A single-base substitution in the coding region of the androgen receptor (AR) gene caused complete androgen insensitivity in a patient with 46,XY karyotype. The mutation was a T-to-G transition in exon 6 and changed the codon 807 from ATG (methionine) to AGG (arginine) in the hormone-binding domain of the protein. The mutation was inserted into the wild-type human AR cDNA and the resulting cDNA expressed in CV-1 cells. Native and mutated AR proteins synthesized in recipient cells had identical molecular masses. Ligand-binding activity of the mutant receptor was less than 5% of that of the wild-type AR. The mutant's interaction with an androgen-response element in vitro was identical to that of the native aporeceptor; however, it did not transactivate a reporter gene construct in transfected CV-1 cells. Androgen insensitivity in our patient was thus due to altered structure of the receptor's steroid-binding region, which prevented the mutated AR from gaining a transcriptionally active form in vivo.
Efficacy of Lactobacillus reuteri as a probiotic for the control of Cryptosporidium parvum infection was evaluated in C57BL/6 female mice that were immunosuppressed by intraperitoneal inoculation with the LP-BM5 leukemia virus. Four months after inoculation, mice developed lymphadenopathy, splenomegaly, and susceptibility to C. parvum infection. After daily prefeeding with L. reuteri (10(8) cfu/day) for 10 days, mice were challenged with 6.5 x 10(6) C. parvum oocysts and fed L. reuteri during the entire study. Mice supplemented with L. reuteri and challenged with C. parvum cleared parasite loads from the gut epithelium. However, unsupplemented animals developed persistent cryptosporidiosis and shed high levels of oocysts in the feces. L. reuteri feeding increased its colonization of the intestinal tract, which was inversely related to the fecal shedding of oocysts. These findings suggest that L. reuteri may help prevent C. parvum infection in immunodeficient subjects.
Gonadal primordia, isolated from fetal mice on the 11th or 12th day of gestation, differentiated in vitro into morphologically distinct testes or ovaries after 7 days in culture. The addition of cAMP analogues into culture media prevented the differentiation of testis cords. Histological examination indicated that the basement membranes of testis cords disintegrated after treatment with cAMP analogues, while development of germ cells and Leydig cells appeared to be unaffected. Fetal testes in culture secreted testosterone which increased following addition of dibutyryl-cAMP (Bt2 c-AMP). Primordial germ cells reached prespermatogonial stage in the presence or absence of Bt2 cAMP, suggesting that progressive differentiation of primordial germ cells is independent of testis cord organization. The Bt2 cAMP-treated explants resumed testicular development after transplantation into a site beneath the kidney capsules of adult mice, although the inhibitory effect appeared irreversible in vitro. The testicular organization-preventing effect of cAMP analogues was mimicked by prostaglandins or forskolin, which are known to stimulate adenylate cyclase. The inhibitory effect of either cAMP analogues or prostaglandins was potentiated when added in combination with phosphodiesterase inhibitors. The present results suggest that increase of intracellular cAMP prevents the development of basement membrane and the assembly of cells to form testicular structures.
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