Gene rearrangements in bone marrow cells of patients with acute myelogenous leukemia

At diagnosis, clonal gene rearrangement probes {[}retinoic acid receptor (RAR)-alpha, major breakpoint cluster region (M-bcr), immunoglobulin (Ig)-JH, T cell receptor (TcR)-beta, myeloid lymphoid leukemia (MLL) or cytokine genes (GM-CSF, G-CSF, IL-3)] were detected in bone marrow samples from 71 of 153 patients with acute myelogenous leukemia (AML) (46%): in 41 patients with primary AML (pAML) (58%) and in 30 patients with secondary AML (42%). In all cases with promyelocytic leukemia (AML-M3) RAR-alpha gene rearrangements were detected (n = 9). Gene rearrangements in the Ig-JH or the TcR-beta or GM-CSF or IL-3 or MLL gene were detected in 12, 10, 16 and 12% of the cases, respectively, whereas only few cases showed gene rearrangements in the M-bcr (6%) or G-CSF gene (3%). Survival of pAML patients with TcR-beta gene rearrangements was longer and survival of pAML patients with IL-3 or GM-CSF gene rearrangement was shorter than in patients without those rearrangements. No worse survival outcome was seen in patients with rearrangements in the MLL, Ig-JH or M-bcr gene. In remission of AML (CR), clonal gene rearrangements were detected in 23 of 48 cases (48%) if samples were taken once in CR, in 23 of 26 cases (88%) if samples were taken twice in CR and in 23 of 23 cases (100%) if samples were studied three times in CR. All cases with gene rearrangements at diagnosis showed the same kind of rearrangement at relapse of the disease (n = 12). Our data show that (1) populations with clonal gene rearrangements can be regularly detected at diagnosis, in CR and at relapse of AML. (2) Certain gene rearrangements that are detectable at diagnosis have a prognostic significance for the patients' outcome. Our results point out the significance of gene rearrangement analyses at diagnosis of AML in order to identify `poor risk' patients - independently of the karyotype. Moreover, the persistence of clonal cells in the further course of AML can be studied by gene rearrangement analysis. Copyright (C) 2000 S. Karger AG, Basel

Unoccluded Retinol Penetrates Human Skin In Vivo More Effectively Than Unoccluded Retinyl Palmitate or Retinoic Acid

The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unocciuded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unocciuded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid

Retinoic Acid Isomers Applied to Human Skin in Vivo Each Induce a 4-Hydroxylase That Inactivates Only Trans Retinoic Acid

Application of all-trans retinoic acid to human skin for 4 d under occlusion produces a marked increase in retinoic acid 4-hydroxylase activity. In this study, the possible induction of other hydroxylases in response to 9-cis and 13-cis retinoic acid applications to adult human skin in vivo was determined. Application of 0.1% all-trans, 0.1% 9-cis, and 0.1% 13-cis retinoic acid to human skin for 2 d resulted in induction of only all-trans retinoic acid 4-hydroxylase activity. The 4-hydroxylase activity in microsomes from the treated tissue ranged from 383 ± 46 to 531 ± 59pg of 4-hydroxy all-trans retinoic acid formed/min/mg protein (n = 6). These same preparations were unable to use 9-cis or 13-cis retinoic acid as substrate for the hydroxylation reaction. Extraction of the retinoic acid isomers from epidermis 48h after application of 0.1% solution of each isomer yielded significant amounts of all-trans retinoic acid (36-72%) regardless of the isomer applied. The all-trans isomer produced by isomerization of both 9-cis and 13-cis retinoic acids is the likely inducer of the 4-hydroxylase. All-trans retinol and all-trans retinal were unable to compete with all-trans retinoic acid as substrate for 4-hydroxylase enzyme. The 4-hydroxylase induced in response to pharmacological doses of retinoic acids is specific for the all-trans isomer. The inability of 9-cis or 13-cis retinoic acid to induce their own hydroxylation and inactivation or act as substrate for the 4-hydroxylase in skin may have considerable implications in light of the clinical use of retinoids in the treatment of various diseases including cancers

Experimental research design in the study of electoral systems

Understanding the effects of electoral systems is of great importance to both scholars and practitioners, and experimental research can be a valuable tool in pursuit of this goal. However, scholars need to think carefully about how to utilize experimental research, especially because the variation in electoral systems in which we are most interested—at the national level—is often impossible or unethical to manipulate. To inform how experiments and related methods of causal inference are then still able to facilitate investigations into the roots and consequences of electoral systems, we situate experimental research within a broader account of research design in the study of electoral systems, summarize existing experimental work, and discuss future avenues. We call for carefully crafting experimental tests in the laboratory and for using “naturally” occurring variation in existing institutions at lower levels of the electoral system

Molecular and clinical pharmacology of psoriasis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/136054/1/cpt1974165part2919.pd

Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study

Several studies have examined environmental factors and inflammatory bowel diseases (IBD) using traditional approaches; however, provided results are still conflicting. Our aim was to determine whether lifestyle and nutrient exposures, related to IBD in observational meta-analyses, influence IBD risk using a Mendelian randomization (MR) approach. A two-sample MR approach was applied on summary-level genome-wide association results. Genetic variants strongly associated with measures of tobacco smoking, obesity and fat distribution, physical activity, and blood levels of vitamins and fatty acids were evaluated on genetic data from international IBD consortia including a total of 25,042 IBD cases (12,194 cases of Crohn's disease (CD) and 12,366 cases of ulcerative colitis (UC)) and 34,915 controls. Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P=0.02), but it was not associated with UC risk (OR 0.99, P=0.88). Body-mass index (BMI) and body fat percentage were positively associated with CD (OR 1.11, P=0.02, per standard deviation (SD) of 4.6 kg/m(2); and OR 1.50, P=3x10(-10), per SD of 6.6%; respectively); while for UC, BMI was inversely associated (OR 0.85, P=5x10(-5); per SD) and body fat percentage showed a OR of 1.11 (P=0.11; per SD). Additionally, among nutrient exposures, omega-3 fatty acids levels were inversely associated with CD (OR 0.67, P=2x10(-6)). Our MR results did not support a protective effect for being a smoker on UC risk; however, they are compatible with a risk effect for higher body fat proportion and a protective role for higher levels of omega-3 fatty acids on CD etiology

Neighborhood Factors and Six-Month Weight Change among Overweight Individuals in a Weight Loss Intervention.

The purpose of this study was to examine the neighborhood environment and the association with weight change among overweight/obese individuals in the first six months of a 12-month weight loss intervention, EMPOWER, from 2011 to 2015. Measures of the neighborhood environment included neighborhood racial composition, neighborhood income, and neighborhood food retail stores density (e.g., grocery stores). Weight was measured at baseline and 6 months and calculated as the percent weight change from baseline to 6 months. The analytic sample (N = 127) was 91% female and 81% white with a mean age of 51 (± 10.4) years. At 6 months, the mean weight loss was 8.0 kg (± 5.7), which was equivalent to 8.8% (± 6%) of baseline weight. Participants living in neighborhoods in which 25–75% of the residents identified as black had the greatest percentage of weight loss compared to those living in neighborhoods with 75% black residents. No other neighborhood measures were associated with weight loss. Future studies testing individual-level behavioral weight loss interventions need to consider the influence of neighborhood factors, and how neighborhood-level interventions could be enhanced with individual-level interventions that address behaviors and lifestyle changes

Genetic Population Structure Analysis in New Hampshire Reveals Eastern European Ancestry

Genetic structure due to ancestry has been well documented among many divergent human populations. However, the ability to associate ancestry with genetic substructure without using supervised clustering has not been explored in more presumably homogeneous and admixed US populations. The goal of this study was to determine if genetic structure could be detected in a United States population from a single state where the individuals have mixed European ancestry. Using Bayesian clustering with a set of 960 single nucleotide polymorphisms (SNPs) we found evidence of population stratification in 864 individuals from New Hampshire that can be used to differentiate the population into six distinct genetic subgroups. We then correlated self-reported ancestry of the individuals with the Bayesian clustering results. Finnish and Russian/Polish/ Lithuanian ancestries were most notably found to be associated with genetic substructure. The ancestral results were further explained and substantiated using New Hampshire census data from 1870 to 1930 when the largest waves of European immigrants came to the area. We also discerned distinct patterns of linkage disequilibrium (LD) between the genetic groups in the growth hormone receptor gene (GHR). To our knowledge, this is the first time such an investigation has uncovered a strong link between genetic structure and ancestry in what would otherwise be considered a homogenous US population