Premature placental aging in term small-for-gestational-age and growth-restricted fetuses.

OBJECTIVE: To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. METHODS: This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3rd and 9th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2-ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups. RESULTS: Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2-ΔΔCt , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2-ΔΔCt , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2-ΔΔCt , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2-ΔΔCt , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. CONCLUSIONS: Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Envejecimiento prematuro de la placenta en fetos pequeños para la edad gestacional y con restricción del crecimiento OBJETIVO: Realizar una evaluación integral del proceso de envejecimiento de la placenta en fetos a término clasificados como pequeños para la edad gestacional (PEG) o con restricción del crecimiento fetal (RCF) mediante el análisis de los marcadores de senescencia y apoptosis. MÉTODOS: Este fue un estudio prospectivo de casos y controles anidados de embarazos únicos a término, que incluyó 21 embarazos de control con fetos de crecimiento normal y 36 con un feto clasificado como PEG (peso al nacer entre los percentiles 3o y 9o y Doppler fetoplacentario normal; n=18) o con RCF (peso al nacer menor del percentil 3o y/o relación cerebroplacentaria anómala y/o Doppler de la arteria uterina; n=18). La actividad de la telomerasa, la longitud de los telómeros (cuantificada comparando la cantidad de producto de amplificación para la secuencia de telómeros (T) con la de una sola copia del gen 36B4 (S)) y la expresión del ARN de la senescencia (Sirtuinas 1, 3 y 6) y los marcadores de apoptosis (p53, p21, BAX y Caspasas 3 y 9) (analizados usando el método 2-∆∆Ct ) se determinaron en muestras de placenta obtenidas en el momento del nacimiento y se compararon entre los tres grupos. RESULTADOS: En comparación con los embarazos con un feto de crecimiento normal, tanto los embarazos PEG y con RCF presentaron signos de envejecimiento placentario acelerado, como una menor actividad de la telomerasa (media ± SD, 12,8 ± 6,6% en los controles frente a 7,98 ± 4,2% en PEG frente a 7,79 ± 4,6% en RCF; P=0,008), telómeros más cortos (media ± SD razón T/S, 1,20 ± 0,6 en los controles frente a 1,08 ± 0,9 en PEG frente a 0,66 ± 0,5 en RCF; P=0,047) y expresión reducida de la Sirtuina 1 en el ARN (media ± SD 2-∆∆Ct , 1,55 ± 0,8 en los controles frente a 0,91 ± 0,8 en PEG frente a 0,63 ± 0,5 en RCF; P=0,001), junto con una mayor expresión del p53 en el ARN (mediana (rango intercuartil) 2-∆∆Ct , 1,07 (0,3-3,3) en los controles frente a 5,39 (0,6-15) en PEG frente a 3,75 (0,9-7,8) en RCF; P=0,040). Los casos de RCF presentaron signos de apoptosis, con un aumento de los niveles en ARN de la Caspasa 3 (mediana (rango intercuartil) 2-∆∆Ct , 0,94 (0,7-1,7) en los controles frente a 3,98 (0,9-31) en RCF; P=0,031) y Caspasa 9 (mediana (rango intercuartil) 2-∆∆Ct , 1,21 (0,6-4,0) en los controles frente a 3,87 (1,5-9,0) en RCF; P=0,037) en comparación con los controles. Además, la expresión de la Sirtuina 1 en el ARN, la actividad de la telomerasa, la longitud de los telómeros y la actividad de la Caspasa 3 mostraron tendencias lineales significativas entre los grupos en función del aumento de la severidad de la anomalía. CONCLUSIONES: Se observó un envejecimiento acelerado de la placenta en ambas formas clínicas de tamaño pequeño del feto de inicio tardío (PEG y RCF), lo que apoya una fisiopatología común y pone en tela de juicio el concepto de que los fetos PEG son en pequeños por su propia condición.

Distinctive patterns of placental lesions in pre-eclampsia vs small-for-gestational age and their association with fetoplacental Doppler.

OBJECTIVES: To describe placental histopathological findings in a large cohort of pregnancies complicated by pre-eclampsia (PE) and/or small-for-gestational age (SGA), and to investigate their association with fetoplacental Doppler parameters. METHODS: This was a prospective observational study of normotensive pregnancies with SGA (defined as birth weight < 10th centile) (n = 184), PE pregnancies with a normally grown fetus (n = 102), pregnancies with both PE and SGA (n = 120) and uncomplicated pregnancies (n = 202). Uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) artery pulsatility indices (PI) were assessed. The cerebroplacental ratio (CPR) was calculated by dividing MCA-PI by UA-PI. Doppler parameters were considered abnormal when UtA-PI or UA-PI was > 95th centile or MCA-PI or CPR was < 5th centile. Placental lesions were categorized as vascular (maternal or fetal side), immunoinflammatory or other, according to the 2014 Amsterdam Placental Workshop Group Consensus Statement. Comparison between the study groups was performed using univariate and multiple regression analysis, and logistic regression was used to determine the relationship between abnormal Doppler parameters and placental lesions. RESULTS: Maternal-side vascular lesions were significantly more common in PE pregnancies with SGA than in the other groups (PE + SGA, 73% vs PE, 46% vs SGA, 38% vs controls, 31%; P = 0.01) and included mainly two types of lesion: developmental (PE + SGA, 13% vs PE, 5% vs SGA, 3% vs controls, 1.5%; P < 0.001) and malperfusion (PE + SGA, 70% vs PE, 39% vs SGA, 32% vs controls, 25%; P = 0.001). In contrast, the incidence of fetal-side developmental lesions was significantly higher in normotensive SGA pregnancies than in controls and PE pregnancies (PE + SGA, 0% vs PE, 3% vs SGA, 8% vs controls, 2%; P = 0.001). All cases displayed a lower prevalence of infectious lesions than did controls, with the highest prevalence of immune lesions observed in pregnancies with both PE and SGA (PE + SGA, 18% vs PE, 8% vs SGA, 10% vs controls, 9%; P = 0.001). All fetoplacental Doppler parameters evaluated were associated with maternal-side vascular lesions, mainly malperfusion (mean UtA-PI: odds ratio (OR), 2.45 (95% CI, 1.51-3.97); UA-PI: OR, 2.05 (95% CI, 1.02-4.47); MCA-PI: OR, 2.75 (95% CI, 1.40-5.42); CPR: OR, 1.75 (95% CI, 1.04-2.95)). This association was evident mainly in the normotensive SGA group, being non-significant in controls or PE pregnancies without SGA. No significant associations were observed between fetoplacental Doppler parameters and other placental lesions in any of the study groups. CONCLUSIONS: PE and SGA are associated with different patterns of placental histopathological lesions in accordance with the clinical manifestation of the placental disorder (maternal vs fetal). Fetoplacental Doppler findings show an association with placental malperfusion lesions on the maternal side, supporting the use of abnormal Doppler as a surrogate for placental insufficiency. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Anal canal duplication and triplication: a rare entity with different presentations.

Anal canal duplication (ACD) is the rarest of gastrointestinal duplications. Few cases have been reported. Most cases present as an opening in the midline, posterior to the normal anus. The aim of our revision is to contribute with eight new cases, some of them with unusual presentations: five presented as the typical form, one with a perianal nodule, and two presented as two separate orifices (anal canal triplication). Complete excision was performed in all patients with no complications. ACD is the most distal and the least frequent digestive duplication. Its treatment should be surgical excision, to avoid complications such as abscess, fistulization, or malignization. Anal canal triplication has never been described before.

Exchange Coupling Inversion in a High-Spin Organic Triradical Molecule.

The magnetic properties of a nanoscale system are inextricably linked to its local environment. In adatoms on surfaces and inorganic layered structures, the exchange interactions result from the relative lattice positions, layer thicknesses, and other environmental parameters. Here, we report on a sample-dependent sign inversion of the magnetic exchange coupling between the three unpaired spins of an organic triradical molecule embedded in a three-terminal device. This ferro-to-antiferromagnetic transition is due to structural distortions and results in a high-to-low spin ground-state change in a molecule traditionally considered to be a robust high-spin quartet. Moreover, the flexibility of the molecule yields an in situ electric tunability of the exchange coupling via the gate electrode. These findings open a route to the controlled reversal of the magnetic states in organic molecule-based nanodevices by mechanical means, electrical gating, or chemical tailoring.

Are French general practitioners consulted before travel to developing countries? A cross-sectional study conducted in a French airport.

BACKGROUND: General practitioners (GPs) could play a central role in preventing travel-related health issues. The aim of this study was to assess, in travellers departing to developing countries from a French airport, the proportion of individuals having sought GP counseling before departure and to identify determinants for having consulted a GP. METHODS: Cross-sectional study conducted between November 2012 and July 2013, in all adults living in France. Sociodemographic, health characteristics, type of travel and resources consulted before departure were collected. A descriptive analysis was performed. Determinants for having consulted a GP before departure were investigated using a logistic regression analysis. RESULTS: Of the 360 travellers included, 230 (64%) sought health counseling before departure. GPs were the main source of information for 134 (58%) travellers having sought health information and the only one for 49 (21%). Almost half of the travellers (48%) departing to sub-Saharan countries did not seek health counseling from a medical doctor (GP, non-GP specialist, specialist consulted in an international vaccination center or occupational physician). Individuals significantly more likely to travel without having consulted a GP were young and male, held foreign nationality, had travelled more than five times before, rarely consulted their GP and were travelling to a non-malarious area. CONCLUSION: GPs were the main but not the only source of information and counseling before traveling to a developing country. This study helps identify the characteristics of individuals likely to travel without having consulted a GP before departure.

[Surgical treatment of giant congenital melanocytic nevi: a change of aim]. / Tratamiento quirúrgico del nevus melanocítico gigante: un cambio de objetivo.

OBJECTIVE: To review the surgical experience in Giant Congenital Melanocytic Nevi (GCMN). MATERIAL AND METHODS: Review of GCMN cases consulting at the Department of Pediatric Surgery since 1994. Data registered were: year and age at 1st consultation, type of treatment, number of surgical procedures and complications, histology, central nervous system MRI and follow-up. RESULTS: Eleven patients with GCMN > 10% of body surface consulted at ages ranging from newborn to 8 years. All of them had multiple surgical procedures (2-19), from nevus removal to only biopsies. Eight patients had tissue expansion, completed in 3 of them with skin grafts on dermal substitute. Six patients had complications: 4 expander extrusions, 5 infections, 3 flap necrosis and 1 dehiscence. In 6 children a total or subtotal resection of the nevus was achieved; in 2 the treatment was interrupted, remaining 20% and 50% of the initial nevus; three patients had not had nevus treatment. None of the patients presented cutaneous melanoma; one died from intracranial melanoma; another one has leptomeningeal melanosis. The first 4 patients underwent an average of 16 surgical procedures each, the last 7 patients only 5. CONCLUSIONS: The aim of GCNM management has changed: GCNM treatment is now surgically conservative. Complete excision is now not the aim when technically unfeasible in few procedures; multiple surgical procedures with poor cosmetical results are not acceptable. The gravity is determined by CNS involvement.

Facial telangiectasia: an unusual manifestation of neonatal lupus erythematosus.

Neonatal lupus erythematosus (NLE) is an uncommon condition usually associated with maternal anti-Ro autoantibodies. The cutaneous lesions of NLE are usually transient, disappearing about six months after birth, but telangiectasia is a rare complication of NLE which persists. Telangiectasias are small focal red macules and papules created by abnormally prominent capillaries, venules, and arterioles and are a characteristic marker of connective tissue diseases. We report the case of an infant diagnosed with NLE presenting typical annular lesions, positive ANA and positive anti-Ro antibodies. By five months of age, both ANA and anti-Ro antibodies were negative and the annular cutaneous lesions had gradually faded, but small scattered focal red macules appeared on the face, especially in the peri-orbital area and scalp. The cutaneous lupus disappeared but the telangiectasia persisted. We would like to suggest that the diagnosis of NLE should be considered when cutaneous telangiectasias are observed in infants.

Proton transfer drives protein radical formation in Helicobacter pylori catalase but not in Penicillium vitale catalase.

Heme catalases prevent cells from oxidative damage by decomposing hydrogen peroxide into water and molecular oxygen. Here we investigate the factors that give rise to an undesirable side reaction competing with normal catalase activity, the migration of a radical from the heme active site to the protein in the principal reaction intermediate compound I (Cpd I). Recently, it has been proposed that this electron transfer reaction takes place in Cpd I of Helicobacter pylori catalase (HPC), but not in Cpd I of Penicillium vitale catalase (PVC), where the oxidation equivalent remains located on the heme active site. Unraveling the factors determining the different radical locations could help engineer enzymes with enhanced catalase activity for detection or removal of hydrogen peroxide. Using quantum mechanics/molecular mechanics metadynamics simulations, we show that radical migration in HPC is facilitated by the large driving force (-0.65 eV) of the subsequent proton transfer from a histidine residue to the ferryl oxygen atom of reduced Cpd I. The corresponding free energy in PVC is significantly smaller (-0.19 eV) and, as we argue, not sufficiently high to support radical migration. Our results suggest that the energetics of oxoferryl protonation is a key factor regulating radical migration in catalases and possibly also in hydroperoxidases.

Porokeratotic eccrine ostial and dermal duct naevus: report of 10 cases.

BACKGROUND: Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a congenital hamartoma that has rarely been documented. OBJECTIVES: To describe the clinical and histological features of 10 patients with PEODDN. METHODS: A retrospective study of 10 patients with PEODDN attended in our paediatric hospital between 1999 and 2009 was performed. The clinical and histopathological features were reviewed. RESULTS: Nine children and one adult were included in the study. In 6 cases the lesion was present at birth and they were unique in 5 cases and systematized in the other 5 cases. Two cases in the same family are reported. The lesions were most commonly found on the extremities, although the palms or soles were involved in 9 cases and only in one case there was not affection of this area. The lesions were mostly asymptomatic but there was moderate itching in two cases. Clinical examination revealed no extracutaneous involvement. CONCLUSIONS: PEODDN is a rare disorder that usually appears at birth or early childhood. It has a linear distribution following the Blaschko lines. To our knowledge this is the largest series reported in English literature and we also describe the first family case.

Granulosa cell tumor and endometrial cancer: a case report and review of the literature.

Granulosa cell tumors (GCTs) of the ovary are an uncommon type of ovarian cancer, representing only 2-5%. Frequently, their tumoral cells present some features of normal granulosa cells, like hormonal production. As a consequence, this neoplasia can be diagnosed either by common ovarian cancer symptoms or endometrial pathologies due to an estrogenic effect. Symptoms caused by estrogen production can also give rise to different clinical manifestations depending on whether they appear in postmenopausal or young women. In the case we present below, a patient was referred for presenting postmenopausal bleeding of one year's duration. Once endometrial cancer was diagnosed and subsequently staged, an ovarian mass was detected. We report an atypical case of ovarian cancer with the aim of reviewing the clinical features of GCT, as well as its prognosis, treatment and follow-up recommendations, according to the available literature.

Enzymatic Cleavage of Glycosidic Bonds: Strategies on How to Set Up and Control a QM/MM Metadynamics Simulation.

Carbohydrates play crucial roles in many biological processes, from cell-cell adhesion to chemical signaling. Their complexity and diversity, related to α/ß anomeric configuration, ring substituents, and conformational variations, require a diverse set of enzymes for their processing. Among them, glycoside hydrolases (GHs) are responsible for the hydrolysis of one of the strongest bonds in nature: the glycosidic bond. These highly specialized biological catalysts select particular conformations their carbohydrate substrates to enhance catalysis. The evolution of this conformation during the reaction of glycosidic bond cleavage, known as the conformational catalytic itinerary, is of fundamental interest in glycobiology, with impact on inhibitor and drug design. Here we review some of the aspects and the main strategies one needs to take into account when simulating a reaction in a GH enzyme using QM/MM metadynamics. Several specific aspects are highlighted, from the importance of the distortion of the substrate at the Michaelis complex to the variable control during the metadynamics simulation or the analysis of the reaction mechanism and conformational itinerary. The increasing speed of computer power and methodological advances have added a vital tool to the study of GH mechanisms, as shown here and recent reviews. It is hoped that this chapter will serve as a first guide for those attempting to perform a metadynamics simulation of these relevant and fascinating enzymes.

Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology. / Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.

INTRODUCTION: Congenital glioblastoma multiforme represents only 3% of congenital central nervous system tumours and an infratentorial location is unusual. CASE REPORT: A newborn with congenital glioblastoma multiforme with no mutation in the TP53 gene or p53 nuclear immunoreactivity that infiltrated practically the whole brainstem and also invaded supratentorial structures. CONCLUSIONS: As far as we know, only four cases with an infratentorial location have been reported previously, three in the cerebellum and one in the brainstem. The biology of congenital glioblastoma multiforme is not well known and, unlike glioblastoma multiforme in adults and children, mutations in the TP53 gene are uncommon. However, this is not associated with a more favourable prognosis. These observations suggest that specific biological processes underlie fetal glioblastoma multiforme development.

TITLE: Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.Introduccion. El glioblastoma multiforme congenito representa solo el 3% de los tumores congenitos del sistema nervioso central, y su ubicacion infrantentorial es excepcional. Caso clinico. Recien nacido con un glioblastoma multiforme congenito sin mutacion en el gen TP53 ni inmunorreactividad nuclear p53, que infiltraba practicamente todo el tronco cerebral e invadia tambien estructuras supratentoriales. Conclusiones. Hasta donde sabemos, solo se han referido previamente cuatro casos de localizacion infratentorial, tres en el cerebelo y uno en el tronco del encefalo. La biologia del glioblastoma multiforme congenito no se conoce bien y, a diferencia del glioblastoma multiforme en la edad adulta, las mutaciones en el gen TP53 son poco frecuentes, sin que eso parezca implicar un mejor pronostico. Estas observaciones sugieren que el glioblastoma multiforme con origen en la vida fetal tiene una biologia diferente del que se presenta en otras etapas de la vida.

Site-specific insertion of a SINE-like element, Cp1, into centromeric tandem repeats from Chironomus pallidivittatus.

A SINE-like dispersed element, Cp1, from the dipteran Chironomus pallidivittatus was found to show site-specific insertion into two different centromeric tandem repeats. The insertions result in identical target site duplications of nine base-pairs. In contrast, extracentromeric Cp1 elements, which are polymorphic and degenerate, are previously known to be surrounded by different target site duplications. The intracentromeric Cp1 is uniform in structure and contains a single pol III unit, upstream of which 87 bp arms of a palindrome surround a 103 bp unique sequence. The numbers of Cp1 elements per centromere were determined in microdissected material and were found to be in the range of five to ten units per centromere. The well-defined insertion properties, correlated to chromosomal localization, suggest that Cp1 is likely to be a component of importance for the centromere. Similarities of Cp1 and its parts to functionally identified centromeres in Saccharomyces cerevisiae and Schizosaccharomyces pombe are discussed.

Polymorphic SINEs in chironomids with DNA derived from the R2 insertion site.

A short interspersed repeat (SINE) in the two sibling species Chironomus pallidivittatus and Chironomus tentans is described. It is present at many sites in the genome and is surrounded by 10 to 14 bp target site duplications. It consists of two sequence modules in different numbers and variable order relative to each other and often has large inversions of different sizes at one end. One of the modules contains pol III promoter consensus sequences. This SINE, nevertheless, is likely to have been dependent on an outside promoter for its formation. It is therefore interesting that both modules start with a 22 bp region with striking similarity to the R2 insertion site in the preribosomal gene of insects. We suggest that this type of SINE, termed Cp1, was formed after a series of events among which the first step was the retroposition of a tRNA gene into the R2 site in the preribosomal gene by the R2 coded protein. The final step is likely to have been due to retroposition from this site.

Opposite actions of muscarinic and nicotinic agents on hippocampal dendritic negative fields recorded in rats.

In rats under urethane anaesthesia, microiontophoretic application of muscarinic or nicotinic agents, in the pyramidal layer of the hippocampus, enhanced the population spike (s) evoked by fimbrial stimulation. In contrast, muscarinic and nicotinic agents had an opposite action on on the dendritic field potentials, they respectively reduced and enhanced the negative fields (field EPSP) recorded in the apical dendrites. These effects were antagonized by muscarinic and nicotinic antagonists, respectively.

Opposite actions of muscarinic and nicotinic agents on hippocampal dendritic negative fields recorded in rats.

In rats under urethane anaesthesia, microiontophoretic application of muscarinic or nicotinic agents, in the pyramidal layer of the hippocampus, enhanced the population spike (s) evoked by fimbrial stimulation. In contrast, muscarinic and nicotinic agents had an opposite action on on the dendritic field potentials, they respectively reduced and enhanced the negative fields (field EPSP) recorded in the apical dendrites. These effects were antagonized by muscarinic and nicotinic antagonists, respectively.

Somatic and dendritic actions of gamma-aminobutyric acid agonists and uptake blockers in the hippocampus in vivo.

In rats under urethane anaesthesia gamma-aminobutyric acid agonists and uptake blockers were microiontophoretically applied in the pyramidal layer of CA1 and in the apical dendrites using a twin set of multibarrelled micropipettes. Thus, the somatic and dendritic field potentials elicited by commissural stimulation were recorded simultaneously and the effects of iontophoretic applications at either site studied. Somatic applications of gamma-aminobutyric acid, isoguvacine or muscimol produced an inhibition of the somatic population spike; this showed rapid fade and was followed by an "off" response i.e. an enhancement of the population spike discharge and the occurrence of a second (and occasionally third) spike. The order of potency with regard to the "off" response was muscimol greater than isoguvacine much greater than gamma-aminobutyric acid. In contrast, the inhibition of the population spike produced by 4,5,6,7-tetrahydroisoxazolo(5,4-C) pyridin 3-OL showed little fade and no prominent "off" response. The fade and "off" response were not associated with significant changes in the dendritic field excitatory postsynaptic potential concommittantly recorded and were exclusively restricted to the immediate vicinity of the pyramidal layer. Ejection of gamma-aminobutyric acid and its agonists in the stratum radiatum produced a reduction of the field excitatory postsynaptic potential and the somatic spike, this effect however showed no fade (even during prolonged applications of high doses) and no "off" response. Somatic applications of the uptake blockers nipecotic acid or guvacine consistently produced: an increase in the effectiveness of the inhibition produced by gamma-aminobutyric acid and its analogues: a decrease in the latency to peak of the inhibition and an increase in the time to recovery; a full blockade of the fade and the "off" response. All of these effects were rapid and fully reversible without significant changes in either the field excitatory postsynaptic potential or the (control) somatic spikes. The more specific glial uptake blocker, 4,5,6,7-tetrahydroisoxazolo(4,5-C) pyridin 3-OL occasionally blocked the "off" response, however it was less potent and also tended to reduce the spike amplitude. Dendritic applications of the uptake blockers reduced the excitatory postsynaptic potential and the somatic spike but failed to produce prominent changes in the action of gamma-aminobutyric acid and its analogues.(ABSTRACT TRUNCATED AT 400 WORDS)

Intra-amygdaloid injections of kainic acid: regional metabolic changes and their relation to the pathological alterations.

Kainic acid was injected unilaterally in the amygdala of the rat. Following various delays, 2-deoxy-D-[14C]glucose was given intravenously. Autoradiographs of frontal brain sections showed increased glucose uptake in a number of cerebral structures as compared with controls. Most of these structures belong to, or are closely related to, what is traditionally called the 'limbic system'. The structures that show an increased glucose consumption subsequent to kainic acid injections are, with few exceptions, identical to those that are sensitive to the toxic effect that kainic acid exerts on structures distant to the site of injection. The findings are discussed in relation to the hypothesis that the latter effect is secondary to the epileptogenic properties of kainic acid.

Pharmacological characterization of D-aminophosphonovaleric acid antagonism of amino acid and synaptically evoked excitations on frog motoneurones in vitro: an intracellular study.

The effect of D-aminophosphonovaleric acid (D-APV) on the depolarizations induced by N-methyl-D-aspartate (NMDA), glutamate, aspartate or quisqualate was studied with intracellular recordings from frog motoneurones in vitro. D-APV (0.5-10 microM) produced a slight hyperpolarization of the motoneuronal membrane without significant changes in input conductance. In control and tetrodotoxin-containing solutions the depolarizations induced by NMDA were strongly reduced by D-APV while quisqualate depolarizations were unaffected. Responses to glutamate and aspartate were antagonized to an intermediate level. The relatively small conductance increases evoked by excitatory amino acids were unaltered in solutions containing D-APV. The amplitude of monosynaptic excitatory postsynaptic potentials (e.p.s.ps) was strongly depressed by D-APV. The amplitude of polysynaptic e.p.s.ps was little changed but their decay time was reduced. It is suggested that D-APV is a powerful and selective NMDA receptor antagonist and that an endogenous amino acid acting via NMDA receptors may be the transmitter of monosynaptic e.p.s.ps on frog motoneurones.

GABAergic mechanisms in the CA3 hippocampal region during early postnatal life.

The developmental pattern of GABAergic neurons in the rat hippocampus during the first week of postnatal life shows several particularities both from a morphological and physiological point of view: (1) GABA immunoreactive neurons which are initially localized in a deep and superficial layer, progressively disappear from these two layers. From the end of the first postnatal week, GABAergic neuronal somata appear throughout the whole hippocampus, but GABA immunoreactive terminal structures are not frequent until the second postnatal week. (2) Intracellular observations in slices reveal the presence in CA3 pyramidal neurons between P0 and P6 (postnatal days) of spontaneous giant depolarizing potentials (GDPs); these are mediated by GABA acting on GABAA receptors and modulated presynaptically by NMDA receptors. During this period of development, GABA and GABAA analogues have a depolarizing action at resting membrane potential. Bicuculline at this developmental stage blocks completely spontaneous and evoked synaptic potentials. During the second postnatal week, when GABA responses shift from depolarizing to hyperpolarizing, bicuculline induces spontaneous interictal discharges. It is suggested that the positive feedback of the GABAergic interneuron on the pyramidal neuron during the first week of life may account for the generation of GDPS which may play an important role in synaptogenesis.