The determination of asymptotic and periodic behavior of dynamic systems arising in control system analysis Final report

Asymptotic and periodic behavior prediction for nonlinear control system with mathematical model of rigid body vehicl

A systematic review of the safety of topical therapies for atopic dermatitis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75613/1/j.1365-2133.2006.07538.x.pd

The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up.

A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at alpha = 0.05 level (P-value \u3c0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for \u3c5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality

Molecular-Basis of Congenital Adrenal-Hyperplasia Due to 3-Beta-Hydroxysteroid Dehydrogenase-Deficiency

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3beta-HSD genes have been analyzed in three male pseudohermaphrodite 3beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3beta-HSD gene, provide unique information on the structure-activity relationships of the 3beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3beta-HSD deficiency. The impairment of steroid formation in both the adrenal and gonadal tissues of patients suffering from classical 3beta-HSD deficiency thus results from mutation(s) in the type II 3beta-HSD gene, causing various levels of impairment of enzymatic activity and, consequently, varying clinical severity of the disease. On the other hand, the finding of a normal type I 3beta-HSD gene provides the basis for the weil recognized intact peripheral intracrine steroidogenesis in these patients