Increased circulating IgG levels, myocardial immune cells and IgG deposits support a role for an immune response in pre- and end-stage heart failure

The chronic inflammatory response plays an important role in adverse cardiac remodelling and the development of heart failure (HF). There is also evidence that in the pathogenesis of several cardiovascular diseases, chronic inflammation is accompanied by antibody and complement deposits in the heart, suggestive of a true autoimmune response. However, the role of antibody-mediated immune responses in HF progression is less clear. We assessed whether immune cell infiltration and immunoglobulin levels are associated with HF type and disease stage, taking sex differences into account. We found IgG deposits and increased infiltration of immune cells in the affected myocardium of patients with end-stage HF with reduced ejection fraction (HFrEF, n = 20). Circulating levels of IgG1 and IgG3 were elevated in these patients. Furthermore, the percentage of transitional/regulatory B cells was decreased (from 6.9% to 2.4%) compared with healthy controls (n = 5). Similarly, increased levels of circulating IgG1 and IgG3 were observed in men with left ventricular diastolic dysfunction (LVDD, n = 5), possibly an early stage of HF with preserved EF (HFpEF). In conclusion, IgG deposits and infiltrates of immune cells are present in end-stage HFrEF. In addition, both LVDD patients and end-stage HFrEF patients show elevated levels of circulating IgG1 and IgG3, suggesting an antibody-mediated immune response upon cardiac remodelling, which in the early phase of remodelling appear to differ between men and women. These immunoglobulin subclasses might be used as marker for pre-stage HF and its progression. Future identification of auto-antigens might open possibilities for new therapeutic interventions

Integrating place-specific livelihood and equity outcomes into global assessments of bioenergy deployment

__Abstract__ Integrated assessment models suggest that the large-scale deployment of bioenergy could contribute to ambitious climate change mitigation efforts. However, such a shift would intensify the global competition for land, with possible consequences for 1.5 billion smallholder livelihoods that these models do not consider. Maintaining and enhancing robust livelihoods upon bioenergy deployment is an equally important sustainability goal that warrants greater attention. The social implications of biofuel production are complex, varied and place-specific, difficult to model, operationalize and quantify. However, a rapidly developing body of social science literature is advancing the understanding of these interactions. In this letter we link human geography research on the interaction between biofuel crops and livelihoods in developing countries to integrated assessments on biofuels. We review case-study research focused on first-generation biofuel crops to demonstrate that food, income, land and other assets such as health are key livelihood dimensions that can be impacted by such crops and we highlight how place-specific and global dynamics influence both aggregate and distributional outcomes across these livelihood dimensions. We argue that place-specific production models and land tenure regimes mediate livelihood outcomes, which are also in turn affected by global and regional markets and their resulting equilibrium dynamics. The place-specific perspective suggests that distributional consequences are a crucial complement to aggregate outcomes; this has not been given enough weight in comprehensive assessments to date. By narrowing the gap between place-specific case studies and global models, our discussion offers a route towards integrating livelihood and equity considerations into scenarios of future bioenergy deployment, thus contributing to a key challenge in sustainability sciences

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

Resequencing PNMT in European hypertensive and normotensive individuals: no common susceptibilily variants for hypertension and purifying selection on intron 1

<p>Abstract</p> <p>Background</p> <p>Human linkage and animal QTL studies have indicated the contribution of genes on Chr17 into blood pressure regulation. One candidate gene is <it>PNMT</it>, coding for phenylethanolamine-N-methyltransferase, catalyzing the synthesis of epinephrine from norepinephrine.</p> <p>Methods</p> <p>Fine-scale variation of <it>PNMT </it>was screened by resequencing hypertensive (n = 50) and normotensive (n = 50) individuals from two European populations (Estonians and Czechs). The resulting polymorphism data were analyzed by statistical genetics methods using Genepop 3.4, PHASE 2.1 and DnaSP 4.0 software programs. <it>In silico </it>prediction of transcription factor binding sites for intron 1 was performed with MatInspector 2.2 software.</p> <p>Results</p> <p><it>PNMT </it>was characterized by minimum variation and excess of rare SNPs in both normo- and hypertensive individuals. None of the SNPs showed significant differences in allelic frequencies among population samples, as well as between screened hypertensives and normotensives. In the joint case-control analysis of the Estonian and the Czech samples, hypertension patients had a significant excess of heterozygotes for two promoter region polymorphisms (SNP-184; SNP-390). The identified variation pattern of <it>PNMT </it>reflects the effect of purifying selection consistent with an important role of PNMT-synthesized epinephrine in the regulation of cardiovascular and metabolic functions, and as a CNS neurotransmitter. A striking feature is the lack of intronic variation. <it>In silico </it>analysis of <it>PNMT </it>intron 1 confirmed the presence of a human-specific putative Glucocorticoid Responsive Element (GRE), inserted by <it>Alu</it>-mediated transfer. Further analysis of intron 1 supported the possible existence of a full Glucocorticoid Responsive Unit (GRU) predicted to consist of multiple gene regulatory elements known to cooperate with GRE in driving transcription. The role of these elements in regulating <it>PNMT </it>expression patterns and thus determining the dynamics of the synthesis of epinephrine is still to be studied.</p> <p>Conclusion</p> <p>We suggest that the differences in PNMT expression between normotensives and hypertensives are not determined by the polymorphisms in this gene, but rather by the interplay of gene expression regulators, which may vary among individuals. Understanding the determinants of PNMT expression may assist in developing PNMT inhibitors as potential novel therapeutics.</p

Human Embryonic and Rat Adult Stem Cells with Primitive Endoderm-Like Phenotype Can Be Fated to Definitive Endoderm, and Finally Hepatocyte-Like Cells

Stem cell-derived hepatocytes may be an alternative cell source to treat liver diseases or to be used for pharmacological purposes. We developed a protocol that mimics mammalian liver development, to differentiate cells with pluripotent characteristics to hepatocyte-like cells. The protocol supports the stepwise differentiation of human embryonic stem cells (ESC) to cells with characteristics of primitive streak (PS)/mesendoderm (ME)/definitive endoderm (DE), hepatoblasts, and finally cells with phenotypic and functional characteristics of hepatocytes. Remarkably, the same protocol can also differentiate rat multipotent adult progenitor cells (rMAPCs) to hepatocyte-like cells, even though rMAPC are isolated clonally from cultured rat bone marrow (BM) and have characteristics of primitive endoderm cells. A fraction of rMAPCs can be fated to cells expressing genes consistent with a PS/ME/DE phenotype, preceding the acquisition of phenotypic and functional characteristics of hepatocytes. Although the hepatocyte-like progeny derived from both cell types is mixed, between 10–20% of cells are developmentally consistent with late fetal hepatocytes that have attained synthetic, storage and detoxifying functions near those of adult hepatocytes. This differentiation protocol will be useful for generating hepatocyte-like cells from rodent and human stem cells, and to gain insight into the early stages of liver development

A new pathway of glucocorticoid action for asthma treatment through the regulation of PTEN expression

<p>Abstract</p> <p>Background</p> <p>"Phosphatase and tensin homolog deleted on chromosome 10" (PTEN) is mostly considered to be a cancer-related gene, and has been suggested to be a new pathway of pathogenesis of asthma. The purpose of this study was to investigate the effects of the glucocorticoid, dexamethasone, on PTEN regulation.</p> <p>Methods</p> <p>OVA-challenged mice were used as an asthma model to investigate the effect of dexamethasone on PTEN regulation. Immunohistochemistry was used to detect expression levels of PTEN protein in lung tissues. The human A549 cell line was used to explore the possible mechanism of action of dexamethasone on human PTEN regulation <it>in vitro</it>. A luciferase reporter construct under the control of PTEN promoter was used to confirm transcriptional regulation in response to dexamethasone.</p> <p>Results</p> <p>PTEN protein was found to be expressed at low levels in lung tissues in asthmatic mice; but the expression was restored after treatment with dexamethasone. In A549 cells, human PTEN was up-regulated by dexamethasone treatment. The promoter-reporter construct confirmed that dexamethasone could regulate human PTEN transcription. Treatment with the histone deacetylase inhibitor, TSA, could increase PTEN expression in A549 cells, while inhibition of histone acetylase (HAT) by anacardic acid attenuated dexamethasone-induced PTEN expression.</p> <p>Conclusions</p> <p>Based on the data a new mechanism is proposed where glucocorticoids treat asthma partly through up-regulation of PTEN expression. The <it>in vitro </it>studies also suggest that the PTEN pathway may be involved in human asthma.</p

Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

T cells modulate neointima formation after arterial injury but the specific T cell population that is activated in response to arterial injury remains unknown. The objective of the study was to identify the T cell populations that are activated and modulate neointimal thickening after arterial injury in mice. Arterial injury in wild type C57Bl6 mice resulted in T cell activation characterized by increased CD4+CD44hi and CD8+CD44hi T cells in the lymph nodes and spleens. Splenic CD8+CD25+ T cells and CD8+CD28+ T cells, but not CD4+CD25+ and CD4+CD28+ T cells, were also significantly increased. Adoptive cell transfer of CD4+ or CD8+ T cells from donor CD8−/− or CD4−/− mice, respectively, to immune-deficient Rag-1−/− mice was performed to determine the T cell subtype that inhibits neointima formation after arterial injury. Rag-1−/− mice that received CD8+ T cells had significantly reduced neointima formation compared with Rag-1−/− mice without cell transfer. CD4+ T cell transfer did not reduce neointima formation. CD8+ T cells from CD4−/− mice had cytotoxic activity against syngeneic smooth muscle cells in vitro. The study shows that although both CD8+ T cells and CD4+ T cells are activated in response to arterial injury, adoptive cell transfer identifies CD8+ T cells as the specific and selective cell type involved in inhibiting neointima formation

Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions

Dysregulated innate and adaptive immune responses discriminate disease severity in COVID-19

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity