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151.
152.
Natália H Mendes Fernando AF Melo Adolfo CB Santos José RC Pandolfi Elisabete A Almeida Rosilene F Cardoso Henri Berghs Suzana David Faber K Johansen Lívia G Espanha Sergio RA Leite Clarice QF Leite 《BMC research notes》2011,4(1):269
Background
Tuberculosis is a major health problem in São Paulo, Brazil, which is the most populous and one of the most cosmopolitan cities in South America. To characterize the genetic diversity of Mycobacterium tuberculosis in the population of this city, the genotyping techniques of spoligotyping and MIRU were applied to 93 isolates collected in two consecutive years from 93 different tuberculosis patients residing in São Paulo city and attending the Clemente Ferreira Institute (the reference clinic for the treatment of tuberculosis).Findings
Spoligotyping generated 53 different spoligotype patterns. Fifty-one isolates (54.8%) were grouped into 13 spoligotyping clusters. Seventy- two strains (77.4%) showed spoligotypes described in the international databases (SpolDB4, SITVIT), and 21 (22.6%) showed unidentified patterns. The most frequent spoligotype families were Latin American Mediterranean (LAM) (26 isolates), followed by the T family (24 isolates) and Haarlem (H) (11 isolates), which together accounted for 65.4% of all the isolates. These three families represent the major genotypes found in Africa, Central America, South America and Europe. Six Spoligo-International-types (designated SITs by the database) comprised 51.8% (37/72) of all the identified spoligotypes (SIT53, SIT50, SIT42, SIT60, SIT17 and SIT1). Other SITs found in this study indicated the great genetic diversity of M. tuberculosis, reflecting the remarkable ethnic diversity of São Paulo city inhabitants. The MIRU technique was more discriminatory and did not identify any genetic clusters with 100% similarity among the 93 isolates. The allelic analysis showed that MIRU loci 26, 40, 23 and 10 were the most discriminatory. When MIRU and spoligotyping techniques were combined, all isolates grouped in the 13 spoligotyping clusters were separated.Conclusions
Our data indicated the genomic stability of over 50% of spoligotypes identified in São Paulo and the great genetic diversity of M. tuberculosis isolates in the remaining SITs, reflecting the large ethnic mix of the São Paulo city inhabitants. The results also indicated that in this city, M. tuberculosis isolates acquired drug resistance independently of genotype and that resistance was more dependent on the selective pressure of treatment failure and the environmental circumstances of patients.153.
154.
Tripathy R McHugh RJ Bacon ER Salvino JM Morton GC Aimone LD Huang Z Mathiasen JR DiCamillo A Huffman MJ McKenna BA Kopec K Lu LD Qian J Angeles TS Connors T Spais C Holskin B Duzic E Schaffhauser H Rossé GC 《Bioorganic & medicinal chemistry letters》2012,22(3):1421-1426
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ~30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test. 相似文献
155.
Sundar BG Bailey TR Dunn DD Bacon ER Salvino JM Morton GC Aimone LD Zeqi H Mathiasen JR Dicamillo A Huffman MJ McKenna BA Kopec K Lu LD Brown R Qian J Angeles T Connors T Spais C Holskin B Galinis D Duzic E Schaffhauser H Rosse GC 《Bioorganic & medicinal chemistry letters》2012,22(1):120-123
7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory. 相似文献
156.
Mihalic JT Kim YJ Lizarzaburu M Chen X Deignan J Wanska M Yu M Fu J Chen X Zhang A Connors R Liang L Lindstrom M Ma J Tang L Dai K Li L 《Bioorganic & medicinal chemistry letters》2012,22(5):2046-2051
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties. 相似文献
157.
Mendoza D Royce C Ruff LE Ambrozak DR Quigley MF Dang T Venturi V Price DA Douek DC Migueles SA Connors M 《Journal of virology》2012,86(7):4014-4018
To better understand the qualitative features of effective human immunodeficiency virus (HIV)-specific immunity, we examined the TCR clonal composition of CD8(+) T cells recognizing conserved HIV p24-derived epitopes in HLA-B*5701-positive long-term nonprogressors/elite controllers (LTNP/EC) and HLA-matched progressors. Both groups displayed oligoclonal HLA-B5701-restricted p24-specific CD8(+) T-cell responses with similar levels of diversity and few public clonotypes. Thus, HIV-specific CD8(+) T-cell responses in LTNP/EC are not differentiated from those of progressors on the basis of clonal diversity or TCR sharing. 相似文献
158.
159.
Background
Annually, 41,000 people in the Netherlands have strokes. This has multiple physical and psychosocial consequences. Most patients return home after discharge from hospital. Quality aftercare by general practitioners is important to support patients at home. The purpose of this study is to examine the wellbeing of patients who returned home immediately after discharge from hospital, one year post stroke, in comparison with the general Dutch population of the same age and to determine factors that could influence wellbeing. 相似文献160.
A M Ardekani S J Walker S J Donohue R E Stitzel J M Connors K E Vrana 《Life sciences》1989,44(14):919-925
Circulating plasma ACTH and corticosterone levels were measured in spontaneously hypertensive rats (SHR) and the corresponding, normotensive Wistar-Kyoto (WKY) strain at 10 and 20 days of age. In addition, stored levels of ACTH were measured in the pituitary glands of these animals. Circulating corticosterone levels were significantly lower, in both strains, at 10 days than at 20 days. Although the glucocorticoid was undetectable in WKY animals at 10 days, significant levels were observed in age-matched SHR. No difference in corticosterone concentrations was observed between the two strains at 20 days. Circulating ACTH levels did not reflect the values for circulating glucocorticoids. There were no significant differences in the levels of ACTH between strains or between age groups. Moreover, pituitary stores of ACTH between animals of different strains and ages were not found to be significantly different among any of the groups tested. These results demonstrate that there is a difference in circulating corticosterone levels between spontaneously hypertensive and Wistar-Kyoto rats at 10 days postnatally which is not evident just prior to weaning (20 days). This difference is not due to variations in stored or circulating ACTH. Indeed, ACTH levels are high at a time (10 days) when corticosterone is low - thus suggesting that the difference may reside within the responsiveness of the adrenal cortex. 相似文献