Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of ...mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
Background: Population-based studies have estimated health risks of short-term exposure to fine particles using mass of${\rm PM}_{2.5}$(particulate matter ≤ 2.5 μm in aerodynamic diameter) as the ...indicator. Evidence regarding the toxicity of the chemical components of the${\rm PM}_{2.5}$mixture is limited. Objective: In this study we investigated the association between hospital admission for cardiovascular disease (CVD) and respiratory disease and the chemical components of${\rm PM}_{2.5}$in the United States. Methods: We used a national database comprising daily data for 2000-2006 on emergency hospital admissions for cardiovascular and respiratory outcomes, ambient levels of major${\rm PM}_{2.5}$chemical components sulfate, nitrate, silicon, elemental carbon (EC), organic carbon matter (OCM), and sodium and ammonium ions, and weather. Using Bayesian hierarchical statistical models, we estimated the associations between daily levels of${\rm PM}_{2.5}$components and risk of hospital admissions in 119 U.S. urban communities for 12 million Medicare enrollees (≥ 65 years of age). Results: In multiple-pollutant models that adjust for the levels of other pollutants, an interquartile range (IQR) increase in EC was associated with a 0.80% 95% posterior interval (PI), 0.34-1.27% increase in risk of same-day cardiovascular admissions, and an IQR increase in OCM was associated with a 1.01% (95% PI, 0.04-1.98%) increase in risk of respiratory admissions on the same day. Other components were not associated with cardiovascular or respiratory hospital admissions in multiple-pollutant models. Conclusions: Ambient levels of EC and OCM, which are generated primarily from vehicle emissions, diesel, and wood burning, were associated with the largest risks of emergency hospitalization across the major chemical constituents of${\rm PM}_{2.5}$.
Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically ...support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.
Systematic literature review.
To examine the current knowledge of how social support and social skills are associated with aspects of health, functioning and quality of life of persons living with ...spinal cord injury (SCI).
A systematic literature review was conducted. The literature search was carried out in Pubmed, PsycINFO, ERIC (Educational Resources Information Centre), CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase and SSCI (Social Sciences Citation Index). Publications were identified according to predefined eligibility criteria; study qualities were evaluated, study results extracted and a narrative synthesis was compiled.
In all, 58 publications about social support and SCI were included. Social support was positively related to physical and mental health, pain, coping, adjustment and life satisfaction. Social skills were assessed in 11 studies: social problem solving (n=7), assertiveness (n=3), verbal communication (n=1) and self-monitoring (n=1) were examined. Effective problem-solving skills were related to better mental health outcomes, health prevention behavior and less secondary conditions. Assertiveness was related to higher depression in rehabilitation setting. Interventions targeted at social support or social skills were scarcely studied. Only one study examined the relationship between social skills and social support in SCI.
Social support is associated with better health and functioning in individuals with SCI. However, the full range of social skills has not yet been studied in people with SCI. Furthermore, the role of social skills in relation to social support, health and functioning remains unclear. Better understanding of social skills and social support in SCI could facilitate the development of targeted and effective interventions to enhance functioning of people with SCI.
Systematic literature review.
The purpose of this study was to gain a systematic overview of the role of psychological resources in the adjustment to spinal cord injury (SCI).
A systematic literature ...review was performed. The literature search was conducted in the databases Pubmed, PsycINFO, the Social Sciences Citation Index, the Education Resources Information Center, Embase and the Citation Index of Nursing and Allied Health Literature. The assessed variables, measurement instruments, results and the methodological quality of the studies were extracted, summarized and evaluated.
A total of 83 mainly cross-sectional studies were identified. Psychological resources were categorized into seven groups: self-efficacy (SE), self-esteem, sense of coherence (SOC), spirituality, optimism, intellect and other personality characteristics. SE and self-esteem were consistently associated with positive adjustment indicators such as high well-being and better mental health. Interrelations between psychological resources and key rehabilitation outcome variables such as participation were rarely studied. Only a few interventions, which were aimed at strengthening psychological resources were identified. Longitudinal studies suggested that SE, SOC, spirituality and purpose in life were potential determinants of adjustment outcomes in the long term.
Research on psychological resources in SCI is broad, but fragmented. Associations of psychological resources with mental health and well-being were frequently shown, while associations with participation were rarely studied. Further development of resource-based interventions to strengthen persons with SCI is indicated. This review can serve as guide for clinical practice and can add to the design of future SCI research.
To describe and explore functioning and health of persons with spinal cord injury from the perspective of psychological-personal factors in the light of the International Classification of ...Functioning, Disability and Health (ICF) framework.
Data from 511 participants regarding feelings, thoughts and beliefs, motives, and patterns of experience and behaviour were analysed. Measurement instruments included the Mental Health Index-5, Positive and Negative Affect Schedule, Hospital Anxiety and Depression Scale, Appraisal of Life Events Scale, 5 items from the World Health Organization Quality of Life Scale, Purpose in Life Test-Short Form, General Self-Efficacy Scale, Big Five Inventory-21, Social Skills Inventory-SF, Brief COPE. The distribution of the selected psychological-personal factors-indicators was examined using descriptive statistics. Differences between SCI subgroups by sex, age, age at injury, time since injury, aetiology and severity of injury were explored using analysis of variance (ANOVA) and F-tests.
Participants who were older and sustained their spinal cord injury more recently experienced more depressed mood, less positive affect, less challenge appraisal, lower life satisfaction, lower purpose in life, and lower self-efficacy. They reported lower social skills, less usage of the coping strategies humour, positive reframing, and acceptance, and more usage of the coping strategies denial and self-distraction. Overall, effect sizes were small.
Although study participants appeared to be well adjusted to spinal cord injury, those who sustained their injury at an older age and more recently reported more negative experiences. Quantitative description and exploration of the psychological-personal aspects of health will enable hypotheses to be formulated for further research, and suggest a need for tailored interventions for those at risk of less favourable outcomes.
Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is ...proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.
We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.
Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 μm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.
PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and β-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.
These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.
The attack on the World Trade Center (WTC) created an acute environmental disaster of enormous magnitude. This study characterizes the environmental exposures resulting from destruction of the WTC ...and assesses their effects on health. Methods include ambient air sampling; analyses of outdoor and indoor settled dust; high-altitude imaging and modeling of the atmospheric plume; inhalation studies of WTC dust in mice; and clinical examinations, community surveys, and prospective epidemiologic studies of exposed populations. WTC dust was found to consist predominantly (95%) of coarse particles and contained pulverized cement, glass fibers, asbestos, lead, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and polychlorinated furans and dioxins. Airborne particulate levels were highest immediately after the attack and declined thereafter. Particulate levels decreased sharply with distance from the WTC. Dust pH was highly alkaline (pH 9.0-11.0). Mice exposed to WTC dust showed only moderate pulmonary inflammation but marked bronchial hyperreactivity. Evaluation of 10,116 firefighters showed exposure-related increases in cough and bronchial hyperreactivity. Evaluation of 183 cleanup workers showed new-onset cough (33%), wheeze (18%), and phlegm production (24%). Increased frequency of new-onset cough, wheeze, and shortness of breath were also observed in community residents. Follow-up of 182 pregnant women who were either inside or near the WTC on 11 September showed a 2-fold increase in small-for-gestational-age (SGA) infants. In summary, environmental exposures after the WTC disaster were associated with significant adverse effects on health. The high alkalinity of WTC dust produced bronchial hyperreactivity, persistent cough, and increased risk of asthma. Plausible causes of the observed increase in SGA infants include maternal exposures to PAH and particulates. Future risk of mesothelioma may be increased, particularly among workers and volunteers exposed occupationally to asbestos. Continuing follow-up of all exposed populations is required to document the long-term consequences of the disaster.
Objective To examine and compare the contents of health-related quality of life (HRQoL) measures used in stroke, based on the ICF as the frame of reference. Design We conducted a systematic ...literature review to select current generic and condition-specific HRQoL measures applied in stroke. We examined the contents of the selected measures by linking the concepts within the instruments' items to the ICF. Results The systematic literature review resulted in the selection of six generic and seven stroke-specific HRQoL measures. Within the selected instruments we identified 979 Concepts. To map these concepts, we used 200 different ICF categories. None of the ICF categories is contained in all of the instruments. The most frequently used category is 'b152 Emotional functions' contained in 53 items from 10 instruments. Stroke-specific measures more often address 'Mental functions', while the selected generic instruments more often include Environmental Factors. Discussion The present study provides an overview on current HRQoL measures in stroke with respect to their covered contents and provides valuable information to facilitate the selection of appropriate instruments for specific purposes in clinical as well as research settings.
Survey of expert opinion, feedback, and development of final consensus.
Present the background, purpose, development process and results for the International Spinal Cord Injury (SCI) Quality of Life ...(QoL) Basic Data Set.
International.
A committee of experts was established to select and define data elements to be included in an International SCI QoL Basic Data Set. A draft data set was developed and disseminated to appropriate organizations for comment. All suggested revisions were considered, and a final version of the QoL data set was completed.
The QoL data set consists of 3 variables: ratings of satisfaction with general quality of life, satisfaction with physical health, and satisfaction with psychological health. All variables are rated on a scale ranging from 0 (completely dissatisfied) to 10 (completely satisfied).
Collection of the International SCI QoL Basic Data Set variables should be a part of all future studies of SCI QoL to facilitate comparison of results across published studies from around the world. Additional standardized instruments to assess other aspects of QoL can be administered based on the purpose of a particular study.
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