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Potential Heterogeneity (potential + heterogeneity)
Selected AbstractsThe sex ratio and age-specific male mortality: Evidence for culling in uteroAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 6 2007Tim Bruckner While adverse conditions early in life reportedly predispose individuals to increased mortality in adulthood, controversy remains as to whether exogenous insults in utero, especially among male fetuses, induce similar cohort "damage" in populations. A rival theory postulates that exogenous stressors in gestation may "cull" frail male members of the cohort before birth, leaving a smaller but hardier cohort with improved survival. Recent tests, which use the sex ratio (i.e., the odds of a male live birth) as a gauge of insults inflicted upon cohorts in gestation, support the culled cohort argument. These tests, however, examined only aggregate male lifespan, thereby obscuring potential heterogeneity of both damaged and culled cohorts at specific ages over the life course. Using time-series methods, we explore associations between the sex ratio and cohort male mortality in infancy (before age 1), childhood (1,4 years), youth (5,19 years), adulthood (20,54 years), and old-age (55,79 years). We examine males born in Sweden (1751,1913), Denmark (1835,1913), and England and Wales (1841,1912). Our findings generally support culled cohorts in that male mortality across all ages fell below its expected value among cohorts in which the sex ratio dropped below its expected level. These findings suggest that exogenous shocks to gestation, as measured by a lower than expected sex ratio, may cull males in utero, leaving behind a less frail cohort over the entire life course. Am. J. Hum. Biol., 2007. © 2007 Wiley-Liss, Inc. [source] The Variety of Ecstasy/MDMA Users: Results from the National Epidemiologic Survey on Alcohol and Related ConditionsTHE AMERICAN JOURNAL ON ADDICTIONS, Issue 6 2009Li-Tzy Wu ScD This study investigates the potential heterogeneity of ecstasy or MDMA (3,4-methylenedioxy-N-methylamphetamine) users. Data came from the 2001,2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Latent class analysis (LCA) and multinomial logistic regression procedures were used to identify subtypes of ecstasy users. Approximately 1.6% (n = 562) of adult participants (N = 43,093) reported lifetime ecstasy use. LCA identified three subtypes of ecstasy users. Class 1 exhibited pervasive use ofmost drug classes (ecstasy-polydrug users, 37%). Class 2 reported a high rate of use of marijuana and cocaine and a moderate use of amphetamines (ecstasy-marijuana-stimulant users, 29%). Class 3 was characterized by a high rate of use of marijuana and a low use ofprimarily prescription-type drugs (ecstasy-marijuana users, 34%). Subtypes were distinguished by family income, history ofsubstance abuse treatment, and familial substance abuse. Class 1 exhibited the highest prevalence of disorders related to the use of marijuana (77%), tobacco (66%), amphetamines (36%), opioids (35%), sedatives (31%), and tranquilizers (30%). The recent resurgence in ecstasy use among adults underscores the need to monitor trends in its use. [source] Changes associated with the development of resistance to imatinib (STI571) in two leukemia cell lines expressing p210 Bcr/Abl protein,CANCER, Issue 7 2004Barbara Scappini M.D. Abstract BACKGROUND Although various mechanisms have been recognized as being associated with the development of resistance to imatinib mesylate in vitro and in clinical situations, their relative significance and contributions remain poorly understood, as is the sequence of events leading to the selection of the resistant phenotype. Experimental in vitro systems involving well defined cell lines and conditions can be used to some advantage to answer specific questions and to develop in vitro models of imatinib resistance that would reflect its potential heterogeneity. METHODS Two cell lines, KBM5 and KBM7, which expressed p210 Bcr/Abl and which differed in their inherent sensitivity to imatinib, the number of copies of the BCR/ABL fusion gene, and the activation of apoptotic pathways, were grown in vitro in the presence of increasing concentrations of imatinib. The resistant cells were analyzed for cell cycle progression, apoptotic response after exposure to imatinib, expression of Bcr/Abl, tyrosine kinase activity, and the presence of mutations within the adenosine triphosphate (ATP) coding domain of BCR/ABL. At various levels of resistance, the cells were transferred into drug-free media, and the stability of the resistant phenotype was determined in the absence of the drug. RESULTS In KBM7 cells, the development of resistance was characterized by loss of apoptotic response to the drug, amplification of BCR/ABL, increased levels of expression of p210 Bcr/Abl, and decreased inhibition of Bcr/Abl tyrosine kinase (TK) activity by imatinib. No mutations within the ATP-binding domain of Bcr/Abl were identified, and resistance remained stable in the absence of the drug. In KBM5 cells, which previously were found to be characterized by the acquisition of a single C-T mutation at ABL nucleotide 944 (T315I) at high levels of resistance, this same mutation was detected at an intermediate level, but not at a low level, of resistance. The response of KBM5 cells to imatinib was characterized by a low level of apoptotic response, a marginal increase in BCR/ABL copy number, a modest increase in p210 expression, and a highly imatinib-resistant Bcr/Abl TK. Partial reversal of resistance was observed in highly resistant KBM5-STI571R1.0 cells, which continued to display the C-T mutation. In KBM5 cells with an intermediate level of resistance, the T315I mutation was no longer detectable upon their reversal to the sensitive phenotype. CONCLUSIONS BCR/ABL amplification with subsequent overexpression of Bcr/Abl protein, loss of apoptotic response, or point mutation of the ATP-binding site of BCR/ABL was associated alternatively with the acquisition of the resistant phenotype, supporting the notion that multiple mechanisms are involved in the induction of resistance to imatinib. The initial number of BCR/ABL copies itself was not related directly to the degree of resistance. The reversibility of the resistance may be complete, partial, or irreversible, depending on the mechanism(s) involved and the degree of resistance. Both cell lines serve as models for further elucidation of various aspects of imatinib-resistance mechanisms. Cancer 2004;100:1459,71. © 2004 American Cancer Society. [source] Heterogeneity Of The Properties Of INa in Epicardial And Endocardial Cells Of Rat VentricleCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2002Bonny N Honen SUMMARY 1. Ventricular INa heterogeneity was investigated in adult rat hearts. Differences in transient outward potassium current (Ito) were used to confirm isolation of subepicardial and subendocardial cells. Mean peak Ito was 6.0 ± 0.7 and 1.6 ± 0.45 pA/pF in epicardial and endocardial cells, respectively (P < < 0.01). 2. Maximum sodium conductance was smaller in subendocardial cells compared with subepicardial cells (2.39 ± 0.11 vs 2.78 ± 0.12 nS/pF, respectively; n = 17 for both; 0.01 < P < 0.05) and 50% activation occurred at a slightly more negative potential (,47.6 ± 0.8 vs,44.9 ± 0.9 mV, respectively; n = 10 for both; 0.01 < P < 0.05). 3. The potential for 50% inactivation was not significantly different in subepicardial compared with subendocardial cells (72.2 ± 1.0 vs 72.8 ± 2.2 mV, respectively; n = 17 for both; NS). 4. Persistent sodium current density appeared smaller in subendocardial (n = 19) compared with subepicardial (n = 11) cells (at a test potential of ,25 mV current, density was 0.118 ± 0.041 vs 0.144 ± 0.085 pA/pF, respectively), although this was not statistically significant due to large variability between cells. 5. Mathematical modelling of the cardiac action potential indicated that the combined effects of differences in current density and voltage dependence of sodium currents are unlikely to contribute to ventricular action potential heterogeneity between epicardial and endocardial cells. [source] | ||||||||||