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Biomedical subjects

S Moseley

Publications and source records attributed to S Moseley.

10 recordsLinked to original sources
PubMed2001

The novel IMPDH inhibitor VX-497 prolongs skin graft survival and improves graft versus host disease in mice.

VX-497 is the first inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor generated in a structure-based drug design program specifically addressing the tolerability problems of currently available immunosuppressive drugs. The pharmacological activity of the compound has been examined in murine skin transplantation and graft versus host disease (GVHD) models. In the skin transplant study, trunk skin grafts from Balb/c mice were grafted onto C57Bl/6 mice. Mice were administered vehicle or VX-497 twice daily until day 10. Mean survival of skin grafts on vehicle-treated animals was 9.9 +/- 0.9 days. Graft survival was prolonged significantly in animals treated with VX-497 to 13.2 +/- 1.2 (p < 0.001, Kaplan Meier Log-Rank test) days in the 50 mg/kg group and 13.9 +/- 1.0 (p < 0.001) days in the 85 mg/kg group. In the GVHD study, 150 x 10(6) nonadherent splenocytes from B6 mice were injected intravenously into the F1 hybrid strain B6DBA/2. Groups of animals (n = 6) were administered vehicle or 50 or 100 mg/kg VX-497 b.i.d for 8 days. Animals were sacrificed and spleen weights and interferon-gamma (IFN-gamma) serum levels were determined by enzyme-linked immunosorbent assay. In addition, spontaneous spleen cell proliferation was measured using a 3H-thymidine uptake assay. Isografted F1 animals served as controls. GVHD developed in the vehicle-treated allografted F1 mice and treatment with VX-497 improved all manifestations of the disease significantly. The 2.9-fold increase in spleen weight in allografted animals was reduced to a 1.6-fold increase in the VX-497-treated mice. Serum IFN-gamma levels were increased 54-fold in the vehicle group while there was a 7.4-fold increase in VX-497-treated animals. Spontaneous spleen cell proliferation was increased 9.9-fold in the absence of VX-497 and there was a 3.5-fold increase in its presence. Thus, VX-497 has been shown to be effective in both a skin transplantation and a GVHD model in the mouse. The demonstrated pharmacological activity of VX-497 in these murine transplantation models warrants further evaluation of the drug in transplantation indications.

Animals↗
PubMed2000

Polymorphic markers for the arylsulfatase A gene reveal a greatly expanded meiotic map for the human 22q telomeric region.

Two microsatellite markers, D22S1743 and D22S1744, were developed for the arylsulfatase A (ARSA) region of chromosome 22q. Linkage analysis for 171 families, using nine reference markers covering all of 22q, placed these new markers 2.0 Kosambi cM distal to D22S526, making them more distal than any microsatellite markers currently on the Généthon or Marshfield linkage maps. Recombination between proximal markers D22S270/D22S683 and D22S446/D22S311 exhibited increased rates of female meiotic recombination compared to male recombination (P < 0.01). In contrast, the region encompassing sJCW16, D22S526, D22S1743, and D22S1744 exhibited relatively greater recombination in males (1.1 cM for females and 7.5 cM for males; chi(2); P < 0.005). These four distal markers lie in a region of hyperrecombination having a sex-averaged recombination ratio of between 8.3 (D22S1843/D22S1744) and 12 cM (sJCW16/D22S526) per megabase.

Cerebroside-Sulfatase↗
PubMed1998

Genetic analysis of brahma: the Drosophila homolog of the yeast chromatin remodeling factor SWI2/SNF2.

The Drosophila brahma (brm) gene encodes an activator of homeotic genes related to the yeast chromatin remodeling factor SWI2/SNF2. Here, we report the phenotype of null and dominant-negative brm mutations. Using mosaic analysis, we found that the complete loss of brm function decreases cell viability and causes defects in the peripheral nervous system of the adult. A dominant-negative brm mutation was generated by replacing a conserved lysine in the ATP-binding site of the BRM protein with an arginine. This mutation eliminates brm function in vivo but does not affect assembly of the 2-MD BRM complex. Expression of the dominant-negative BRM protein caused peripheral nervous system defects, homeotic transformations, and decreased viability. Consistent with these findings, the BRM protein is expressed at relatively high levels in nuclei throughout the developing organism. Site-directed mutagenesis was used to investigate the functions of conserved regions of the BRM protein. Domain II is essential for brm function and is required for the assembly or stability of the BRM complex. In spite of its conservation in numerous eukaryotic regulatory proteins, the deletion of the bromodomain of the BRM protein has no discernible phenotype.

Amino Acid Sequence↗
PubMed1991

Urovirulence determinants in Escherichia coli isolates causing first-episode and recurrent cystitis in women.

To assess the prevalence of urovirulence determinants among Escherichia coli isolates from women with acute uncomplicated cystitis, 121 isolates from 87 women with first-episode or recurrent cystitis and 156 fecal isolates from 52 women without recent urinary tract infection were tested using DNA probes for P fimbriae, hemolysin, aerobactin, and diffuse adhesin and for expression of hemolysin and P and F adhesins. P fimbrial genotype (P = .002), hemolysin phenotype (P = .007), and the diffuse adhesin determinant (P = .03), but not aerobactin, were found more frequently in E. coli from women with acute cystitis, and expression of the F adhesin (41%) was more common than the P adhesin (24%; P = .001). E. coli isolates that caused cystitis in women using diaphragms had fewer virulence determinants than those from nonusers (P = .04), suggesting that diaphragm use may allow infection with less virulent E. coli.

Acute Disease↗
PubMed1990

The Dr hemagglutinin, afimbrial adhesins AFA-I and AFA-III, and F1845 fimbriae of uropathogenic and diarrhea-associated Escherichia coli belong to a family of hemagglutinins with Dr receptor recognition.

The receptor specificities of four Escherichia coli cloned hemagglutinins, AFA-I, AFA-III, F1845 fimbriae, and the Dr hemagglutinin were studied. Evidence is provided that all four hemagglutinins recognize as their receptor the Dr blood group antigen. However, results of experiments using enzyme-treated erythrocytes and monoclonal antibodies indicate that the four adhesins recognize different epitopes on the Dr antigen and thus constitute a family of Dr receptor-recognizing bacterial adhesins. Furthermore, the same results suggest that the Dr antigen itself may be divided into subcomponents on the basis of bacterial adhesins.

Adhesins, Escherichia coli↗
PubMed1987

Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial.

To determine the role of chemotherapy in the multidisciplinary treatment of patients with osteosarcoma, a randomized prospective trial of postoperative adjuvant chemotherapy was begun in 1981. Fifty-nine patients with nonmetastatic classic intramedullary osteosarcoma were randomized; 32 received postoperative adjuvant chemotherapy consisting of high-dose methotrexate, Adriamycin (Adria Laboratories, Columbus, OH), and BCD (bleomycin, cytoxan, actinomycin D), and 27 patients received no adjuvant chemotherapy. At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free and overall survival in those who received adjuvant chemotherapy. In addition, there was no difference in the less than 20% disease-free or overall survival of patients treated in the 1970s who did not receive chemotherapy, as compared with the concurrent nontreatment controls. Therefore, with identical staging procedures, uniform surgical management, and standard pathologic evaluation, postoperative adjuvant chemotherapy definitely improves disease-free and overall survival in patients with osteosarcoma.

Adolescent↗
PubMed1985

Enhancement of the horseradish peroxidase-catalyzed chemiluminescent oxidation of cyclic diacyl hydrazides by 6-hydroxybenzothiazoles.

6-Hydroxybenzothiazole, 2-cyano-6-hydroxybenzothiazole, and 2-(6-hydroxy-2-benzothiazolyl)thiazole-4-carboxylic acid (dehydroluciferin) dramatically enhance light emission from the horseradish peroxidase conjugate catalyzed oxidation of luminol, isoluminol, N-(6-aminobutyl)-N-ethyl isoluminol, and 7-dimethylaminonaphthalene-1,2-dicarboxylic acid hydrazide by either peroxide or perborate. Light emission is enhanced by up to 1000-fold, which is an improvement over the enhancement previously observed using firefly luciferin (4,5-dihydro-2-(6-hydroxy-2-benzothiazolyl)thiazole-4-carboxylic acid). Enhancement is influenced by enhancer concentration and pH. Spectral scans of light emitted in enhanced and unenhanced reactions are similar, suggesting that aminophthalate products, and not the enhancers, are the emitters.

Catalysis↗