre observadores y en el observador para la caracterización de la placa y evaluar la implantación del stent en pacientes a los que se practican intervenciones coronarias percutáneas.
No abstract is provided for this article.
Abstract The efficacy of trastuzumab in the treatment of primary breast cancer has mandated accurate and timely testing of all patients with a new diagnosis of breast cancer. Testing is centralized in designated laboratories across Canada with adherence to guidelines and mandatory participation in quality assurance programs. The Canadian testing algorithm recommends starting with immunohistochemistry (IHC) followed by in situ hybridization (ISH) for equivocal cases. Early HER2 testing showed that approximately 25–30% of invasive breast cancer is HER2 positive. Recent data shows that the HER2/neu positive rate in breast cancer in Canada is 17.6%. Design: The study was designed to assess the rate of false-negative HER2 tests based on the IHC-first algorithm used in 8 pathology centres across Canada. Surgical excisions with invasive carcinoma were tested using the standardized local methodology for both IHC and ISH. The cases were scored by the local breast pathologist and in 2 of 8 centers image analysis was used in the evaluation of ISH. We compared consecutive HER2-negative IHC results (score 0/1+) to the corresponding ISH (either silver or fluorescence) result. False negative cases were defined as a negative IHC with an ISH ratio of≥ 2, since these patients are eligible for trastuzumab therapy. Results: 715 cases were analyzed by IHC using Ventana 4B5 (287), HercepTest (253), or SP3 (175), and by ISH kits: Vysis FISH (303), Ventana SISH (412). The HER2 and CEP17 counts were available in all cases. There were 4 cases with an ISH score ≥2 (4B5: 2/4, HercepTest 1/4, SP3 1/4). In 3 additional cases the absolute HER2 copy number was ≥6 but the HER2/CEP17 amplification ratio was <2 due to an increased number of CEP 17 signal (“polysomy 17”) or amplification of the pericentromeric region. The overall rate of false negative cases was 0.98% (7/715). These cases had a low level of amplification (ratio 2 to 2.45) or an absolute HER2 count of 6–8. Conclusion: Our observation confirms that IHC is an adequate test to predict negative HER2 status in primary breast cancer in surgical excision specimens, even when different antibodies and IHC platforms are used. The study supports and justifies the Canadian algorithm of IHC followed by ISH in equivocal cases in view of the extremely low percentage of false negative cases observed. This reflects the strict adherence to internal protocols and mandatory participation in quality assurance programs. These results provide further confirmation that the vast majority of patients eligible for trastuzumab are not deprived from an effective treatment by using this algorithm. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-09.
"Cholinergic Control of Airway Smooth Muscle." American Review of Respiratory Disease, 136(4_pt_2), pp. S42–S45
