Signs of Reduced Basal Progenitor Levels and Cortical Neurogenesis in Human Fetuses with Open Spina Bifida at 11-15 Weeks of Gestation.

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on fetal neocortex development, we analyzed human fetuses of both sexes diagnosed with OSB between 11 and 15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB fetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early fetal therapy (i.e., in the first trimester of pregnancy).SIGNIFICANCE STATEMENT Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS. This study provides novel data on neocortex development of human OSB fetuses. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB fetuses. Our findings support the need for an early fetal therapy and expand our understanding of the pathophysiology of OSB.

Effect of blood on ROM diagnosis accuracy of PAMG-1 and IGFBP-1 detecting rapid tests.

Vaginal bleeding may be present in up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM). The presence of blood may lead to false positive results with biochemical markers. The data presented in this study came from a multi-centric prospective observational clinical study that, for the first time, systematically evaluated the performance of placental alpha microglobulin-1 (PAMG-1) and insulin-like growth factor binding protein-1 (IGFBP-1) detecting tests in 151 women with vaginal bleedings as well as signs and symptoms indicative of ROM. Our data showed better performance for the PAMG-1 compared with the IGFBP-1 detecting tests in all quality parameters evaluated. In detail, sensitivity (SN) was 97.8% (91.0%), specificity (SP) was 91.5% (75.0%), positive predictive value (PPV) was 94.6% (83.5%) and negative predictive value (NPV) was 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). A major difference between both tests was related to the number of non-evaluable test results (e.g., hidden bands due to blood smear on the test strips). While 2% of all results were not evaluable for PAMG-1 tests, this artifact appeared in 11% of the results obtained with IGFBP-1 tests. This difference and also those in Specificity and PPV were statistically significant, demonstrating superiority of PAMG-1 over IGFBP-1 detecting tests. In conclusion, the PAMG-1 detecting test was significantly less susceptible to interference by blood than the IGFBP-1 detecting test.

Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance.

OBJECTIVES: The identification of novel molecular biomarkers, predicting outcome of ovarian cancer, is highly desirable. Considering that angiogenesis is a critical factor for ascites development and peritoneal dissemination in ovarian cancer and given that the vascular endothelial growth factor (VEGF) receptor signaling axis is a major driver of angiogenesis, we sought to analyze expression and compartmental distribution of VEGF-receptor family in ovarian cancer and to assess its clinical relevance with regard to established clinicopathological parameters, tumor cell dissemination to the bone marrow (BM) and the patient's survival. METHODS: A total of 73 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGF-R1, VEGF-R2 and VEGF-R3 by immunohistochemistry. The presence of disseminated tumor cells (DTC) in the BM was analyzed by immunocytochemistry using the pancytokeratin antibody A45B/B3 and subsequent automatic detection based on staining and cytomorphology. RESULTS: In primary ovarian cancer tissue, VEGF-receptor expression, detected with an overall frequency of 44%, was mostly located in the vascular wall and across the stroma; positivity rates for VEGF-R1, VEGF-R2 and VEGF-R3 were 34%, 18% and 26%, respectively. Total VEGF-receptor expression correlated with residual tumor after primary debulking surgery and the presence of DTC at primary diagnosis (p=0.035, p=0.023, respectively). Interestingly, VEGF-R1 positivity significantly correlated with decreased progression-free survival (p=0.026). CONCLUSIONS: This is the first report, suggesting total VEGF-receptor status as a molecular biomarker for monitoring tumor cell spread to the BM and, particularly, revealing prognostic significance of VEGF-R1.

Posterior brain in fetuses with Dandy-Walker malformation with complete agenesis of the cerebellar vermis at 11-13 weeks: a pilot study.

OBJECTIVE: This study aimed to measure the changes in the posterior brain in fetuses with Dandy-Walker malformation (DWM) with complete agenesis of the cerebellar vermis between 11(+0) and 13(+6) weeks of gestation. METHODS: In the midsagittal view, the brain stem (BS) diameter and the brain stem to occipital bone (BSOB) diameter were measured, and the BS/BSOB ratio was calculated in four fetuses with confirmed DWM and 40 normal fetuses. Delta values corrected for CRL were compared between both groups. RESULTS: In contrast to the normal controls, in fetuses with DWM at 11(+0) to 13(+6) weeks of gestation, the border between the fourth ventricle and the cisterna magna was not visible. There were no significant differences in the BS diameter between the two groups (p<0.3). In the DWM group, the mean diameter of the BSOB was found to be significantly higher than in the controls (p=0.0011), and it was above the 95th centile in all four cases. In addition, the BS/BSOB ratio was significantly decreased in fetuses with DWM (p=0.0011). CONCLUSIONS: At 11-13 weeks, fetuses with DWM have measurable abnormalities in the posterior brain. An abnormal appearance of the fourth ventricle-cisterna magna complex was present in all four cases of DWM.

Temporal effect of Afro-Caribbean race on serum pregnancy-associated plasma protein-a at 9-13 weeks' gestation in screening for aneuploidies.

OBJECTIVE: It was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9(+0)-13(+6) weeks' gestation. METHODS: In singleton pregnancies attending for routine care, serum-free ß-hCG and PAPP-A were measured at 9(+0)-13(+6) weeks' gestation and fetal nuchal translucency was measured at 11(+0)-13(+6) weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free ß-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. RESULTS: Serum-free ß-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1-7.8). CONCLUSIONS: Serum-free ß-hCG and PAPP-A concentrations at 9(+0)-13(+6) weeks' gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.

Posterior brain in fetuses with open spina bifida at 11 to 13 weeks.

OBJECTIVE: To measure the changes in the posterior fossa in first-trimester fetuses with open spina bifida (OSB). METHODS: The brain stem diameter and brain stem to occipital bone (BSOB) diameter were measured in stored images of the mid-sagittal view of the fetal face at 11(+0) to 13(+6) weeks from 30 fetuses with OSB and 1000 normal controls. RESULTS: In the control group, the brain stem and BSOB diameter increased significantly with crown-rump length (CRL) and the brain stem to BSOB ratio decreased. In the spina bifida group, the brain stem diameter was above the 95th percentile of the control group in 29 (96.7%) cases, the BSOB diameter was below the 5th percentile in 26 (86.7%) and the brain stem to BSOB ratio was above the 95th percentile in all cases. CONCLUSIONS: At 11 to 13 weeks the majority of fetuses with OSB have measurable abnormalities in the posterior brain.

Sevoflurane ameliorates gas exchange and attenuates lung damage in experimental lipopolysaccharide-induced lung injury.

BACKGROUND: Acute lung injury is a common complication in critically ill patients. Several studies suggest that volatile anesthetics have immunomodulating effects. The aim of the current study was to assess possible postconditioning with sevoflurane in an in vivo model of endotoxin-induced lung injury. METHODS: Rats were anesthetized, tracheotomized, and mechanically ventilated. Lipopolysaccharide (saline as control) was administered intratracheally. Upon injury after 2 h of propofol anesthesia, general anesthesia was continued with either sevoflurane or propofol for 4 h. Arterial blood gases were measured every 2 h. After 6 h of injury, bronchoalveolar lavage was performed and lungs were collected. Total cell count, albumin content, concentrations of the cytokines cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1, and phospholipids were analyzed in bronchoalveolar lavage fluid. Expression of messenger RNA for the two cytokines and for surfactant protein B was determined in lung tissue. Histopathologic examination of the lung was performed. RESULTS: Significant improvement of the ratio of oxygen tension to inspired oxygen fraction was shown with sevoflurane (mean + or - SD: 243 + or - 94 mmHg [32.4 kPa]) compared with propofol (88 + or - 19 mmHg [11.7 kPa]). Total cell count representing effector cell recruitment as well as albumin content as a measure of lung permeability were significantly decreased in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group in bronchoalveolar lavage fluid. Expression of the cytokines protein in bronchoalveolar lavage fluid as well as messenger RNA in lung tissue was significantly lower in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group. CONCLUSIONS: Postconditioning with sevoflurane attenuates lung damage and preserves lung function in an in vivo model of acute lung injury.

Phosphoinositide 3-OH kinase inhibition prevents ventilation-induced lung cell activation.

In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-kappaB (NF-kappaB) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-kappaB and the subsequent release of interleukin-6 and macrophage inflammatory protein-2alpha in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-kappaB activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-kappaB by endotoxin.

Open lung in ARDS.

Every year, millions of patients worldwide receive ventilator support during surgery. Mechanical ventilation has become an important therapy in the treatment of patients with impaired pulmonary function and particularly in patients suffering from adult respiratory distress syndrome (ARDS). ARDS is caused by multiple factors and is characterized by respiratory dysfunction including hypoxemia and decreased lung compliance. It is known that the decrease in lung distensibility is due to a disturbed surfactant system with an elevated surface tension. This increase in surface tension leads to an increase in forces acting at the air-liquid interface, resulting finally in end-expiratory collapse, atelectasis, an increase in right-to-left shunt and a decrease in paO2.