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.

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

OBJECTIVES: To examine the consequences of changing precipitation levels on southern California's 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.

Patterns of recovery following percutaneous coronary intervention: a pilot study.

Percutaneous coronary intervention (PCI) is the most common type of cardiac revascularization performed. However, there has been limited research examining the recovery of PCI patients after their hospital discharge. This descriptive, longitudinal study examined patterns of recovery (cardiac symptoms experienced, impact of cardiac symptoms on physical functioning and enjoyment of life, postprocedure problems experienced, and functioning) of 37 PCI patients at 2, 4, and 6 weeks following PCI. Fatigue was the most frequent and persistent symptom, and significantly, F(2, 26) = 3.6, p < .05, it impacted physical functioning at 4 weeks following PCI. Both physical and psychosocial functioning improved over time. Coronary restenosis and heart rhythm disturbance were the most common self-reported heart-related problems. Understanding normal variation in recovery patterns can assist clinicians in developing interventions to facilitate optimal outcomes.

The kinetics of clonal dominance in myeloproliferative disorders.

To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSCs) have been experimentally defined. We determined the consequence if 1 HSC became able to survive without the support of a microenvironmental niche while the rest of its behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats, requiring mean times of 2.5 +/- 0.5 and 7.0 +/- 1.2 years, respectively (n=1000 simulations/species). In both species, when the number of neoplastic HSCs exceeded 0.5% of all HSCs, clonal dominance was inevitable. Our results can explain the absence of clonal myeloproliferative disorders in mice (lifetime, 2 years), are consistent with clinical observations in cats, and provide insight into the progression of chronic myelogenous leukemia (CML) in humans. They also demonstrate that competition for microenvironmental support can lead to the suppression of normal hematopoiesis as neoplasia evolves. Toxic or immunologic suppression of normal HSCs is not required.

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 individual's 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.

Evidence that the number of hematopoietic stem cells per animal is conserved in mammals.

Humans and larger mammals require more blood cells per lifetime than mice because of their larger size and longer life expectancy. To investigate this evolutionary adaptation, we calculated the total number of nucleated marrow cells (NMCs) per cat, observing the distribution of (59)Fe to marrow, then multiplied this value (1.9 +/- 0.9 x 10(10) [mean +/- SD]) times the frequency of feline hematopoietic stem cells (HSCs) (6 HSCs/10(7) NMCs) to derive the total number of HSCs per cat (11 400 +/- 5400). Surprisingly, when the total number of HSCs per mouse was calculated with a similar experimental and computational approach, the value was equivalent. These data imply that the output of differentiated cells per feline HSC must vastly exceed that of murine HSCs. Furthermore, if the total number of human HSCs were also equivalent to the total number of HSCs in cat and mouse, the frequency of human HSCs would be 0.7 to 1.5 HSCs/10(8) NMCs, a frequency that is 20-fold less than estimated by the NOD/SCID repopulating assay.