Critical role and therapeutic control of the lectin pathway of complement activation in an abortion-prone mouse mating

The abortion-prone mating combination CBA/J 7 DBA/2 has been recognized as a model of preeclampsia, and complement activation has been implicated in the high rate of pregnancy loss observed in CBA/J mice. We have analyzed the implantation sites collected from DBA/2-mated CBA/J mice for the deposition of the complement recognition molecules using CBA/J mated with BALB/c mice as a control group. MBL-A was observed in the implantation sites of CBA/J 7 DBA/2 combination in the absence of MBL-C and was undetectable in BALB/c-mated CBA/J mice. Conversely, C1q was present in both mating combinations. Searching for other complement components localized at the implantation sites of CBA/J 7 DBA/2, we found C4 and C3, but we failed to reveal C1r. These data suggest that complement is activated through the lectin pathway and proceeds to completion of the activation sequence as revealed by C9 deposition. MBL-A was detected as early as 3.5 d of pregnancy, and MBL-A deficiency prevented pregnancy loss in the abortion-prone mating combination. The contribution of the terminal complex to miscarriage was supported by the finding that pregnancy failure was largely inhibited by the administration of neutralizing Ab to C5. Treatment of DBA/2-mated CBA/J mice with Polyman2 that binds to MBL-A with high affinity proved to be highly effective in controlling the activation of the lectin pathway and in preventing fetal loss

Pulmonary hypertension in chronic obstructive pulmonary disease

Pulmonary hypertension (PH) is a common complication of advanced chronic obstructive pulmonary disease (COPD) and is defined by a mean pulmonary artery pressure (PAP) ≥ 25 mm Hg at rest in the supine position. Owing to its frequency, COPD is a common cause of PH; in fact, it is the second most frequent cause of PH, just after left heart diseases. PH is due to the elevation of pulmonary vascular resistance, which is caused by functional and morphological factors, chronic alveolar hypoxia being the most important. In COPD PH is generally mild to moderate, PAP usually ranging between 25 and 35 mm Hg in a stable state of the disease. A small proportion of COPD patients may present a severe or “disproportionate” PH with a resting PAP > 35–40 mm Hg. The prognosis is particularly poor in these patients. In COPD PH worsens during exercise, sleep and severe exacerbations of the disease, and these acute increases in afterload may favour the development of right heart failure. The diagnosis of PH relies on Doppler echocardiography, and right heart catheterization is needed in a minority of patients. Treatment of PH in COPD relies on long-term oxygen therapy (≥ 16h/day) which generally stabilizes or at least attenuates the progression of PH. Vasodilator drugs, which are commonly used in idiopathic pulmonary arterial hypertension, have rarely been used in COPD, and we lack studies in this field. Patients with severe PH should be referred to a specialist PH centre where the possibility of inclusion in a controlled clinical trial should be considered.Pulmonary hypertension (PH) is a common complication of advanced chronic obstructive pulmonary disease (COPD) and is defined by a mean pulmonary artery pressure (PAP) ≥ 25 mm Hg at rest in the supine position. Owing to its frequency, COPD is a common cause of PH; in fact, it is the second most frequent cause of PH, just after left heart diseases. PH is due to the elevation of pulmonary vascular resistance, which is caused by functional and morphological factors, chronic alveolar hypoxia being the most important. In COPD PH is generally mild to moderate, PAP usually ranging between 25 and 35 mm Hg in a stable state of the disease. A small proportion of COPD patients may present a severe or “disproportionate” PH with a resting PAP > 35–40 mm Hg. The prognosis is particularly poor in these patients. In COPD PH worsens during exercise, sleep and severe exacerbations of the disease, and these acute increases in afterload may favour the development of right heart failure. The diagnosis of PH relies on Doppler echocardiography, and right heart catheterization is needed in a minority of patients. Treatment of PH in COPD relies on long-term oxygen therapy (≥ 16h/day) which generally stabilizes or at least attenuates the progression of PH. Vasodilator drugs, which are commonly used in idiopathic pulmonary arterial hypertension, have rarely been used in COPD, and we lack studies in this field. Patients with severe PH should be referred to a specialist PH centre where the possibility of inclusion in a controlled clinical trial should be considered

Free surface flows emerging from beneath a semi-infinite plate with constant vorticity

The free surface flow past a semi-infinite horizontal plate in a finite-depth fluid is considered. It is assumed that the fluid is incompressible and inviscid and that the flow approaches a uniform shear flow downstream. Exact relations are derived using conservation of mass and momentum for the case where the downstream free surface is flat. The complete nonlinear problem is solved numerically using a boundary integral method and these waveless solutions are shown to exist only when the height of the plate above the bottom is greater than the height of the uniform shear flow. Interesting results are found for various values of the constant vorticity. Solutions with downstream surface waves are also considered, and nonlinear results of this type are compared with linear results found previously. These solutions can be used to model the flow near the stern of a (two-dimensional) ship

Conception de nouveaux systèmes de formulation d'actifs dépigmentants, en vue de leur utilisation par voie cutanée

L'encapsulation de molécules actives est au centre de la boîte à outils du formulateur du troisième millénaire. Le recours à cette technique est de plus en plus employée car cette dernière présente de nombreux avantages ; libération contrôlée de molécules actives de leur environnement, diminution de la toxicité des actifs ou encore véhiculer le principe actif jusqu'à sa cible. La peau qui constitue une barrière physiologique a pour fonction d'assurer une protection biologique et physiologique en empêchant la pénétration d'agents pathogènes et de xénobiotiques. L'industrie ne développant pas de nouvelles molécules actives spécialement destinée à la voie topique, l'enjeu majeur de ce mode d'administration est de trouver des techniques pour parer aux inconvénients de cette voie d'administration. Ce travail réalisé en collaboration avec les laboratoires Pierre Fabre consiste en la mise au point de nouveaux systèmes d'actifs dépigmentants, en vue de leur utilisation par voie topique. Pour ce faire nous avons voulu exploité les nombreuses propriétés du chitosan, polysaccharide biocompatible, biodégradable, afin d'inscrire ce travail dans une démarche de développement durable. Il s'agit alors, dans ce travail, de mettre au point de systèmes associant actifs dépigmentants et promoteur de pénétration cutanée, encapsulés par un sel de chitosan, afin de former des complexes aux propriétés dépigmentantes. Les complexes formés, pourront grâce au promoteur de pénétration faciliter le passage de la molécule active à travers les différentes couches de l'épiderme, afin de favoriser l'acheminement de l'actif jusqu'à son site d'action, c'est-à-dire, le mélanocyte. Ces systèmes originaux sont alors mis à profit pour l'élaboration de nouvelles formulations bioactives qui pourront être utilisés dans le cadre de thérapies des hyperpigmentations.The encapsulation of active molecules is central to the toolbox of the formulator of the third millennium. The use of this technique is increasingly used because it has many advantages; controlled release of active molecules in their environment, decrease the toxicity of assets or carry the active ingredient to the target. The skin which is a physiological barrier function is to protect biological and physiological preventing the penetration of pathogens and xenobiotics. The industry does not develop new active molecules specifically designed to topically; the major challenge of this mode of administration is to find techniques to counter the disadvantages of this route of administration. This work done in collaboration with Pierre Fabre Laboratories consists in developing new systems depigmenting agents, to use topically. To do this we wanted to operate numerous properties of chitosan, polysaccharide biocompatible, biodegradable, to place this work in a sustainable development approach. It is then, in this work, to develop systems combining active depigmenting skin penetration enhancer, salt encapsulated chitosan to form complexes with depigmenting properties. Complexes formed, may through penetration enhancer facilitate the passage of the active molecule through the different layers of the epidermis, to facilitate the delivery of the asset to its site of action, ie ie, the melanocyte. These original systems are then used to develop new bioactive formulations that can be used in therapy hyperpigmentation

Magnetic resonance imaging in pulmonary hypertension: an overview of current applications and future perspectives.

Pulmonary hypertension is an heterogeneous group of diseases characterised by increased pulmonary arterial pressures which impact on the upstream right ventricle. Pulmonary hypertension can be challenging to diagnose, classify and monitor when specific therapies are applicable. Cardiac magnetic resonance (CMR) imaging has greatly evolved in the last decades and is a promising tool to non-invasively follow pulmonary hypertension patients. CMR provides a comprehensive evaluation of the heart and is therefore the gold standard for quantification of right ventricular volumes, mass and function, which are critical for pulmonary hypertension prognosis. In addition, innovative MR techniques allow an increasingly precise evaluation of pulmonary haemodynamics and lung perfusion. This review highlights the main advantages offered by CMR in pulmonary hypertension and gives an overview of putative future applications. Although right heart catheterisation remains mandatory in the diagnostic algorithm, CMR could play an increasingly important role in the coming years in monitoring pulmonary hypertension patients

A framework for convection and boundary layer parameterization derived from conditional filtering

A new theoretical framework is derived for parameterization of subgrid physical processes in atmospheric models; the application to parameterization of convection and boundary layer fluxes is a particular focus. The derivation is based on conditional filtering, which uses a set of quasi-Lagrangian labels to pick out different regions of the fluid, such as convective updrafts and environment, before applying a spatial filter. This results in a set of coupled prognostic equations for the different fluid components, including subfilter-scale flux terms and entrainment/detrainment terms. The framework can accommodate different types of approaches to parameterization, such as local turbulence approaches and mass-flux approaches. It provides a natural way to distinguish between local and nonlocal transport processes, and makes a clearer conceptual link to schemes based on coherent structures such as convective plumes or thermals than the straightforward application of a filter without the quasi-Lagrangian labels. The framework should facilitate the unification of different approaches to parameterization by highlighting the different approximations made, and by helping to ensure that budgets of energy, entropy, and momentum are handled consistently and without double counting. The framework also points to various ways in which traditional parameterizations might be extended, for example by including additional prognostic variables. One possibility is to allow the large-scale dynamics of all the fluid components to be handled by the dynamical core. This has the potential to improve several aspects of convection-dynamics coupling, such as dynamical memory, the location of compensating subsidence, and the propagation of convection to neighboring grid columns

Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects.

Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools

Regulatory B cells in pregnancy: lessons from autoimmunity, graft tolerance, and cancer

The success of pregnancy is contingent on the maternal immune system recognizing and accommodating a growing semi-allogeneic fetus. Specialized subsets of lymphocytes capable of negative regulation are fundamental in this process, and include the regulatory T cells (Tregs) and potentially, regulatory B cells (Bregs). Most of our current understanding of the immune regulatory role of Bregs comes from studies in the fields of autoimmunity, transplantation tolerance, and cancer biology. Bregs control autoimmune diseases and can elicit graft tolerance by inhibiting the differentiation of effector T cells and dendritic cells (DCs), and activating Tregs. Furthermore, in cancer, Bregs are hijacked by neoplastic cells to promote tumorigenesis. Pregnancy therefore represents a condition that reconciles these fields-mechanisms must be in place to ensure maternal immunological tolerance throughout gravidity to allow the semi-allogeneic fetus to grow within. Thus, the mechanisms underlying Breg activities in autoimmune diseases, transplantation tolerance, and cancer may take place during pregnancy as well. In this review, we discuss the potential role of Bregs as guardians of pregnancy and propose an endocrine-modulated feedback loop highlighting the Breg-Treg-tolerogenic DC interface essential for the induction of maternal immune tolerance.Ruth Marian Guzman-Genuino and Kerrilyn R. Diene

Differential actions of glycodelin-A on Th-1 and Th-2 cells: A paracrine mechanism that could produce the Th-2 dominant environment during pregnancy

Background: The maternalfetal interface has a unique immunological response towards the implanting placenta. It is generally accepted that a T-helper type-2 (Th-2) cytokine prevailing environment is important in pregnancy. The proportion of Th-2 cells in the peripheral blood and decidua is significantly higher in pregnant women in the first trimester than in non-pregnant women. Glycodelin-A (GdA) is a major endocrine-regulated decidual glycoprotein thought to be related to fetomaternal defence. Yet the relationship between its immunoregulatory activities and the shift towards Th-2 cytokine profile during pregnancy is unclear. Methods GdA was immunoaffinity purified from human amniotic fluid. T-helper, T-helper type-1 (Th-1) and Th-2 cells were isolated from the peripheral blood. The viability of these cells was studied by XTT assay. Immunophenotyping of CD4/CD294, cell death and GdA-binding were determined by flow cytometry. The mRNA expression, surface expression and secretion of Fas/Fas ligand (FasL) were determined by quantitative polymerase chain reaction, flow cytometry and ELISA, respectively. The activities of caspase-3, -8 and -9 were measured. The phosphorylation of extracellular signal-regulated kinases (ERK), p38 and, c-Jun N-terminal kinase was determined by western blotting. Results Although GdA bound to both Th-1 and Th-2 cells, it had differential actions on the two cell-types. GdA induced cell death of the Th-1 cells but not the Th-2 cells. The cell death was mediated through activation of caspase -3, -8 and -9 activities. GdA up-regulated the expression of Fas and inhibited ERK activation in the Th-1 cells, which might enhance the vulnerability of the cells to cell death caused by a trophoblast-derived FasL. Conclusions The data suggest that GdA could be an endometrial factor that contributes to the Th-2/Th-1 shift during pregnancy. © 2011 The Author.postprin