Effect of lumen narrowing within sirolimus-eluting stents on proximal and distal vessel segments.

BACKGROUND: Flow dynamics and shear stress may influence downstream vessel segments. The aim of this study was to investigate the potential impact of lumen narrowing within sirolimus-eluting stents (SES) on vessel response at adjacent reference sites. METHODS AND RESULTS: In 135 patients after SES implantation, minimal lumen area (MLA) within the stent and average lumen area at distal or proximal adjacent reference segments (5 mm) were obtained at baseline and follow up. In the smaller in-stent MLA group (MLA <3 mm(2)), lumen area decreased significantly at the distal reference compared with the larger in-stent MLA group (MLA >or=3 mm(2)), although no significant difference was seen at the proximal reference. CONCLUSION: In-stent lumen patency may influence vascular responses at adjacent reference segments after SES implantation.     

TNF-alpha induces thromboxane receptor signaling-dependent microcirculatory dysfunction in mouse liver

TNF-alpha is a critical mediator of hepatic microcirculatory dysfunction during endotoxemia. The present study was to investigate the role of thromboxane A2 (TXA2) and the biological significance of thromboxane prostanoid (TP) receptor signaling in TNF-alpha-mediated hepatic microcirculatory dysfunction in male C57Bl/6 mice. The number of leukocytes adhering to the endothelial cells of the hepatic microvessels (the portal venules, sinusoids, and central venules) and the percentage of nonperfused sinusoids were determined using in vivo fluorescence microscopy. FR167653, an inhibitor of TNF-alpha, was administered 0 and 2 h after LPS injection. A TXA2 synthase inhibitor, OKY-046, was administered 30 min before TNF-alpha injection. Thromboxane prostanoid receptor knockout mice were used to investigate whether TNF-alpha-induced hepatic microcirculatory dysfunction is mediated by endogenously produced TXA2. FR167653 reduced LPS-induced leukocyte adhesion (50%-80%) and the percentage of nonperfused sinusoids (55%). The leukocyte adhesion was increased in the portal venules (8-fold), sinusoids (51-fold), and central venules (73-fold) in TNF-alpha-treated mice, accompanied with an increase in sinusoidal perfusion deficits (8-fold). Alanine aminotransferase levels rose as the adhesion of leukocytes increased. OKY-046 administration before TNF-alpha administration reduced leukocyte adhesion (41%-49% decrease) and sinusoid perfusion deficits (34% decrease). In TP receptor knockout mice, the number of adhering leukocytes, the percentage of nonperfused sinusoids, and alanine aminotransferase levels were lower (by 43%-56%, 41%, and 29%, respectively) than in wild-type counterparts. The results suggest that TP receptor signaling may promote hepatic microcirculatory dysfunction elicited by TNF-alpha. Blockade of TNF-alpha generation and TP receptor signaling may be a good strategy for managing endotoxin-induced hepatic injury.     

Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients

The G-protein β3 subunit (GNB3) gene is a key modulator of signal transduction and is a major candidate for SSRIs response. The aim of the present study is to test a possible effect of the C825T polymorphism on the antidepressant response and intolerance to selective serotonin reuptake inhibitors (SSRIs) in 146 Japanese samples with major depression treated with paroxetine or fluvoxamine for 6 weeks. The severity of depression symptom was assessed using the 21-item Hamilton Rating Scale for Depression (HAM-D) and adverse drug reactions were evaluated bi-weekly. No association with SSRIs treatment response was observed in 107 completers also including HAM-D baseline scores, SSRI type or/and 5-HTTLPR variants in the model as covariates. Furthermore, no significant association could be observed with intolerance to SSRIs in the whole subjects. The result suggests that C825T variants of GNB3 cannot play a major role as a predictor of treatment response as well as intolerance to SSRIs in Japanese patients with major depression.     

Organization of connectivity of the rat presubiculum: II. Associational and commissural connections

The regional, laminar, and longitudinal organization of intrinsic projections in the presubiculum was examined in the rat with the retrograde tracer horseradish peroxidase conjugated to wheat germ agglutinin and the anterograde tracer Phaseolus vulgaris-leucoagglutinin. Cells of origin of intrinsic projections in the presubiculum were distributed in layers II and V, with almost none in layers III and VI. Projections from layer II cells were bilateral and confined to layers II and V and also to the deep portion of layer I, whereas projections from layer V cells were ipsilateral and confined largely to layer V, with fewer projections to layer II. Septotemporal and proximodistal differences in both the projection and the distribution of layer II cells were found: layer II cells in the septal and mid presubiculum, especially those located in the distal part, provided long projections to the temporal presubiculum, whereas layer II cells in the temporal presubiculum provided slightly shorter projections almost entirely within the mid and temporal presubiculum. Layer II cells aggregated massively in the distal portions of the septal and mid presubiculum, but very few layer II cells were found in the most proximal part, especially in the temporal presubiculum. On the other hand, in layer V, cells of origin and their terminals were diffusely and equally distributed throughout the entire proximodistal extent of the presubiculum. Layer V cells did not project longitudinally as far as layer II cells. These longitudinal connections, in layers II and V, make it possible to merge information conveyed by parallel pathways in the presubiculum.     

Biotransformation of phenolic 1-benzyl-N-methyltetrahydroisoquinolines in plant cell cultures followed by LC/NMR, LC/MS, and LC/CD

(+/-)-1-Benzyl- N-methyltetrahydroisoquinolines 7-10 and 11-14 with one and two hydroxy groups on the aromatic rings, respectively, were fed individually to cultured cells of Corydalis and Macleaya species, respectively. The structures of the metabolites were determined by using combinatorial techniques, including LC/NMR, LC/MS-MS, and LC/CD. The enantiomeric excesses of the metabolites were derived from LC/CD and LC/MS-MS analyses. In cell cultures of Corydalis and Macleaya species, laudanine (7), with a hydroxy group at C-3', can form the berberine bridge at C-2' and C-6' to produce S- and R-enantiomers of 2,3,9,10- and 2,3,10,11-oxygenated protoberberines (20 and 21), respectively, whereas reticuline (11) and protosinomenine (12), incoporating a hydroxy group at C-3', form the berberine bridge at C-2' to furnish the S-enantiomer of 2,3,9,10-oxygenated protoberberines (23 and 21), respectively.     

SPF-5506-A4, a new peptaibol inhibitor of amyloid beta-peptide formation produced by Trichoderma sp

A new peptaibol compound, SPF-5506-A4, was isolated from the fermentation broth of Trichoderma sp. SPF-5506. The chemical structure of the 14-residue peptide was determined by MS, NMR and amino acid sequence analyses. The absolute configuration of amino acid residues in the acid hydrolysate was determined by Marfey's method. The structure of SPF-5506-A4 was established as Ac-Aib-L-Asn-L-Ile-Aib-L-Pro-L-Ser-L-Ile-Aib-L-Pro-L-Leu-L-Leu-Aib-L-Pro-L-leucinol. The compound inhibited amyloid beta-peptide formation in primary guinea pig cerebral cortex neuron cell culture dose-dependently with an IC50 of 0.1 microg/ml. Cytotoxicity was not observed at concentrations of <3 microg/ml.     

Regional differences in the functional and biochemical properties of endothelin receptor subtypes in the rabbit prostatic urethra

OBJECTIVE: To examine the regional differences in the functional (pharmacological) and biochemical properties of endothelin (ET) receptors in the rabbit prostatic urethra. MATERIALS AND METHODS: The properties of ET receptors in 6-month-old male rabbit prostatic urethras were examined using isolated muscle-bath and radioligand receptor-binding techniques. Using plasma membrane suspensions, saturation and inhibition experiments with [(125)I]ET-1 and unlabelled agonists and antagonists (ET(A)-selective antagonist BQ123, and ET(B)-selective agonist sarafotoxin 6c, STX6c) were done to determine the ET receptor densities and their subtype specificities in the different regions of the urethra. RESULTS: The ETs (ET-1 and ET-3) produced significant concentration-dependent contractile responses in the smooth muscle strips from the different regions of the urethra. Although the maximum contractile responses induced by ET-1 were similar in the different regions, the maximum contractile responses induced by ET-3 were greater in the distal region than in the proximal or middle regions, suggesting that the contractile response to ET-1 is more potent than that to ET-3 in all regions, and that there are region-specific differences in the responses to ET-3 but not ET-1. Moreover, the ET-3-induced contractile response was suppressed by BQ788 (a selective antagonist of the ET(B) receptor) suggesting that the ET(B) receptor subtype contributes to the contractile responses mediated by ET-3. The ET receptors were expressed in higher concentrations in the distal than in the proximal or middle regions. BQ123 and STX6c inhibited [(125)I]ET-1 binding in all regions with high and low affinity constants, indicating the presence of both ET(A) and ET(B) receptor subtypes. The proportions of high-affinity binding sites for BQ123, representing ET(A) receptors, were approximately 68%, 63% and 42% in the proximal, middle and distal regions, respectively. By contrast, the proportions of high-affinity binding sites for STX6c, representing ET(B) receptors, were approximately 27%, 35% and 52% in the proximal, middle, and distal regions, respectively. These data indicate the presence of regional differences in the densities and subtype specificities of ET receptor subtypes, and the existence of regional differences in the rabbit prostatic urethra. CONCLUSION: The results suggest regional differences in ET(B) receptor subtypes that mediate contractile responses to ET-3, reflecting differences in the densities and specificities of the ET receptor subtypes in the rabbit prostatic urethra.