Facile synthesis of high affinity styrylpyridine systems as inherently fluorescent ligands for the estrogen receptor

A series of styrylpyridine derivatives containing two phenols was prepared via an efficient two-step synthesis. These compounds were designed to maximize the estrogen receptor binding affinity of a known series of inherently fluorescent styrylpyridines. While significant improvements were achieved in receptor affinity, the fluorescence intensity of this series of compounds is poor.     

EMT defibrillation does not increase survival from sudden cardiac death in a two-tiered urban-suburban EMS system

BACKGROUND: The aim of this article was to analyze the perioperative mortality and stroke risk rates and late benefits of carotid endarterectomy (CE) contralateral to an occluded internal carotid artery (ICA), on the basis of our surgical experience from July 1990 to June 1996. METHODS: In 57 (14.7%) of 336 patients undergoing 388 CEs, the contralateral ICA was occluded (group I). All operations were performed under general anesthesia with selective shunting based on electroencephalographic criteria. Shunting was used in 36 (63.1%) of 57 revascularizations in group I and 47 (14.2%) of 331 operations performed on the remaining 279 patients with patent contralateral ICAs (group II) (p < 0.001). RESULTS: Perioperative strokes occurred in two patients (3.5%) in group I and three patients (1%) in group II (difference not significant). The only perioperative death, which occurred in one patient (1.7%) in group I, was the result of a perioperative stroke; two patients (0.7%) in group II died within 30 days of operation (difference not significant). Life-table cumulative stroke-free rates at 1, 3, and 5 years were 95%, 95%, 95% in group I and 98.8%, 98.2%, and 98.2% in group II, respectively (p = 0.272). Life-table cumulative survival rates at 1, 3, and 5 years were 97.5%, 94.2%, and 78.1% in group I and 99.2%, 94.8%, and 71.7% in group II, respectively (p = 0.306). CONCLUSIONS: The results of this analysis indicate that CE contralateral to an occluded ICA can be performed with acceptable perioperative mortality and stroke risk rates and late stroke-free and survival rates comparable to those seen in patients without contralateral ICA occlusion who have undergone operation. Nevertheless, we think it is misleading to imply that the risks of operating on the two groups are the same. Moreover, because no late stroke-related death occurred in patients with contralateral ICA occlusion, it would appear that superior late stroke-free rates did not translate into a prolonged survival advantage.     

Vesiculobullous Hailey-Hailey disease: successful treatment with oral retinoids

A 56-year-old male presented with a pruritic, generalized vesiculobullous eruption. His past history revealed classical symptoms of limited Hailey-Hailey disease for 34 years. Clinically, vesicles, bullae and occasional pustules were present and multiple biopsies confirmed this to be an unusual presentation of Hailey-Hailey disease. Various therapeutic modalities including topical and oral antibiotics, oral prednisone and dapsone failed to achieve sustained remission. Treatment with low-dose oral etretinate (25 mg daily) produced marked clinical improvement with complete suppression of new vesicle formation after 6 weeks.     

Receptors for the 5-oxo class of eicosanoids in neutrophils

5-Hydroxy- and 5-oxo-eicosatetraenoate (5-HETE and 5-oxoETE) activate polymorphonuclear neutrophils (PMNs) through a common, receptor-like recognition system. To define this system, we examined the interaction of these eicosanoids with human PMNs. PMNs esterified 5-[3H]HETE to glycerolipids at 37 and 4 degreesC. At 37 but not 4 degreesC, the cells also hydroxylated the label to 5, 20-[3H]diHETE. The acyl:CoA synthetase blocker, triacsin C, inhibited esterification but also led to an increase in the hydroxylation of the label. PMNs processed 5-[3H]oxoETE through the same pathways but only or principally after reducing it to 5-[3H]HETE (37 or 4 degreesC). In the presence of these varying metabolic reactions, PMNs (37 or 4 degreesC; +/- triacsin C) could not be shown to receptor bind either radiolabel. Plasma membranes isolated from PMNs esterified but unlike whole cells did not reduce or hydroxylate 5-[3H]oxoETE. Triacsin C blocked esterification, thereby rendering the membranes unable to metabolize this radiolabel. Indeed, triacsin C-treated membranes bound (Kd = 3.8 nM) 5-[3H]oxoETE specifically and reversibly to 86 pmol of sites per 25 micrograms of membrane protein. 5-OxoETE, 5-HETE, and 5,15-diHETE displaced this binding at concentrations correlating with their potency in eliciting PMN Ca2+ transients. GTP and GTPgammaS, but not ATP or ATPgammaS, also reduced 5-[3H]oxoETE binding, whereas 15-HETE, leukotriene B4, platelet-activating factor, IL-8, C5a, and N-formyl-Met-Leu-Phe lacked this effect. We conclude that PMNs and their plasma membranes use an acyl:CoA synthetase-dependent route to esterify 5-HETE and 5-oxoETE into lipids. Blockade of the synthetase uncovers cryptic plasmalemma sites that bind 5-oxoETE with exquisite specificity. These sites apparently mediate responses to the 5-oxo class of eicosanoids and are likely members of the serpentine superfamily of G protein-linked receptors.     

Bacteriologic detection and sensitivity determination combined: a rapid test for use in practice?

In this investigation the results obtained with a testkit for detecting bacteria and their antibiotic sensitivity (ABcheck, Vétoquinol) were compared with those obtained using standard bacteriological procedures. Ten urine samples, ten skin samples, and ten cerumen samples were examined in parallel. The results indicate that the testkit is not reliable with respect to whether antibiotics should be administered and with respect to which antibiotics should be used.     

Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells

Evidence suggests that cholinergic input to the hippocampus plays an important role in learning and memory and that degeneration of cholinergic terminals in the hippocampus may contribute to the memory loss associated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists. Here, we employ traditional pharmacological reagents as well as m1-toxin, an m1 antagonist with unprecedented selectivity, to demonstrate that this potentiation of NMDA-receptor currents in hippocampal CA1 pyramidal cells is mediated by the genetically defined m1 muscarinic receptor. Furthermore, we demonstrate the colocalization of the m1 muscarinic receptor and the NR1a NMDA receptor subunit at the electron microscopic level, indicating a spatial relationship that would allow for physiological interactions between these two receptors. This work demonstrates that the m1-muscarinic receptor gene product modulates excitatory synaptic transmission, and it has important implications in the study of learning and memory as well as the design of drugs to treat neurodegenerative diseases such as Alzheimer's.     

Role of type specific herpes simplex virus serology in the diagnosis and management of genital herpes

Chromogenic hexapeptides Dnp-Ala-Ala/Ser-Phe-Phe-Ala-Arg-NH2 containing a Phe-Phe bond, which is sensitive to aspartic proteinases, were used as substrates for assaying the activity of pepsin, chymosin, and aspergillopepsin A. The assay was performed after the separation of hydrolyzates on SP-Sephadex by measuring at 360 nm the absorbance of the dinitrophenylpeptide lacking the cationic group, which was formed upon the cleavage of the substrate. The kinetic parameters of the hydrolysis of the substrates were evaluated. It is shown that replacing the Ala residue with Ser in the P2 position does not substantially change the kinetic parameters. The substrates were hydrolyzed by pepsin several times faster than by aspergillopepsin A or chymosin. The method is sensitive and enables the activity of aspartic proteinases to be determined easily.     

In vitro genotoxicity studies of chrysotile asbestos fibers dispersed in simulated pulmonary surfactant

Micronucleus (MN) formation and sister-chromatid exchange (SCE) assays were performed for asbestos in cultured Chinese hamster lung (V79) cells to determine the effect of surfactant treatment on the genotoxicity of two chrysotile asbestos samples of different fiber lengths. The cells were challenged in vitro with NIEHS intermediate- and short-length chrysotile fibers in both their native state and with surfactant pretreatment. For the surfactant pretreatment, the fibers were incubated in a simulated pulmonary surfactant which was prepared by ultrasonically dispersing dipalmitoyl lecithin (DPL), a primary component of pulmonary surfactant, in minimal essential medium (MEM). Chrysotile asbestos was ultrasonically mixed into the prepared surfactant dispersion or into MEM. V79 cells were exposed to DPL-treated intermediate-length chrysotile (TICA), intermediate-length chrysotile (ICA), DPL-treated short-length chrysotile (TSCA) or short-length chrysotile (SCA) fibers for 48 h. For each treatment, 2000 mononucleated cells were scored for MN formation, and 30 M2 metaphase cells were scored for SCE induction. The results showed that all samples, TICA, ICA, TSCA and SCA, caused significant elevation in the frequency of cells with micronuclei and of cells with two or more nuclei. The increase in micronucleus frequency was greatest in cells challenged with untreated intermediate-length fibers, and was greater for untreated than for DPL-treated short-length fibers. For the short-length fiber samples, DPL surfactant treatment decreased activity for multiple nucleus formation, while DPL treatment did not result in consistent changes in that activity for intermediate-length fibers. Results of SCE assays were either negative or inconclusive. Cells were more viable following TICA and TSCA than following ICA and SCA challenge as measured by cell counts after 48 h of incubation.     

Technical report: Cystic air spaces in the lung: change in size on expiratory high-resolution CT in 23 patients

BACKGROUND: Urticaria is a common disease that is always a challenge to the dermatologist due to its evasive etiology. PATIENTS AND METHODS: One hundred and seven chronic urticaria patients were studied. Routine laboratory investigations were performed and Helicobacter pylori (H. pylori) immunoglobulin G (IgG) antibody determinations, autoimmune reactivity, infections, allergies, and hyperreactivities were investigated. RESULTS: Pathologic findings were seen in 92 patients. Concomitant diseases suggesting autoimmune reactivity were detected in nine patients and, in 16 patients, infections including maxillary sinusitis, streptococcal tonsillitis, and tooth infection were found. Elevated total IgE level was detected in 37 out of 75 patients and positive skin prick test results in 47 out of 91 patients. Fifty-five patients had a history of recent dyspeptic symptoms. A diagnosis of adult celiac disease was made in two patients and, additionally, IgA antigliadin antibodies were seen in four patients. H. pylori IgG antibodies were found in 40 out of 107 patients. Active gastritis was verified by esophagogastroduodenoscopy in 30 out of 32 patients with positive Helicobacter staining in 24 samples. An elevated IgE level was detected in 64% of H. pylori-positive and in 39% of H. pylori-negative patients. CONCLUSIONS: In this study, several findings suggesting aberrant immunologic activation were detected in chronic urticaria patients. Inflammation in the gastrointestinal tract, e.g. caused by H. pylori infection, may have an important role in the etiology of chronic urticaria.