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排序方式: 共有157条查询结果,搜索用时 11 毫秒
1.
Olson RE Sielecki TM Wityak J Pinto DJ Batt DG Frietze WE Liu J Tobin AE Orwat MJ Di Meo SV Houghton GC Lalka GK Mousa SA Racanelli AL Hausner EA Kapil RP Rabel SR Thoolen MJ Reilly TM Anderson PS Wexler RR 《Journal of medicinal chemistry》1999,42(7):1178-1192
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent. 相似文献
2.
Yang OO Boscardin WJ Matud J Hausner MA Hultin LE Hultin PM Shih R Ferbas J Siegal FP Shodell M Shearer GM Grene E Carrington M O'Brien S Price CB Detels R Jamieson BD Giorgi JV 《AIDS research and human retroviruses》2002,18(14):1051-1065
The host immune factors that determine susceptibility to HIV-1 infection are poorly understood. We compared multiple immunologic parameters in three groups of HIV-1-seronegative men: 14 highly exposed (HR10), 7 previously reported possibly to have sustained transient infection (PTI), and a control group of 14 low risk blood bank donors (BB). Virus-specific cellular immune assays were performed for CD4(+) T helper cell responses, CD8(+) cytotoxic T lymphocyte activity, CD8(+) cell chemokine release, and CD8(+) cell-derived antiviral soluble factor activity. General immune parameters evaluated included CCR5 genotype and phenotype, interferon alpha production by PBMCs, leukocyte subset analysis, and detailed T lymphocyte phenotyping. Comparisons revealed no detectable group-specific differences in measures of virus-specific immunity. However, the HR10 group differed from the BB group in several general immune parameters, having higher absolute monocyte counts, higher absolute CD8(+) T cell counts and percentages, lower naive and higher terminal effector CD8(+) cells, and lower levels of CD28(+)CD8(+) cells. These changes were not associated with seropositivity for other chronic viral infections. The PTI men appeared to have normal levels of monocytes and slightly elevated levels of CD8(+) T cells (also with increased effector and decreased naive cells). Although we cannot entirely exclude the contribution of other chronic viral infections, these findings suggest that long-lived systemic cellular antiviral immunity as detected by our assays is not a common mechanism for resistance to infection, and that resistance may be multifactorial. General immune parameters reflected by CD8(+) T cell levels and activation, and monocyte concentrations may affect the risk of infection with HIV-1, and/or serve as markers of exposure. 相似文献
3.
Prof. MUDr. L. Šrámková DrSc. MUDr. M. Bielaszewská CSc. doc. MUDr. J. Janda CSc. MUDr. K. Bláhová CSc O. Hausner 《Infection》1990,18(4):204-209
Summary The presence of verotoxin-producing strains ofEscherichia coli (VTEC) was examined in six children with haemolytic uraemic syndrome and one child with haemorrhagic colitis. Stools were screened for strains of serogroup O157 on sorbitol-MacConkey agar for VTEC of other serogroups by serotyping. Verotoxin (VT) was tested on Vero cell monolayers: the antigenic variant of VT was assessed by neutralization experiments. Strains producing verotoxin 1 or verotoxin 2 or both were detected in the stools of all seven children. Three strains belonged to serogroup O157 (two of them to serotype O157:H7, one was non-motile) and another five belonged to serogroups O26 (two strains), O1, O5 and O18. The faeces of five children available for testing contained free VT. Production of VT was also examined retrospectively in 32E. coli strains of serotype O26:H11 isolated from children with diarrhoea; eight (25%) of them produced moderate to high levels of verotoxin 1 despite several years storagein vitro. In conclusion, VTEC including strains of serogroup O157 seem to be an important cause of haemolytic uraemic syndrome, haemorrhagic colitis and diarrhoea in children in Czechoslovakia.
Vero Cytotoxin bildende Stämme von Escherichia coli bei Kindern mit hämolytisch-urämischem Syndrom und Diarrhoe in der Tschechoslowakei
Zusammenfassung Bei sechs Kindern mit hämolytisch-urämischem Syndrom und einem Kind mit hämorrhagischer Kolitis wurde nach Verotoxin bildenden Stämmen vonEscherichia coli (VTEC) gesucht. Das Stuhl-Screening auf Stämme derSerogruppe O157 erfolgte auf Sorbitol-MacConkey Agar; zum Nachweis von VTEC und anderen Serogruppen wurde die Serotypisierung eingesetzt. Verotoxin (VT) wurde auf Monolayer-Verozellkulturen nachgewiesen; die Bestimmung der Antigenvariante von VT erfolgte durch Neutralisationsversuche. Bei allen sieben Kindern konnten im Stuhl Stämme nachgewiesen werden, die Verotoxin 1 oder Verotoxin 2 bildeten. Drei Stämme gehörten der Serogruppe O157 an (zwei davon Serotyp O157:H7, einer war ohne Motilität) und die übrigen fünf gehörten zu den Serogruppen O26 (zwei Stämme), O1, O5 und O18. Freies VT konnte in fünf Stühlen nachgewiesen werden; diese Untersuchung war nur bei fünf Kindern durchführbar. 32E. coli-Stämme vom Serotyp O26:H11, Isolate von Kindern mit Diarrhoe, wurden retrospektiv ebenfalls auf Bildung von VT untersucht. Davon bildeten achtin vitro (25%) noch mittel- bis hohe Spiegel von Verotoxin 1 obwohl sie schon mehrere Jahre lang gelagert waren. VTEC einschließlich der Stämme der Serogruppe O157 stellen folglich wichtige Erreger des hämolytischurämischen Syndroms, der hämorrhagischen Kolitis und anderer Formen der Diarrhoe bei Kindern in der Tschechoslowakei dar.相似文献
4.
Tkaczuk KH Zamboni WC Tait NS Meisenberg BR Doyle LA Edelman MJ Hausner PF Egorin MJ Van Echo DA 《Cancer chemotherapy and pharmacology》2000,46(6):442-448
Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor,
have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the
overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of
DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2,
4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.)
on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h
for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort
II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80
and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two
patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in
cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary
metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial
response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of
12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC
given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on
day 4 and TOPO on days 1–4 is not recommended.
Received: 18 February 2000 / Accepted: 19 July 2000 相似文献
5.
6.
Single measurements of enterolactone (ENL) used in epidemiologic studies are influenced by intraindividual variation. The objective of this controlled study was to investigate short-term intraindividual variations in serum and urine ENL. Based on these variations, the number of samples required to describe the basal ENL level was estimated. Healthy Danish postmenopausal women (n = 6) aged 54-67 y completed 3 study periods of 24 h within 2 mo. Blood samples were collected at 0, 4, 6, 8, 12, and 24 h and 24-h urine samples were collected. A low-lignan, standardized diet of 3 meals was served. ENL was measured by time-resolved fluoroimmunoassay. Intraindividual and interindividual variations were estimated using a mixed model with repeated measurements. Significant and systematic intraindividual within-day variations (CV) of 31% were observed in serum. Intraindividual day-to-day variations were 56% and overall intraindividual variation of samples collected at random times and on different days was estimated to be 64%. Describing this overall variation required 7 blood samples when estimated with a precision of 50% and 95% confidence. Day-to-day variations in 24-h urine samples were 49%. Large within-day and day-to-day variations suggest that a single measurement of ENL is inadequate to estimate the basal ENL level. 相似文献
7.
Shacklett BL Yang O Hausner MA Elliott J Hultin L Price C Fuerst M Matud J Hultin P Cox C Ibarrondo J Wong JT Nixon DF Anton PA Jamieson BD 《Journal of immunological methods》2003,279(1-2):17-31
The majority of HIV-1 infections occur via sexual transmission at mucosal epithelia lining the vagina, cervix or rectum. Mucosal tissues also serve as viral reservoirs. However, our knowledge of human mucosal T-cell responses is limited. There is a need for reliable, sensitive, and reproducible methods for assessing mucosal immunity. Here we report on the collaborative efforts of two laboratories to optimize methods for processing, culturing, and analyzing mucosal lymphocytes. Rectal biopsy tissue was obtained by flexible sigmoidoscopy, which is rapid, minimally invasive, and well tolerated. Of the four methods compared for isolating mucosal mononuclear cells (MMC), collagenase digestion reproducibly yielded the most lymphocytes (4-7 x 10(6)). Furthermore, 0.5-1 x 10(6) MMC could be polyclonally expanded to yield 17 x 10(6) CD8+ T cells allowing mapping of responses to overlapping peptides spanning the HIV-1 genome using IFN-gamma enzyme-linked immunospot (ELISpot). Expansion also reduced the spontaneous IFN-gamma production normally detected in fresh MMC. Piperacillin-tazobactam and amphotericin B reduced contamination of MMC cultures to 4%. Taken together, these methods will be useful for studies of mucosal immunity to HIV-1 and other pathogens during natural infection and following vaccination. 相似文献
8.
The "comparative growth assay": examining the interplay of anti-cancer agents with cells carrying single gene alterations 下载免费PDF全文
We have developed a “comparative growth assay” that complements current assays of drug effects based on cytotoxicity. A co-culture of two cell lines, one of which is fluorescently labeled, is exposed to a cytotoxic agent and the proportion of fluorescent cells is compared with that of a baseline unexposed co-culture. For demonstration purposes, two HCT116 cell lines (an hMLH1 homozygous and an hMLH1 heterozygous mutant), altered by insertion of vector alone or the same vector carrying an insert for the expression of enhanced green fluorescent protein (EGFP), were exposed to numerous “anti-cancer” agents. The assay was further validated in a system of two cell lines differing only in the expression of the breast cancer resistance protein (BRCP). The assay allowed the estimation of the duration of action of a particular agent. Assessment of the agent's differential activity over a given time in culture could be expressed as a selection rate, which we chose to describe on an “average selection per day” basis. We conclude that this assay: 1) provides insight into the differential dynamic effects of chemotherapeutic agents or radiation; and 2) allows, through the use of matched cell lines, the investigation of critical physiologic features that govern cell sensitivity. 相似文献
9.
Monteiro-Vitorello CB Baidyaroy D Bell JA Hausner G Fulbright DW Bertrand H 《Current genetics》2000,37(4):242-256
In the chestnut-blight fungus Cryphonectria parasitica, a plasmid, pCRY1, occurs in the mitochondria of several strains isolated at various locations in the northeastern United
States and Canada. The monomer of this plasmid is a 4.2-kb circular double-stranded DNA that has no detectable sequence homology
with the 160–kb mitochondrial DNA of Ep155, a standard virulent laboratory strain of C. parasitica. The circular nature and oligomeric characteristics of the plasmid were deduced from the heterogeneous size of plasmid DNA
molecules as detected by one- and two-dimensional gel-electrophoresis, the nature and alignment of restriction fragments,
and the lack of detectable termini in the nucleotide sequence. The cytoplasmic location of the plasmid was deduced from its
co-purification with mitochondria, uniparental (maternal) transmission in sexual crosses, dissociation from the nuclei of
the donor strain during its horizontal transfer between vegetatively compatible strains through hyphal anastomoses, and mitochondrial
codon usage (UGA=Try). The pCRY1 plasmid contains a long open reading frame that is transcribed and potentially encodes a
unique 1214 amino-acid, B-family DNA polymerase similar to those encoded by the LaBelle and Fiji circular mitochondrial plasmids
of Neurospora. In this subgroup of proteins, the DTD motif characteristic of B-family DNA polymerases is replaced by TTD. Amino-acid motifs
related to those that are characteristic of the 3′→5′ exonuclease domains of B-family DNA polymerases have been located in
the amino-terminal portion of the proteins. A comparison of isogenic plasmid-free and plasmid-containing cultures indicates
that pCRY1 is an infectious agent that effects a reduction in the pathogenicity of some, but not all, strains of C. parasitica.
Received: 12 August / 9 December 1999 相似文献
10.