bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in mRNA Levels for Heat‐Shock/Stress Proteins (Hsp) and a Secretory Vesicle Associated Cysteine‐String Protein (Csp1) after Amphetamine (AMPH) Exposure
Authors: BOWYER JOHN F. , DAVIES DAVID L.
Published: February 2006

ABSTRACT:Damage to nerve terminals, reactive gliosis and somatic degeneration can result when pronounced hyperthermia occurs during amphetamine (AMPH) exposure. The effects of AMPH‐induced hyperthermia and damage on the relative mRNA levels for several heat shock/stress proteins (Hsp27, Hsp60, Hsp70 and Hsc70), as well as secretory vesicle associated cysteine‐string protein (Csp1) were determined in both the striatum and substantia nigra using reverse transcriptase polymerase chain reaction (RT‐PCR). These changes were compared to changes in Hsp mRNA levels seen in primary rat cerebral astrocyte cultures after heat shock/stress. Striatal Hsp70 mRNA increased about 2‐fold over control levels at 16 hr after AMPH‐induced hyperthermia, and was the only Hsp species to significantly increase in response to AMPH. Hsp70 mRNA levels returned to control within 14 days after AMPH. Two‐fold increases in Hsp70 mRNA were also seen in primary cultures of rat cerebrum 24 hr after heat shock. In primary cultures and brain tissue, the increased Hsp70 mRNA levels were still more than 500‐fold less than constitutive Hsc70 mRNA and 50‐fold less than Hsp60 levels. Hsp27 mRNA was not present in the striatum, nigra and primary cell cultures. Thus, the expression of Hsp species mRNA measured was very similar in brain tissue and primary cell cultures. Because only a modest induction of Hsp 70 mRNA occurred, the Hsp species evaluated may only play a minor role in AMPH neurotoxicity. However, further studies are necessary to determine whether large increases in Hsp 70 are occurring in selected neurons or glia in the striatum. RT‐PCR products for Csp1 were produced in total RNA obtained from brain but not from cultured astrocytes, suggesting that the Csp1 mRNA measured by RT‐PCR is of neuronal origin. Csp1 mRNA levels were acutely downregulated in neurons in the substantia nigra, possibly in response to damage, but not the striatum after AMPH exposure. A slight long‐term upregulation at 4 months of Csp1 mRNA may occur in the striatum but not in nigra.
Ion Channel Modulation as the Basis for Neuroprotective Action of MS‐153
Authors: UENISHI HIROAKI , HUANG CHAO‐SHENG , SONG JIN‐HO , MARSZALEC WILLIAM , NARAHASHI TOSHIO
Published: February 2006

ABSTRACT:MS‐153, (R)‐(‐)‐5‐methyl‐1‐nicotinoyl‐2‐pyrazoline, is a new neuroprotective durg. Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKCγ). The present study was undertaken to prove the hypothesis that MS‐153 blocks neuroreceptors and ion channels involved in glutamate accumulation. Neurons isolated from rat dorsal root ganglia and frontal cortex were used for recording channel currents by the whole‐cell patch clamp technique. The effects of bath‐applied MS‐153 were examined on tetrodotoxin‐sensitive and tetrodotoxin‐resistant sodium channels and high voltage‐gated calcium channels of dorsal root ganglion neurons, and channels activated by glutamate,N‐methyl‐d‐aspartate (NMDA), kainate, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxarole propionic acid (AMPA), γ‐aminobutyric acid (GABA) and acetyloholine (ACH) in cortical neurons.

MS‐153 at a concentration of 300 μM had no effect on either tetrodotoxin‐sensitive or tetrodotoxin‐resistant sodium channels. High voltage‐gated calcium channels were either suprressed or not affected by 1–300 μM MS‐153. The variable blocking effect of MS‐153 was due to the variable activity of intracellular components in individual neurons, especially that of PKC, whose translocation is known to be inhibited by MS‐153. When 100 nM phorbol 12‐Myristate‐13‐acetate (PMA) was applied to neurons, MS‐153 suppressed the calcium channel current more frequently. Calphostin C (0.5 μM), a specific PKC inhibitor, applied intracellularly via recording patch pipette, completely abolished MS‐153 suppression of the calcium channel current. Currents induced by glutamate, NMDA, kainate, AMPA, GABA or ACH were not affected by MS‐153 at 300 μM. It was concluded that MS‐153 inhibited high voltage‐gated calcium channels through interactions with PKC, thereby preventing massive release of glutamate from nerve terminals in ischemic conditions.
The Low‐Affinity, Use‐Dependent NMDA Receptor Antagonist AR‐R 15896AR: An Update of Progress in Stroke
Authors: PALMER GENE C. , CREGAN EDWARD F. , BIALOBOK PAUL , SYDSERFF SIMON G. , HUDZIK THOMAS J. , McCARTHY DENNIS J.
Published: February 2006

ABSTRACT:Use‐dependentN‐methyl‐d‐aspartate (NMDA) receptor antagonists protect neurons from the lethal consequences of excessive stimulation by excitatory amino acids. Clinical development of high‐affinity compounds such as MK801 have been limited due to untoward side effects. Toward this end, the lower‐affinity use‐dependent NMDA antagonists have greater margins of safety and have advanced to clinical trials for stroke, epilepsy, head trauma and chronic neurodegenerative disorders. AR‐R 15896AR is currently in Phase II trials for stroke and has been repeatedly demonstrated to afford neuroprotection in a variety ofin vivoandin vitromodels associated with ischemia/excitotoxic conditions.
Neuroprotective Effects of HU‐211 on Brain Damage Resulting from Soman‐Induced Seizures
Authors: FILBERT MARGARET G. , FORSTER JEFFRY S. , SMITH C. DAHLEM , BALLOUGH GERALD P. H.
Published: February 2006

ABSTRACT: Neuroprotective effects of HU‐211 (dexanabinol), a synthetic nonpsychotropic analog of tetrahydrocannabinol, on brain damage resulting from soman‐induced seizures were examined in male Sprague‐Dawley rats challenged with 1.6 LD50 soman. At 5 or 40 min after onset of seizures, the rats were given an intraperitoneal injection of 25 mg/kg HU‐211. All rats that received soman showed electrocorticographic (ECoG) evidence of sustained seizures and status epilepticus for 4–6 hr. HU‐211 had no effect on either the strength or duration of seizure activity. Administration of HU‐211 at 5 min after seizure onset reduced median lesion volume 86% (as assessed by microtubule‐associated protein 2 (MAP2)‐negative staining), and when administered 40 min post‐onset, the reduction in necrosis was 81.5% despite the presence of continuous seizures for 4–5 hr. These observations were corroborated by hemotoxylin and eosin (H&E) histopathological assessment that showed a significant reduction in piriform cortical neuronal damage in HU‐211‐treated animals. It is concluded that HU‐211 provides considerable neuroprotection against brain damage produced by soman‐induced seizures.
Contemporary Global Movement of Emerging Plant Diseases
Authors: BANDYOPADHYAY RANAJIT , FREDERIKSEN RICHARD A.
Published: February 2006

Abstract: Plant diseases are a significant constraint to agricultural productivity. Exotic plant diseases pose a continued threat to profitable agriculture in the United States. The extent of this threat has increased dramatically in the 1980s and 1990s due to the expansion of international trade in agricultural products and frequent movement of massive volume of people and goods across national boundaries. Introduction of new diseases has not only caused farm losses, but has also diminished export revenue since phytosanitary issues are linked to international commerce. Plant pathogens and their vectors have also moved across national boundaries, sometimes naturally and at other times influenced by the recent changes in trade practices. Sorghum ergot, Karnal bunt of wheat, potato late blight, and citrus tristeza are some of the most recent examples of enhanced importance of diseases due to the introduction of plant pathogens or vectors.
Risk Assessment for Children and Other Sensitive Populations
Authors: LANDRIGAN PHILIP J.
Published: February 2006

Abstract: Children form a unique subgroup within the population who require special consideration in risk assessment. Children are not little adults. Their tissues and organs grow rapidly, developing and differentiating. These development processes create windows of great vulnerability to environmental toxicants. Furthermore, the exposure patterns of children to environmental chemicals are very different from those of adults. Traditional risk assessment has generally failed to consider the special exposures and the unique susceptibilities of infants and children. Adoption of a new child‐centered agenda for research and risk assessment is necessary if disease in children of toxic environmental origin is to be identified, understood, controlled, and prevented. This agenda needs to be multidisciplinary. Specific requirements within the agenda include: (1) exploration and quantification of unique patterns of exposure for children; (2) adoption of new, more sensitive approaches to testing chemicals that can recognize the consequences of exposure during early development; (3) identification, through clinical and epidemiologic studies, of etiologic associations between environmental exposures and pediatric diseases; and (4) elucidation, at the cellular and molecular levels, of the pathogenetic mechanisms of pediatric environmental illness. In the United States, an important start toward adoption of this new agenda has occurred since passage of the Food Quality Protection Act in 1996. A Presidential Executive Order on Children's Health and the Environment has been promulgated. This Order requires all federal agencies to make protecting the health of children against environmental hazards a high priority. A new Office of Children's Health Protection has been established at the U.S. Environmental Protection Agency. Programs in children's environmental health have been created at the Centers for Disease Control and Prevention, the Agency for Toxic Substances and Disease Registry, and the National Institute of Environmental Health Sciences. A national network of eight new Children's Environmental Health Research and Disease Prevention Centers has been formed. These developments will enhance research on previously understudied issues in the environmental health of children and will provide a scientific basis for child‐centered risk assessment.
The Scientific and Methodological Bases of Experimental Studies for Detecting and Quantifying Carcinogenic Risks
Authors: MALTONI CESARE , SOFFRITTI MORANDO , BELPOGGI FIORELLA
Published: February 2006

Abstract: This paper outlines the aims and potential scope of experimental research for risk identification and assessment in industrial carcinogenesis (environmental and occupational). It then reviews the basic, general, and specific requisites of a rigorously scientific nature that are required to render experiments to be more appropriate and better geared to the information they seek. A range of experimental approaches to risk assessment are illustrated by results achieved in the Cancer Research Centre of the Ramazzini Foundation (CRC/RF). The paper ends with a call for closer relations and integration among experimental, epidemiologic, and biostatistical studies.
A Bayesian Approach to Hazard Identification: The Case of Electromagnetic Fields and Cancer
Authors: AHLBOM ANDERS , FEYCHTING MARIA
Published: February 2006

Abstract: This paper discusses certain issues related to uncertainty in hazard identification. Research on the hypothesis that exposure to 50–60‐Hz magnetic and electric fields (EMF) increases the risk of cancer has been ongoing for two decades. Epidemiological studies provide a somewhat consistent pattern indicating an increased risk for childhood leukemia and adult chronic lymphatic leukemia and possibly also for other leukemias and brain cancer. However, there is still no good candidate for a mechanism. Epidemiological studies have throughout the two decades been interpreted with great caution, and final evaluations as to carcinogenicity have been deferred. The reason for this carefulness may be the lack of knowledge about a plausible mechanism. The purpose of this paper is to discuss the process of weighing epidemiological data, experimental data, and other background information into a synthesis such that the evaluation can be based on all data combined. A Bayesian approach to this weighing is discussed along with some alternatives. The Bayesian approach provides a structure for the pooling of evidence and points out where subjective judgments come into play.
Mega‐experiments to Identify and Assess Diffuse Carcinogenic Risks
Authors: SOFFRITTI MORANDO , BELPOGGI FIORELLA , MINARDI FRANCO , BUA LUCIANO , MALTONI CESARE
Published: February 2006

Abstract: Diffuse carcinogenic risks, that is, those of low potency involving large areas of population and sometimes all mankind, pose a serious public health problem. Controlling these risks might help to reduce the incidence of, and mortality from, cancer. Because of their low expected carcinogenic potential, these risks are difficult to expose or assess. Epidemiologic investigation is of limited use in this field and yields its data too late to be useful. Experimental studies offer the only possible approach for assessing such risks. To increase experimental sensitivity and consistency of results, mega‐experiments must be designed. That is, experiments that use a large number of animals with a well‐known basic tumorigram, that extend the exposure and the biophase for as long as possible, that carefully observe the effects, and that are performed with suitable standardized methods. In the last 15 years the Ramazzini Foundation, in its Cancer Research Center at Bentivoglio, has conducted or planned five mega‐experiments. Initial results indicate the great potential of these methods for identifying and assessing diffuse risks.
Uncertainty in Biomonitoring and Kinetic Modeling
Authors: EDLER LUTZ
Published: February 2006

Abstract: Uncertainty in exposure assessment and uncertainty in kinetic models of early effects after exposure to a toxin are addressed in this paper. Sources of uncertainty in the determination of exposure of workers in chemical industry exposed to dioxins are exhibited and a simple kinetic model for biomonitor measurements of the concentrations from occupational exposure is derived. Model uncertainty, and uncertainty in the model parameters of physiologically‐based pharmacokinetic models (PBPK models) are addressed when these models are used to estimate the effective dose in risk assessment. Uncertainty in the model parameters originating from the use of different statistical analysis methods is exhibited for Hill type nonlinear kinetics of enzyme induction mediated by a toxin.
Uncertainty in Estimating Exposure Using a Toxicokinetic Model: The Example of 2,3,7,8‐Tetrachlorodibenzo‐p‐Dioxin
Authors: SALVAN ALBERTO , THOMASETH KARL , BORTOT PAOLA , SARTORI NICOLA
Published: February 2006

Abstract:This paper deals with sources of uncertainty in the use of a minimal physiological toxicokinetic model to obtain dose estimates for a dose‐response analysis of cancer in an occupational cohort. Toxicokinetic models make it possible to construct exposure parameters that are more closely related to the individual dose than traditional measures of exposures to toxic agents. However, the process introduces a wide array of sources of uncertainty. Selecting a model structure to describe the kinetics of a toxic agent implies necessarily making simplifications and assumptions that influence the range of applicability of the model. Once a model has been selected, the value of certain model parameters (constants) must be assigned, for example, from anthropometric data. The question then arises of how sensitive the model predictions are to variations in the values of these constants. Other model parameters, typically those describing the kinetics of the agent, are next estimated from actual data. There may be limitations in the data concerning, for example, sparseness (too few observations per subject) or missing values. The methods used for parameter estimation carry their own set of assumptions that need to be appropriate to the situation at hand. In summary, the dioxin example is used to characterize the sources of uncertainty at different levels, such as model structure, methods and data used for parameter estimation, estimation of occupational exposure, and imputation of missing values in exposure indices derived from the kinetic model.
Uncertainty in the Relation between Exposure to Magnetic Fields and Brain Cancer due to Assessment and Assignment of Exposure and Analytical Methods in Dose‐Response Modeling
Authors: KROMHOUT HANS , LOOMIS DANA P. , KLECKNER ROBERT C.
Published: February 2006

Abstract: Incomplete scientific knowledge ensures that, in every study, uncertainty will enter the processes of exposure estimation and exposure‐response modeling. In the light of the heated debate about the health effects of magnetic fields resulting from power production and usage, we undertook a sensitivity analysis to evaluate uncertainty related to key decisions in a previous study of brain cancer and occupational exposure to magnetic fields. The findings appeared to be relatively insensitive to most variations in the methods of exposure assessment, exposure assignment, and data analysis. The results can be visualized by defining bands of uncertainty about a best‐bet estimate of the association based on our original study. These bands of methodological uncertainties were similar in magnitude to the conventional 95% confidence interval, but they rovide a measure of the potential range of systematic bias in the results, rather than reflecting statistical variability alone. The methodology employed here can be applied to other studies, and other researchers are encouraged to conduct sensitivity analysis in order to estimate methodological uncertainty as an alternative to statistical confidence intervals.
The Contribution of Environmental Monitoring in the Epidemiological Assessment of Exogenous Risk: The Experience of ARPA in the Emilia‐Romagna Region of Italy
Authors: ZAVATTI A. , LAURIOLA P.
Published: February 2006

Abstract:The aim of the Emilia Romagna‐Region Agency for Prevention and Environment (ARPA) is to define and improve interactions among the various prevention departments of the Emilia‐Romagna Local Health Authorities in order to attain better knowledge about the health status of the population by using epidemiology and etiology studies, as well as predictive models. This is the basis for the environmental health risk assessment strategy of ARPA. The priority activity areas for ARPA are: urban areas, environmental and health effects of traffic (atmospheric pollution and noise pollution); industrial areas (Ravenna chemical plants, Modena/Reggio‐Emilia ceramic factories and Ferrara chemical plants); high‐speed trains; pesticides; asbestos; and pollution of the Adriatic Sea.
Sources of Uncertainty in Dose‐Response Modeling of Epidemiological Data for Cancer Risk Assessment
Authors: STAYNER LESLIE , BAILER A. JOHN , SMITH RANDALL , GILBERT STEPHEN , RICE FAYE , KUEMPEL EILEEN
Published: February 2006

Abstract: Epidemiologic data is increasingly being used for dose‐response analysis in risk assessment. The Environmental Protection Agency (EPA) and other U.S. agencies have expressed a preference for using epidemiologic data rather than toxicologic data when possible. However, there are a number of important sources of uncertainty in using epidemiologic data for this purpose that need to be clearly recognized and, when possible, quantified. This paper presents a critical review of the major sources of uncertainty in the use of epidemiologic data for cancer risk assessment. These may include: (1) study design issues such as potential confounding and other biases, inadequate sample size, and followup, (2) the choice of the data set, (3) specification of the dose‐response model, (4) estimation of exposure and dose, and (5) unrecognized variability in susceptibility. Examples from risk assessments for cadmium, asbestos, and diesel exhaust are used to illustrate the potential magnitude of some of these sources of uncertainty. It is shown that the overall uncertainty from these various sources combined may often result in highly uncertain risk estimates from dose‐response modeling of epidemiologic data. For this reason, we believe it is best to present a range of possible risk estimates, which, to the extent possible, reflects the variability and uncertainty inherent in the dose‐response evaluation of epidemiologic data.
Uncertainty in Risk Characterization of Weak Carcinogens
Authors: YAMAGUCHI NAOHITO
Published: February 2006

Abstract: Epidemiologic inference is subject to uncertainty that is inherent to observational approaches. It was shown by the present analysis that an SMR of 1.4, as observed for 2,3,7,8‐tetrachlorodibenzo‐para‐dioxin in the pooled analysis by IARC, would be observed in the absence of carcinogenic risk, if the smoking prevalence of cohort members was as low as 80%. It was also shown that a 1.4‐fold increase in lung cancer risk among nonsmokers, which roughly corresponds to a daily consumption of one cigarette, might be extremely difficult to identify if the subjects are exposed to strong carcinogens such as those that result from cigarette smoking. On the other hand, a genotoxic agent that increases the lung cancer risk of smokers 1.4‐fold, could increase the risk to nonsmokers by as much as 6.3‐fold. In light of these uncertainties in epidemiologic inference, attempts to estimate the absolute risk in human populations by epidemiologic studies should be made with caution.
Reducing Uncertainty in the Derivation and Application of Health Guidance Values in Public Health Practice: Dioxin as a Case Study
Authors: DE ROSA CHRISTOPHER T. , POHL HANA R. , HANSEN HUGH , LEONARD ROBIN C. , HOLLER JAMES , JONES DENNIS
Published: February 2006

Abstract: We were requested by the U.S. Environmental Protection Agency (EPA) to clarify the relationships among the minimal risk level (MRL), action level, and environmental media evaluation guide (EMEG) for dioxin established by the Agency for Toxic Substances and Disease Registry (ATSDR). In response we developed a document entitled “Dioxin and Dioxin‐Like Compounds in Soil, Part I: ATSDR Interim Policy Guideline”; and a supporting document entitled “Dioxin and Dioxin‐Like Compounds in Soil, Part II: Technical Support Document”. In these documents, we evaluated the key assumptions underlying the development and use of the ATSDR action level, MRL, and EMEG for dioxin. We described the chronology of events outlining these different health guidance values for dioxin and identified the areas of uncertainty surrounding these values. Four scientific assumptions were found to have had a great impact on this process; these were: (1) the specific uncertainty factors used, (2) the toxicity equivalent (TEQ) approach, (3) the fractional exposure from different pathways, and (4) the use of body burdens in the absence of exposure data. This information was subsequently used to develop a framework for reducing the uncertainties in public health risk assessment associated with exposure to other chemical contaminants in the environment. Within this framework are a number of future directions for reducing uncertainty, including physiologically based pharmacokinetic modeling (PBPK), benchmark dose modeling (BMD), functional toxicology, and the assessment of chemical mixture interactions.
Uncertainty in Risk Assessment: Current Efforts and Future Hopes
Authors: BAILER A. JOHN
Published: February 2006

Abstract: The incorporation of sampling variability in estimates of excess risk has been part of risk assessment practice for decades. Currently, there is a strong desire to incorporate understanding of biological mechanisms into the models used for exposure assessment and exposure‐response modeling. In addition, representing population heterogeneity in the assessment of risks and the identification of sensitive subpopulations is of great concern. Finally, the communication of uncertainty and variability remains a challenge to risk assessors. Based upon the presentations of workshop faculty, a summary of current practice when addressing uncertainty together with conjectures concerning future challenges for addressing uncertainty, are presented.
Socioeconomic Status and Health: What We Know and What We Don't
Authors: ADLER NANCY E. , OSTROVE JOAN M.
Published: February 2006

Abstract: In the past 15 years, we have seen a marked increase in research on socioeconomic status (SES) and health. Research in the first part of this era examined the nature of the relationship of SES and health, revealing a graded association; SES is important to health not only for those in poverty, but at all levels of SES. On average, the more advantaged individuals are, the better their health. In this paper we examine the data regarding the SES‐health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES. In the most recent era, researchers are increasingly exploring the mechanisms by which SES exerts an influence on health. There are multiple pathways by which SES determines health; a comprehensive analysis must include macroeconomic contexts and social factors as well as more immediate social environments, individual psychological and behavioral factors, and biological predispositions and processes.
Protective and Damaging Effects of Mediators of Stress: Elaborating and Testing the Concepts of Allostasis and Allostatic Load
Authors: McEWEN BRUCE S. , SEEMAN TERESA
Published: February 2006

Abstract: Stress is a condition of human existence and a factor in the expression of disease. A broader view of stress is that it is not just the dramatic stressful events that exact their toll but rather the many events of daily life that elevate activities of physiological systems to cause some measure of wear and tear. We call this wear and tear “allostatic load,” and it reflects not only the impact of life experiences but also of genetic load; individual habits reflecting items such as diet, exercise, and substance abuse; and developmental experiences that set life‐long patterns of behavior and physiological reactivity (see McEwen 1). Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease. This will be illustrated for the immune system and brain. Among the most potent of stressors are those arising from competitive interactions between animals of the same species, leading to the formation of dominance hierarchies. Psychosocial stress of this type not only impairs cognitive function of lower ranking animals, but it can also promote disease (e.g. atherosclerosis) among those vying for the dominant position. Social ordering in human society is also associated with gradients of disease, with an increasing frequency of mortality and morbidity as one descends the scale of socioeconomic status that reflects both income and education. Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events and the allostatic load that this burden places on the physiological systems involved in coping and adaptation.
The Biological Embedding of Early Experience and Its Effects on Health in Adulthood
Authors: HERTZMAN CLYDE
Published: February 2006

Abstract:Explanations of the socioeconomic gradient in health status must account for the observations that the gradient cuts across a wide range of disease processes and is capable of replicating itself on new disease processes as they emerge in society. Understanding this pattern requires an understanding of how human organisms can become generally vulnerable or resilient to disease over time: a huge collation task across different disciplines. The hypothesis that best fits current evidence is that the gradient is an “emergent property” of the interaction between the developmental status of people and the material and psychosocial conditions they encounter over their life course. Within this broad formulation, special attention is given to child development, and the prospect that socioeconomic differences in the quality of early life experiences contribute to subsequent gradients in health status through socioeconomic differences in brain sculpting and the conditioning of host defense systems that depend on communication with the developing brain. The contribution to the gradient in health is theorized to occur through a combination of latent effects, pathway effects, and cumulative disadvantage.
Socioeconomic Status and Chronic Stress: Does Stress Account for SES Effects on Health?
Authors: BAUM ANDREW , GAROFALO J. P. , YALI ANN MARIE
Published: February 2006

Abstract: Socioeconomic status (SES) is an important predictor of a range of health and illness outcomes. Research seeking to identify the extent to which this often‐reported effect is due to protective benefits of higher SES or to toxic elements of lower social status has not yielded consistent or conclusive findings. A relatively novel hypothesis is that these effects are due to chronic stress that is associated with SES; lower SES is reliably associated with a number of important social and environmental conditions that contribute to chronic stress burden, including crowding, crime, noise pollution, discrimination, and other hazards or stressors. In other words, chronic stress may capture much of the variance in health and social outcomes associated with harmful aspects of lower social status. Low SES is generally associated with distress, prevalence of mental health problems, and with health‐impairing behaviors that are also related to stress. Research targeting this hypothesis is needed to determine the extent to which stress is a pathway linking SES and health.
Status, Stress, and Atherosclerosis: The Role of Environment and Individual Behavior
Authors: KAPLAN JAY R. , MANUCK STEPHEN B.
Published: February 2006

Abstract: Atherosclerosis induced by moderate hyperlipoproteinemia in group‐housed cynomolgus monkeys differs significantly between animals of dominant and subordinate social status. The nature of this association also varies by sex, and in males, by stability of the social environment. Dominant males develop more extensive atherosclerosis than subordinates when housed in unstable, but not stable, social groups; in contrast, subordinate females develop greater atherosclerosis than dominants, and do so irrespective of the conditions of social housing. Experimental investigations reveal that the first of these associations (males) is mediated by concomitant sympathoadrenal activation and the second (females) by ovarian impairment associated with the stress of social subordination. We believe our findings offer clues to the neuroendocrine mediation of behavioral influences on coronary artery disease in humans. This is particularly true where these influences reflect asymmetries in the power or status relationships among individuals within similar social environments, or when dimensions of temperament or disposition give rise to such relationships. We propose that these data also may be informative regarding the pathophysiological sequelae of social stratification (in which disease incidence varies by class membership within populations), but only where social environments engendered by class inequalities exacerbate status‐dependent behavioral differences among individuals within communities of associates.
Stress Responses in Low‐Status Jobs and Their Relationship to Health Risks: Musculoskeletal Disorders
Authors: LUNDBERG ULF
Published: February 2006

Abstract:Conditions typical of many low‐status jobs are known to induce elevated stress. In keeping with this, blue‐collar workers show elevated psychophysiological stress levels both during and after work compared with workers in more stimulating and flexible jobs. Health‐related behaviors, such as cigarette smoking and drug abuse, that are known to contribute to the social gradient in health, can be seen as ways of coping with a stressful work situation in order to get short‐term relief. Negative emotional states associated with low‐status jobs, combined with a lack of economic resources, are also likely to reduce the individual's motivation to seek proper medical treatment and, thus, increase the risk that transient symptoms develop into chronic illness. With regard to musculoskeletal disorders, it is well documented that physically monotonous or repetitive work is associated with an increase in neck, shoulder, and low back pain problems. However, recent studies also report an association between psychosocial factors and muscle pain syndromes. Possible mechanisms explaining these findings involve the assumption that psychological stress may induce sustained activation of small, low‐threshold motor units that may lead to degenerative processes, damage, and pain. Analysis of short periods of very low muscular electrical activity (EMG gaps) shows that female workers with a high frequency of EMG gaps seem to have less risk of developing myalgia problems than do workers with fewer gaps. Stress induced by psychosocial conditions at work, which is usually more lasting than that resulting from physical demands, may prevent the individual from shutting off their physiological activation and reduces the time for rest and recovery. In the modern work environment, with strong emphasis on a high work pace, competitiveness, and efficiency, it is possible that lack of relaxation is an even more important health problem than is the absolute level of contraction or the frequency of muscular activation.
Race, Socioeconomic Status, and Health The Added Effects of Racism and Discrimination
Authors: WILLIAMS DAVID R.
Published: February 2006

Abstract:Higher disease rates for blacks (or African Americans) compared to whites are pervasive and persistent over time, with the racial gap in mortality widening in recent years for multiple causes of death. Other racial/ethnic minority populations also have elevated disease risk for some health conditions. This paper considers the complex ways in which race and socioeconomic status (SES) combine to affect health. SES accounts for much of the observed racial disparities in health. Nonetheless, racial differences often persist even at “equivalent” levels of SES. Racism is an added burden for nondominant populations. Individual and institutional discrimination, along with the stigma of inferiority, can adversely affect health by restricting socioeconomic opportunities and mobility. Racism can also directly affect health in multiple ways. Residence in poor neighborhoods, racial bias in medical care, the stress of experiences of discrimination and the acceptance of the societal stigma of inferiority can have deleterious consequences for health.
Sleep as a Mediator of the Relationship between Socioeconomic Status and Health: A Hypothesis
Authors: VAN CAUTER EVE , SPIEGEL KARINE
Published: February 2006

Abstract: This article discusses the hypothesis that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. In a recent study, we examined carbohydrate metabolism, endocrine function, and sympatho‐vagal balance in young, healthy adults studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bedtime period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo‐pituitary‐adrenal function were qualitatively and quantitatively similar to those observed in normal aging. These results indicate that sleep loss can increase the “allostatic load” and facilitate the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups.
Public Policy Frameworks for Improving Population Health
Authors: TARLOV ALVIN R.
Published: February 2006

Abstract: Four conceptual frameworks provide bases for constructing comprehensive public policy strategies for improving population health within wealthy (OECD) nations. (1) Determinants of population health. There are five broad categories: genes and biology, medical care, health behaviors, the ecology of all living things, and social/societal characteristics. (2) Complex systems: Linear effects models and multiple independent effects models fail to yield results that explain satisfactorily the dynamics of population health production. A different method (complex systems modeling) is needed to select the most effective interventions to improve population health. (3) An intervention framework for population health improvement. A two‐by‐five grid seems useful. Most intervention strategies are either ameliorative or fundamentally corrective. The other dimension of the grid captures five general categories of interventions: child development, community development, adult self‐actualization, socioeconomic well‐being, and modulated hierarchical structuring. (4) Public policy development process: the process has two phases. The initial phase, in which public consensus builds and an authorizing environment evolves, progresses from values and culture to identification of the problem, knowledge development from research and experience, the unfolding of public awareness, and the setting of a national agenda. The later phase, taking policy action, begins with political engagement and progresses to interest group activation, public policy deliberation and adoption, and ultimately regulation and revision. These frameworks will be applied to help understand the 39 recommendations of the Independent Inquiry into Inequalities in Health, the Sir Donald Acheson Report from the United Kingdom, which is the most ambitious attempt to date to develop a comprehensive plan to improve population health.
Introduction to Stem Cell Biology in Vitro: Threshold to the Future
Authors: EAVES C. , MILLER C. , CONNEALLY E. , AUDET J. , OOSTENDORP R. , CASHMANP J. , ZANDSTRA P. , ROSE‐JOHN S. , PIRET J. , EAVES A.
Published: February 2006

Abstract: Transplantable hematopoietic cells with multilineage reconstituting ability can be quantitated in suspensions of human or murine cells using similar assay procedures. The incorporation into these assays of stringently defined functional endpoints ensures a high degree of specificity for the cells detected. Application of these assays to stem cell‐containing suspensions after they have been stimulated for several days with defined cytokines in vitro, or by a mixture of defined and/or undefined factors in vivo, has shown that net amplifications in these populations can be obtained under both circumstances. Such studies have allowed cytokine conditions that support stem cell self‐renewal divisions to be identified and have also provided evidence that stem cell regeneration can be manipulated both in vitro and in vivo by altering the molecular milieu of the responding cells. These observations pave the way to future delineation of mechanisms that control the normal behavior, pathology and future clinical exploitation of hematopoietic stem cell populations.
Hematopoietic Commitment during Embryogenesis
Authors: ROBERTSON SCOTT , KENNEDY MARION , KELLER GORDON
Published: February 2006

Abstract: Hematopoiesis develops initially as discrete blood islands in the extraembryonic yolk sac of the embryo. These blood islands consist of clusters of primitive erythrocytes surrounded by developing angioblasts that ultimately form the yolk sac vasculature. The close developmental association of these early hematopoietic and endothelial cells has led to the hypothesis that they develop from a common precursor, a cell known as the hemangioblast. Using a developmental model system based on the in vitro differentiation capacity of embyronic stem (ES) cells, we have identified a precursor with the capacity to generate endothelial as well as primitive and definitive hematopoietic progeny. The developmental potential of this precursor population suggests that it represents the in vitro equivalent of the hemangioblast.
Humoral Regulation of Hematopoietic Stem Cellsa
Authors: OGAWA MAKIO , MATSUNAGA TAKUYA
Published: February 2006

Abstract: During the last two decades, studies using primarily cell culture methods disclosed that a number of hematopoietic cytokines possess stimulatory effects on primitive hematopoietic progenitors. More recently, investigators in a number of laboratories, including ours, used murine transplantation models to characterize the cytokines regulating the hematopoietic stem cells. The results are in general agreement with the cytokine interactions defined in culture. The positive cytokines may be separated into two groups: one consisting of steel factor and flt3/flt2 ligand and the other consisting of interleukin (IL)‐6, IL‐11, IL12, leukemia inhibitory factor, granulocyte colony‐stimulating factor (G‐CSF) and thrombopoietin. Interactions of two cytokines belonging to different groups appear necessary to positively regulate the kinetics of stem cells. Surprisingly, IL‐3 and IL‐1 proved to have profound negative effects on hematopoietic stem cells. Studies of human hematopoietic stem cells are now necessary.
Homing of Long‐Term and Short‐Term Engrafting Cells In Vivoa
Authors: LANZKRON SOPHIE M. , COLLECTOR MICHAEL I. , SHARKIS SAUL J.
Published: February 2006

Abstract: Long‐term repopulating hematopoietic stem cells can be separated from cells which provided radioprotection (short‐term repopulating cells) on the basis of size. This might be a result of the quiescent nature of long‐term repopulating cells. To define the activity of these populations we utilized a dye, PKH26+, which incorporates into the membrane of cells and is equally distributed to daughter cells when they divide. We were able to retrieve PKH26+‐labeled cells posttransplant in the hematopoietic tissues of the recipients. We could also assess their cell cycle status and their ability, short‐and long‐term, to reconstitute secondary lethally irradiated hosts in limiting dilution. The results suggest that long‐term repopulating cells remain quiescent in the bone marrow shortly after engraftment, whereas cells which radioprotect are more rapidly dividing. We could not detect labeled cells in the peripheral blood posttransplant, and even though cells homed to both the spleen and bone marrow the cells in the bone marrow were significantly more competent at reconstituting lethally irradiated secondary hosts.
Further Characterization of CD34‐Low/Negative Mouse Hematopoietic Stem Cells
Authors: NAKAUCHI HIROMITSU , TAKANO HINA , EMA HIDEO , OSAWA MASATAKE
Published: February 2006

Abstract: We have previously reported that in adult mouse bone marrow, CD34low/− c‐kit+ Sca‐1+ lineage markers negative (Lin−) (CD34−KSL) cells represent hematopoietic stem cells with long‐term marrow repopulating ability whereas CD34+ c‐kit+ Sca‐1+ Lin− (CD34+KSL) cells are progenitors with short‐term reconstitution capacity. To further characterize cells in those two populations, relative expression of various genes wereee examniend by reverse transcriptase polymerase chain reaction (RT‐PCR). In CD34−KSL Cells, none of the genes sturied was found to be expressed with the exception of GATA‐2, IL‐1Rα, IL‐2Rγ, AIC‐2B, c‐kit, EPO‐R, and c‐mpl. In contrast, expression of GATA‐1 and all cytokine receptor genes examined except IL‐2Rβ, IL‐7Rα and IL‐9Rα were found in CD34+KSL.

The difference between these two populations was also shown in single cell culture analysis of these cells. when cells were clone sorted and cultured in the presence of SCF, IL‐3 and EPO, CD34−KSL cells required much more time to undergo the first cell division than CD34+KSL cells. dormancy and random fashion of cell division by CD34−KSL cells were also evident by the analysis of the second cell division, which was found to be delayed and unsynchronous comapred with CD34+KSL cells. Clonal culture analusis showed that CD34−KSL cells were more potent in proliferation and multilineage differentiation capacities than CD34+KSL cells. In a paired‐daughter cell experiment, 75% of CD34−KSL and 50% of CD34+KSL paired‐daughter‐derived colonies were nonidentical wiht wide vairety of lineage combinations. Taken together, these data support our previous notion that CD34−KSL cells are at higher rank in hematopoietic hierarchy than CD34+KSL cells. In addition, our results using highly enriched stem cell population directly obtained from mouse bone marrow support the proposed stochastic nature of lineage commitment.
Amphotropic Retrovirus Transduction of Hematopoietic Stem Cells
Authors: ORLIC DONALD , GIRARD LAURIE J. , ANDERSON STACIE M. , BARRETTE STEPHANE , BROXMEYER HAL E. , BODINE DAVID M.
Published: February 2006

Abstract: Mice treated with cytokines for 5 days have large numbers of hematopoietic stem cells (HSCs) in their peripheral blood and bone marrow at 1 and 14 days after the last injection. We fractionated the HSCs from the bone marrow of these mice using elutriation at flow rates of 25, 30 and 35 ml/min. The subpopulations of HSCs from cytokine‐treated mice show a 3‐ to 8‐fold higher level of mRNA encoding the amphotropic retrovirus receptor (amphoR) compared with the corresponding HSC subpopulation from untreated mouse bone marrow. In an earlier study with mouse HSCs we showed a direct correlation between high levels of amphoR mRNA and efficient retrovirus transduction. We have now utilized our gene transfer protocol to assay amphotropic retrovirus transduction efficiency using HSCs from the bone marrow of mice treated with granulocytecolony stimulating factor/stem cell factor (G‐CSF/SCF). To extend these findings to a more clinically relevant protocol we analyzed the amphoR mRNA levels in HSCs from human cord blood and adult bone marrow. The amphoR mRNA level in HSCs from human bone marrow and fresh cord blood was detectable at an extremely low level compared with the HSC population in cryopreserved cord blood samples. The 12‐ to 22‐fold increase in amphoR mRNA in HSCs from cryopreserved cord blood renders these HSCs likely candidates for high efficiency, gene transfer.
Effects of Retroviral‐Mediated MDR1 Expression on Hematopoietic Stem Cell Self‐Renewal and Differentiation in Culturea
Authors: BUNTING KEVIN D. , GALIPEAU JACQUES , TOPHAM DAVID , BENAIM ELY , SORRENTINO BRIAN P.
Published: February 2006

Abstract: Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications. Toward this goal, we have investigated whether retrovirally‐transduced murine stem cells could be expanded in culture with hematopoietic cytokines. Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene (HaMDR1), a variant of human dihydrofolate reductase (HaDHFR), or both MDR1 and DHFR in an internal ribosomal entry site (IRES)‐containing bicistronic vector (HaMID). Cells were then expanded for 15 days in cultures stimulated with interleukin (IL)‐3, IL‐6, and stem cell factor. When very low marrow volumes were injected into lethally irradiated recipient mice, long‐term reconstitution with 100% donor cells was seen in all mice injected with HaMDR1‐ or HaMID‐transduced cells. By contrast, engraftment with HaDHFR‐ or mock‐transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes. In addition, mice transplanted with expanded HaMDR1‐ or HaMID‐transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes. These results show that MDR1‐transduced stem cells can be expanded in vitro with hematopoietic cytokines, but indicate that an increased stem cell division frequency can lead to stem cell damage.