Molecular programs in the venous pole of the developing murine heart

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A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups

Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia

Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34

Tbx18 and the fate of epicardial progenitors

Uncovering the origins of myocardial cells is important for understanding and treating heart diseases. Cai et al. suggest that Tbx18-expressing epicardium provides a substantial contribution to myocytes in the ventricular septum and the atrial and ventricular walls. Here we show that the T-box transcription factor gene 18 (Tbx18) itself is expressed in the myocardium, showing that their genetic lineage tracing system does not allow conclusions of an epicardial origin of cardiomyocytes in vivo to be draw

Partial Absence of Pleuropericardial Membranes in <em>Tbx18</em>- and <em>Wt1</em>-Deficient Mice

<div><p>The pleuropericardial membranes are fibro-serous walls that separate the pericardial and pleural cavities and anchor the heart inside the mediastinum. Partial or complete absence of pleuropericardial membranes is a rare human disease, the etiology of which is poorly understood. As an attempt to better understand these defects, we wished to analyze the cellular and molecular mechanisms directing the separation of pericardial and pleural cavities by pleuropericardial membranes in the mouse. We found by histological analyses that both in <em>Tbx18</em>- and <em>Wt1</em>-deficient mice the pleural and pericardial cavities communicate due to a partial absence of the pleuropericardial membranes in the hilus region. We trace these defects to a persisting embryonic connection between these cavities, the pericardioperitoneal canals. Furthermore, we identify mesenchymal ridges in the sinus venosus region that tether the growing pleuropericardial membranes to the hilus of the lung, and thus, close the pericardioperitoneal canals. In <em>Tbx18-</em>deficient embryos these mesenchymal ridges are not established, whereas in <em>Wt1-</em>deficient embryos the final fusion process between these tissues and the body wall does not occur. We suggest that this fusion is an active rather than a passive process, and discuss the interrelation between closure of the pericardioperitoneal canals, lateral release of the pleuropericardial membranes from the lateral body wall, and sinus horn development.</p> </div

PPM development in control and <i>Tbx18</i>-deficient embryos.

<p>(A–P), Histological analysis by haematoxylin and eosin stainings of PPM development was performed on transverse sections of a posterior and a mid-transverse section plane of control and <i>Tbx18</i>-deficient hearts from E11.5 to E14.5. Magnifications (C, D, G, H) highlight the sinuatrial mesenchymal ridges that protrude into the PPCs in control embryos at E11.5 and E12.5, and their absence in <i>Tbx18</i>-deficient embryos, respectively. Genotypes and stages are as indicated. Asterisks highlight the subcoelomic lateral body wall mesenchyme; black arrowheads mark the attachment point of the PPMs to the lateral body wall; black arrows point to the remaining PPCs; and green arrowheads mark the mesenchymal ridge that is necessary for the closure of the PPCs. icv, inferior cardinal vein; la, left atrium; lcv, left cardinal vein; li, liver; lu, lung; lsh, left sinus horn; lv, left ventricle; pc, pericardial cavity; ppc, pericardioperitoneal canal; pl, pleural cavity; ppm, pleuropericardial membrane; ra, right atrium; rcv, right cardinal vein; rsh, right sinus horn; rv, right ventricle.</p

Schematic diagram of murine PPM development.

<p>(A–D) Scheme of PPM development based on transverse sections through the cardiac venous pole of wildtype embryos from E11.5 to E14.5. The lumen of the caval veins and the heart is marked in pale pink, the lung and trachea in pale blue, the (parietal) pleura in blue, the (parietal) pericardium in red, and the degenerating subcoelomic mesenchyme in green. Blue arrows demonstrate the direction of the detachment of the PPMs from the subcoelomic mesenchyme. Note the PPMs are double-layered consisting of the parietal layer of the pleura and the pericardium. Dorsal is up, ventral is down. h, heart; lu, lung; pc, pericardial cavity; pl, pleural cavity; ppc, pericardioperitoneal canal; ppm, pleuropericardial membranes.</p

PPM defects in <i>Tbx18</i>-mutant embryos.

<p>(A–H) Histological stainings with haematoxylin and eosin were performed on transverse (A–D) and sagittal (E–H) sections of the venous pole region of the heart at E18.5. They reveal that PPMs are only partly released from the lateral body wall and that they are not attached to the mediastinum resulting in bilateral communication between the pleural and pericardial cavities in the mutant. Arrowheads mark the attachment point of the PPMs to the lateral body wall; arrows highlight the persisting PPC in <i>Tbx18</i>-deficient embryos. lu, lung; lsh, left sinus horn; lv, left ventricle; pc, pericardial cavity; pl, pleural cavity; ppm, pleuropericardial membrane; ra, right atrium; rsh, right sinus horn; th, thymus.</p