A gene involved in psoriasis susceptibility was localized to the distal region of human chromosome 17q as a result of a genome-wide linkage analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. In the family which showed the strongest evidence for linkage, the recombination fraction between a psoriasis susceptibility locus and D17S784 was 0.04 with a maximum two-point lod score of 5.33. There was also evidence for genetic heterogeneity and although none of the linked families showed any association with HLA-Cw6, two unlinked families showed weak levels of association. This study demonstrates that in some families, psoriasis susceptibility is due to variation at a single major genetic locus other than the human lymphocyte antigen locus.
Profiling studies using microarrays to measure messenger RNA (mRNA) expression frequently identify long lists of differentially expressed genes. Differential expression is often validated using real-time reverse transcription PCR (RT-PCR) assays. In conventional real-time RT-PCR assays, expression is normalized to a control, or housekeeping gene. However, no single housekeeping gene can be used for all studies. We used TaqMan Low-Density Arrays, a medium-throughput method for real-time RT-PCR using microfluidics to simultaneously assay the expression of 96 genes in nine samples of chronic lymphocytic leukemia (CLL). We developed a novel statistical method, based on linear mixed-effects models, to analyze the data. This method automatically identifies the genes whose expression does not vary significantly over the samples, allowing them to be used to normalize the remaining genes. We compared the normalized real-time RT-PCR values with results obtained from Affymetrix Hu133A GeneChip oligonucleotide microarrays. We found that real-time RT-PCR using TaqMan Low-Density Arrays yielded reproducible measurements over seven orders of magnitude. Our model identified numerous genes that were expressed at nearly constant levels, including the housekeeping genes PGK1, GAPD, GUSB, TFRC, and 18S rRNA. After normalizing to the geometric mean of the unvarying genes, the correlation between real-time RT-PCR and microarrays was high for genes that were moderately expressed and varied across samples.
We attempted to determine whether the administration of aspirin or ursodeoxycholic acid during loss of weight could prevent the development of lithogenic changes in bile and the formation of gallstones. Sixty-eight obese subjects without gallstones who were entered in a program (520 kcal per day) to lose weight were randomly assigned to receive ursodeoxycholic acid (1200 mg per day), aspirin (1300 mg per day), or placebo in double-blind fashion for up to 16 weeks. At entry, at four weeks of treatment, and at three weeks after the completion of treatment, the subjects underwent ultrasonography to detect gallstones and duodenal drainage of bile to detect cholesterol crystals and to determine the bile saturation index and glycoprotein concentration. No gallstones or cholesterol crystals formed in the patients treated with ursodeoxycholic acid. Among the patients given placebo, gallstones formed in five (P less than 0.05 vs. ursodeoxycholic acid) and cholesterol crystals in six (P less than 0.001 vs. ursodeoxycholic acid); among those given aspirin, gallstones formed in two and cholesterol crystals in one (no significant difference from ursodeoxycholic acid treatment). By the fourth week, the bile saturation index increased in the placebo group (from 1.07 +/- 0.26 to 1.29 +/- 0.27; P less than 0.001), decreased in the ursodeoxycholic acid group (from 1.11 +/- 0.34 to 0.91 +/- 0.24; P less than 0.001), and did not change significantly in the aspirin group. The concentration of glycoprotein in bile increased in the placebo group (27.9 +/- 14.5 percent; P less than 0.001) but did not change significantly in the groups treated with ursodeoxycholic acid or aspirin. We conclude that ursodeoxycholic acid prevents lithogenic changes in bile and the formation of gallstones in obese subjects during loss of weight.
The acyclic nucleoside phosphonate (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was used topically for the treatment of persistent mucocutaneous infections in two cases. One patient with AIDS suffered from a perineal lesion due to infection with herpes simplex virus type 2 (HSV-2) and did not respond to acyclovir and was intolerant of foscarnet. A bone marrow transplant recipient developed orofacial lesions due to infection with herpes simplex virus type 1 (HSV-1) that failed to respond to therapy with both acyclovir and foscarnet. After topical application of HPMPC, the HSV-2 lesions completely resolved. However, the lesions recurred 3 weeks later, and, upon subsequent treatment with HPMPC, regressed. On recurrence, the virus was found to be sensitive to acyclovir, which the patient was given. Again HSV-2, which was resistant to acyclovir, emerged; similar observations were made after another cycle of HPMPC therapy. The HSV-1 isolates were resistant to acyclovir and foscarnet. Following local HPMPC treatment, the lesions regressed, but after 1 week, a second course of topical HPMPC therapy had to be instituted for recurrent infection. The lesions again regressed, and as the recurrent virus was sensitive to acyclovir, the patient was successfully treated with the drug. The results of this study point to the potential usefulness of topical HPMPC in the treatment of immunocompromised patients with HSV-related mucocutaneous infections that are refractory to therapy with acyclovir and/or foscarnet.
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