TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells.

TNF-α, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body γ-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1-5 h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3-5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γ-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC γ-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-α and rmIL-1α, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general.

The validation of a French-language version of the Aging Perceptions Questionnaire (APQ) and its extension to a population aged 55 and over.

BACKGROUND: Several studies have shown the influence of the perceptions of aging on the cognitive functioning and the mental and physical health of older people. These relationships have not to date been studied in France where validated instruments are lacking. The primary objective of this study was to validate a French-language version of the Aging Perceptions Questionnaire (APQ) in the French general population aged 65 and over. The secondary objective was to study the stability of the dimensions of this instrument among participants aged 55 to 64. METHODS: The study was proposed to the cohort of the Observatoire Régional du Vieillissement (OPREVI) (observatory of aging), located in a small town in Poitou-Charentes (western France). An anonymous questionnaire including the APQ was sent by mail to inhabitants aged 55 and over. The original English language APQ was described with adults aged 65 and older. It has 32 items distributed on 7 dimensions: timeline chronic and cyclical, positive and negative consequences, positive and negative control and emotional representations. RESULTS: 656 adults participated in this survey (286 men, 370 women). Among those aged 65 and over (n = 94), the seven-factor structure estimated by confirmatory factor analysis was coherent with original findings. Internal consistency as evaluated by Cronbach alpha, was between 0.83 for consequences negative and 0.52 for control negative. Several dimensions were strongly correlated. Among participants aged 55 to 64 (n = 262), the same factorial model yielded an acceptable fit. Multi-group confirmatory factor analysis concluded to approximate factorial invariance between the two age groups with a null delta in comparative fit index. CONCLUSION: This study among French people aged 65 and over, added further evidence of the multidimensional structure of the French version of the APQ which is superimposed to the dimensions of the original Irish version. The same factorial structure applies acceptably to the younger group (aged 55-64). The OPREVI study is ongoing, and will collect data on the physical, material and social characteristics of participants. It will therefore be possible to analyse the variables associated with the perceptions of aging. On the basis of an individual's perceptions of aging as captured by this questionnaire, and his or her clinical profile, tailored multi-dimensional assistance could be made available aiming to provide incentives to anticipate or to adapt to difficulties.

A 10 year (2000-2010) systematic review of interventions to improve quality of care in hospitals.

BACKGROUND: Against a backdrop of rising healthcare costs, variability in care provision and an increased emphasis on patient satisfaction, the need for effective interventions to improve quality of care has come to the fore. This is the first ten year (2000-2010) systematic review of interventions which sought to improve quality of care in a hospital setting. This review moves beyond a broad assessment of outcome significance levels and makes recommendations for future effective and accessible interventions. METHODS: Two researchers independently screened a total of 13,195 English language articles from the databases PsychInfo, Medline, PubMed, EmBase and CinNahl. There were 120 potentially relevant full text articles examined and 20 of those articles met the inclusion criteria. RESULTS: Included studies were heterogeneous in terms of approach and scientific rigour and varied in scope from small scale improvements for specific patient groups to large scale quality improvement programmes across multiple settings. Interventions were broadly categorised as either technical (n = 11) or interpersonal (n = 9). Technical interventions were in the main implemented by physicians and concentrated on improving care for patients with heart disease or pneumonia. Interpersonal interventions focused on patient satisfaction and tended to be implemented by nursing staff. Technical interventions had a tendency to achieve more substantial improvements in quality of care. CONCLUSIONS: The rigorous application of inclusion criteria to studies established that despite the very large volume of literature on quality of care improvements, there is a paucity of hospital interventions with a theoretically based design or implementation. The screening process established that intervention studies to date have largely failed to identify their position along the quality of care spectrum. It is suggested that this lack of theoretical grounding may partly explain the minimal transfer of health research to date into policy. It is recommended that future interventions are established within a theoretical framework and that selected quality of care outcomes are assessed using this framework. Future interventions to improve quality of care will be most effective when they use a collaborative approach, involve multidisciplinary teams, utilise available resources, involve physicians and recognise the unique requirements of each patient group.

The origin and evolution of modern metabolism.

One fundamental goal of current research is to understand how complex biomolecular networks took the form that we observe today. Cellular metabolism is probably one of the most ancient biological networks and constitutes a good model system for the study of network evolution. While many evolutionary models have been proposed, a substantial body of work suggests metabolic pathways evolve fundamentally by recruitment, in which enzymes are drawn from close or distant regions of the network to perform novel chemistries or use different substrates. Here we review how structural and functional genomics has impacted our knowledge of evolution of modern metabolism and describe some approaches that merge evolutionary and structural genomics with advances in bioinformatics. These include mining the data on structure and function of enzymes for salient patterns of enzyme recruitment. Initial studies suggest modern metabolism originated in enzymes of nucleotide metabolism harboring the P-loop hydrolase fold, probably in pathways linked to the purine metabolic subnetwork. This gateway of recruitment gave rise to pathways related to the synthesis of nucleotides and cofactors for an ancient RNA world. Once the TIM beta/alpha-barrel fold architecture was discovered, it appears metabolic activities were recruited explosively giving rise to subnetworks related to carbohydrate and then amino acid metabolism. Remarkably, recruitment occurred in a layered system reminiscent of Morowitz's prebiotic shells, supporting the notion that modern metabolism represents a palimpsest of ancient metabolic chemistries.

Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart.

Deep-space travel presents risks of exposure to ionizing radiation composed of a spectrum of low-fluence protons (1H) and high-charge and energy (HZE) iron nuclei (e.g., 56Fe). When exposed to galactic cosmic rays, each cell in the body may be traversed by 1H every 3-4 days and HZE nuclei every 3-4 months. The effects of low-dose sequential fractionated 1H or HZE on the heart are unknown. In this animal model of simulated ionizing radiation, middle-aged (8-9 months old) male C57BL/6NT mice were exposed to radiation as follows: group 1, nonirradiated controls; group 2, three fractionated doses of 17 cGy 1H every other day (1H × 3); group 3, three fractionated doses of 17 cGy 1H every other day followed by a single low dose of 15 cGy 56Fe two days after the final 1H dose (1H × 3 + 56Fe); and group 4, a single low dose of 15 cGy 56Fe followed (after 2 days) by three fractionated doses of 17 cGy 1H every other day (56Fe + 1H × 3). A subgroup of mice from each group underwent myocardial infarction (MI) surgery at 28 days postirradiation. Cardiac structure and function were assessed in all animals at days 7, 14 and 28 after MI surgery was performed. Compared to the control animals, the treatments that groups 2 and 3 received did not induce negative effects on cardiac function or structure. However, compared to all other groups, the animals in group 4, showed depressed left ventricular (LV) functions at 1 month with concomitant enhancement in cardiac fibrosis and induction of cardiac hypertrophy signaling at 3 months. In the irradiated and MI surgery groups compared to the control group, the treatments received by groups 2 and 4 did not induce negative effects at 1 month postirradiation and MI surgery. However, in group 3 after MI surgery, there was a 24% increase in mortality, significant decreases in LV function and a 35% increase in post-infarction size. These changes were associated with significant decreases in the angiogenic and cell survival signaling pathways. These data suggest that fractionated doses of radiation induces cellular and molecular changes that result in depressed heart functions both under basal conditions and particularly after myocardial infarction.

Cardiovascular risks associated with low dose ionizing particle radiation.

Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ((1)H; 0.5 Gy, 1 GeV) and iron ion ((56)Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in (56)Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, (56)Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.

Divergent modification of low-dose 56Fe-particle and proton radiation on skeletal muscle.

It is unknown whether loss of skeletal muscle mass and function experienced by astronauts during space flight could be augmented by ionizing radiation (IR), such as low-dose high-charge and energy (HZE) particles or low-dose high-energy proton radiation. In the current study adult mice were irradiated whole-body with either a single dose of 15 cGy of 1 GeV/n 56Fe-particle or with a 90 cGy proton of 1 GeV/n proton particles. Both ionizing radiation types caused alterations in the skeletal muscle cytoplasmic Ca²âº ([Ca²âº]i) homeostasis. 56Fe-particle irradiation also caused a reduction of depolarization-evoked Ca²âº release from the sarcoplasmic reticulum (SR). The increase in the [Ca²âº]i was detected as early as 24 h after 56Fe-particle irradiation, while effects of proton irradiation were only evident at 72 h. In both instances [Ca²âº]i returned to baseline at day 7 after irradiation. All 56Fe-particle irradiated samples revealed a significant number of centrally localized nuclei, a histologic manifestation of regenerating muscle, 7 days after irradiation. Neither unirradiated control or proton-irradiated samples exhibited such a phenotype. Protein analysis revealed significant increase in the phosphorylation of Akt, Erk1/2 and rpS6k on day 7 in 56Fe-particle irradiated skeletal muscle, but not proton or unirradiated skeletal muscle, suggesting activation of pro-survival signaling. Our findings suggest that a single low-dose 56Fe-particle or proton exposure is sufficient to affect Ca²âº homeostasis in skeletal muscle. However, only 56Fe-particle irradiation led to the appearance of central nuclei and activation of pro-survival pathways, suggesting an ongoing muscle damage/recovery process.