Le syndrome parkinsonien d'Adolf Hitler, étiologie et chronologie

Adolf Hitler présentait un syndrome parkinsonien. Par une étude de la littérature médicale, nous en proposons une chronologie d'évolution. Le syndrome parkinsonien typique avec tremblement de repos prédominant à gauche, hypertonie plastique et akinésie, était présent à partir de 1941. La cause était une maladie de Parkinson certaine selon les critères européens actuels. Il existe peu d'arguments positifs pour les diagnostics différentiels : encéphalite léthargique, neurosyphilis, troubles psychiatriques, troubles iatrogènes. Plusieurs signes accessoires viennent conforter le caractère idiopathique. Ce travail met à jour une facette méconnue de la vie d'Hitler, figure marquante du XXème siècle.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias.: Cardiac cell and Cx43-gene therapy for arrhythmias

International audienceCell-based therapies have great potential for the treatment of cardiovascular diseases. Recently, using a transgenic mouse model Roell et al. reported that cardiac engraftment of connexin43 (Cx43)-overexpressing myoblasts in vivo prevents post-infarct arrhythmia, a common cause of death in patients following heart attack. We carried out a similar study but in a clinically relevant context via transplantation of autologous connexin43-overexpressing myoblasts in infarcted rats. Seven days after coronary ligation, rats were randomized into three groups: a control group injected with myoblasts, a null group injected with myoblasts transduced with an empty lentivirus vector (null) and a Cx43 group injected with myoblasts transduced with a lentivirus vector encoding connexin43. In contrast to Roell's report, arrhythmia occurrence was not statistically different between groups (58%, 64% and 48% for the control (n= 12), null (n= 14) and Cx43 (n= 23) groups, respectively, P= 0.92). Using ex vivo intramural monophasic action potential recordings synchronous electrical activity was observed between connexin43-overexpressing myoblasts and host cardiomyocytes, whereas such synchrony did not occur in the null-transduced group. This suggests that ex vivo connexin43 gene transfer and expression in myoblasts improved intercellular electrical coupling between myoblasts and cardiomyocytes. However, in our model such electrical coupling was not sufficient to decrease arrhythmia induction. Therefore, we would suggest a note of caution on the use of combined Cx43 gene and cell therapy to prevent post-infarct arrhythmias in heart failure patients

Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation.

Embryo implantation requires extensive angiogenesis at the maternal-fetal interface. Hyperglycosylated human chorionic gonadotropin (hCG-H), a trophoblast invasive signal produced by extravillous cytotrophoblasts and by choriocarcinoma, was evaluated for its angiogenic role. hCG-H was purified by HPLC from choriocarcinoma supernatant, and the glycosylation pattern was determined by 2D gel analysis. Angiogenesis models used were aortic ring assay with wild-type and LHCGR-knockout mice, endothelial and mural cell proliferation, and migration assays. The TGF-beta signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF-beta reporter gene assays, and Smad immunoblotting. hCG-H displayed a potent angiogenic effect [3.2-fold increase of number of vessel intersections in wild-type aortic rings (11.406 to 36.964)]. hCG-H-induced angiostimulation was independent of the classic hCG signaling pathway since it persisted in LHCGR-knockout mice [4.73-fold increase of number of vessel intersections (10.826 to 51.288)]. Using TGF-beta signaling inhibitors, Tbeta-RII was identified as the hCG-H receptor responsible for its angiogenic switch. hCG-H exposure enhanced phosphorylation of Smad 2 in endothelial and mural cells and genomic activation of Smad-responsive elements. Interaction between hCG-H and Tbeta-RII was demonstrated by coimmunoprecipitation and binding competition with (125)I-TGF-beta. This new paracrine interaction between trophoblast and endothelial cells through the hCG-H and the TGF-beta receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

International audienceThe effects of fluid shear stress (FSS) on the human syncytiotrophoblast and its biological functions have never been studied. During pregnancy, the syncytiotrophoblast is the main source of placental growth factor (PlGF), a proangiogenic factor involved in the placental angiogenesis and the vascular adaptation to pregnancy. The role of FSS in regulating PlGF expression in syncytiotrophoblasts is unknown. We investigated the impact of FSS on the production and secretion of the PlGF by the human syncytiotrophoblasts in primary cell culture. Laminar and continuous FSS (1 dyn cm-2) was applied to human syncytiotrophoblasts cultured in a parallel-plate flow chambers. Secreted levels of PlGF, sFlt-1 (soluble fms-like tyrosin kinase-1), and prostaglandin E2 were tested by immunologic assay. PlGF levels of mRNA and intracellular protein were examined by RT-PCR and Western blot, respectively. Intracellular cAMP levels were examined by time-resolved fluorescence resonance energy transfer cAMP accumulation assay. Production of cAMP and PlGF secretion was significantly increased in FSS conditions compared with static conditions. Western blot analysis of cell extracts exposed to FSS showed an increased phosphorylation of protein kinase A substrates and cAMP response element-binding protein on serine 133. FSS-induced phosphorylation of cAMP response element-binding protein and upregulation of PlGF were prevented by inhibition of protein kinase A with H89 (3 μmol/L). FSS also triggers intracellular calcium flux, which increases the synthesis and release of prostaglandin E2. The enhanced intracellular cAMP in FSS conditions was blocked by COX1/COX2 (cyclooxygenase) inhibitors, suggesting that the increase in prostaglandin E2 production could activate the cAMP/protein kinase A pathway in an autocrine/paracrine fashion. FSS activates the cAMP/protein kinase A pathway leading to upregulation of PlGF in human syncytiotrophoblast

Transcriptome analysis of PPARγ target genes reveals the involvement of lysyl oxidase in human placental cytotrophoblast invasion.

Human placental development is characterized by invasion of extravillous cytotrophoblasts (EVCTs) into the uterine wall during the first trimester of pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) plays a major role in placental development, and activation of PPARγ by its agonists results in inhibition of EVCT invasion in vitro. To identify PPARγ target genes, microarray analysis was performed using GeneChip technology on EVCT primary cultures obtained from first-trimester human placentas. Gene expression was compared in EVCTs treated with the PPARγ agonist rosiglitazone versus control. A total of 139 differentially regulated genes were identified, and changes in the expression of the following 8 genes were confirmed by reverse transcription-quantitative polymerase chain reaction: a disintegrin and metalloproteinase domain12 (ADAM12), connexin 43 (CX43), deleted in liver cancer 1 (DLC1), dipeptidyl peptidase 4 (DPP4), heme oxygenase 1 (HMOX-1), lysyl oxidase (LOX), plasminogen activator inhibitor 1 (PAI-1) and PPARγ. Among the upregulated genes, lysyl oxidase (LOX) was further analyzed. In the LOX family, only LOX, LOXL1 and LOXL2 mRNA expression was significantly upregulated in rosiglitazone-treated EVCTs. RNA and protein expression of the subfamily members LOX, LOXL1 and LOXL2 were analyzed by absolute RT-qPCR and western blotting, and localized by immunohistochemistry and immunofluorescence-confocal microscopy. LOX protein was immunodetected in the EVCT cytoplasm, while LOXL1 was found in the nucleus and nucleolus. No signal was detected for LOXL2 protein. Specific inhibition of LOX activity by β-aminopropionitrile in cell invasion assays led to an increase in EVCT invasiveness. These results suggest that LOX, LOXL1 and LOXL2 are downstream PPARγ targets and that LOX activity is a negative regulator of trophoblastic cell invasion

The immune molecule CD3zeta and its downstream effectors ZAP-70/Syk mediate ephrin signaling in neurons to regulate early neuritogenesis

Recent studies have highlighted the key role of the immune protein CD3ζ in the maturation of neuronal circuits in the CNS. Yet, the upstream signals that might recruit and activate CD3ζ in neurons are still unknown. In this study, we show that CD3ζ functions early in neuronal development and we identify ephrinA1-dependent EphA4 receptor activation as an upstream regulator of CD3ζ. When newly born neurons are still spherical, before neurite extension, we found a transient CD3ζ aggregation at the cell periphery matching the initiation site of the future neurite. This accumulation of CD3ζ correlated with a stimulatory effect on filopodia extension via a Rho-GEF Vav2 pathway and a repression of neurite outgrowth. Conversely, cultured neurons lacking CD3ζ isolated from CD3ζ−/− mice showed a decreased number of filopodia and an enhanced neurite number. Stimulation with ephrinA1 induces the translocation of both CD3ζ and its activated effector molecules, ZAP-70/Syk tyrosine kinases, to EphA4 receptor clusters. EphrinA1-induced growth cone collapse was abrogated in CD3ζ−/− neurons and was markedly reduced by ZAP-70/Syk inhibition. Moreover, ephrinA1-induced ZAP-70/Syk activation was inhibited in CD3ζ−/− neurons. Altogether, our data suggest that CD3ζ mediates the ZAP-70/Syk kinase activation triggered by ephrinA-activated pathway to regulate early neuronal morphogenesis

Representation of a chorionic villus at the implantation site.

<p>Villous cytotrophoblasts (yellow) fuse to form the syncytiotrophoblast (green). The extravillous trophoblasts (red) proliferate to form multilayered columns of cells and then invade the decidua up to the upper third of the myometrium and the uterine arterioles. At the deciduo-muscular junction, EVCTs undergo final differentiation into multinucleated giant cells. Adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079413#pone-0079413-g001" target="_blank">figure 1</a> of Tarrade <i>et al. </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079413#pone.0079413-Tarrade2" target="_blank">[12]</a>.</p

Microarray and transcriptome analyses of rosiglitazone-treated EVCTs compared to paired controls: top 7 networks.

<p>The 175 probe sets were loaded into Ingenuity Pathway Analysis software (IPA) and converted into gene networks. Genes shown in bold type are present in the input data list as upregulated (red) or downregulated (green). Genes involved in the network that are not included in the transcriptome results are shown in black. * genes with several probes present in the input data list.</p

Expression analyses of LOXs in early placental villi and EVCTs.

<p><b>A</b>) LOX, LOXL1 and LOXL2 RNA copy numbers per ng of total RNA in 48 h-cultured EVCTs were determined by absolute RT-qPCR. Each bar represents the mean ± SEM of five independent experiments performed in duplicate. *: p<0.05 for differences between isoforms; ns: not significant. <b>B</b>) Western blot analyses of LOX and LOXL1 proteins. Protein (20 µg) extracted with the T-PER reagent (Pierce) from 8- to 9-WA placental villous tissue (Vill), or with the M-PER reagent from 72 h-cultured primary EVCTs purified from placental tissue at the same term (EVCT, C), as well as 40 µg of protein from cell conditioned medium (CM) and the insoluble M-PER cell extract fraction (IF) taken up in Laemmli buffer were separated on 4–12% polyacrylamide Bis-Tris gels. Detection was achieved by using LOX and LOXL1 isoform-specific antibodies; ß -actin was used as a control.</p