Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice

We compared in vivo radioprotective efficacy of 5-androstenediol (5-AED) to that of ten other steroids: 17alpha-androstenediol, dehydroepiandrosterone, 5-androstenetriol (AET), 4-androstenedione (AND), testosterone, estradiol, fluasterone, 16alpha-bromoepiandrosterone, 16alpha-fluoro-androst-5-en-17alpha-ol (alpha-fluorohydrin, AFH), and 16alpha-fluoro-androst-5-en-17beta-ol (beta-fluorohydrin). Steroids were administered 24 or 48 hr before, or 1 hr after, whole-body gamma-irradiation. Two days after irradiation at 3 Gy, blood elements were counted. In addition, after irradiation at 9-12.5 Gy, survival was recorded for 30 days. The results showed radioprotective efficacy was specific for 5-AED. One other steroid, AFH, demonstrated appreciable survival effects but was less efficacious than 5-AED. AND and AET produced slight enhancement of survival in some experiments. This is the first demonstration that the prophylactic window for survival enhancement by 1 subcutaneous (s.c.) injection of 5-AED is as long as 48 hr in mice. Moreover, the results indicate that 1 s.c. injection of 5-AED 1 hr after irradiation is much less effective than 1 injection 24-48 hr before irradiation. Comparing the molecular features of steroids with radioprotective efficacy leads to the following conclusions: 1) these effects are due to interaction with specific receptors, since s.c. injection of extremely similar molecules with the same physicochemical properties as 5-AED were not radioprotective; 2) the 17-hydroxyl group is essential; 3) this group must be in the beta configuration in the absence of nearby side groups; 4) a halogen atom at 16 changes the 17-hydroxyl specificity to alpha; 5) the 3beta-hydroxyl group is not essential; 6) addition of a 7beta-hydroxyl group is deleterious; and 7) the effects are not due to activation of sex steroid receptors.     

Steroid-refractory ulcerative colitis treated with corticosteroids,metronidazole and vancomycin: a case report

Background  

Increasing evidence elucidating the pathogenic mechanisms of ulcerative colitis (UC) has accumulated and the disease is widely assumed to be the consequence of genetic susceptibility and an abnormal immune response to commensal bacteria. However evidence regarding an infectious etiology in UC remains elusive.     

Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy

Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.     

Cost-Effectiveness of Project ADAM

Public access defibrillation (PAD) in the adult population is thought to be both efficacious and cost-effective. Similar programs aimed at children and adolescents have not been evaluated for their cost-effectiveness. This study evaluates the potential cost-effectiveness of implementing Project ADAM, a program targeting children and adolescents in high schools in the Milwaukee Public School System. Project ADAM provides education about cardiopulmonary resuscitation (CPR) and the warning signs of sudden cardiac death (SCD) and training in the use and placement of automated external defibrillators (AEDs) in high schools. We developed decision analysis models to evaluate the cost-effectiveness of the decision to implement Project ADAM in public high schools in Milwaukee. We examined clinical model and public policy applications. Data on costs included estimates of hospital-based charges derived from a pediatric medical center where a series of patients were treated for SCD, educational programming, and the direct costs of one AED and training for 15 personnel per school. We performed sensitivity analyses to assess the variation in outputs with respect to changes to input data. The main outcome measures were Life years saved and incremental cost-effectiveness ratios. At an arbitrary societal willingness to pay $100,000 per life year saved, the policy to implement Project ADAM in schools is a cost-effective strategy at a threshold of approximately 5 patients over 5 years for the clinical model and approximately 8 patients over 5 years for the public policy model. Implementation of Project ADAM in high schools in the United States is potentially associated with an incremental cost-effectiveness ratio that is favorable.     

Molecular characterization of Streptococcus pyogenes isolates collected during periods of increased acute rheumatic fever activity in Utah

BACKGROUND: Salt Lake City, Utah has seen a continuing resurgence of rheumatic fever (RF) since 1985. METHODS: emm genotyping and multilocus sequence typing of streptococcal isolates from periods of increased RF activity were performed. RESULTS: Multiple genotypes were present during 1985 and 1998, two peak years of RF activity, and in 1992, a year with reduced RF activity. emm3 and emm18.1 were present in 1985 and 1998, but not in 1992. Two other emm types, 12 and L28, were significantly elevated in 1998 (a peak RF year) over 1992 (a non-peak RF year). Allelic profiles for the emm3 and emm18.1 isolates exhibited clonality. CONCLUSIONS: During years of increased RF activity multiple emm types, including emm18.1 and emm3, were circulating in the community. During a year of decreased RF activity, emm3 and emm18.1 genotypes were absent. The clonality of the emm3 and emm18.1 types suggests that specific clones of both types are important in the resurgence of RF during these peak years. Two other genotypes, emm12 and emmL28, may also be associated with the persistence of RF in the Salt Lake City, UT area.