Trophoblastic and decidual response to RU486: effects on human chorionic gonadotrophin, human placental lactogen, prolactin and pregnancy-associated plasma protein-A production in vitro

RU486 [17β-hydroxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-oestra-4,9-dien-3-one] a potent progesterone antagonist, was shown to induce abortions in humans. Human chorionic gonadotrophin (HCG) and pregnancy-associated plasma protein-A (PAPP-A) decreased after RU486 administration, but it was not clear whether these effects were due to RU486 or secondary to trophoblast damage. To answer this question we tested the in-vitro effects of RU486 on short-term cultures of trophoblastic and decidual explants. It was observed that RU486 induced a significant inhibition of the trophoblastic production rate of βHCG and PAPP-A but not human placental lactogen. This effect could be overcome by addition of progesterone (for PAPP-A and βHCG) or cortisol (for βHCG). Decidual prolactin (Prl) or PAPP-A secretions were also inhibited by RU486. Progesterone antagonized these effects, whereas cortisol was ineffective. These results suggest that PAPP-A is a progesterone-dependent protein and that the abortifacknt effect of RU486 in humans could at least partially be due to an inhibition of the production of HCG and/or PAPP-

Functional Deficit and Recovery of Developing Sensorimotor Networks following Neonatal Hypoxic-Ischemic Injury in the Rat

Neonatal hypoxia-ischemia (HI) is the most important cause of brain injury in the newborn. Here we studied structural alterations and functional perturbations of developing large-scale sensorimotor cortical networks in a rat model of moderate HI at postnatal day 3 (P3). At the morphological level, HI led to a disorganized barrel pattern in the somatosensory cortex without detectable histological changes in the motor cortex. Functional effects were addressed by means of epicranial mapping of somatosensory-evoked potentials (SEPs) during the postischemic recovery period. At P10, SEPs were immature and evoked activity was almost restricted to the somatosensory and motor cortices of the contralateral hemisphere. Peak and topographic analyses of epicranial potentials revealed that responses were profoundly depressed in both sensory and motor areas of HI-lesioned animals. At the end of the postnatal period at P21, responses involved networks in both hemispheres. SEP amplitude was still depressed in the injured sensory region, but it completely recovered in the motor area. These results suggest a process of large-scale network plasticity in sensorimotor circuits after perinatal ischemic injury. The model provides new perspectives for investigating the temporal and spatial characteristics of the recovery process following HI and eventually developing therapeutic intervention

Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain.

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI

Developmental Changes and Injury Induced Disruption of the Radial Organization of the Cortex in the Immature Rat Brain Revealed by In Vivo Diffusion Tensor MRI

During brain development, morphological changes modify the cortex from its immature radial organization to its mature laminar appearance. Applying in vivo diffusion tensor imaging (DTI), the microstructural organization of the cortex in the immature rat was analyzed and correlated to neurohistopathology. Significant differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were detected between the external (I-III) and deep (IV-VI) cortical layers in postnatal day 3 (P3) and P6 pups. With cortical maturation, ADC was reduced in both cortical regions, whereas a decrease in FA was only seen in the deep layers. A distinct radial organization of the external cortical layers with the eigenvectors perpendicular to the pial surface was observed at both ages. Histology revealed maturational differences in the cortical architecture with increased neurodendritic density and reduction in the radial glia scaffolding. Early DTI after hypoxia-ischemia at P3 shows reduced ADC and FA in the ipsilateral cortex that persisted at P6. Cortical DTI eigenvector maps reveal microstructural disruption of the radial organization corresponding to regions of neuronal death, radial glial disruption, and astrocytosis. Thus, the combined use of in vivo DTI and histopathology can assist in delineating normal developmental changes and postinjury modifications in the immature rodent brai

Mapping the Early Cortical Folding Process in the Preterm Newborn Brain

In the developing human brain, the cortical sulci formation is a complex process starting from 14 weeks of gestation onward. The potential influence of underlying mechanisms (genetic, epigenetic, mechanical or environmental) is still poorly understood, because reliable quantification in vivo of the early folding is lacking. In this study, we investigate the sulcal emergence noninvasively in 35 preterm newborns, by applying dedicated postprocessing tools to magnetic resonance images acquired shortly after birth over a developmental period critical for the human cortex maturation (26-36 weeks of age). Through the original three-dimensional reconstruction of the interface between developing cortex and white matter and correlation with volumetric measurements, we document early sulcation in vivo, and quantify changes with age, gender, and the presence of small white matter lesions. We observe a trend towards lower cortical surface, smaller cortex, and white matter volumes, but equivalent sulcation in females compared with males. By precisely mapping the sulci, we highlight interindividual variability in time appearance and interhemispherical asymmetries, with a larger right superior temporal sulcus than the left. Thus, such an approach, included in a longitudinal follow-up, may provide early indicators on the structural basis of cortical functional specialization and abnormalities induced by genetic and environmental factor

Expression of FGF-2 in neural progenitor cells enhances their potential for cellular brain repair in the rodent cortex

Strategies to enhance the capacity of grafted stem/progenitors cells to generate multipotential, proliferative and migrating pools of cells in the postnatal brain could be crucial for structural repair after brain damage. We investigated whether the over-expression of basic fibroblast growth factor 2 (FGF-2) in neural progenitor cells (NPCs) could provide a robust source of migrating NPCs for tissue repair in the rat cerebral cortex. Using live imaging we provide direct evidence that FGF-2 over-expression significantly enhances the migratory capacity of grafted NPCs in complex 3D structures, such as cortical slices. Furthermore, we show that the migratory as well as proliferative properties of FGF-2 over-expressing NPCs are maintained after in vivo transplantation. Importantly, after transplantation into a neonatal ischaemic cortex, FGF-2 over-expressing NPCs efficiently invade the injured cortex and generate an increased pool of immature neurons available for brain repair. Differentiation of progenitor cells into immature neurons was correlated with a gradual down-regulation of the FGF-2 transgene. These results reveal an important role for FGF-2 in regulating NPCs functions when interacting with the host tissue and offer a potential strategy to generate a robust source of migrating and immature progenitors for repairing a neonatal ischaemic corte

Primary cortical folding in the human newborn: an early marker of later functional development

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early ‘endophenotypes' of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants' outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infant's behaviour (APIB

Модифікована модель агрегованої мертвої зони на прикладах переносу радіонуклідів у природних гідродинамічних системах

This paper presents the results obtained during a detailed study of the aggregate dead zone model designed to describe the longitudinal transport and dispersion of dissolved substances in a channel flow. This model is based on a new approach to the description of advection and dispersion, which allows to adequately reproduce the concentrations of solutes observed in natural hydrodynamic systems with a high degree of accuracy. Instead of modelling the dissolved solute concentration continuously in both distance and time along the watercourse, the aggregate dead zone model uses a black box approach and considers the concentration at the chamber outlet (from the aggregate dead zone) as a function of the concentration at the chamber inlet and the current time. This approach significantly reduces the computational time and reduces the requirements for the amount of initial and boundary data. The mathematical apparatus of the extended model of the aggregated dead zone is presented, designed to analyse the transport of non-conservative radioactive contamination in real water bodies, taking into account the possible interaction of the radionuclide with suspended sediments and a layer of bottom sediments. The equations of the proposed model are a system of ordinary differential equations with a delayed argument. The results of modelling the distribution of 3 H as a result of releases from 14 nuclear reactors in the Russian section of the Loire River for six months with an hourly discreteness are presented. The results of modelling the propagation of sudden 90Sr releases in the Kyiv reservoir, which occurred in 1999 as a result of the Chornobyl disaster, are presented. The modelling was carried out with a daily discreteness. A comparison of the obtained model values of radionuclide concentrations and measurement data was carried out. The proposed model has a comparative simplicity, much lower requirements for the amount of initial and boundary data, and very little time required for calculations.Prombles in programming 2024; 2-3: 45-52У роботі представлено результати, отримані під час детального дослідження моделі агрегованої мертвої зони, призначеної для опису поздовжнього перенесення і розсіювання розчинених речовин у русловому потоці. Ця модель ґрунтується на новому підході до опису адвекції та дисперсії, який дає змогу адекватно відтворювати спостережувані у природних гідродинамічних системах концентрації розчинених речовин із високим ступенем точності. Замість того, щоб моделювати концентрацію розчиненої речовини безперервно як за відстанню, так і за часом уздовж водотоку, модель агрегованої мертвої зони використовує підхід "чорної скриньки" і розглядає концентрацію на виході камери (з агрегованої мертвої зони) як функцію концентрації на вході камери та поточного часу. Такий підхід значно скорочує час обчислень і зменшує вимоги до обсягу вихідних і граничних даних. Наведено математичний апарат розширеної моделі агрегованої мертвої зони, призначеної для аналізу транспортування неконсервативного радіоактивного забруднення в реальних водних об'єктах, з урахуванням можливої взаємодії радіонукліда зі зваженими намулами і шаром донних відкладень. Рівняння запропонованої моделі складають систему звичайних диференційних рівнянь із запізнілим аргументом. Показано результати моделювання поширення 3 H в результаті викидів від 14 ядерних реакторів у русловій ділянці р. Луара протягом півроку із щогодинною дискретністю. Наведено результати моделювання розповсюдження різких викидів 90 Sr у Київському водосховищі, що мали місце в 1999 р. внаслідок Чорнобильської катастрофи. Моделювання виконано з добовою дискретністю. Проведено порівняння отриманих модельних значень концентрацій радіонуклідів і даних вимірювань. Запропонована модель має порівняльну простоту, значно менші вимоги до кількості початкових і граничних даних, дуже короткий час, необхідний для проведення розрахунків.Prombles in programming 2024; 2-3: 45-5