Refinement of the Primate Corticospinal Pathway During Prenatal Development.

Perturbation of the developmental refinement of the corticospinal (CS) pathway leads to motor disorders. While non-primate developmental refinement is well documented, in primates invasive investigations of the developing CS pathway have been confined to neonatal and postnatal stages when refinement is relatively modest. Here, we investigated the developmental changes in the distribution of CS projection neurons in cynomolgus monkey (Macaca fascicularis). Injections of retrograde tracer at cervical levels of the spinal cord at embryonic day (E) 95 and E105 show that: (i) areal distribution of back-labeled neurons is more extensive than in the neonate and dense labeling is found in prefrontal, limbic, temporal, and occipital cortex; (ii) distributions of contralateral and ipsilateral projecting CS neurons are comparable in terms of location and numbers of labeled neurons, in contrast to the adult where the contralateral projection is an order of magnitude higher than the ipsilateral projection. Findings from one largely restricted injection suggest a hitherto unsuspected early innervation of the gray matter. In the fetus there was in addition dense labeling in the central nucleus of the amygdala, the hypothalamus, the subthalamic nucleus, and the adjacent region of the zona incerta, subcortical structures with only minor projections in the adult control.

Unique Features of Subcortical Circuits in a Macaque Model of Congenital Blindness.

There is an extensive modification of the functional organization of the brain in the congenital blind human, although there is little understanding of the structural underpinnings of these changes. The visual system of macaque has been extensively characterized both anatomically and functionally. We have taken advantage of this to examine the influence of congenital blindness in a macaque model of developmental anophthalmia. Developmental anophthalmia in macaque effectively removes the normal influence of the thalamus on cortical development leading to an induced "hybrid cortex (HC)" combining features of primary visual and extrastriate cortex. Here we show that retrograde tracers injected in early visual areas, including HC, reveal a drastic reduction of cortical projections of the reduced lateral geniculate nucleus. In addition, there is an important expansion of projections from the pulvinar complex to the HC, compared to the controls. These findings show that the functional consequences of congenital blindness need to be considered in terms of both modifications of the interareal cortical network and the ascending visual pathways.

How Areal Specification Shapes the Local and Interareal Circuits in a Macaque Model of Congenital Blindness.

There is little understanding of the structural underpinnings of the functional reorganization of the cortex in the congenitally blind human. Taking advantage of the extensive characterization of the macaque visual system, we examine in macaque the influence of congenital blindness resulting from the removal of the retina during in utero development. This effectively removes the normal influence of the thalamus on cortical development leading to an induced hybrid cortex (HC) combining features of primary visual and extrastriate cortex. Retrograde tracers injected in HC reveal a local, intrinsic connectivity characteristic of higher order areas and show that the HC receives a uniquely strong, purely feedforward projection from striate cortex but no ectopic inputs, except from subiculum, and entorhinal cortex. Statistical modeling of quantitative connectivity data shows that HC is relatively high in the cortical hierarchy and receives a reinforced input from ventral stream areas while the overall organization of the functional streams are conserved. The directed and weighted anophthalmic cortical graph from the present study can be used to construct dynamic and structural models. These findings show how the sensory periphery governs cortical phenotype and reveal the importance of developmental arealization for understanding the functional reorganization in congenital blindness.

The "RESEAU MATER": An efficient infection control for endometritis, but not for urinary tract infection after vaginal delivery.

"RESEAU MATER" is useful to monitor nosocomial infections in maternity and contributes to the decreasing trend of it, since its implementation. Specifically, this network demonstrates its efficiency in the control of endometritis following vaginal deliveries, but not in the control of urinary tract infections. The aim of this study is to determine whether the difference between the control of endometritis and of urinary tract infection could be explained by an unsuitable regression model or by an unsuitable care policy concerning urinary cares. This study includes (1) the analysis of historic data of the network and (2) the description of French guidelines for maternity cares and available evaluations, concerning endometritis and urinary tract infection prevention. Univariate and multivariate odds ratios (ORs) were calculated for the total study period of 1999-2013, for these infections and their risk factors. The endometritis frequency is decreasing, in association with no significant evolution of associated risk factors, but urinary tract infection frequency is constant, in association with a increasing trend of its risk factors such as intermittent catheterization and epidural analgesia. In French guidelines, all preventive measures against endometritis are clearly broadcasted by all field operators, and repeated audits have reinforced the control of their application. But preventive measures against urinary tract infection seem to be broadcasted exclusively in the circle of infection prevention agencies and not in the obstetrics societies or in the Health Ministry communication. Urinary tract infection prevention requires a clearer public and professional policy in favor of a more efficient urinary cares, with a specific target to maternity.

Does forceps training on a birth simulator allow obstetricians to improve forceps blade placement?

OBJECTIVE: The aim of this study was to evaluate whether forceps training on a birth simulator allows obstetricians to improve forceps blade placement. STUDY DESIGN: Analysis was based on 600 forceps blade placements performed by ten trainees on a simulator. The trajectories used by the trainees were assessed using reference spheres that reflected an optimal bimalar placement. Three definitions of success were used: small-sphere success, medium-sphere success and large-sphere success were respectively defined by the forceps blade tip being within 5, 10 or 15mm of the center of the sphere (the small-sphere being nested within the medium-sphere and the small and medium being nested within the large-sphere). Wilcoxon paired analysis was performed to compare the first (50 trajectories) and final (50 trajectories) sets of five forceps placements. Graphical representation and linear regression were used to visualize the learning process. RESULTS: 596 trajectories were available for analysis. During the last set of five forceps the success rate was respectively 28%, 72% and 86% for small-sphere, medium-sphere and large-sphere success with the right blade and 8%, 32% and 70% for the left blade. Wilcoxon analysis showed a highly significant improvement for all kinds of success in the right blade and for large-sphere success in the left blade. Linear regression slopes were significant. Using a projection, the theoretical numbers of placements needed to achieve a 100% success rate for small-sphere, medium-sphere and large-sphere were respectively 80, 45 and 35. CONCLUSION: These results strongly suggest that performing forceps blade placement on birth simulator allows obstetricians to improve their skills.

Maternal infection rates after cesarean delivery by Pfannenstiel or Joel-Cohen incision: a multicenter surveillance study.

OBJECTIVE: Our purpose was to evaluate maternal nosocomial infection rates according to the incision technique used for caesarean delivery, in a routine surveillance study. STUDY DESIGN: This was a prospective study of 5123 cesarean deliveries (43.2% Joel-Cohen, 56.8% Pfannenstiel incisions) in 35 maternity units (Mater Sud Est network). Data on routine surveillance variables, operative duration, and three additional variables (manual removal of the placenta, uterine exteriorization, and/or cleaning of the parieto-colic gutter) were collected. Multiple logistic regression analysis was used to identify independent risk factors for infection. RESULTS: The overall nosocomial infection and endometritis rates were higher for the Joel-Cohen than Pfannenstiel incision (4.5% vs. 3.3%, 0.8% vs. 0.3%, respectively). The higher rate of nosocomial infections with the Joel-Cohen incision was due to a greater proportion of patients presenting risk factors (i.e., emergency delivery, primary cesarean, blood loss > or =800 mL, no manual removal of the placenta and no uterine exteriorization). However, the Joel-Cohen technique was an independent risk factor for endometritis. CONCLUSION: The Joel-Cohen technique is faster than the Pfannenstiel technique but is associated with a higher incidence of endometritis.

A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study.

Patients with thrombophilia and/or a history of venous thromboembolism (VTE) exhibit a high risk of thrombosis during pregnancy. The present multicentre study prospectively assessed a prophylaxis strategy, based on a risk score, in pregnancies with increased risk of VTE. Among 286 patients included in the study, 183 had a personal history of VTE (63.98%) and 191 patients (66.8%) had a thrombophilia marker. Eighty nine (46.6%) thrombophilic women had a personal history of VTE. Patients were assigned to one of three prophylaxis strategies according to the risk scoring system. In postpartum, all patients received low molecular weight heparin (LMWH) prophylaxis for at least 6 weeks. In antepartum, LMWH prophylaxis was prescribed to 61.8% of patients with high risk of VTE. Among them, 37.7% were treated in the third trimester only and 24.1% were treated throughout pregnancy. In this cohort, one antepartum-related VTE (0.35%) and two postpartum-related VTE (0.7%) occurred. No case of pulmonary embolism was observed during the study period. The rate of serious bleeding was 0.35%. There was no evidence of heparin-induced thrombocytopenia or osteoporosis. The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.

Coagulation assessment by rotation thrombelastometry in normal pregnancy.

We analysed changes in coagulation during normal pregnancy with a novel point-of-care device based on thrombelastometry (ROTEM). We compared the results obtained with those of standard coagulation tests in 104 patients: 20 non-pregnant women (controls) and 84 women in the first (T1, n = 17), second (T2, n = 9) and third (T3, n = 58) trimesters of pregnancy. We measured the clotting time (CT), the maximum clot firmness (MCF), the early clot amplitude at 5 and 15 minutes (CA(5), CA(15)) and the clot lysis index (CLI(30)) with four tests containing specific reagents. (a) The INTEM test involving ellagic acid activated the intrinsic pathway and (b) the EXTEM test using tissue factor triggered the extrinsic pathway; (c) The FIBTEM test based on a platelet inhibitor (cytochalasin D) evaluated the contribution of fibrinogen to clot formation and (d) the APTEM test was similar to the EXTEM but was based on inhibition in vitro of fibrinolysis by aprotinin. CT and CLI(30) were not significantly modified during pregnancy whereas MCF, CA(5) and CA(15) (INTEM, EXTEM, FIBTEM) increased significantly between the second and third trimesters (e.g. median [interquartile range]: MCF-FIBTEM, 13 [11-16] mm vs. 19 [17-23] mm, respectively, in controls and T3, p < 0.001). EXTEM values were not significantly different from those measured with APTEM. There were significant correlations between the results obtained with ROTEM and those from standard coagulation tests. ROTEM analysis showed a marked increase in coagulability during normal pregnancy. ROTEM values may serve as the basis for future studies in pregnant women.

Red, orange and green Caesarean sections: a new communication tool for on-call obstetricians.

OBJECTIVE: To evaluate the effect of a novel communication tool, related to the degree of urgency for Caesarean sections (CSs), on the decision-to-delivery interval for emergency CS. STUDY DESIGN: Red CS are very urgent cases corresponding to life-threatening maternal or foetal situations, orange CS are urgent cases and green CS are non-urgent intrapartum CS. We carried out this cohort study in a French maternity hospital. The study included all emergency Caesarean sections during two 6-month periods, before and after introduction of the code. We compared the decision-to-delivery interval of the two study periods. RESULTS: Our study included 174 emergency CS. The mean decision-to-delivery interval after introduction of the code was 31.7 min, significantly shorter (p=0.02) than the 39.6 min interval before introduction of the colour code. Except for the preparation time, each time interval decreased. This included transporting the patient into the operating theatre, and the incision-to-delivery time interval. CONCLUSION: This study suggests that the use of the three-colour code could significantly shorten the decision-to-delivery interval in emergency CS. Further prospective studies are needed to confirm this result.

Effect of intrapartum antibiotic prophylaxis against group B streptococcal infection on comparisons of rates of endometritis and urinary tract infection in multicenter surveillance.

OBJECTIVE: To establish whether antibiotic prophylaxis against group B streptococcal infection may be a confounding factor in comparisons of rates of endometritis and urinary tract infection after vaginal delivery. DESIGN: Prospective study. SETTING: Maternity units at 48 hospitals in a regional surveillance network in France during 2001-2004. METHODS: The maternity units used a common protocol to establish whether antibiotic prophylaxis was indicated. Risk factors for endometritis and urinary tract infections were evaluated using multiple logistic regression. RESULTS: We analyzed 49,786 vaginal deliveries. The percentage of women receiving antibiotic prophylaxis varied widely and significantly among the maternity units (range, 4.4%-26.0%; median, 15.8%; 25th percentile, 12.1%; 75th percentile, 19.0%) (P < .001, by Mantel-Haenszel chi(2) test). The incidence rate of endometritis was significantly reduced from 0.25% to 0.11% by antibiotic prophylaxis (P = .001). There was a decrease in the incidence of urinary tract infection from 0.37% to 0.32%, but it was not statistically significant (P = .251). CONCLUSIONS: A reduction in the incidence of endometritis was observed when intrapartum antibiotic prophylaxis against group B streptococcal infection was used. However, the proportion of women considered to be at risk of infection varied widely among institutions. Comparisons of rates of endometritis among maternity units, but not urinary tract infection rates, should take into account antibiotic prophylaxis as a significant confounding factor.

Specific information about the WHO guidelines for gestational diabetes screening improves clinical practices.

RATIONALE, AIMS AND OBJECTIVE: To evaluate the impact of specific information on World Health Organization (WHO) guidelines for gestational diabetes mellitus (GDM) screening on clinical practices and to estimate its acceptance by women. METHODS: A non-randomized interventional study, comparing two periods, that is, before (period I) and after (period II) the implementation of the WHO guidelines during year 2000 in three obstetrical units, using reminders, meetings and pre-printed prescription sheets. Women were interviewed on GDM screening acceptance. RESULTS: A total of 333 pregnant women were included in period I and 345 in period II. The proportion of women who were screened significantly increased between period I and period II (0.9% in period I, 59.1% in period II, P < 10(-3)). The screening test was realized in accordance with guidelines for 80% of women in period II. The acceptability of the test by women was estimated at 98%. Furthermore, 90% of them would accept to be screened again during another pregnancy. DISCUSSION: Specific information about WHO screening guidelines improves doctor practices. Moreover, the high rate of acceptance by women is an argument to promote more widespread WHO screening for GDM during pregnancy.

The concerted modulation of proliferation and migration contributes to the specification of the cytoarchitecture and dimensions of cortical areas.

Regionalization of cell cycle kinetics of cortical precursors has been described in nonhuman primates and rodents indicating a fate map of areas as distinct proliferative programs in the germinal zones of the neocortex. It remains to be understood how proliferative gradients during corticogenesis are transcribed into a stepwise function to form adult areal borders. Here we have used the monkey areas 17 and 18, which show striking cytoarchitectonic differences, as a model system for studying how developmental events establish areal boundaries in the adult. We present data indicating that the events that are involved in the formation of a sharp border separating 2 areas involve an orchestration of diverse phenomena including differential rates of proliferation, migration, and tangential expansion.

G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex.

We have investigated the cell cycle-related mechanisms that lead to the emergence of primate areas 17 and 18. These areas are characterized by striking differences in cytoarchitectonics and neuron number. We show in vivo that (1) area 17 precursors of supragranular neurons exhibit a shorter cell cycle duration, a reduced G1 phase, and a higher rate of cell cycle reentry than area 18 precursors; (2) area 17 and area 18 precursors show contrasting and specific levels of expression of cyclin E (high in area 17, low in area 18) and p27Kip1 (low in area 17, high in area 18); (3) ex vivo up- and downmodulation of cyclin E and p27Kip1 show that both regulators influence cell cycle kinetics by modifying rates of cell cycle progression and cell cycle reentry; (4) modeling the areal differences in cell cycle parameters suggests that they contribute to areal differences in numbers of precursors and neuron production.

Early and rapid targeting of eye-specific axonal projections to the dorsal lateral geniculate nucleus in the fetal macaque.

The emergence of eye-specific axonal projections to the dorsal lateral geniculate nucleus (dLGN) is a well established model system for exploring the mechanisms underlying afferent targeting during development. Using modern tract tracing methods, we examined the development of this feature in the macaque, an Old World Primate with a visual system similar to that of humans. Cholera toxin beta fragment conjugated to Alexa 488 was injected into the vitreous of one eye, and CTbeta conjugated to Alexa 594 into the other eye of embryos at known gestational ages. On embryonic day 69 (E69), which is approximately 100 d before birth, inputs from the two eyes were extensively intermingled in the dLGN. However, even at this early age, portions of the dLGN were preferentially innervated by the right or left eye, and segregation is complete within the dorsalmost layers 5 and 6. By E78, eye-specific segregation is clearly established throughout the parvocellular division of the dLGN, and substantial ocular segregation is present in the magnocellular division. By E84, segregation of left and right eye axons is essentially complete, and the six eye-specific domains that characterize the mature macaque dLGN are clearly discernable. These findings reveal that targeting of eye-specific axonal projections in the macaque occurs much earlier and more rapidly than previously reported. This segregation process is completed before the reported onset of ganglion cell axon loss and retino-dLGN synapse elimination, suggesting that, in the primate, eye-specific targeting occurs independent of traditional forms of synaptic plasticity.

Cost-effectiveness analysis of gestational diabetes mellitus screening in France.

OBJECTIVE: To compare three strategies for gestational diabetes screening (i) screening of high-risk pregnant women with the 50 g oral glucose tolerance test (OGTT); (ii) screening of all pregnant women with the 50 g OGTT; (iii) screening of all pregnant women according to the 75 g OGTT. STUDY DESIGN: Cost-effectiveness analysis. The outcome measures, i.e. macrosomia, prematurity, perinatal mortality, hypertensive disorders rates were estimated from published studies and the costs from a prospective study involving 120 pregnant women. RESULTS: Compared to the first strategy, the cost to obtain one unit of additional effectiveness with the second screening strategy, was up to 1.1 times more expensive, and with the third strategy was up to 3.7 times more expensive. CONCLUSION: The costs per case prevented reflect a favourable cost-effectiveness ratio (CER) for screening of high-risk pregnant women by 50 g oral glucose test.

Early specification of the hierarchical organization of visual cortical areas in the macaque monkey.

The laminar organization of cortico-cortical projection neurons (expressed by the percentage of supragranular projecting neurons - SLN%) characterizes cortical pathways as feedforward (FF) or feedback (FB) and determines the hierarchical ranking of cortical areas. There is evidence of a developmental reduction in SLN% of pathways to area V1. Here, by analyzing pre- and postnatal projections to area V4, we have been able to address whether developmental reductions of SLN% impact on information processing in the immature cortex. FB pathways to area V4 exhibit 28-84% reduction of SLN%. This contrasts with the FF projections, which show little or no SLN% reduction. However, SLN% values in the immature cortex allocated cortical areas to the same hierarchical levels as in the adult. The developmental reduction of SLN% is a widespread phenomenon in the neocortex and is a distinctive feature of FB pathways. Two mechanisms contribute to developmental changes in SLN%: (i) delayed ingrowth of axons into the cortical target from infragranular layer neurons and (ii) prolonged developmental reduction of the divergence of projections from supragranular layer neurons. The present results show that FF and FB projections exhibit different developmental processes and patterns of connections linking cortical areas and their hierarchical relations are established prenatally, independently of regressive phenomena.

Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey.

We examined the development of the occipital lobe in fetal monkeys between embryonic day 37 (E37) and E108 in Nissl-stained and acetylcholine esterase (AChE)-reacted sections. We paid particular attention to features that distinguish the development of presumptive area 17. At E46 the neuroepithelium consists of a ventricular zone and a monolayer cortical plate sandwiched between a thin marginal zone and a minimal presubplate. Between E55 and E65 an augmented subplate emerges and continues to expand up to E94 to become a major compartment of the developing cortex. A mitotic subventricular zone is established by E55. Peaking in depth at E72, it constitutes the principal germinal zone. By E78 an invading fibre tract divides it into an outer radially organized zone and a more conventional inner zone. AChE staining reveals the future area 17/18 border from E86 onwards. Proceeding from presumptive area 17 to area 18 there is a progressive thinning of the radially structured subventricular zone. Comparison of these results with corticogenesis in rodents suggests a number of potentially unique primate features: (i) a minimal preplate stage; (ii) a radially augmented germinal zone not previously described in non-primates; (iii) a fibre tract dividing the subventricular zone into two laminae; (iv) late generation and expansion of the subplate.