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81.
Michael Krause Agns Rouleau Holger Stark Peter Luger Monique Garbarg Jean-Charles Schwartz Walter Schunack 《Archiv der Pharmazie》1996,329(4):209-215
The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H3-receptor agonist (R)-α-methyl-histamine ( 1 ) a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1 , and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl]phenol ( 8c ), the 2-furanyl analogue 8d , and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use. 相似文献
82.
83.
Introns and gene evolution 总被引:5,自引:0,他引:5
Sandro J. de Souza Manyuan Long & Walter Gilbert 《Genes to cells : devoted to molecular & cellular mechanisms》1996,1(6):493-505
In one scenario of gene evolution, exon shuffling has a fundamental role in increasing gene diversity. As DNA sequences accumulate in the databases, the picture of the intron/exon structures of genes becomes more and more clear. We discuss in this review some features of this picture that suggest that introns have been present since the early stages of evolution, and that exon shuffling was a fundamental process in the construction of ancient as well as modern genes. 相似文献
84.
Summary The effect of the complement-derived polypeptide C3adesArg as a mediator of inflammation in the central nervous system was examined. Twenty-five anesthetized cats received 4 mg of this polypeptide by intraventricular injection, 20 cats who served as controls received saline. Cerebrospinal fluid (CSF) was sampled 3 h after intraventricular injection and the brains were removed. For assessment of the permeability of the blood-brain barrier the CSF penetration of four antibiotics, which were given intravenously, was measured. Five control animals were employed for each antibiotic (tobramycin, ampicillin, imipenem, fosfomycin), whereas six C3adesArg-treated animals were used for each antibiotic and seven for tobramycin. Besides CSF levels of glucose, the prostanoids 6-keto-prostaglandin F1, thromboxane B2 and prostaglandin E2 were measured. The morphological examinations in the CSF sediments and histological brain sections in the C3adesArg-treated animals disclosed a distinct inflammation with leptomeningeal and perivascular infiltration of polymorphonuclear granulocytes compared to normal findings in the controls. The CSF/serum ratios of all of the antibiotics were markedly elevated compared to controls, indicating a blood-brain barrier disruption. The levels of all prostanoids were significantly higher in the treatment group than in the control group, whereas the glucose levels were lower. These findings are in accordance with a granulocytic meningitis as seen in some infections at the acute stage. It is concluded that C3adesArg acts as a mediator of inflammation in the central nervous system. 相似文献
85.
Heinz Schurawitzki M.D. Paul C. Hajek Josef Kramer Florian Grabenwöger Walter Klepetko Anton Moritz 《Cardiovascular and interventional radiology》1989,12(1):10-13
In a radiologic search for embolized leaflets of Edwards-Duromedics bileaflet valves in 2 patients, the embolized fragments were localized in the iliac vessels using computed tomography. Sonography was successful in one case and standard X-ray films of the abdomen were negative in both cases.In vitro investigations with Björk-Shiley and Edwards-Duromedics leaflets suggested that standard X-ray films of the abdomen and pelvis should be considered as the first investigational technique. If negative, computed tomography of the lower abdomen should be done. 相似文献
86.
Localization of SNARE proteins and secretory organelle proteins in astrocytes in vitro and in situ 总被引:1,自引:0,他引:1
Wilhelm A Volknandt W Langer D Nolte C Kettenmann H Zimmermann H 《Neuroscience research》2004,48(3):249-257
Astrocytes are capable of regulated release of messenger molecules. Astrocytes cultured from new born rodent brain express a variety of classical presynaptic proteins. We investigated the question whether the capability to express synaptic proteins in culture was a feature only of immature astrocytes, and whether these proteins were also expressed by astrocytes in situ. Experiments were performed with transgenic mice expressing the enhanced green fluorescent protein under the control of the human glial fibrillary acidic protein promoter. Using double fluorescence and astrocytes cultured from 1 to 16 day-old animals we show that the astrocytic expression of synaptic proteins in culture is invariant of the age of donor animals. Culturing can induce the astrocytic expression of specific synaptic proteins such as SV2, synaptophysin and SNAP-25. Astrocytes in brain sections of 1-16 day-old animals revealed a punctuate immunofluorescence for secretory carrier membrane protein (SCAMP), SNAP-23, synaptobrevin II, and cellubrevin, to a minor extent for SNAP-25 and synaptophysin, and none for SV2. Our results demonstrate that cultured astrocytes express synaptic proteins not present in situ. Nevertheless, astrocytic organelles in situ are equipped with molecules that could be involved in regulated exocytosis of messenger substances. 相似文献
87.
The Modality Specificity of the Slow Negative Wave 总被引:1,自引:0,他引:1
Event-related potentials were recorded in a simple reaction time task using a 3-sec interval between S1 and S2. The sensory modalities of S1 and S2 were varied across 4 conditions to yield all possible combinations of tones and flashes. A negative component which peaked between 600 and 800 msec after S1 was specific in scalp distribution to the modality of S1 but not S2. It was concluded that this negative component is a response to S1 and not related to processes associated with anticipation of S2. A slow negative shift which peaked at S2 was largest at the vertex in all conditions, suggesting its motor origin. A trend for the latter activity to be more negative in posterior recordings when S2 was visual than auditory leaves open the possibility that the terminal CNV is a combination of motor activities and anticipation of the sensory modality of S2. 相似文献
88.
Summary A simple organ culture method for culturing embryonic skin was developed. A piece of skin with a part of the neural tube from mouse embryo (11 to 12 d) was placed on a 25 mm d membrane filter. The filter was folded to wrap the explant and inserted into glass tubing. The explant and filter in the glass tubing were placed in a rotating tissue culture tube containing 5 ml culture medium (Ham's F12 supplemented with 15 to 20% fetal bovine serum) and filled with a mixture of 95% air:5% CO2. In explants cultured for 6 d fully differentiated melanocytes were observed in the epidermis. 相似文献
89.
Stephan A. Wacker Franz Oswald Jörg Wiedenmann Walter Knöchel 《Developmental dynamics》2007,236(2):473-480
Lineage labeling is one of the most important techniques in developmental biology. Most recently, a set of photoactivatable fluorescent proteins originating from marine cnidarians became available. Here, we introduce the application of the green to red photoconvertible protein EosFP as a novel technique to analyze early vertebrate development. Both injection of EosFP mRNA and purified, recombinant EosFP followed by a light-driven green to red conversion allow lineage labeling in virtually any temporal and spatial dimension during embryonic development for at least 2 weeks. Specific staining of cells from nonsurface layers is greatly facilitated by light-driven conversion of EosFP compared with traditional methods. Therefore, green to red photoactivatable proteins promise to be a powerful tool with the potential to satisfy the increasing demand for methods enabling detailed phenotypical analyses after manipulations of morphogenetic events, gene expression, or signal transduction. 相似文献
90.
Cytogenetic and comparative genomic hybridization findings in four cases of breast cancer after neoadjuvant chemotherapy 总被引:1,自引:0,他引:1
Fazeny-Dörner B Piribauer M Wenzel C Fakhrai N Pirker C Berger W Sedivy R Rudas M Filipits M Okamoto I Marosi C 《Cancer Genetics and Cytogenetics》2003,146(2):161-166
To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer. 相似文献