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.

Objectives To establish whether reagent-supported thrombelastometry with the rotation thrombelastometry system (ROTEM Ò ) point-of-care device correlated with fibrinogen level in postpartum haemorrhages.Design Prospective observational study.Population and setting Ninety-one women at the third trimester of pregnancy: 37 with postpartum haemorrhage (study group) and 54 without abnormal bleeding (control group).Methods Standard laboratory test results were compared with those obtained at bedside from the ROTEM with the FIBTEM Ò test (54 tests in the control group and 51 in the study group). Results Median fibrinogen level was significantly lower in the haemorrhage group than in the control group (3.4 and 5.1 g/l, respectively, P < 0.0001). Median CT was higher in the haemorrhage group than in the control group (P = 0.05). CA 5 , CA 15 and MCF were significantly lower in the haemorrhage group than in controls (P < 0.0001) and strongly correlated with fibrinogen levels in both groups (r = 0.84-0.87, P < 0.0001). A cut-off value of CA 5 at 5 mm and CA 15 at 6 mm presented an excellent sensitivity (100% for both parameters) and a good specificity (respectively 85 and 88%) to detect fibrinogen levels <1.5 g/l in postpartum haemorrhage.Conclusions The early parameters obtained from the FIBTEM test correlated well with fibrinogen levels. ROTEM might be helpful in guiding fibrinogen transfusion during postpartum haemorrhage.

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.

In several species, the peripheral input from the eyes partly determines the pattern of interconnections between the visual areas of the two cerebral hemispheres through the fibre tract termed the corpus callosum. In the macaque monkey, the neurons projecting through the callosum are largely restricted to area 18 throughout ontogeny, whereas area 17 is characterized by few or no callosal projections. Here, we show that suppressing the peripheral input by prenatal removal of the eyes leads to a marked reduction in the extent of area 17, resulting in a large shift in the position of the histologically identifiable boundary between the two areas. Even so, the boundary continues to separate an area rich with callosal connections (area 18) from one poor in such projections (area 17), indicating there is no effect on the callosal connectivity of area 17. In contrast, in area 18, eye removal results in many more neurons with callosal projections than in normal animals. The results suggest that the factors that determine the parcellation of cortical areas also specify their connectivity.

An as-yet unresolved issue in developmental neurobiology is whether the discrete areas that form the mammalian cortex emerge from a uniform cortical plate or whether they are already specified in the germinal zone. A feature of the primate striate cortex is that the number of neurons per unit area is twice that of anywhere else in the cerebral cortex. Here we take advantage of this unique structural feature to investigate whether the extra striate cortical cells are due to increased neuron production during neurogenesis. We labelled precursors undergoing terminal cell division with 3H-thymidine and allowed them to migrate to the cortical plate. Cell counts revealed that their rate of production in the germinal zone of striate cortex is higher than in that given rise to extrastriate cortex. Also, we used 3H-thymidine pulse injections to investigate cell cycle dynamics and found that this phase of increased production of striate cortical cells is associated with changes in the parameters of the cell cycle. These results show that cortical area identity is at least partially determined at the level of the ventricular zone.

The pre- and postnatal developmental changes of the cortical afferents to area 17 were studied in the macaque monkey. Paired injections of the retrograde tracers fast blue and diamidino yellow were made in area 17. Quantitative techniques were used to examine the spatial patterns of labeling in three distinct locations of the extrastriate cortex that correspond to known visual areas. In the adult, each cortical region has a characteristic laminar distribution. In the fetus the proportion of supragranular layer neurons in all cortical regions was much higher than in the adult. The present study shows that despite the very high levels of labeled supragranular layer neurons, there is some early areal specialization so that the adult configuration does not emerge from a uniform distribution. The developmental decline in the proportion of labeled supragranular neurons is complete by 1 month after birth. Each injection of tracer gave rise in each cortical area to dense labeling in a restricted region (projection zone). Areal measurements of projection zones in the supra- and infragranular layers showed that the developmental decrease in the proportion of labeled supragranular layer neurons is accompanied by a relative change of the dimensions of supra- and infragranular projection zones: the supragranular projection zone in the fetus is larger than the infragranular projection zone and vice versa in the adult. In the fetus, the two projection zones corresponding to each of the two tracers overlap in the supragranular layers whereas they are largely separated in the infragranular layers. During development there is a progressive decrease in the overlap of the supragranular projection zones and an increase in the overlap in the infragranular layers. Again, the adult configuration is achieved 1 month after birth. This developmental inversion of the areal dimensions of the projection zones in supra- and infragranular layers is accompanied by a drastic decrease in the proportion of double-labeled neurons located in supragranular layers. These results clearly show that early in development, axonal projections to area V1 are modified in very different ways according to whether they originate from supra- or infragranular layers. This developmental process lasts for about 80 d. These findings show that in the primate there is a prolonged remodeling of axonal projections that is a highly characteristic feature of this species.

Bilateral enucleation was performed at different fetal ages during corticogenesis, and the brains were prepared for histological examination. Early-enucleated fetuses (operated prior to embryonic day 77) showed morphological changes at the level of the thalamus and the cortex. In the thalamus, there was a loss of lamination and a decrease in size of the lateral geniculate nucleus. There was a decrease in the size of the inferior pulvinar, but there was no change in the lateral pulvinar. The border of striate cortex was as sharp in the enucleates as it was in the normal monkeys. In three of the four early enucleates, we observed an interdigitation of striate and extrastriate cortex. In three of the early enucleates, we observed a small island of nonstriate cortex near the striate border that was surrounded entirely by striate cortex. Enucleation led to an age-related reduction of striate cortex. This reduction was greater in the operculum than in the calcarine fissure. The reduction of striate cortex was accompanied by an increase in the dimensions of extrastriate visual cortex, so that the overall dimensions of the neocortex remained invariant. The extrastriate cortex in the enucleated animals presented a uniform cytoarchitecture and was indistinguishable from area 18 in the normal animal. There were changes in the gyral pattern that were restricted mainly to the cortex on the operculum. A deepening of minor dimples as well as the induction of a variable number of supplementary sulci led to an increase in the convolution of the occipital lobe. These results are discussed with respect to the specification of cortical areas. They demonstrate that the reduction in striate cortex was not accompanied by an equivalent reduction in the neocortex; rather, there was a border shift, and a large volume of cortex that was destined to become striate cortex appears to be cytoarchitectonically normal extrastriate cortex.

Summary 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.