Effect of sex on the cardiovascular response to adrenaline in humans

Cardiovascular responsiveness to stress conditions differs between men and women. It is not known to what extent this observation is explained by differences in the release of stress hormones like adrenaline, or by differences in the response to adrenaline. Therefore, we quantified the hemodynamic response to infusion of adrenaline (0.04, 0.06, and 0.08 microg x kg(-1) x min(-1) for 20 minutes each) in 8 healthy men and 8 healthy premenopausal women. Arterial plasma adrenaline levels were measured before and after infusion. Heart rate and intra-arterial blood pressure were monitored throughout the experiment. Arterial plasma adrenaline levels increased similarly in both sexes. There was a larger increase in systolic blood pressure in women compared with men (17.6 +/- 2.8 versus 5.1 +/- 3.1 mm Hg, P < 0.01). In contrast, men showed a larger increase in heart rate compared with women (20.3 +/- 1.4 versus 11.2 +/- 2.8 bpm, P < 0.01). In conclusion, these data suggest that the cardiovascular response to adrenaline is predominantly alpha-adrenergic in premenopausal women, and predominantly beta-adrenergic in age-matched men.     

Prognostic role of cyclooxygenase-2 in neoadjuvant-treated patients with squamous cell carcinoma of the esophagus

Based on our previous demonstration that elevated cyclooxygenase-2 (COX-2) expression is a prognostic factor for reduced survival in patients with adenocarcinoma of the esophagus, the aim of our study was to analyze the role of COX-2 expression in esophageal squamous cell carcinoma. We analyzed COX-2 protein expression from 117 consecutive patients by immunohistochemistry using a COX-2 specific monoclonal antibody. Eighty-one patients had not received any therapy before surgery whereas 36 patients received neoadjuvant chemotherapy as part of a randomized controlled trial. In the patients who received no chemotherapy, COX-2 expression was low in 75% and high in 25% of the specimens. In this patient group, high COX-2 expression associated with distal location of the tumor (p = 0.02), but did not correlate with any other clinicopathological parameter tested, including overall survival. In the patient group who received neoadjuvant chemotherapy, postoperative COX-2 expression was low in 69% and high in 31%. Interestingly, in this patient group low COX-2 expression correlated with development of distant metastases (p = 0.03) and to reduced overall survival (p = 0.02). Our results show that the prognostic significance of COX-2 depends on the histological type of esophageal carcinoma and preoperative treatment of the patient. In conclusion, COX-2 is not a prognostic marker in squamous cell carcinoma of the esophagus, but low COX-2 expression is associated with poor prognosis in the neoadjuvant-treated patients.     

Development and validation of an LC-UV method for the quantification and purity determination of the novel anticancer agent C1311 and its pharmaceutical dosage form

C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. The pharmaceutical development of C1311 necessitated the availability of an assay for the quantification and purity determination of C1311 active pharmaceutical ingredient (API) and its pharmaceutical dosage form. A reversed-phase liquid chromatographic method (RP-LC) with ultraviolet (UV) detection was developed, consisting of separation on a C18 column with phosphate buffer (60 mM; pH 3 with 1 M citric acid)-acetonitrile-triethylamine (83:17:0.05, v/v/v) as the mobile phase and UV-detection at 280 nm. The method was found to be linear over a concentration range of 2.50-100 microg/mL, precise and accurate. Accelerated stress testing showed degradation products, which were well separated from the parent compound, confirming its stability-indicating capacity. Moreover, the use of LC-MS and on-line photo diode array detection enabled us to propose structures for four degradation products. Two of these products were also found as impurities in the API and more abundantly in an impure lot of API.     

EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report

Soft tissue myoepithelial tumors, a recently defined entity, include benign and malignant lesions showing a considerable morphological and immunohistochemical heterogeneity. EWSR1 rearrangements are well recognized in this tumor type, and some of the partner genes have been identified. Herein we describe a soft tissue myoepithelioma arising in the pelvis with an EWSR1-ATF1 fusion, therefore extending the spectrum of partner genes of EWSR1. In addition, this case indicates that there are overlapping genetic features of myoepithelial tumors, clear cell sarcoma, angiomatoid fibrous histiocytoma, and hyalinizing clear-cell carcinoma of the salivary gland.     

Survival of adhering staphylococci during exposure to a quaternary ammonium compound evaluated by using atomic force microscopy imaging

Effects of a quaternary ammonium compound (QAC) on the survival of adhering staphylococci on a surface were investigated using atomic force microscopy (AFM). Four strains with different minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) for the QAC were exposed to three different concentrations of the QAC in potassium phosphate buffer (0.5×, 1×, and 2× MBC) while adhering to glass. Adhering staphylococci were repeatedly imaged with AFM in the contact mode, and the cell surface was found to wrinkle upon progressive exposure to the QAC until bacteria disappeared from the substratum. Higher concentrations of QAC yielded faster wrinkling and the disappearance of bacteria during imaging. Two slime-producing staphylococcal strains survived longer on the surface than two non-slime-producing strains despite similar MICs and MBCs. All staphylococci adhering in unscanned areas remained adhering during exposure to QAC. Since MICs and MBCs did not relate to bacterial cell surface hydrophobicities and zeta potentials, survival on the surface is probably not determined by the direct interaction of QAC molecules with the cell surface. Instead, it is suggested that the pressure of the AFM tip assists the incorporation of QAC molecules in the membrane and enhances their bactericidal efficacy. In addition, the prolonged survival under pressure from slime-producing strains on a surface may point to a new protective role of slime as a stress absorber, impeding the incorporation of QAC molecules. The addition of Ca(2+) ions to a QAC solution yielded longer survival of intact, adhering staphylococci, suggesting that Ca(2+) ions can impede the exchange of membrane Ca(2+) ions required for QAC incorporation.     

Characterization of New Amphiphilic Block Copolymers of N‐Vinyl Pyrrolidone and Vinyl Acetate, 1 – Analysis of Copolymer Composition,End Groups,Molar Masses and Molar Mass Distributions

New amphiphilic block copolymers consisting of N‐vinyl pyrrolidone and vinyl acetate were synthesized via controlled radical polymerization using a reversible addition/fragmentation chain transfer (RAFT)/macromolecular design via the interchange of xanthates (MADIX) system. The synthesis was carried out in 1,4‐dioxane as process solvent. In order to get conclusions on the mechanism of the polymerization the molecular structure of formed copolymers was analysed by means of different analytical techniques. ¹³C NMR spectroscopy was used for the determination of the monomer ratios. End groups were analysed by means of matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry. This technique was also used to determine possible fragmentations of the RAFT end groups. By means of a combination of size exclusion chromatography, ¹³C NMR and static light scattering molar mass distributions and absolute molar masses could be analysed. The results clearly show a non‐ideal RAFT mechanism.

     

Imaging alveolar-capillary gas transfer using hyperpolarized 129Xe MRI

Effective pulmonary gas exchange relies on the free diffusion of gases across the thin tissue barrier separating airspace from the capillary red blood cells (RBCs). Pulmonary pathologies, such as inflammation, fibrosis, and edema, which cause an increased blood-gas barrier thickness, impair the efficiency of this exchange. However, definitive assessment of such gas-exchange abnormalities is challenging, because no methods currently exist to directly image the gas transfer process. Here we exploit the solubility and chemical shift of (129)Xe, the magnetic resonance signal of which has been enhanced by 10(5) with hyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchange regions of the lung. Based on a simple diffusion model, we estimate that this MR imaging method for measuring (129)Xe alveolar-capillary transfer is sensitive to changes in blood-gas barrier thickness of approximately 5 microm. We validate the successful separation of tissue barrier and RBC images and show the utility of this method in a rat model of pulmonary fibrosis where (129)Xe replenishment of the RBCs is severely impaired in regions of lung injury.