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101.
Allosteric effects on muscarinic acetylcholine M(2) receptors were examined in a series of bisquaternary salts of the Strychnos alkaloid caracurine V (6) and related iso-caracurine V, tetrahydrocaracurine V, and bisnortoxiferine ring systems. The compounds inhibited dissociation of the orthosteric antagonist [(3)H]N-methylscopolamine (NMS) from porcine cardiac M(2) receptors with EC(0.5,diss) values from 4 to 3270 nM. The majority of compounds hardly changed [(3)H]NMS equilibrium binding, indicating similar binding affinities in free and NMS-occupied M(2) receptors. The most potent agents were found in the caracurine V, iso-caracurine V, and tetrahydrocaracurine V series and carried nonpolar alkyl groups with a maximal chain length of three carbon atoms. 3D QSAR (CoMSIA) analysis explained the wide range of binding affinities by steric and electrostatic properties of the side chains. Furthermore, the findings suggest that the spatial orientation of the "caracurine" aromatic rings compared with the bisnortoxiferine ring skeleton is favorable to optimal allostere-receptor interactions. 相似文献
102.
Schlitt A Heine GH Blankenberg S Espinola-Klein C Dopheide JF Bickel C Lackner KJ Iz M Meyer J Darius H Rupprecht HJ 《Thrombosis and haemostasis》2004,92(2):419-424
Monocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-alpha, and are elevated in various inflammatory diseases. We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-alpha, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16+ monocytes than controls (13.6% versus 11.4%; p<0.001). Logistic regression analysis including quartiles of CD14+CD16+ monocytes showed that CD14+CD16+ monocytes were associated with prevalence of CAD (OR 4.9, 95% CI 2.5-19.1, for subjects in the fourth quartile in comparison to subjects in the first quartile). The association between CD14+CD16+ monocytes and CAD remained independently significant after adjustment for most potential confounders (OR 5.0, 95% CI 1.2-20.0). Serum concentrations of TNF-alpha were elevated in subjects within the highest quartiles of CD14+CD16+ monocytes (p=0.018). Our study showed that increased numbers of CD14+CD16+ monocytes are associated with coronary atherosclerosis and TNF-alpha. In accordance, recent animal studies suggest a possibly important role of these monocytes in the development of atherosclerosis. 相似文献
103.
Relationship between lipid parameters and the presence of peripheral arterial disease in elderly patients 总被引:1,自引:0,他引:1
Diehm C Lange S Trampisch HJ Haberl R Darius H von Stritzky B Pittrow D Tepohl G Allenberg JR;GetABI Study Group 《Current medical research and opinion》2004,20(12):1873-1875
OBJECTIVE: To investigate the relationship between various lipid parameters and the presence of peripheral arterial disease (PAD). METHODS: Cross-sectional analysis of the observational epidemiological getABI study (German epidemiological trial on Ankle Brachial Index) with 6,880 unselected elderly patients in 344 primary care centers. RESULTS: In the multivariate analysis, the strength of the association between the various lipid parameters and PAD was found to be generally limited, when accounting for other risk factors. CONCLUSION: These findings are in contrast to previous studies. While lipid levels alone cannot be used for supporting the PAD diagnosis or the risk factor for these patients, this should not preclude PAD patients from receiving adequate lipid lowering treatment. 相似文献
104.
Hildebrand GD Timms C Thompson DA Atherton DJ Malone M Levitt G Laidlaw DA Russell-Eggitt I Taylor DS 《Arch. Ophthalmol.》2004,122(10):1551-1555
105.
Ductal lavage of the breast is a minimally invasive procedure used to collect epithelial cells from the lumen of the ductolobular system for cytologic analysis. The purpose of this study was to determine the safety of using an aseptic technique in performing ductal lavage. The study included 114 consecutive patients at high risk for breast cancer with clinically negative mammograms and no palpable masses. Ductal lavage could not be performed on 32 of the 114 patients (28%): 26 because nipple aspirate fluid could not be obtained, and 6 because a fluid-yielding duct could not be cannulated. Ductal lavage was successfully performed on 82 patients (72%). Local anesthetic cream was used on the nipple area and local anesthetic was infused into each duct. The nipple, the cup of the nipple aspirator device, and any dilator tools were cleansed with alcohol before use. Separate sterile microcatheters were used for each duct. Sterile saline solution was used for the infusions. No patient reported any symptoms indicating infection after lavage. Cytologic analysis from the 82 lavage cases showed 45 benign cells (55%), 17 cases of mild atypia (21%), 1 case of marked atypia, and 1 case with malignant cells. Eighteen samples (22%) had inadequate cellularity for medical diagnosis. The results of the study indicate that an aseptic technique is safe and appropriate for ductal lavage of the breast. 相似文献
106.
Pacht ER DeMichele SJ Nelson JL Hart J Wennberg AK Gadek JE 《Critical care medicine》2003,31(2):491-500
OBJECTIVE: Previously, we showed that acute respiratory distress syndrome patients fed an enteral diet containing eicosapentaenoic acid and gamma-linolenic acid and elevated antioxidants (EPA+GLA; Oxepa) had significantly reduced pulmonary inflammation, increased oxygenation, and improved clinical outcomes. In a subset of acute respiratory distress syndrome patients from this trial, we performed a preliminary examination of the potential mechanisms underlying these clinical improvements by retrospectively testing the hypothesis that enteral feeding with EPA+GLA could reduce alveolar-capillary membrane protein permeability and the production of interleukin (IL)-8, IL-6, tumor necrosis factor-alpha, and leukotriene B4 that are responsible, in part, for pulmonary inflammation. DESIGN: Prospective, randomized, double-blind, controlled clinical trial. SETTING: Intensive Care Unit of the Ohio State University Medical Center. PATIENTS: A total of 67 patients were enrolled who met defined criteria for acute lung injury/acute respiratory distress syndrome. INTERVENTIONS: A total of 43 of 67 evaluable patients randomly received either EPA+GLA or an isonitrogenous, isocaloric standard diet that was tube fed at a minimum caloric delivery of 75% of basal energy expenditure times 1.33 for at least 4 to 7 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage (BAL) was performed at baseline and study days 4 and 7 to obtain BAL fluid (BALF) for measurement of total protein, ceruloplasmin, and transferrin, total neutrophil count, IL-8, IL-6, tumor necrosis factor-alpha, and leukotriene B4. Oxygenation, measured as Pao2/Fio2, was assessed before BAL. Patients fed EPA+GLA had a significant reduction in BALF ceruloplasmin and IL-8 during the study as compared with patients fed the control diet. BALF levels of total protein, neutrophils, and leukotriene B4 tended to decrease in EPA+GLA patients over the course of the study as compared with control patients. BALF levels of IL-6 declined similarly during the study in both groups. A trend toward a reduction in BALF tumor necrosis factor-alpha was observed on study day 7 in the EPA+GLA group as compared with control patients. Significant improvements in oxygenation (Pao2/Fio2) occurred in EPA+GLA patients on study day 4 as compared with controls. Correlation analysis revealed significant relationships between BALF neutrophil counts and indices of alveolar-capillary membrane protein permeability, IL-8, and leukotriene B4. CONCLUSIONS: This preliminary investigation showing a decrease in BALF levels of IL-8 and leukotriene B4 and the associated reduction of BALF neutrophils and alveolar membrane protein permeability in acute respiratory distress syndrome patients fed EPA+GLA support, in part, the potential mechanisms underlying the previously described clinical improvements with this diet. Additional controlled studies are needed to confirm these findings. 相似文献
107.
The influence of inner hair cell loss on the instantaneous frequency of the cochlear microphonic 总被引:2,自引:0,他引:2
The purpose of this study was to examine whether outer hair cells (OHCs), inner hair cells and the brainstem auditory pathway are impaired due to a mutation in a gap junction protein, connexin 26 (Cx26), 35delG. Fifty-six individuals, from a village with widespread consanguinity and profound, non-syndromic congenital deafness, due to 35delG mutation, were selected among relatives of deaf people. The individuals were either non-carriers (n=20), heterozygous (n=20) or homozygous (n=16) for the mutation. Distortion product oto-acoustic emissions (DPOAEs) and auditory brainstem evoked potentials (ABEPs) in mutation non-carriers, in heterozygotes (carriers) and in subjects homozygous for the mutation were compared in addition to audiometric evaluation. Most deaf homozygotes had no DPOAEs, except some sporadic responses at 1000, 8000 and 10000 Hz. This was also observed in audiometry which showed profound hearing loss in most cases. Two cases were unique: one had moderate to severe hearing loss and the other had severe to profound hearing loss. A significant difference was found between non-carriers and carriers of 35delG: non-carriers had larger DPOAE responses than heterozygotes at all frequencies. The prevalence of responses got lower with higher frequencies in both groups, but between 6000 and 10000 Hz 50-70% of the carriers had no DPOAE responses, compared to 30-60% of non-carriers. In both groups responses diminished with age, but no significant interaction was found between age and the genetic group. ABEPs among homozygotes were variable: in most homozygotes ABEPs were absent or partial (waves III, V) with prolonged latencies, but two subjects had ABEPs within normal limits, in one ear. ABEPs were normal with no differences between carriers and non-carriers. We suggest that OHC function is affected by the 35delG mutation in Cx26. In addition, the hearing of carriers of this mutation may be impaired at very high frequencies (8000-10000 Hz), which are not assessed in routine audiometry or ABEP testing. 相似文献
108.
Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy 总被引:3,自引:0,他引:3
Moshfeghi DM Kaiser PK Grossniklaus HE Sternberg P Sears JE Johnson MW Ratliff N Branco A Blumenkranz MS Lewis H 《American journal of ophthalmology》2003,135(3):343-350
PURPOSE: To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy. DESIGN: Interventional case series. METHODS: Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 microm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy. RESULTS: Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen.CONCLUSIONS: This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed. 相似文献
109.
Foley MR Moshfeghi DM Wilson MW Haik BG Pappo AS Hill DA 《Ophthalmic plastic and reconstructive surgery》2003,19(4):324-327
Physical examination of a 9-year-old girl with a 2-month history of swelling of the left orbit demonstrated an orbital mass, blepharoptosis, and proptosis. Computed tomography revealed a 2 x 3-cm mass in the superior left orbit that expanded orbital dimensions. Radiography showed abnormalities in the parietal and frontal bones and distal right tibia. Magnetic resonance imaging demonstrated an 8.5-cm abnormality of the marrow space of the right mid-tibia. Bone marrow biopsy was unremarkable. Orbital and tibial biopsies showed a nonspecific chronic inflammation. Idiopathic inflammation that involves the orbit (orbital pseudotumor) and that has systemic manifestations may mimic more serious conditions, such as metastases from rhabdomyosarcoma or Ewing sarcoma, chronic recurrent multifocal osteomyelitis (CRMO), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis). Accurate diagnosis requires careful clinical and pathologic examinations. 相似文献
110.
Chan L Reddy TJ Proulx M Das SK Pereira O Wang W Siddiqui A Yannopoulos CG Poisson C Turcotte N Drouin A Alaoui-Ismaili MH Bethell R Hamel M L'Heureux L Bilimoria D Nguyen-Ba N 《Journal of medicinal chemistry》2003,46(8):1283-1285
The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described. 相似文献