DIANNEXIN DOWN-MODULATES TNF-INDUCED ENDOTHELIAL MICROPARTICLE RELEASE BY BLOCKING MEMBRANE BUDDING PROCESS.

BACKGROUND: Microparticles are now recognised as true biological effectors with a role in immunopathology through their ability to disseminate functional properties. Diannexin, a homodimer of annexin V, binds to PS with a higher affinity and longer blood half-life than the monomer, inhibits prothrombinase complex activity thereby diminishing coagulation and reperfusion injury mediators and prevent microvesicle-mediated material transfer. Our aim was to determine if Diannexin could modulate microparticle production by endothelial cells by interacting with the phosphatidylserine exposure occurring during the release of these vesicles. RESULTS: In this study we showed that fluorescently labelled Diannexin binds to calcimycin-activated endothelial cells but not to resting cells. After overnight incubation, Diannexin enters cells and their released MP carry Diannexin. Some Diannexin seems to be processed via early endosomes and later is found in lysosomes. Both unlabelled Diannexin and fluorescent Diannexin inhibit MP release from TNF-activated endothelial cells. However, Diannexin treatment does not prevent endothelial activation by TNF. In addition, the inhibitory effect of Diannexin on MP release could be observed when cells were pre-, concomitantly or post-treated with cytokines. Scanning electron microscopy showed differences in the numbers and types of protuberances at the cell surface when cells were treated or not with Diannexin. Finally, there is no apparent congruency between fluorescent Diannexin labelling and surface protuberances as shown by correlative microscopy. CONCLUSIONS: Altogether these data suggest that Diannexin can inhibit endothelial vesiculation by binding PS present either at the cell surface or at the level of the inner leaflet of the plasma membrane

Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis

It has been 100 years since the first report of sickle haemoglobin (HbS). More than 50 years ago, it was suggested that the gene responsible for this disorder could reach high frequencies because of resistance conferred against malaria by the heterozygous carrier state. This traditional example of balancing selection is known as the 'malaria hypothesis'. However, the geographical relationship between the transmission intensity of malaria and associated HbS burden has never been formally investigated on a global scale. Here, we use a comprehensive data assembly of HbS allele frequencies to generate the first evidence-based map of the worldwide distribution of the gene in a Bayesian geostatistical framework. We compare this map with the pre-intervention distribution of malaria endemicity, using a novel geostatistical area-mean comparison. We find geographical support for the malaria hypothesis globally; the relationship is relatively strong in Africa but cannot be resolved in the Americas or in Asia

Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.

Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures

Social network size, loneliness, physical functioning and depressive symptoms among older adults: Examining reciprocal associations in four waves of the Longitudinal Aging Study Amsterdam (LASA)

Previous research indicates that social isolation, loneliness, physical dysfunction and depressive symptoms are interrelated factors, little is known about the potential pathways among them. The aim of the study is to analyse simultaneously reciprocal relationships that could exist between the four factors to clarify potential mediation effects. METHODS Within a large representative sample of older people in the Longitudinal Aging Study Amsterdam (LASA), participants aged 75 and over were followed up over a period of 11 years (four waves). We tested cross-lagged and autoregressive longitudinal associations of social network size, loneliness, physical functioning and depressive symptoms using structural equation modelling (SEM). RESULTS Several statistically significant cross-lagged associations were found: decreasing physical functioning (Coef.=-0.03; p<0.05), as well as social network size (Coef.=-0.02; p<0.05), predicted higher levels of loneliness, which predicted an increase in depressive symptoms (Coef.=0.17; p<0.05) and further reduction of social network (Coef.=-0.20; p<0.05). Decreasing physical functioning also predicted an increase in depressive symptoms (Coef.=-0.08; p<0.05). All autoregressive associations were statistically significant. CONCLUSION Interventions focused on promoting social activities among older adults after negative life events, such as loss of social contacts or declining physical function, may alleviate feelings of loneliness and act as mental health protector

Sensitivity of an Ultrasonic Technique for Axial Stress Determination

In machine assembly it is often required that bolts used to fasten machine parts be installed with specific design preloads. Because it is inconvenient to measure preload directly, preload specifications are usually based on some more easily measured quantity with which the level of preload may be correlated. Most often this quantity is the torque to be applied to the bolt at installation. Studies by Blake and Kurtz [1] and Heyman [2] have shown that when bolts are torqued into place, the fraction of applied torque which translates into useful preload is small and widely variable. This is so because the large majority of applied torque is absorbed in overcoming friction in the bolt’s threads and at the underside of the bolt’s head. Consequently, even though the torque to install different bolts may be identical, small variations in frictional conditions from one installation to the next can result in large variations in preload. The unreliability of torque as an indicator of preload has been the motivating factor behind the development of a number of alternate methods of measurement [2–5]

Untargeted metabolomic analysis investigating links between unprocessed red meat intake and markers of inflammation.

BACKGROUND: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships. OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation. METHODS: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance (1H NMR) metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors, lifestyle behaviors, and body mass index (BMI). RESULTS: In analyses that adjust for BMI, neither processed nor unprocessed forms of red meat were associated with any markers of inflammation (all P > 0.01). However, when adjusting for BMI, unprocessed red meat was inversely associated with spectral features representing the metabolite glutamine (sentinel hit: β = -0.09 ± 0.02, P = 2.0 × 10-5), an amino acid which was also inversely associated with CRP level (β = -0.11 ± 0.01, P = 3.3 × 10-10). CONCLUSIONS: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations, compared with diet metabolite-inflammation associations, warrant further investigation to understand the extent that these arise from the following: 1) a reduction in measurement error with metabolite measures; 2) the extent that which factors other than unprocessed red meat intake contribute to glutamine levels; and 3) the ability of plasma metabolites to capture individual differences in how food intake is metabolized

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans

Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology

SHIFTING THE PARADIGM IN RADIATION SAFETY

The current radiation safety paradigm using the linear no-threshold (LNT) model is based on the premise that even the smallest amount of radiation may cause mutations increasing the risk of cancer. Autopsy studies have shown that the presence of cancer cells is not a decisive factor in the occurrence of clinical cancer. On the other hand, suppression of immune system more than doubles the cancer risk in organ transplant patients, indicating its key role in keeping occult cancers in check. Low dose radiation (LDR) elevates immune response, and so it may reduce rather than increase the risk of cancer. LNT model pays exclusive attention to DNA damage, which is not a decisive factor, and completely ignores immune system response, which is an important factor, and so is not scientifically justifiable. By not recognizing the importance of the immune system in cancer, and not exploring exercise intervention, the current paradigm may have missed an opportunity to reduce cancer deaths among atomic bomb survivors. Increased antioxidants from LDR may reduce aging-related non-cancer diseases since oxidative damage is implicated in these. A paradigm shift is warranted to reduce further casualties, reduce fear of LDR, and enable investigation of potential beneficial applications of LDR