Rapid bactericidal activities of carbapenems against Pseudomonas aeruginosa in simulating human plasma concentrations

The rapid bactericidal activities of panipenem (PAPM), imipenem (IPM), and meropenem (MEPM) against Pseudomonas aeruginosa were investigated by using in vitro pharmacodynamic model simulating the human plasma concentrations after intravenous drip infusion at 500 mg for 0.5 hours. Against P. aeruginosa PAO1, PAPM and IPM showed rapider reduction in viable cell counts than MEPM at 0.5 hours after exposure. All drugs showed more than 3 log10 reduction in viable cell counts at 2 hours after exposure and bacterial regrowth was not observed throughout 6 hours. The initial bactericidal activities of the drugs against 4 clinical isolates within 1 hour after exposure were also investigated by the same method. Against P. aeruginosa strain 12,475, the 3 drugs showed similar initial bactericidal activity but PAPM and IPM showed stronger initial bactericidal activity than MEPM against the other strains as did against P. aeruginosa PAO1. The morphological change of a strain 12,489, for which the initial bactericidal activities were different largely, after 0.5 hours exposure to simulated drug-concentrations was investigated by scanning electron microscope. PAPM and IPM induced morphological changes in most of the cells and cell lysis and bulge formation. On the other hand, MEPM induced changes of the surface structure of cells and slightly elongated cells, but not cell lysis.     

Dimerumic acid as an antioxidant from the mold, Monascus anka: the inhibition mechanisms against lipid peroxidation and hemeprotein-mediated oxidation

This study aimed to investigate the antioxidant mechanism of dimerumic acid isolated as the active component with a radical scavenging action from the mold Monascus anka, traditionally used for the fermentation of foods. Dimerumic acid inhibited NADPH- and iron(II)-dependent lipid peroxidation (LPO) of rat liver microsomes at 20 and 200 microM, respectively. When ferrylmyoglobin was incubated with dimerumic acid, the myoglobin was scavenged and an electron spin resonance (ESR) signal with nine peaks was observed. The spin adduct was identified as a nitroxide radical by analysis of hyperfine structure. Similar ESR signal was also detected by incubation of dimerumic acid with peroxyl radicals. Thus, it was clarified that the antioxidant action of dimerumic acid is due to one electron donation of the hydroxamic acid group in the dimerumic acid molecule toward oxidants resulting in formation of nitroxide radical.     

2a-[4-(Tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole derivatives: new selective antagonists of the 5-hydroxytryptamine7 receptor

A series of tetrahydrobenzindoles was prepared, and the affinity of these compounds for the 5-hydroxytryptamine7 (5-HT7) receptor and other receptors was evaluated. Most of the compounds showed high affinity for the 5-HT7 receptor, and 2a-[4-(tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole derivatives (26a-j) exhibited high selectivity for this receptor. The nature of the substituent at the 9-position of the tetrahydropyridindole ring affected the affinity for the 5-HT7 receptor, and the 9-carbamoyl moiety afforded increased selectivity. Compound 26j exhibited high affinity for the 5-HT7 receptor, with at least 280-fold selectivity over the 5-HT2 receptor. In a functional model of 5-HT7 receptor activation, this compound was confirmed to have 5-HT7 receptor antagonist activity. It should be a useful tool for clarifying the biological role of the 5-HT7 receptor.     

Antineoplastic agents. 489. Isolation and structures of meliastatins 1-5 and related euphane triterpenes from the tree Melia dubia

The bark of the giant neem tree Melia dubia was found to contain 11 euphane-type triterpenes. Five new compounds, meliastatins 1-5 (1-5), proved to inhibit growth of the P388 lymphocytic leukemia cell line (ED(50) 1.7-5.6 microg/mL). Four of the others, the previously known methyl kulonate (8), kulinone (9), 16-hydroxybutyrospermol (10), and kulactone (11), were also found to inhibit (ED(50) 2.5-6.2 microg/mL) the P388 cancer cell line. In addition, two new euphane triterpenes were isolated and named dubione A (6) and dubione B (7). Structures for each of the 11 euphane triterpenes were established by spectral techniques that included HRMS and 2D NMR.     

Autocrine signaling through Ras regulates cell survival activity in human glioma cells: potential cross-talk between Ras and the phosphatidylinositol 3-kinase-Akt pathway

Autocrine fibroblast growth factor (FGF) signaling mediates an uncontrollable growth of human gliomas. We investigated the intracellular signaling of FGF on cell survival activity. U251MG human glioma cells were infected with adenovirus vectors expressing dominant negative type I FGF receptor (DNFR), constitutive active Ras (RasL61), or dominant negative Ras (RasN17). DNFR reduced glioma cell accumulation with apoptosis and this reduction was alleviated with exogenous epidermal growth factor (EGF), which can activate Ras independent of FGFR but not with bFGF. RasL61 prevented but RasN17-enhanced DNFR-induced apoptosis. Reportedly, cell survival signaling through Akt was constitutively active in U251MG cells and this effect may be dependent on autocrine signaling and dysfunction of PTEN, a tumor suppressor gene limiting phosphatidylinositol 3-kinase (PI3K) activity. DNFR dose-dependently inhibited Akt activity and this inhibition was recovered by RasL61, whereas RasN17 inhibited Akt activity. Wortmannin (a PI3K inhibitor) inhibited Akt activity and mildly promoted apoptosis. RasL61 prevented the down-regulation of Akt activity and apoptosis induced by wortmannin, but RasN17 plus wortmannin strongly inhibited Akt activity and promoted marked apoptosis. Our data suggested that the cell survival activity of human gliomas is largely dependent on cross-talk between Ras and the PI3K-Akt pathway, and this cross-talk could be a potential target for molecular-based therapeutics.     

Assessment of the signal intensity distribution pattern within the unruptured cerebral aneurysms using color-coded 3D MR angiography

To evaluate the interaction between the MR signal intensity distribution pattern and bleb formation/ deformation of the aneurysmal dome, fifty cases of the unruptured cerebral aneurysms were investigated with the color-coded 3D MR angiography. Patterns were categorized into central-type, neck-type and peripheral-type according to the distribution of MR signals with low-, moderate- and high signal intensity areas. Imaging analysis revealed the significant relationship (P < 0.02) of the peripheral-type aneurysms to the bleb formation and deformation of the dome, compared with those of central- and neck-type. Additionally, peripheral-type signal intensity distribution pattern was shown with aneurysms harboring relatively large dome size and lateral-type growth including internal carotid aneurysms. Prospective analysis of intraaneurysmal flow pattern with the color-coded 3D MR angiography may provide patient-specific analysis of intraaneurysmal flow status in relation to the morphological change of the corresponding aneurysmal dome in the management of unruptured cerebral aneurysms.     

Ischemia of the sternocleidomastoid muscle following occipital artery embolization for dural arteriovenous fistula

We report a case of localized ischemia of the sternocleidomastoid muscle (SCM) occurring after occipital artery embolization of a dural arteriovenous fistula (dAVF). A 45-year-old man presented intracerebral hemorrhage from a dAVF at the left transverse-sigmoid sinus. The dAVF had a high flow fistula from the left occipital artery (OA). Endovascular therapy was carried out one month later. Transarterial embolization of the OA was carried out prior to the transvenous approach to decrease the shunt flow. During obliteration of the proximal portion of the OA with fiber platinum coils and polyvinyl alcohol particles, the patient reported severe neck pain. The fistula was successfully embolized after transvenous packing of the left sigmoid sinus with detachable coils. The neck pain persisted for one week and disappeared after conservative treatment. T2-MR imaging 3 days after the embolization showed a hyperintensity in the left SCM. This ischemic lesion was probably induced by occlusion of the muscular branch of the OA. We discuss this common but rarely reported complication of OA embolization.     

Expression of tubulin beta II in neuroepithelial tumors: reflection of architectural changes in the developing human brain

Tubulin beta II (Tub-II) is widely distributed in the developing neuronal axons and dendrites. Recent studies have demonstrated that Tub-II is also important in the early development of the human brain, and Tub-II represents a marker for progenitor and neural stem cells. To elucidate the correlation between the developing brain and neuroepithelial tumors (NETs), the present study assessed Tub-II expression by NETs and normal brain tissue using immunohistochemical and immunoblot analyses. In the gliomas, decreased numbers and staining intensities of Tub-II-positive cells tended to be associated with increased differentiation. Conversely, neuronal neoplasms displayed high percentages and strong staining intensities among the Tub-II-positive cells, irrespective of differentiation. In neuronal neoplasms and neoplasms with neuronal differentiation, Tub-II staining was far more intense and more homogeneous than Tub-II staining in gliomas. These results indicate that the expression of Tub-II in NETs may reflect architectural changes in the developing brain and may support the hypothesis that neuroepithelial tumors originate from glioneuronal progenitor cells capable of generating astrocytic, and neuronal cell types.     

The first trial of phase contrast imaging for digital full-field mammography using a practical molybdenum x-ray tube

RATIONALE AND OBJECTIVES: The image quality of a newly developed full-field digital phase contrast mammography (PCM) system and of a conventional screen-film (SF) mammography system were compared via images of a phantom and receiver operating characteristic (ROC) analysis of clinical images. METHODS: Magnified (1.75X) PCM images were scanned (sampling rate, 43.75 microm) and then reduced to original-sized, 25-micron pixel images printed on photothermographic film. Along with corresponding SF images, the phantom images were evaluated subjectively, and the clinical images of 38 patients were subjected to ROC analysis of mass and microcalcification. RESULTS: In the image quality of a phantom, the PCM exceeded the SF. In both mass and microcalcification, the ROC analysis Az values of the PCM clinical images surpassed those of the SF images. CONCLUSION: The PCM provides better images than the SF. Clinical trials suggest superior detection of both mass and microcalcification by full-field digital PCM over conventional SF mammography.