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

The effects of adjuvant chemotherapy on growth in children with medulloblastoma.

BACKGROUND: Current therapy for children with medulloblastoma includes craniospinal radiation therapy (CSRT) with or without adjuvant chemotherapy. The difference in growth of children after the two different therapeutic modalities is unknown. METHODS: The growth of 38 prepubertal children who survived medulloblastoma was reviewed retrospectively. Fifteen of these patients received CSRT alone; 23 received chemotherapy in addition to the radiation therapy. RESULTS: The average growth velocity of all patients with medulloblastoma during the 4 years of the study was below the mean for age and sex in all patients except one. Most patients grew at velocities more than two standard deviations below the mean. The overall growth of children who received chemotherapy in conjunction with CSRT was significantly worse than the growth of those who received only CSRT. The children who received chemotherapy showed little or no improvement in growth velocity by year 4; those who did not receive chemotherapy had some improvement. CONCLUSIONS: These findings suggest that chemotherapy potentiates the deleterious effects of radiation on growth

Characterization of the murine lbx2 promoter, identification of the human homologue, and evaluation as a candidate for alstrom syndrome.

The murine Lbx2 gene is a member of the ladybird family of homeobox genes, which is expressed in the developing urogenital system, eye, and brain. Using transgenic mice, we demonstrate that 9 kb of the 5\u27 flanking region of mouse Lbx2 is able to direct expression of a reporter gene in a tissue-specific manner recapitulating the endogenous expression pattern. This regulatory region provides a novel reagent allowing for transgenic expression in the developing urogenital ridge. In addition, we describe the identification of the human homologue, LBX2. Comparison of the human LBX2 and mouse Lbx2 sequences upstream of the coding regions reveals sequence conservation suggesting conserved regulatory regions. Both the human LBX2 and the mouse Lbx2 genes have similar genomic structures and are composed of two exons separated by an intron. We mapped the mouse Lbx2 gene to 35 cM on chromosome 6 and the human LBX2 gene to a homologous region of chromosome 2p13. This is a candidate region for several inherited disorders, including Alstrom syndrome, a disorder that includes ocular, urogenital, and renal abnormalities. Given the expression pattern of Lbx2, the chromosomal location in humans, and the potential function of mammalian ladybird genes, we have begun to analyze patients with ocular disorders and those with Alstrom syndrome for mutations in LBX2. Although polymorphisms were identified, our results indicate that mutations in the coding region of LBX2 do not account for Alstrom syndrome in the six kindreds analyzed. Copyright 2001 Academic Press

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