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排序方式: 共有6624条查询结果,搜索用时 15 毫秒
61.
1. Acute SR 58611A (0.25 mg kg-1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg-1 glibenclamide in lean mice. 2. Neither brown (BAT) nor white (WAT) adipose tissue lipogenesis was altered by acute SR 58611A (2 - 8 mg kg-1) in lean mice, but both increased significantly at the higher doses in the obese mice. 3. Acute SR 58611A produced a hypoglycaemia 40 min after dosing in lean and obese animals, the duration and potency of which was less than that of glibenclamide. Plasma insulin levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese mice. 4. Chronic treatment (0.25 mg kg-1, 15 days) with SR 58611A increased its effectiveness in improving glucose tolerance, but did not affect the body weight (BW) or food intake of either lean or obese mice. 5. Acute and chronic SR 58611A prolonged the hypoglycaemic effect of exogenous insulin in lean but not obese mice. 6. In fed and fasted lean mice and in fasted obese mice chronic SR 58611A produced an acute hypoglycaemia 30 min post administration which was greater than after a single dose. 7. SR 58611A maintained its effectiveness in improving glucose tolerance in lean and obese mice over a dosing period of 15 days. The improvement in glucose tolerance was achieved at a dose less than that required to stimulate adipose tissue lipogenesis and which did not affect food intake or body weight. 相似文献
62.
Q Chao L Deng H Shih L M Leoni D Genini D A Carson H B Cottam 《Journal of medicinal chemistry》1999,42(19):3860-3873
A series of isoquinolin-1-ones and quinazolin-4-ones and related derivatives were prepared and evaluated for their ability to inhibit tumor necrosis factor alpha (TNFalpha) production in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). In an effort to optimize the TNFalpha inhibitory activity, a homologous series of N-alkanoic acid esters was prepared. Several electrophilic and nucleophilic substitutions were also carried out. Alkanoic acid esters of four carbons were found to be optimum for activity in both the isoquinoline and quinazoline series. Ring substituents such as fluoro, bromo, nitro, acetyl, and aminomethyl on the isoquinoline ring resulted in a significant loss of activity. Likewise, similar groups on the quinazoline ring also reduced inhibitory activity. However, the 6- and 7-aminoquinazoline derivatives, 75 and 76, were potent inhibitors, with IC(50) values in the TNFalpha in vitro assay of approximately 5 microM for each. An in vivo mouse model of pulmonary inflammation was then used to evaluate promising candidate compounds identified in the primary in vitro assay. Compound 75 was selected for further study in this inhalation model, and was found to reduce the level of TNFalpha in brochoalveolar lavage fluid of LPS-treated mice by about 50% that of control mice. Thus, compounds such as 75, which can effectively inhibit proinflammatory cytokines such as TNFalpha in clinically relevant animal models of inflammation and fibrosis, may have potential as new antiinflammatory agents. Finally, a quinazoline derivative suitable to serve as a photoaffinity radiolabeled compound was prepared to help identify the putative cellular target(s) for these TNFalpha inhibitors. 相似文献
63.
M Y Maeda A Longatto Filho D R Santos M J Cavaliere L W Shih M S Oyafuso A De Andrea Filho 《Pathologica》1991,83(1083):105-109
Two methods of staining (Papanicolaou versus direct immunofluorescence) and two methods of collection of the samples (Ayre's wooden spatula versus cervical Cytobrush) were compared in order to verify the efficiency in detecting Chlamydia trachomatis (CT) infections in the female genital tract. Out of 166 asymptomatic patients, 59 were positive for CT by means of direct immunofluorescence: 36 were detected in Cytobrush samples, 16 in Ayre's spatula samples, and 7 in the samples collected by both methods. Papanicolaou smears showed "moth-eaten" features suggestive of CT infection in a great number of metaplastic cells present in 35 cases: 24 collected by Cytobrush, 4 by Ayre's spatula and 7 by both methods. Our data show that Cytobrush is more efficient that Ayre's spatula in concentrating cellular material. It is thus possible to detect CT infection with more accuracy by means of direct immunofluorescence, and to suspect CT infection in smears collected by means of Cytobrush and stained by Papanicolaou's method. 相似文献
64.
Biomechanical analysis of the mechanism of interlocking nail failure 总被引:24,自引:3,他引:21
Summary From December 1986 to May 1989, 412 patients with 274 femoral and 144 tibial fractures were treated with Grosse-Kempf interlocking nails at our hospital. 324 cases (78.6%) were followed-up for at least 1 year (average 23 months). There were 13 breakages in the locking nails in femora and none in tibiae. The recorded incidence of breakage in the femur is therefore 4.7% (13/274). The mechanisms of locking nail failure are stress concentration around screw hole and nail slot, nicking of the nail during drilling of the screw holes, too close proximity of the screw hole to the fracture, and larger loading over the proximal femur. The incidence of failure is 4.9% in the upper third, 1.9% in the mid-third, and 8.2% in the distal third (P > 0.05, 2 test). The site most at risk is the first screw hole of the distal third, especially if it is near the fracture site. Prevention of failure involves using a nail of larger diameter and sufficient length, improving the surgical drilling technique, and allowing only protected weight bearing. Management of nail breakage by insertion of a new implant and supplementary cancellous bone grafting can gain satisfactory results. 相似文献
65.
Summary This study was designed to compare the degree of reactive astrogliosis occurring around a puncture wound in the brain of normal rats and at different intervals after a similar puncture wound in rats with a portocaval anastomosis. The gliosis was evaluated by the number of astrocytes, the thickness of their processes and the intensity of the glial fibrillary acidic protein immunoreactivity. After the puncture wound in the brain of rats with a portocaval anastomosis, the gliosis varied at different intervals being: (1) decreased at 10 days, (2) markedly increased at 5 weeks and (3) significantly decreased at 8, 12, and 16 weeks. These findings suggest that 5 weeks after portocaval anastomosis, an active proliferation of the metabolically altered astrocytes occurs with heightened synthesis of glial fibrillary acidic protein in the period of adaptive compensation, the so-called compensatory rebound. At 8 weeks or more after portocaval anastomosis, these altered astrocytes were considered to be in the phase of decompensation and incapable of maintaining the reactive response which occurred in normal rats. The compensatory rebound and decompensatory decline illustrate the dynamic plasticity of the reactive astrogliosis.Supported by grant from the National Foundation of Natural Sciences No. 386-0956. This paper was read at the XIth International Congress of Neuropathology, September 7, 1990 in Kyoto, Japan 相似文献
66.
FLT3-TKD mutation in childhood acute myeloid leukemia. 总被引:8,自引:0,他引:8
D-C Liang L-Y Shih I-J Hung C-P Yang S-H Chen T-H Jaing H-C Liu L-Y Wang W-H Chang 《Leukemia》2003,17(5):883-886
Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation. 相似文献
67.
68.
69.
John L. Tonkinson Philip Marder Sherri L. Andis Richard M. Schultz Lynn S. Gossett Chuan Shih L. G. Mendelsohn 《Cancer chemotherapy and pharmacology》1997,39(6):521-531
Purpose: Cell cycle-related events in CCRF-CEM lymphocytic leukemia cells were examined subsequent to inhibition of thymidylate synthase
(TS) or GAR formyltransferase (GARFT) and prior to cell death or stasis. Methods: Cell populations were treated with the GARFT inhibitors 6R-5,10-dideazatetrahydrofolate (lometrexol) or LY309887, the TS inhibitor ZD1694, or the multitargeted antifolate LY231514.
DNA content, nucleoside precursor incorporation and proliferating cell nuclear antigen (PCNA) expression as functions of drug
treatment were assessed by multiparameter flow cytometry. Cellular respiration was measured by MTT analysis and apoptosis
was detected by extraction of DNA fragments. Results: Cell populations treated for up to 96 h with lometrexol or LY309887 did not replicate and maintained a cell cycle distribution
with distinct G1, S and G2/M regions. The number of S phase cells in treated populations was slightly elevated relative to control as measured by DNA
content and PCNA. However, these cells were unable to incorporate 5-bromodeoxyuridine (BrdU). Throughout treatment, cells
incubated with GARFT inhibitors maintained intact membranes and respired at a level comparable to untreated cells. In contrast,
ZD1694 as well as LY231514, induced synchronization of the treatment population at the G1/S interface within 12 h of drug addition. This was followed by synchronous entry of the population into S phase. After 24 h
of treatment, more than 90% of the cells were capable of incorporating BrdU and stained positive for PCNA. DNA fragmentation
occurred in cells treated with ZD1694 or LY231514 but not in those treated with GARFT inhibitors. In addition, the viable
cells remaining after 24–48 h of treatment with ZD1694 or LY231514 were respiring at twice the level of untreated cells. Conclusion: These results demonstrate that the distinct endpoints of GARFT and TS inhibition are preceded by distinct cell cycle and
metabolic alterations.
Received: 1 April 1996 / Accepted: 5 September 1996 相似文献
70.
Wang WS; Hsieh RK; Chiou TJ; Liu JH; Fan FS; Yen CC; Tung SL; Chen PM 《Japanese journal of clinical oncology》1998,28(9):551-554
A 54-year-old man was treated with weekly 24-h infusion of high-dose
5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon
cancer. At first, he tolerated the treatment well and no significant
toxicity was identified. After a total of eight courses of treatment, a
stable disease was observed, but mild shortness of breath was found on
occasion. The patient had no previous history of cardiac disease and the
heart performance assessed by left ventricular ejection fraction before
treatment was normal. Unfortunately, acute pulmonary edema with lethal
cardiogenic shock occurred during the ninth course of treatment, in spite
of intensive medical treatment. The chest X-ray showed extreme
cardiomegaly. Repeated assessment of his heart function by echocardiogram
and ventricular ejection fraction revealed a very poor cardiac performance.
Toxic cardiogenic shock during weekly 24-h infusion of high-dose
5-fluorouracil and leucovorin is extremely rare. To the best of our
knowledge, no case has been reported in the English literature. We report a
case and the relevant literature about the incidence, clinical picture and
possible pathophysiology on 5-fluorouracil-related cardioxicity is
reviewed.
相似文献