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

Mucus glycoproteins from 'normal' human tracheobronchial secretion.

Mucous secretions were collected from tracheas of patients undergoing minor surgery under general anaesthesia with tracheal intubation, and mucus glycoproteins were isolated by using isopycnic density-gradient centrifugation in CsCl/guanidinium chloride. 'Whole' mucins were excluded from a Sepharose CL-2B gel, whereas subunits obtained after reduction were included. Trypsin digestion of subunits afforded high-Mr glycopeptides (T-domains), which were further included in the gel. The latter fragments are heterogeneous and comprise two or three populations, as indicated by gel chromatography and ion-exchange h.p.l.c. Rate-zonal centrifugation showed that the 'whole' mucins are polydisperse in size, with a weight-average Mr of (14-16) x 10(6). The macromolecules were observed by electron microscopy, as linear and apparently flexible thread-like structures. Subunits and T-domains had weight-average contour lengths of 490 nm and 160 nm respectively. It is concluded that mucus glycoproteins are present in secretions from the healthy lower respiratory tract. The 'whole' tracheal mucins are assembled from subunits, which in turn can be fragmented into high-Mr glycopeptides corresponding to the oligosaccharide domains typically found in mucus glycoproteins. The size and macromolecular architecture of the tracheal mucins is thus similar to that observed for mucins from human cervical mucus, chronic bronchitic sputum and pig stomach, providing yet another example of this general design of these macromolecules, i.e. subunits assembled end-to-end into very large linear and flexible macromolecules

Defining the Optimal Treatment Strategy in Patients With Uterine Serous Carcinoma.

AIMS: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. MATERIALS AND METHODS: A retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan-Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. RESULTS: In total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. CONCLUSION: Women with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC

Unreal Goal Bots

It remains a challenge with current state of the art technology to use BDI agents to control real-time, dynamic and complex environments. We report on our effort to connect the GOAL agent programming language to the real-time game UNREAL TOURNAMENT 2004. We focus in particular on the design of a suitable interface to manage agent-bot interaction and argue that the use of a recent toolkit for developing an agent-environment interface provides many advantages.Intelligent SystemsElectrical Engineering, Mathematics and Computer Scienc

Defining the Optimal Treatment Strategy in Patients With Uterine Serous Carcinoma

AIMS: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. MATERIALS AND METHODS: A retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan-Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. RESULTS: In total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. CONCLUSION: Women with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC