Sandra N. Catlin

Evidence that hematopoiesis may be a stochastic process in vivo.

To study the behavior of hematopoietic stem cells in vivo, hematopoiesis was simulated by assuming that all stem cell decisions (that is, replication, apoptosis, initiation of a differentiation/maturation program) were determined by chance. Predicted outcomes from simulated experiments were compared with data obtained in autologous marrow transplantation studies of glucose 6–phosphate dehydrogenase (G6PD) heterozygous female Safari cats. With this approach, we prove that stochastic differentiation can result in the wide spectrum of discrete outcomes observed in vivo, and that clonal dominance can occur by chance. As the analyses also suggest that the frequency of feline hematopoietic stem cells is only 6 per 107 nucleated marrow cells, and that stem cells do not replicate on average more frequently than once every three weeks, these large–animal data challenge clinical strategies for marrow transplantation and gene therapy.

Lethality of firearms relative to other suicide methods: a population based study

Objectives: (1) To quantify lethality of firearms relative to other suicide methods, (2) to quantify the extent to which suicide mortality may be reduced by limiting access to firearms. Methods: Data on suicides and hospitalised para-suicides that occurred in the state of Illinois from 1990 to 1997 were combined. Total number of episodes for each suicide method was estimated as the sum of the number of suicides and the number of para-suicides for that method. Gender and suicide method were used as proxies for intention to die, and estimated lethality of suicide methods within method-gender groups (for example, male firearm users). Logistic regression was used to quantify the lethality of firearms relative to other suicide methods. Excess mortality associated with the use of firearms was estimated by conservatively assuming that in the absence of firearms the next most lethal suicide method would be used. Results: From January 1990 to December 1997, among individuals 10 years or older in the state of Illinois, there were 37 352 hospital admissions for para-suicide and 10 287 completed suicides. Firearms are the most lethal suicide method. Episodes involving firearms are 2.6 times (95% CI 2.1 to 3.1) more lethal than those involving suffocation—the second most lethal suicide method. Preventing access to firearms can reduce the proportion of fatal firearms related suicides by 32% among minors, and 6.5% among adults. Conclusions: Limiting access to firearms is a potentially effective means of reducing suicide mortality.

The replication rate of human hematopoietic stem cells in vivo

Hematopoietic stem cells (HSCs) replicate (self-renew) to create 2 daughter cells with capabilities equivalent to their parent, as well as differentiate, and thus can both maintain and restore blood cell production. Cell labeling with division-sensitive markers and competitive transplantation studies have been used to estimate the replication rate of murine HSCs in vivo. However, these methods are not feasible in humans and surrogate assays are required. In this report, we analyze the changing ratio with age of maternal/paternal X-chromosome phenotypes in blood cells from females and infer that human HSCs replicate on average once every 40 weeks (range, 25-50 weeks). We then confirm this estimate with 2 independent approaches, use the estimate to simulate human hematopoiesis, and show that the simulations accurately reproduce marrow transplantation data. Our simulations also provide evidence that the number of human HSCs increases from birth until adolescence and then plateaus, and that the ratio of contributing to quiescent HSCs in humans significantly differs from mouse. In addition, they suggest that human marrow failure, such as the marrow failure that occurs after umbilical cord blood transplantation and with aplastic anemia, results from insufficient numbers of early progenitor cells, and not the absence of HSCs.

Determinants of temporal variability in NHEXAS-Maryland environmental concentrations, exposures, and biomarkers

The longitudinal NHEXAS-Maryland study measured metals, PAHs, and pesticides in several media to capture temporal variability. Questionnaires were concurrently administered to identify factors that influenced changes in contaminant levels over time. We constructed mixed-effects regression models for lead, phenanthrene, and chlorpyrifos (including metabolites) in indoor air, dust, dermal wipes, and biological fluids. Significant predictors represented time-varying activities as well as unchanging housing and demographic factors. There was little overlap among the models, with predictors generally reflecting the diverse characteristics of the target compounds. We estimated between- and within-person variance components to evaluate the reliability of the measurements. While only one measurement of lead in blood or chlopyrifos in dust was needed for a dependable estimate of an individuals average level, three to eight measurements were needed for most other compound/exposure medium combinations because of considerable temporal variability. Measurements in biological fluids and dust were generally more consistent than those in indoor air. The significant covariates in the full models preferentially reduced the between-person variance component. Since the regression models explained only 1–37% of the within-person variance, the questionnaires in this study provided only modest insight into the factors responsible for the temporal variability in the contaminant levels.

Stochastic modeling of early hematopoiesis

Abstract Hematopoiesis is the bodys way of making the cellular constituents of blood. Oxygen transport, response to infections, and control of bleeding are among the functions of different mature blood cells. These specific functions are acquired as cells mature in the bone marrow. Stem cells are the “master cells” at the top of this pedigree, having within them the capacity to reconstitute the entire system. Although the latter stages of hematopoiesis are fairly well understood, the functioning of stem cells and other multipotential cells is currently a matter of intense research. This article presents a statistical analysis providing support for the clonal succession model of early hematopoiesis. J. L. Abkowitz and colleagues at the University of Washington have developed an experimental method for studying the kinetics of early hematopoiesis in a hybrid cat. The essence of the method is to analyze G6PD, an enzyme linked to the X chromosome. The G6PD type of a cell forms a binary marker that is passed ...

Influence of variable precipitation on coastal water quality in southern California.

OBJECTIVES To examine the consequences of changing precipitation levels on southern Californias recreational coastal water quality, and compare the responses of watersheds with differing levels of urban development. METHODS The geo-temporal relationship for six years (2000-2005) of precipitation levels, discharge rates for the ten primary waterways, and coastal water bacteria concentrations at seventy-eight southern California beaches were examined. RESULTS Precipitation levels, river-creek discharge rates, and coastal water bacteria concentrations were significantly correlated (p < 0.01) for all ten watersheds investigated. Water bacteria concentrations significantly increased with higher levels of precipitation across 95% of the seventy-eight beaches investigated. A heavily developed watershed had significantly higher median bacteria concentrations (186 cfu) in the adjoining coastal waters compared to an undeveloped watershed (10 cfu) of similar size. CONCLUSIONS Precipitation and ensuing runoff strongly control the rate of polluted water delivered to most beaches in southern California. Variable precipitation generates a greater response in coastal water bacteria concentrations in developed watersheds compared to undeveloped areas. Projected declines in regional precipitation as a consequence of climate change may result in less contaminated water delivered to coastal waters, thus decreasing risk of water associated illnesses during winter months.

Facing Time Limits and Kinship Placements

The study examines the relationship between temporary welfare time limits and foster care relative placement in Nevada. A logit model was specified with a binary dependent variable capturing placement with relatives as opposed to nonrelative family foster care placement or group care. The findings reveal that, all else constant, children from welfare families with more months counted toward their Nevadas time limits are not more likely to be placed with relatives than their counterparts. The findings also show that children from African American families, from large families, or from families receiving cash during removal are more likely to be placed with relatives. The authors suggest that casework activities need to occur before, during, and after children experience foster care placements with relatives.

Hematopoiesis as a competitive exclusion process: Estimation of a stem cell selective advantage

Female Safari cats are offspring of domestic and Geoffroy parents, and are balanced heterozygotes with equal numbers of Blood cells containing domestic and Geoffroy-type glucose 6-phosphate dehydrogenase (G6PD),an X-chromosome derived enzyme. In previous studies, however, we observed increasing percentages of Blood cells with Geoffroy G6PD in cats aged 4–12 years. Similarly, ratios of parental X-chromosome phenotypes greater than three to one are common in women over age 60, while women under 40 typically exhibit one to one ratios. Using a two-compartment hidden-Markov model of the distribution of phenotype in samples taken during the second stage of hematopoiesis (Blood cell production), we estimate, through simulation and mathematical calculation, the Geoffroy selective advantages necessary to reproduce the data obtained from female Safari cats. It is shown that small differences in the kinetics of hematopoietic stem cells (HSC), less than might be detected by in vitro assays, can explain the “clonal dominance” observed with aging in cats, and by extension, human females. Conceptually, hematopoiesis in females can be viewed as a competitive exclusion process in which two populations of HSC (defined by parental X-chromosome phenotype) compete for environmental resources. As in many ecological examples, dominance may occur only after long periods of time.

Simulation of Hematopoiesis: Implications for the Gene Therapy of Lysosomal Enzyme Disorders

Although the hematopoietic stem cell is an attractive target for gene transfer, little is known about its biology in vivo in large animals (including humans). We have studied the in vivo behavior of hematopoietic stem cells in glucose-6-phosphate dehydrogenase heterozygous (female Safari) cats, and demonstrated that clonal instability persists for up to 4.5 years after autologous marrow transplantation. This contrasts with the 2-6 months of clonal disequilibrium reported in comparable murine studies. Our data also suggest that hematopoietic stem cells do not self-renew more than once every 3 weeks. These data may have relevance for strategies to optimize gene therapy in large animals and, by extension, in humans.

The Simulation of Hematopoiesis

Although the hematopoietic stem cell is an attractive target cell for gene transfer, little is known about its biology in vivo in large animals (or man). We have studied the in vivo behavior of hematopoietic stem cells in glucose-6-phosphate dehydrogenase (G6PD) heterozygous (female Safari) cats, and demonstrated that clonal instability persists for up to 4.5 years after autologous marrow transplantation. This contrasts the 2–6 months of clonal disequilibrium reported in comparable murine studies. Our data also suggests that hematopoietic stem cells do not self-renew more frequently than once per three weeks. These data may impact strategies for optimizing gene therapy in large animals, and by extension in man.