Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A

Background and purpose: Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C‐type natriuretic peptide (CNP) are raised in animal models and humans with endotoxic shock and correlate with the associated cardiovascular dysfunction. Since both NO and natriuretic peptides play important roles in cardiovascular homeostasis via activation of guanylate cyclase‐linked receptors, we used mice lacking natriuretic peptide receptor (NPR)‐A (NPR1) to establish if natriuretic peptides contribute to the cardiovascular dysfunction present in endotoxic shock. Experimental approach: Wild‐type (WT) and NPR‐A knockout (KO) mice were exposed to lipopolysaccharide (LPS) and vascular dysfunction (in vitro and in vivo), production of pro‐inflammatory cytokines, and iNOS expression and activity were evaluated. Key results: LPS‐treated WT animals exhibited a marked fall in mean arterial blood pressure (MABP) whereas NPR‐A KO mice maintained MABP throughout. LPS administration caused a greater suppression of vascular responses to the thromboxane‐mimetic U46619, ANP, acetylcholine and the NO‐donor spermine‐NONOate in WT versus NPR‐A KO mice. This differential effect on vascular function was paralleled by reduced pro‐inflammatory cytokine production, iNOS expression and activity (plasma [NOx] and cyclic GMP). Conclusions and implications: These observations suggest that NPR‐A activation by natriuretic peptides facilitates iNOS expression and contributes to the vascular dysfunction characteristic of endotoxic shock. Pharmacological interventions that target the natriuretic peptide system may represent a novel approach to treat this life‐threatening condition.This work was supported by the Wellcome Trust

Разработка магнитной оправки для алмазного выглаживания

Объектом исследования является магнитная оправка. Актуальность разработки оправки для алмазного выглаживания заключается в том, что в процессе выглаживания требуется стабильное усилие выглаживания независимо от неточности геометрической формы детали и погрешностей установки. Целью данной выпускной квалификационной работы является разработка оправки для алмазного выглаживания, которая не имеет пару трения и позволяет проводить выглаживание с маленьким колебанием усилия выглаживания. Рассматриваемые вопросы: как проводить алмазное выглаживание без силы трения, как регулировать усилия выглаживания для магнитной оправки и и т. д.The object of study is a magnetic mandrel. The relevance of the development of the mandrel for diamond smoothing is that the smoothing process requires a stable smoothing force, regardless of the inaccuracy of the geometric shape of the part and the installation errors. The purpose of this final qualifying work is to develop a mandrel for diamond smoothing, which does not have a friction pair and allows smoothing with a small fluctuation in the effort of smoothing. Questions to be addressed: how to carry out diamond smoothing without friction, how to adjust the smoothing efforts for a magnetic mandrel and etc

Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T-and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg -1daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2′ deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels. © 2012 The Japanese Society of Hypertension All rights reserved

RUPTURES ET PLAIES DIAPHRAGMATIQUES CHEZ L’ENFANT : A PROPOS DE 6 CAS.

Les ruptures et les plaies diaphragmatiques chez l’enfant sont rares, et s’intègrent, le plus souvent, dans le cadre d’un polytraumatisme dont elle est un critère de gravité. Nous rapportons une étude rétrospective s’étalant sur 5 ans allant de 2007 à 2012, portant sur 6 cas de traumatismes diaphragmatiques pris en charge au sein du service des urgences chirurgicales pédiatriques de Rabat, et dont le but est d’analyser les différentes particularités épidémiologique, clinique, paraclinique et thérapeutique de ces traumatismes ainsi que la place de la laparoscopie dans leur prise en charge diagnostique et thérapeutique. La rupture était à gauche chez quatre patients tandis qu’elle était à droite chez deux patients. Les signes cliniques ne sont pas spécifiques d’une lésion diaphragmatique ; ils sont dominés par l’état de choc. La radiographie thoracique est le premier examen à demander, elle a permis de suggérer le diagnostic dans 50% des patients en montrant une ascension de la coupole diaphragmatique droite avec une opacité de l’hémithorax droit. Quant à l’échographie qui est un examen opérateur dépendant, elle était non concluante sauf chez un seul patient où elle a montré un foie en intrathoracique, et elle était toujours complétée par une TDM thoraco-abdominale qui reste le moyen le plus sensible pour détecter ces traumatismes quoiqu’elle n’a posé le diagnostic que dans 50% des patients. Tous nos patients avaient des lésions associées ,5 patients ont été abordés par une laparotomie tandis que le sixième a été abordé par une thoracotomie. Le geste est simple, et consiste en une réintégration des organes herniés et la suture de la plaie diaphragmatique. Le taux de mortalité dans notre série est nul

Increased sensitivity to endothelial nitric oxide (NO) contributes to arterial normotension in mice with vascular smooth muscle-selective deletion of the atrial natriuretic peptide (ANP) receptor

Atrial natriuretic peptide (ANP) plays a key regulatory role in arterial blood pressure homeostasis. We recently generated mice with selective deletion of the ANP receptor, guanylyl cyclase-A (GC-A), in vascular smooth muscle (SMC GC-A knockout (KO) mice) and reported that resting arterial blood pressure was completely normal in spite of clear abolition of the direct vasodilating effects of ANP (Holtwick, R., Gotthardt, M., Skryabin, B., Steinmetz, M., Potthast, R., Zetsche, B., Hammer, R. E., Herz, J., and Kuhn M. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7142–7147). The purpose of this study was to clarify mechanisms compensating for the missing vasodilator responses to ANP. In particular, we analyzed the effect of the endothelial, cGMP-mediated vasodilators C-type natriuretic peptide and nitric oxide (NO). In isolated arteries from SMC GC-A KO mice, the vasorelaxing sensitivity to sodium nitroprusside and the endothelium-dependent vasodilator, acetylcholine, was significantly greater than in control mice. There was no difference in responses to C-type natriuretic peptide or to the activator of cGMP-dependent protein kinase I, 8-para-chlorophenylthio-cGMP. The aortic expression of soluble GC (sGC), but not of endothelial NO synthase or cGMP-dependent protein kinase I, was significantly increased in SMC GC-A KO mice. Chronic oral treatment with the NO synthase inhibitor Nw-nitro-l-arginine methyl ester increased arterial blood pressure, the effect being significantly enhanced in SMC GC-A KO mice. We conclude that SMC GC-A KO mice exhibit a higher vasodilating sensitivity to NO. This can be attributed to an enhanced expression of sGC, whereas the expression and/or activity levels of downstream cGMP-effector pathways are not involved. Increased vasodilating responsiveness to endothelial NO contributes to compensate for the missing vasodilating effect of ANP in SMC GC-A KO mice

The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II

Summary Urotensin-II (U-II) has been considered as one of the most potent vasoactive peptides, although its physiological and pathophysiological role is still not finally resolved. Recent evidence suggests that it promotes angiogenic responses in endothelial cells, although the underlying signalling mechanisms are unclear. Reactive oxygen species derived from NADPH oxidases are major signalling molecules in the vasculature. Because NOX2 is functional in endothelial cells, we investigated the role of the NOX2-containing NADPH oxidase in U-II-induced angiogenesis and elucidated a possible contribution of hypoxia-inducible factor-1 (HIF-1), the master regulator of hypoxic angiogenesis, in the response to U-II. We found that U-II increases angiogenesis in vitro and in vivo, and these responses were prevented by antioxidants, NOX2 knockdown and in Nox2 -/-mice. In addition, U-II-induced angiogenesis was dependent on HIF-1. Interestingly, U-II increased NOX2 transcription involving HIF-1, and chromatin immunoprecipitation confirmed NOX2 as a target gene of HIF-1. In support, NOX2 levels were greatly diminished in U-II-stimulated isolated vessels derived from mice deficient in endothelial HIF-1. Conversely, reactive oxygen species derived from NOX2 were required for U-II activation of HIF and upregulation of HIF-1. In line with this, U-II-induced upregulation of HIF-1 was absent in Nox2 -/-vessels. Collectively, these findings identified HIF-1 and NOX2 as partners acting in concert to promote angiogenesis in response to U-II. Because U-II has been found to be elevated in cardiovascular disorders and in tumour tissues, this feed-forward mechanism could be an interesting anti-angiogenic therapeutic option in these disorders

Syndrome de blépharophimosis: une forme particulière du ptosis congénital

Le syndrome de blépharophimosis est une malformation palpébrale  congénitale caractérisée par l'association d'un ptosis majeur bilatéral à  d'autres anomalies palpébrales. Il constitue une forme particulière du ptosis congénital qui doit être connue par tout ophtalmologue afin d'optimiser la prise en charge des patients présentant cette affection

Understanding vulnerability and resilience of urban food initiatives in Morocco

In this chapter, we use (an adapted version of) the vulnerability framework to study four urban agriculture initiatives in Morocco. Using a mixed-methods approach, we aim to understand what makes these cases vulnerable, but also what strengthens their resilience. Zooming in on a number of specific perturbations, or troubles, we show that while all cases struggle with certain perturbations, some cases are better able to turn these into more hopeful situations. In fact, dealing with perturbations can be a source of change, as finding solutions for these perturbations means that different directions are taken, resources are used differently, or strategies are adjusted. In some cases, this creates hope: in other cases, however, it may lead to new perturbations or increased vulnerability towards others. Taken together, the four cases represent a kaleidoscopic picture of hopes and troubles that is highly case specific and that relates to the resources already present. Our work therefore corroborates the main premise of this book, that it is essential to go beyond either an “all good” narrative or an essentialist critical stance and to rather look at the hybrid complexity and fluidity of initiatives