Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH

Can scenario-planning support community-based natural resource management? Experiences from three countries in latin america

Community Based Natural Resource Management (CBNRM) is a concept critical to managing socio-ecological systems, but whose implementation needs strengthening. Scenario-planning is one approach that may offer benefits relevant to CBNRM, but whose potential is not yet well understood. We therefore designed, trialled and evaluated a scenario-planning method intended to support CBNRM at three cases, located in Colombia, Mexico and Argentina. Implementing scenario-planning was judged as worthwhile in all three cases, although aspects of it could be challenging to facilitate. The benefits generated were relevant to strengthening CBNRM: encouraging the participation of local people and using their knowledge; enhanced consideration and adaption of future change; and supporting the development of systems thinking. Tracing exactly when and how these benefits arise is challenging, but two elements of the method seemed particularly useful. Firstly, using a systematic approach to discuss how drivers of change may affect local socio-ecological systems helped to foster systems thinking and identify connections between issues. Secondly, explicitly focusing on how to use and respond to scenarios helped identify specific practical activities ('response options') that would support CBNRM despite the pressures of future change. Discussions about response options also highlighted the need for support by other actors (e.g. policy groups): this raises the question of when and how other actors and other sources of knowledge should be involved in scenario-planning, so as to encourage their buy-in to actions identified by the process. We suggest other CBNRM initiatives may benefit from adapting and applying scenario-planning. However, these initiatives should be carefully monitored since further research is required to understand how and when scenario-planning methods may produce benefits, and their strengths and weaknesses versus other methods

Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro

Huangqi Injection (a Traditional Chinese Patent Medicine) for Chronic Heart Failure: A Systematic Review

Chronic heart failure (CHF) is a global public health problem. Therefore, novel and effective drugs that show few side-effects are needed. Early literature studies indicated that Huangqi injection is one of the most commonly used traditional Chinese patent medicines for CHF in China. As a large number of clinical studies has been carried out and published, it is essential to evaluate the effectiveness and safety of Huangqi injection. Therefore, we carried out this systematic review under the support of the framework of the Joint Sino-Italian Laboratory (JoSIL).To evaluate the efficacy and safety of Huangqi injection for CHF according to the available scientific knowledge.An extensive search including PubMed, EMBASE, CBM, the Cochrane Library and Chinese literature databases was performed up to July 2008. Clinical trials regarding Huangqi injection for the treatment of CHF were searched for, irrespective of languages. The quality of each trial was assessed according to the Cochrane Reviewers' Handbook 5.0, and RevMan 5.0 provided by the Cochrane Collaboration and STATA 9.2 were used for data analysis.After selection of 1,205 articles, 62 RCTs and quasi-RCTs conducted in China and published in Chinese journals were included in the review. The methodological quality of the trials was low. In most trials inclusion and exclusion criteria were not specified. Furthermore, only one study evaluated the outcomes for drug efficacy after an adequate period of time. For these reasons and because of the different baseline characteristics we did not conduct a meta-analysis.Although available studies are not adequate to draw a conclusion on the efficacy and safety of Huangqi injection (a traditional Chinese patent medicine), we hope that our work could provide useful experience on further studies on Huangqi injections. The overall level of TCM clinical research needs to be improved so that the efficacy of TCM can be evaluated by the international community and possibly some TCM can enter into the international market

Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells

Background-Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells. Methods and Results-O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the rnitogenic branch, ie. ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced CNOS activity in vivo was reduced by hyperglycemia and hexosamine activation. which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9: these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics. Conclusions-Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity