Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

La Montagne

Les textes rassemblés dans ce numéro ont été présentés lors du colloque International « La Montagne entre image et langage dans les territoires anglophones », organisé par l'équipe d'accueil Cultures Anglo-Saxonnes, et qui s'est tenu à l'Université de Toulouse- Le Mirail et à Gavarnie du 4 au 7 octobre 2007. En parcourant les continents, de l'Europe à l'Amérique, de l'Afrique à l'Océanie, ce volume s'attache à analyser les facettes de la perception et de la représentation de la montagne en littérature et en peinture, pour dégager les invariants qui font des montagnes un lieu mythique source d'inspiration. Liées au sacré, au mythique, au rêve et à la quête géographique et intérieure à la fois, les montagnes posent aussi le problème très concret de la conservation d'un patrimoine et du rapport ambigu à la modernité. Ce volume s'interroge donc sur la tradition esthétique liée au sublime, mais aussi sur les aspects politiques, culturels ou juridiques, qu'impliquent les modalités de représentation. Le paysage est étroitement lié à l'écriture, depuis le parcours des voyageurs anglais, réels ou imaginaires, dans les Alpes et les Pyrénées, l'approche d'un montagnard et pyrénéiste anglais comme Kev Reynolds, jusqu'à la vision d'un défenseur passionné de l'environnement tel que Rick Bass. Et en croisant les perspectives d'écrivains (comme l'auteur canadien Rudy Wiebe ou le poète nigérian Niyi Osundare) et d'universitaires, une cartographie de la montagne s'esquisse, espace traversé ou habité, lieu obsédant, matrice maïeutique d'une oeuvre. Les divers articles posent le problème du regard porté sur la montagne, des codes de lectures et d'écriture de l'espace, de la place de l'humain dans ce lieu difficilement accessible, lieu d'élévation littérale et symbolique à la fois. This collection of papers was presented at the International Conference "The Mountain in Image and Word in the English- Speaking World" organized by the research center Cultures Anglo-Saxonnes, University of Toulouse II. By confronting visions of mountains on various continents, from Europe and America to Africa and Australia, this volume attempts to redefine hiking, climbing and writing or painting as intertwined activities, leading from a mythical, visionary approach to a radical political awareness. Mountains may cast a mystical spell; they also raise very concrete problems of conservation and biodiversity. These essays trace the aesthetic approach derived from the picturesque and the sublime, but also map cultural and economic constraints. Following (for instance) the footsteps of genuine or imaginary English wanderers roaming the Alps or the Pyrenees, mapping like Kev Reynolds an English mountaineer's delight in the Pyrenees, or exploring artistic commitment like Rick Bass's fierce fight to preserve his valley of Yaak, the papers reveal how tightly walking and writing are connected. Straying from Romantic nostalgia, writers like Canadian novelist Rudy Wiebe or Nigerian poet Niyi Osundare present a forceful view of mountains. Thus mountains high and low appear as a multiple, unreachable or inhabited space, the haunting origin of creativity and inspiration, raising the question of perception and perspective, codes of reading and writing landscapes, the relationship between human beings and nature, in this challenging realm of physical, mental, but also rhetorical and symbolic elevation