Decreased rejection and improved survival of first and second marrow transplants for severe aplastic anemia (a 26-year retrospective analysis)

Between 1970 and 1996, 333 patients with severe aplastic anemia underwent HLA-matched related marrow transplant after conditioning with cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group 3 v 2). In group 3, 92% of rejecting patients underwent a second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas group 3 patients received MTX combined with cyclosporine (CSP). Over the three time periods studied, first graft rejection decreased from 35% to 9%, and the proportion of rejecting patients undergoing second transplants increased from 77% to 92%. The 10-year probability of survival after second transplants increased from 5% to 83%. Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a significant factor accounting for the increase in patient survival after second transplant.     

Ability of 16 priority PAHs to be directly cytotoxic to a cell line from the rainbow trout gill

Sixteen polycyclic aromatic hydrocarbons (PAHs) were screened for their ability to be directly cytotoxic to a cell line from the rainbow trout gill, RTgill-W1. Exposure times of 2 h or less were sufficient for direct cytotoxicity to be detected, which appeared to be caused by a common mechanism, the general perturbation of membranes. This was judged by the similarity of results obtained for three fluorescent indicator dyes, alamar Blue, 5-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM) and neutral red. Among the 16 PAHs tested, just two- and three-ring PAHs were found to be directly cytotoxic. These were naphthalene approximately = acenaphthylene approximately = acenaphthene > fluorene approximately = phenanthrene. The results suggest that water solubility and lipophilicity are the critical properties determining the direct cytotoxicity of PAHs and that they do so by influencing PAH accumulation in membranes. Only naphthalene was effective at concentrations well below its water solubility limit. Therefore, direct cytotoxicity is likely to be most environmentally relevant only with naphthalene.     

Effects of insulin-like growth factor I combined with growth hormone on glucocorticoid-induced whole-body protein catabolism in man

Treatment with insulin-like growth factor I (IGF-I) alone failed to affect glucocorticoid-induced protein catabolism in a previous study from our laboratory. To assess the effects of the combination of IGF-I and GH in a similar protocol, 24 normal subjects received (in a double-blind, randomized, placebo-controlled manner) s.c. injections of either GH alone (0.3 IU/kg.day), the combination of IGF-I (80 micrograms/kg.day) and GH (0.3 IU/kg.day), or placebo for a period of 6 days during which they were treated with methylprednisolone (0.5 mg/kg.day). Whole-body protein kinetics measured, using the [1-13C]-leucine infusion technique, demonstrated that leucine flux (a parameter of protein breakdown) increased during administration of glucocorticoids alone (placebo group) and during GH-treatment, whereas the glucocorticoid-induced increase was abolished during IGF-I plus GH (P < 0.03 vs. GH). Leucine oxidation (a parameter of irreversible protein catabolism) increased in the placebo group (+60 +/- 14.5%, P < 0.005, day 7 vs. day 1), remained unchanged in the GH group (+2.5 +/- 10%), and decreased in the combination group (-17.7 +/- 3.3%, P < 0.002, day 7 vs. day 1). Glucose MCR decreased in the group receiving placebo (P < 0.05) and remained unchanged during combined treatment with IGF-I plus GH. It is concluded that glucocorticoid-induced protein, catabolism (leucine oxidation) is abolished during coadministration of GH (anticatabolic effect), whereas treatment with IGF-I and GH results in a net anabolic effect without adverse effects on peripheral glucose clearance.     

Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): a role for nautilus in embryonic somatic muscle formation

The expression of the MyoD gene homolog, nautilus (nau), in the Drosophila embryo defines a subset of mesodermal cells known as the muscle "pioneer" or "founder" cells. These cells are thought to establish the future muscle pattern in each hemisegment. Founders appear to recruit fusion-competent mesodermal cells to establish a particular muscle fiber type. In support of this concept every somatic muscle in the embryo is associated with one or more nautilus-positive cells. However, because of the lack of known (isolated) nautilus mutations, no direct test of the founder cell hypothesis has been possible. We now have utilized toxin ablation and genetic interference by double-stranded RNA (RNA interference or RNA-i) to determine both the role of the nautilus-expressing cells and the nautilus gene, respectively, in embryonic muscle formation. In the absence of nautilus-expressing cells muscle formation is severely disrupted or absent. A similar phenotype is observed with the elimination of the nautilus gene product by genetic interference upon injection of nautilus double-stranded RNA. These results define a crucial role for nautilus in embryonic muscle formation. The application of RNA interference to a variety of known Drosophila mutations as controls gave phenotypes essentially indistinguishable from the original mutation. RNA-i provides a powerful approach for the targeted disruption of a given genetic function in Drosophila.     

Hypomethylation in cervical tissue: is there a correlation with folate status?

5-Aminolevulinic acid (ALA) is the first intermediate substrate in the heme synthetic pathway and is the substrate of aminolevulinic acid dehydratase (ALAD, porphobilinogen synthase). Because lead effectively inhibits ALAD activity, resulting in accumulation of ALA in urine and blood, urinary ALA (ALAU) has been used as a biomarker for lead exposure or early biologic effect of lead. Intraindividual variation in urinary excretion of ALA requires the use of 24-hour urine samples or adjustment of single urine samples by other normalizing variables, such as urinary creatinine concentration. Previous studies of ALAU concentration have used various adjustment methods; however, few have compared creatinine-adjusted ALAU concentration with ALA concentration in plasma (ALAP) from subjects with low (< 30 micrograms/dL) to moderate (< 60 micrograms/dL) levels of blood lead. To determine if creatinine-adjusted ALAU is associated with ALAP, we measured ALAU, ALAP, and urinary creatinine in 65 Korean lead workers with blood lead concentrations in the range of 14-60 micrograms/dL. ALAU, ALAU/creatinine, or ALAU/log creatinine all correlated with ALAP. However, ALAU/creatinine correlated more closely with ALAP based on Spearman's r (rs = 0.40, P, = 0.0009), supporting the use of ALA/creatinine in single urine samples as a surrogate for ALAP.     

Informed consent: how much information is enough?

BACKGROUND: Recent judicial decisions involving informed consent have led to some medical practitioners altering the way they obtain consent. The aim of this study was to determine the degree to which patients understood the risks associated with a surgical procedure after giving routine consent and whether providing additional detailed verbal and/or written information improved their understanding. It was further determined whether the provision of more extensive information altered patients' anxiety levels. METHODS: Patients undergoing femoral popliteal bypass or carotid surgery were randomized to obtain either routine consent only or routine consent with verbal or written or verbal and written consent. Patients undertook a pre-operative risk and complication questionnaire, a pre- and postoperative anxiety and depression evaluation and a follow-up questionnaire 6 weeks after discharge. RESULTS: Thirty-two patients were included in the trial. The comprehension questionnaire resulted in a correct percentage response of 48% for the routine information only, 59% with added verbal information, 59% with added written information and 55% with added written and verbal information. Twenty-five per cent of patients stated that they had a poor understanding of the risks and complications of the procedure. CONCLUSIONS: Additional written or verbal information did not improve a patient's understanding of risks and complications of the procedure. It also did not improve patients' perceived understanding of the operation or its complications. Patients' anxiety levels were unaltered by the increase in the information they were given. The information provided to patients should be simple, easy to understand and list any possible major complications to enable the patient to determine whether to undergo or decline a procedure.