Interleukin-1 Receptor-Associated Kinase-3 Is a Key Inhibitor of Inflammation in Obesity and Metabolic Syndrome

BACKGROUND: Visceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders. OBJECTIVE: We searched a cluster of molecules that support interactions between these stress conditions in monocytes. METHODS: RNA expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells. RESULTS: Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in IRAK3 and a decrease in SOD2, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells in vitro. CONCLUSION: IRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention

The effect of microcredit on women's control over household spending in developing countries: a systematic review

Background: Over the past three decades, microfinance activities have spread across the globe, reaching tens of millions of poor households with tailored financial services. Microfinance can best be described as a field of intervention rather than a particular instrument. Initially, microfinance usually meant microcredit for working capital and very small investments, but increasingly it has been broadened to include savings/deposits, a limited range of micro-insurance and payment services (including micro-leasing) as well as a somewhat broader range of credit products for more substantial investments. In this study we focused on microcredit activities, constituting the bulk of microfinance activities across the globe. Microcredit activities have affected the lives of clients and others in multiple ways. The most frequently reported types of effects of credit at individual, enterprise and household level are the following: income, expenditure smoothing, and poverty alleviation effects; business growth and employment effects; schooling effects; and effects in terms of women's empowerment. Despite the diversity in microcredit schemes, many share two characteristics: they target poor women and often rely on some type of group-based lending. Women's empowerment in relation to microcredit has been studied extensively within the context of this type of microcredit scheme. Most of these studies have been carried out in the context of microcredit group schemes in South Asia. It has been argued that access to microcredit can foster changes in individual attitudes of women (e.g. increased self-reliance), power relations within the household (e.g. control over resources) and social status. An important dimension of empowerment concerns women's control over household spending. The main assumption is that by providing credit to poor women, their direct control over expenditures within the household increases, with subsequent implications for the status of women and the well-being of women and other household members. Women's control over household spending is a frequently recurring aspect analyzed within the context of microcredit interventions, which allows us to study whether microcredit targeted at women affects women's control over household spending decisions and the circumstances in which this occurs. Despite the central and recurrent role across studies of this aspect of women's empowerment in relation to microcredit activities, there has been no previous review on this topic. The growing importance of microcredit has resulted in a vast number of research and evaluation studies, including impact studies. Consequently, the microfinance literature harbors a substantial number of synthesis studies which discuss a set of microcredit interventions and aim to generate overall conclusions on their effects. However, most of these studies face limitations in terms of depth of empirical assessment and the extent to which the identified effects can be attributed to microcredit. Moreover, methodological principles regarding comprehensive searches and principles of selection, coding, extraction and aggregation are often lacking in review studies. Partial exceptions are three recent systematic reviews which all differ in scope from the present one (Stewart et al., 2010; Duvendack et al. 2011; Stewart et al., 2012). The reviews respectively focus on microfinance (credit and savings) in Sub-Sahara Africa, microcredit worldwide, and microfinance worldwide (credit, saving and leasing). Overall, these reviews suggest that the effects of microcredit on women's empowerment are at best mixed. In part this can be explained by the heterogeneity in microcredit interventions, contexts and target groups. However, the existing reviews did not use statistical meta-analysis to synthesise evidence of effects, nor context-mechanism-outcome synthesis to understand the variation in effects. Objectives: The main objective of this study was to provide a systematic review of the evidence on the effects of microcredit on women's control over household spending in developing countries. More specifically, we aimed to answer two related research questions: 1) what does the impact evaluative evidence say about the causal relationship between microcredit and specific dimensions of women's empowerment (women'ss control over household spending); and 2) what are the mechanisms which mediate this relationship. We prioritise depth of analysis over breadth, thus the scope of this review is narrower than previous systematic reviews on microfinance (Stewart et al., 2010; Duvendack et al. 2011; Stewart et al., 2012). We focused on specific aspects of women's empowerment which allowed us to combine statistical meta-analysis and realist (context-mechanism-outcome) synthesis. Criteria for considering studies for this review: We included studies that analyzed the effects of microcredit schemes targeting poor women in low and middle income countries, as defined by the World Bank. Studies that did not include analysis on microcredit and the effect on one or more dimensions (specified in main body of the report) of women's control over household expenditures were excluded. Studies which gave evidence of addressing the attribution problem either through randomised design, quasi-experimental matching, or regression analysis, were included. In practice, women's control over household spending (as a key dimension of empowerment) is influenced by many different factors. By focusing on those studies which explicitly addressed the challenge of separating the effect of microcredit from other influencing factors, we developed what we consider to be the most credible evidence base for drawing conclusions about the effects of microcredit on women's control over household expenditures in different contexts. SEARCH STRATEGY We conducted a comprehensive search covering all relevant academic databases, internet search engines and web sites with published and unpublished research, and also carried out extensive manual searches of books and additional journals not included in electronic data bases (searches were concluded on December 31, 2011). We used back-referencing from recent studies as well as citation-tracking to identify additional relevant studies. Finally, authors of studies which we were unable to retrieve were contacted. In addition, we contacted experts on microcredit and women's empowerment for additional references which we might have missed. Search strategies in databases and journals were adapted for each source. Where possible we used the existing keyword indices of particular databases. In addition, we applied our own list of combinations of keywords covering all relevant terms relating to the independent variable (i.e. credit and its variations) and the dependent variable (i.e. dimensions of women's control over household spending, empowerment). Data collection and analysis: From the different searches we identified an initial number of 310 papers that were selected for full text examination. Eventually, 29 papers were retained for further analysis, corresponding to 25 unique studies. These 25 independent findings were included in the synthesis. However, based on a systematic risk of bias assessment we found that more than half of the included studies had high threats to internal validity. Moreover, only about half of the studies show a clear and coherent link between a theoretical framework on microcredit and women's control over household spending and empirical data analysis. It should be noted that reviewing and synthesizing quantitative results from studies is only one side of the coin. The other side is to understand what makes them work, or what prevents them from working. Consequently, we conducted a qualitative synthesis of the included studies, which focused on identifying the mechanisms which underlie the causal relationship between microcredit and women's control over household spending. RESULTS The results of the meta-analysis indicated that the effect sizes from experimental studies examining effects of microcredit on women's control over household spending are not statistically significantly different from zero. The effects from quasi-experimental studies are statistically insignificant overall, and at best of small magnitude for those studies assessed of being of high risk of bias. We conclude that there is no consistent evidence for an effect of microcredit on women's control over household spending. In the qualitative analysis, using Coleman's (1986, 1990) typology of mechanisms, we identified five different situational mechanisms and eight different action-formation mechanisms. Due to the combination of substantial heterogeneity in contexts (e.g. existing gender relations) and interventions (e.g. microcredit versus microcredit and additional services), and the lack of information in the studies on this heterogeneity, it was not possible to go beyond the identification of mechanisms, in terms of generating empirically tested articulated theories of change which are representative beyond a specific study context. Authors' conclusions: In line with three recent other reviews on microfinance (Stewart et al., 2010; Duvendack et al., 2011; Stewart et al. 2012) we found that the microcredit evidence base is extensive, yet most studies are weak methodologically. From those studies deemed comparable and of minimum acceptable quality, we concluded that overall there is no evidence for an effect of microcredit on women's control over household spending. Women's control over household resources constitutes an important intermediary dimension in processes of women's empowerment. Given the overall lack of evidence for an effect of microcredit on women's control over household resources it is therefore very unlikely that, overall, microcredit has a meaningful and substantial impact on empowerment processes in a broader sense. While impacts on empowerment may appear to have occurred in particular studies, the high risk of bias of studies providing positive assessments suggests that such findings are of limited validity. Our conclusions on the effects of microcredit on empowerment are also in line with previous systematic reviews by Duvendack et al. (2011) and Stewart (et al. 2010) who report to a limited extent on empowerment effects. Consequently, there appears to be a gap between the often optimistic societal belief in the capacity of microcredit to ameliorate the position of women in decision-making processes within the household on the one hand, and the empirical evidence base on the other hand. However, our review markedly differs from previous reviews in two regards. First, we specifically focused on microcredit and women's empowerment captured through women's control over household expenditures. Second, as a result of this narrower focus, we were able to conduct statistical meta-analysis and extract behavioral mechanisms which can help to explain why and how microcredit can make a difference. The advantage of our approach was that the identified mechanisms all stem from studies which show evidence of addressing the attribution problem. Consequently, we can be quite confident of the insights that they provided on the effects of microcredit on women's control over household spending for particular populations of microcredit female clients and their families. Those studies that showed evidence of addressing the attribution problem were relatively weak on underlying theory. Moreover, they often lacked essential information such as the nature of the intervention and how it related to empowerment (e.g. how solidarity groups affect empowerment processes) or the slowly evolving gender relations in different contexts (e.g. the evolution of societal norms and the relationship with power relations in the household). A next logical step would be to undertake a systematic review of qualitative studies which often provide rich and context-specific information on microcredit and women's decision-making power in the household. Such a review should ideally build on the mechanisms identified in the present review and would bring us closer to uncovering credible theories of microcredit and the circumstances in which it may change women's decision-making power

Association between exposure to environmental tobacco smoke and biomarkers of oxidative stress among patients hospitalised with acute myocardial infarction

Objective To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction.<p></p> Design An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction.<p></p> Setting Nine acute hospitals in Scotland.<p></p> Participants Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine ≥3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine ≤0.1 ng/mL).<p></p> Intervention None.<p></p> Main outcome measures Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders.<p></p> Results After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI −8.94, 13.21, p = 0.703).<p></p> Conclusions Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction.<p></p&gt

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

First measurement of the Gerasimov-Drell-Hearn integral for Hydrogen from 200 to 800 MeV

A direct measurement of the helicity dependence of the total photoabsorption cross section on the proton was carried out at MAMI (Mainz) in the energy range 200 < E_gamma < 800 MeV. The experiment used a 4$\pi$ detection system, a circularly polarized tagged photon beam and a frozen spin target. The contributions to the Gerasimov-Drell-Hearn sum rule and to the forward spin polarizability $\gamma_0$ determined from the data are 226 \pm 5 (stat)\pm 12(sys) \mu b and -187 \pm 8 (stat)\pm 10(sys)10^{-6} fm^4, respectively, for 200 < E_\gamma < 800 MeV.Comment: 6 pages, 3 figures, 3 table

The helicity amplitudes A1/2_{1/2} and A3/2_{3/2} for the D13(1520)_{13}(1520) resonance obtained from the γ⃗p⃗→pπ0\vec{\gamma} \vec{p} \to p \pi^0 reaction}

The helicity dependence of the $\vec{\gamma} \vec{p} \to p \pi^0$ reaction has been measured for the first time in the photon energy range from 550 to 790 MeV. The experiment, performed at the Mainz microtron MAMI, used a 4$\pi$-detector system, a circularly polarized, tagged photon beam, and a longitudinally polarized frozen-spin target. These data are predominantly sensitive to the $D_{13}(1520)$ resonance and are used to determine its parameters.Comment: 5 pages, 4 figure

Ligation of Macrophage Fcγ Receptors Recapitulates the Gene Expression Pattern of Vulnerable Human Carotid Plaques

Stroke is a leading cause of death in the United States. As ∼60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (FcγR, higher in vulnerable) and FcγR signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C-reactive protein, or TNF-α, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of FcγR recapitulates the pattern of gene expression in vulnerable plaques suggests that the FcγR → macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated

Traffic Air Pollution and Oxidized LDL

BACKGROUND: Epidemiologic studies indirectly suggest that air pollution accelerates atherosclerosis. We hypothesized that individual exposure to particulate matter (PM) derived from fossil fuel would correlate with plasma concentrations of oxidized low-density lipoprotein (LDL), taken as a marker of atherosclerosis. We tested this hypothesis in patients with diabetes, who are at high risk for atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study of non-smoking adult outpatients with diabetes we assessed individual chronic exposure to PM by measuring the area occupied by carbon in airway macrophages, collected by sputum induction and by determining the distance from the patient's residence to a major road, through geocoding. These exposure indices were regressed against plasma concentrations of oxidized LDL, von Willebrand factor and plasminogen activator inhibitor 1 (PAI-1). We could assess the carbon load of airway macrophages in 79 subjects (58 percent). Each doubling in the distance of residence from major roads was associated with a 0.027 µm(2) decrease (95% confidence interval (CI): -0.048 to -0.0051) in the carbon load of airway macrophages. Independently from other covariates, we found that each increase of 0.25 µm(2) [interquartile range (IQR)] in carbon load was associated with an increase of 7.3 U/L (95% CI: 1.3 to 13.3) in plasma oxidized LDL. Each doubling in distance of residence from major roads was associated with a decrease of -2.9 U/L (95% CI: -5.2 to -0.72) in oxidized LDL. Neither the carbon load of macrophages nor the distance from residence to major roads, were associated with plasma von Willebrand factor or PAI-1. CONCLUSIONS: The observed positive association, in a susceptible group of the general population, between plasma oxidized LDL levels and either the carbon load of airway macrophages or the proximity of the subject's residence to busy roads suggests a proatherogenic effect of traffic air pollution

Potential Involvement of LOX-1 in Functional Consequences of Endothelial Senescence

Numerous studies have described the process of senescence associated with accumulation of oxidative damage, mutations and decline in proliferative potential. Although the changes observed in senescent cells are likely to result in significant phenotypic alterations, the studies on consequences of endothelial senescence, especially in relation to aging-associated diseases, are scarce. We have analyzed effects of senescence on the functions of endothelial cells relevant to the development of atherosclerosis including angiogenesis, adhesion, apoptosis and inflammation. In the course of progressing through the passages, human umbilical vein endothelial cells (HUVECs) displayed significant increase in size (+36% passage 12 vs. passage 4 , p<0.001) and reduction in both basal and VEGF-stimulated tube formation. The analysis of a scavenger receptor LOX-1, a key molecule implicated in atherogenesis, revealed a significant decline of its message (mRNA) and protein content in senescent endothelial cells (−33%) and in aortas of 50 wk (vs. 5 wk) old mice (all p<0.01). These effects were accompanied by a marked reduction of the basal expression of VCAM-1 and ICAM-1. Compared to early cultures, late passage HUVECs also exhibited nuclear translocation of NF-κB (p65) and reciprocal shifts in BAX and BCL2 protein content resulting in almost 2-fold increase in BAX/BCL2 ratio and 3-fold increase in apoptotic response to TNFα exposure (p<0.04). These changes in senescent endothelial cells are suggestive of aberrant responses to physiological stimuli resulting in a less permissive environment for tissue remodeling and progression of diseases requiring angiogenesis and cell adhesion in elderly, possibly, mediated by LOX-1

Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC