Evolutionary rates of Jurassic ammonites in relation to sea-level fluctuations

An analysis is presented of the diversity and faunal turnover of Jurassic ammonites related to transgressive /regressive events. The data set contained 400 genera and 1548 species belonging to 67 ammonite zones covering the entire Jurassic System. These data were used in the construction of faunal turnover curves and ammonite diversities, that correlate with sea-level fluctuation curves. Twenty-four events of ammonite faunal turnover are analyzed throughout the Jurassic. The most important took place at the Sinemurian-Carixian boundary, latest Carixian-Middle Domerian, Domerian-Toarcian boundary, latest Middle Toarcian-Late Toarcian, Toarcian-Aalenian boundary, latest Aalenian-earliest Bajocian, latest Early Bajocian-earliest Late Bojocian, Early Bathonian-Middle Bathonian boundary, latest Middle Bathonian-earliest Late Bathonian, latest Bathonian-Early Callovian, earliest Early Oxfordian-Middle Oxfordian, earliest Late Oxfordian-latest Oxfordian, latest Early Kimmeridgian, Late Kimmeridgian, middle Early Tithonian and Early Tithonian-Late Tithonian boundary. More than 75 percent of these turnovers correlate with regressive-transgressive cycles in the Exxon, and /or Hallam's sea-level curves. Inmost cases the extinction events coincide with regressive intervals, whereas origination and radiation events are related to transgressive cycles. The turnovers frequently coincide with major or minor discontinuities in the Subbetic basin (Betic Cordillera).

Linking supply to demand: the neuronal monocarboxylate transporter MCT2 and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor GluR2/3 subunit are associated in a common trafficking process.

MCT2 is the major neuronal monocarboxylate transporter (MCT) that allows the supply of alternative energy substrates such as lactate to neurons. Recent evidence obtained by electron microscopy has demonstrated that MCT2, like alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, is localized in dendritic spines of glutamatergic synapses. Using immunofluorescence, we show in this study that MCT2 colocalizes extensively with GluR2/3 subunits of AMPA receptors in neurons from various mouse brain regions as well as in cultured neurons. It also colocalizes with GluR2/3-interacting proteins, such as C-kinase-interacting protein 1, glutamate receptor-interacting protein 1 and clathrin adaptor protein. Coimmunoprecipitation of MCT2 with GluR2/3 and C-kinase-interacting protein 1 suggests their close interaction within spines. Parallel changes in the localization of both MCT2 and GluR2/3 subunits at and beneath the plasma membrane upon various stimulation paradigms were unraveled using an original immunocytochemical and transfection approach combined with three-dimensional image reconstruction. Cell culture incubation with AMPA or insulin triggered a marked intracellular accumulation of both MCT2 and GluR2/3, whereas both tumor necrosis factor alpha and glycine (with glutamate) increased their cell surface immunolabeling. Similar results were obtained using Western blots performed on membrane or cytoplasm-enriched cell fractions. Finally, an enhanced lactate flux into neurons was demonstrated after MCT2 translocation on the cell surface. These observations provide unequivocal evidence that MCT2 is linked to AMPA receptor GluR2/3 subunits and undergoes a similar translocation process in neurons upon activation. MCT2 emerges as a novel component of the synaptic machinery putatively linking neuroenergetics to synaptic transmission.

Formation of a direct arterial blood supply to the anterior pituitary gland following complete or partial interruption of the hypophyseal portal vessels

If regions of the anterior pituitary gland received systemic blood via a direct arterial blood supply these regions would escape hypothalamic regulation and thus be a sequela in endocrine disorders. Since, in the untreated rat, all of the blood supply to the anterior pituitary gland is via the hypophyseal portal vessels, we hypothesized that partial interruption of the portal vessels could provoke the establishment of a direct arterial blood supply (arteriogenesis). We utilized the injection of polystyrene microspheres (15 or 9 micron diameter) into the left ventricle of the heart to test this hypothesis. Microspheres are trapped in the first capillary plexus they reach since they are too large to traverse the capillaries. No microspheres reached the anterior pituitary gland of control rats, a finding consistent with the fact that the anterior pituitary gland receives all of its blood supply via the hypophyseal portal blood vessels. Microspheres were observed in the primary portal capillary plexus in the infundibulum (median eminence), infundibular stalk (pituitary stalk), and infundibular process (pars nervosa), the first capillary plexus which they reached. A lesion of the medial basal hypothalamus (MBH) which destroyed the long portal vessels did not result in arteriogenesis since few, if any, microspheres were observed in the anterior pituitary gland. We confirmed, using vascular casts, that these lesions resulted in the long-term destruction of the primary portal capillaries in the infundibulum and of the long portal vessels. In MBH-lesioned animals it appears that all of the blood supply of the anterior pituitary gland is via short portal vessels arising from the infundibular stem and process.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric supply manipulation to modulate ghrelin production and enhance vascularization to the cardia: proof of the concept in a porcine model.

Introduction. Selective embolization of the left-gastric artery (LGA) reduces levels of ghrelin and achieves significant short-term weight loss. However, embolization of the LGA would prevent the performance of bariatric procedures because the high-risk leakage area (gastroesophageal junction [GEJ]) would be devascularized. Aim. To assess an alternative vascular approach to the modulation of ghrelin levels and generate a blood flow manipulation, consequently increasing the vascular supply to the GEJ. Materials and methods. A total of 6 pigs underwent a laparoscopic clipping of the left gastroepiploic artery. Preoperative and postoperative CT angiographies were performed. Ghrelin levels were assessed perioperatively and then once per week for 3 weeks. Reactive oxygen species (ROS; expressed as ROS/mg of dry weight [DW]), mitochondria respiratory rate, and capillary lactates were assessed before and 1 hour after clipping (T0 and T1) and after 3 weeks of survival (T2), on seromuscular biopsies. A celiac trunk angiography was performed at 3 weeks. Results. Mean (±standard deviation) ghrelin levels were significantly reduced 1 hour after clipping (1902 ± 307.8 pg/mL vs 1084 ± 680.0; P = .04) and at 3 weeks (954.5 ± 473.2 pg/mL; P = .01). Mean ROS levels were statistically significantly decreased at the cardia at T2 when compared with T0 (0.018 ± 0.006 mg/DW vs 0.02957 ± 0.0096 mg/DW; P = .01) and T1 (0.0376 ± 0.008mg/DW; P = .007). Capillary lactates were significantly decreased after 3 weeks, and the mitochondria respiratory rate remained constant over time at the cardia and pylorus, showing significant regional differences. Conclusions. Manipulation of the gastric flow targeting the gastroepiploic arcade induces ghrelin reduction. An endovascular approach is currently under evaluation.

Effect of hypoxia on cerebral blood flow regulation during rest and exercise : role of cerebral oxygen delivery on performance

Adequate supply of oxygen to the brain is critical for maintaining normal brain function. Severe hypoxia, such as that experienced during high altitude ascent, presents a unique challenge to brain oxygen (O2) supply. During high-intensity exercise, hyperventilation-induced hypocapnia leads to cerebral vasoconstriction, followed by reductions in cerebral blood flow (CBF), oxygen delivery (DO2), and tissue oxygenation. This reduced O2 supply to the brain could potentially account for the reduced performance typically observed during exercise in severe hypoxic conditions. The aims of this thesis were to document the effect of acute and chronic exposure to hypoxia on CBF control, and to determine the role of cerebral DO2 and tissue oxygenation in limiting performance during exercise in severe hypoxia. We assessed CBF, arterial O2 content (CaO2), haemoglobin concentration ([Hb]), partial pressure of arterial O2 (PaO2), cerebrovascular CO2 reactivity, ventilatory response to CO2, cerebral autoregulation (CA), and estimated cerebral DO2 (CBF ⨉ CaO2) at sea level (SL), upon ascent to 5,260 m (ALT1), and following 16 days of acclimatisation to 5,260 m (ALT16). We found an increase in CBF despite an elevated cerebrovascular CO2 reactivity at ALT1, which coincided with a reduced CA. Meanwhile, PaO2 was greatly decreased despite increased ventilatory drive at ALT1, resulting in a concomitant decrease in CaO2. At ALT16, CBF decreased towards SL values, while cerebrovascular CO2 reactivity and ventilatory drive were further elevated. Acclimatisation increased PaO2, [Hb], and therefore CaO2 at ALT16, but these changes did not improve CA compared to ALT1. No differences were observed in cerebral DO2 across SL, ALT1, and ALT16. Our findings demonstrate that cerebral DO2 is maintained during both acute and chronic exposure to 5,260 m, due to the reciprocal changes in CBF and CaO2. We measured middle cerebral artery velocity (MCAv: index of CBF), cerebral DO2, ventilation (VE), and performance during incremental cycling to exhaustion and 15km time trial cycling in both normoxia and severe hypoxia (11% O2, normobaric), with and without added CO2 to the inspirate (CO2 breathing). We found MCAv was higher during exercise in severe hypoxia compared in normoxia, while cerebral tissue oxygenation and DO2 were reduced. CO2 breathing was effective in preventing the development of hyperventilation-induced hypocapnia during intense exercise in both normoxia and hypoxia. As a result, we were able to increase both MCAv and cerebral DO2 during exercise in hypoxia with our CO2 breathing setup. However, we concomitantly increased VE and PaO2 (and presumably respiratory work) due to the increased hypercapnic stimuli with CO2 breathing, which subsequently contributed to the cerebral DO2 increase during hypoxic exercise. While we effectively restored cerebral DO2 during exercise in hypoxia to normoxic values with CO2 breathing, we did not observe any improvement in cerebral tissue oxygenation or exercise performance. Accordingly, our findings do not support the role of reduced cerebral DO2 in limiting exercise performance in severe hypoxia. -- Un apport adéquat en oxygène au niveau du cerveau est primordial pour le maintien des fonctions cérébrales normales. L'hypoxie sévère, telle qu'expérimentée au cours d'ascensions en haute altitude, présente un défi unique pour l'apport cérébral en oxygène (O2). Lors d'exercices à haute intensité, l'hypocapnie induite par l'hyperventilation entraîne une vasoconstriction cérébrale suivie par une réduction du flux sanguin cérébral (CBF), de l'apport en oxygène (DO2), ainsi que de l'oxygénation tissulaire. Cette réduction de l'apport en O2 au cerveau pourrait potentiellement être responsable de la diminution de performance observée au cours d'exercices en condition d'hypoxie sévère. Les buts de cette thèse étaient de documenter l'effet de l'exposition aiguë et chronique à l'hypoxie sur le contrôle du CBF, ainsi que de déterminer le rôle du DO2 cérébral et de l'oxygénation tissulaire comme facteurs limitant la performance lors d'exercices en hypoxie sévère. Nous avons mesuré CBF, le contenu artériel en oxygène (CaO2), la concentration en hémoglobine ([Hb]), la pression partielle artérielle en O2 (PaO2), la réactivité cérébrovasculaire au CO2, la réponse ventilatoire au CO2, et l'autorégulation cérébrale sanguine (CA), et estimé DO2 cérébral (CBF x CaO2), au niveau de la mer (SL), au premier jour à 5.260 m (ALT1) et après seize jours d'acclimatation à 5.260 m (ALT16). Nous avons trouvé des augmentations du CBF et de la réactivité cérébrovasculaire au CO2 après une ascension à 5.260 m. Ces augmentations coïncidaient avec une réduction de l'autorégulation cérébrale. Simultanément, la PaO2 était grandement réduite, malgré l'augmentation de la ventilation (VE), résultant en une diminution de la CaO2. Après seize jours d'acclimatation à 5.260 m, le CBF revenait autour des valeurs observées au niveau de la mer, alors que la réactivité cérébrovasculaire au CO2 et la VE augmentaient par rapport à ALT1. L'acclimatation augmentait la PaO2, la concentration en hémoglobine, et donc la CaO2, mais n'améliorait pas l'autorégulation cérébrale, comparé à ALT1. Aucune différence n'était observée au niveau du DO2 cérébral entre SL, ALT1 et ALT16. Nos résultats montrent que le DO2 cérébral est maintenu constant lors d'expositions aiguë et chronique à 5.260m, ce qui s'explique par la réciprocité des variations du CBF et de la CaO2. Nous avons mesuré la vitesse d'écoulement du sang dans l'artère cérébrale moyenne (MCAv : un indice du CBF), le DO2 cérébral, la VE et la performance lors d'exercice incrémentaux jusqu'à épuisement sur cycloergomètre, ainsi que des contre-la-montres de 15 km en normoxie et en hypoxie sévère (11% O2, normobarique) ; avec ajout ou non de CO2 dans le mélange gazeux inspiré. Nous avons trouvé que MCAv était plus haute pendant l'exercice hypoxique, comparé à la normoxie alors que le DO2 cérébral était réduit. L'ajout de CO2 dans le gaz inspiré était efficace pour prévenir l'hypocapnie induite par l'hyperventilation, qui se développe à l'exercice intense, à la fois en normoxie et en hypoxie. Nous avons pu augmenter MCAv et le DO2 cérébral pendant l'exercice hypoxique, grâce à l'ajout de CO2. Cependant, nous avons augmenté la VE et la PaO2 (et probablement le travail respiratoire) à cause de l'augmentation du stimulus hypercapnique. Alors que nous avons, grâce à l'ajout de CO2, efficacement restauré le DO2 cérébral au cours de l'exercice en hypoxie à des valeurs obtenues en normoxie, nous n'avons observé aucune amélioration dans l'oxygénation du tissu cérébral ou de la performance. En conséquence, nos résultats ne soutiennent pas le rôle d'un DO2 cérébral réduit comme facteur limitant de la performance en hypoxie sévère.

Circum-Alpine marine circulation and paleoenvironmental conditions during the Miocene

Trace element and isotopic compositions of marine fossils and sediment were analyzed from several Miocene deposits in the circum-Alpine region in order to reconstruct the paleoceanographic and paleoclimatic changes related to sea level changes, basin evolution and Alpine orogeny. To the north and the east the Alps were border by an epicontinental sea, the Paratethys, while to the south the Mediterranean surrounded the uplifting mountains during the Miocene. The thesis mainly focused on sediments and fossils sampled from Miocene beds of these two oceanic provinces. The north Alpine Molasse, the Vienna and Pannonian Basins were located in the Western and Central Paratethys. O-isotope compositions of well-preserved phosphatic fossils in these sediments support deposition under sub-tropical to warm-temperate climate with water temperatures between 14 to 28 °C for the Miocene. δ18O values of fossil shark teeth from different horizons vary similarly to those of the global trend until the end of the Badenian, however the δ18O values show wider range, which indicates local effects iii the sub-basins. The trend of 87Sr/86Sr in the samples roughly agrees with an open ocean environment for the Miocene. Yet a number of samples deviate from typical open ocean compositions with higher ratios suggesting modification of seawater by local and old terrestrial sources. In contrast, two exceptional teeth from the locality of La Moliere have extremely low δ18O values and low 87Sr/86Sr. However, the REE patterns of their enameloid are similar to those of teeth having O and Sr isotopic compositions typical of a marine setting at this site. Collectively, this suggests that the two teeth formed while the sharks frequented a freshwater environment with very low 18O-content and 87Sr/86Sr controlled by Mesozoic calcareous rocks. This is consistent with a paleogeography of high-elevation (~2300m) Miocene Alps adjacent to a marginal sea. The local effects are also reflected in the εNd values of the Paratethyan fossils, which is compatible with input from ancient crystalline rocks and Mesozoic sediments, while other samples with elevated εNd values indicate an influence of Neogene volcanism on the water budget. Excluding samples whose isotopic compositions reflect a local influence on the water column, an average εNd value of -7.9 ± 0.5 may be inferred for the Paratethys seawater. This value is indistinguishable from the Miocene value of the Indian Ocean, supporting a dominant role of ludo-Pacific water masses in the Paratethys. Regarding the Mediterranean, stable C-and O-isotope compositions of benthic and planktonic foraminifera from the Umbria-Marche region (UMC) have an offset typical for their habitats and the changes in composition mimic global changes, suggesting that the regional conditions of climate and the carbon cycle were controlled by global changes. The radiogenic isotope compositions of the fossil assemblages allow for distinction of periods. From 25 to 19 Ma, high εNd values and low 87Sr/86Sr of sediments and fossils support intense tectonism and volcanism, related to the opening of the western Mediterranean. Between 19 and 13 Ma the Mediterranean has εNd values that are largely controlled by incursion of Indian Ocean water. Brief periods of local hinterland control on seawater compositions are indicated by spikes in the εNd record, coinciding with volcanic events and a short sea-level decrease at about 15.2 Ma. Lower 87Sr/86Sr compared to the open ocean is compatible with rapid uplift of the hinterland and intense influx of Sr from Mesozoic carbonates of the western Apennines, while higher 87Sr/86Sr for other sites indicates erosion of old crustal silicate rocks. Finally, from 13 to 7 Ma the fossils have 87Sr/86Sr similar to those of Miocene seawater and their εNd values indicates fluctuating influence of Atlantic, and Indian Ocean or Paratethys sources of seawater entering the Mediterranean, driven by global sealevel changes and local tectonism. RÉSUMÉ DE LA THÈSE Les compositions en éléments traces et isotopiques de fossiles marins et de sédiments on été analysées à partir de nombreux dépôts marins dans la région circum Alpine dans le but de reconstruire les changements paléocéanographiques et paléoclimatiques liés aux changements du niveau marin, à l'évolution en bassins et à l'orogénie alpine. Au nord et à l'est des Alpes, une mer épicontinentale appelée Paratéthys s'est ouverte, alors que plus au sud la mer Méditerranée bordait au Miocène les Alpes naissantes. Le but de cette recherche est de se concentrer sur les sédiments et les fossiles provenant des couches du Miocènes de ces deux provinces marines. Les bassins de la Molasse Alpine du nord, de Vienne et Pannonien étaient situés au niveau de la Paratéthys Occidentale et Centrale. Les compositions isotopiques de l'oxygène de fossiles phosphatés bien préservés dans ces sédiments étayent la théorie d'un dépôt sous un climat subtropical à tempéré chaud avec des températures entre 14 et 28°C pendant le Miocène. Les valeurs δ18O des fossiles sont similaires à la tendance globale jusqu'à la fin du Badénien. Cependant les larges fluctuations en δ18O indiquent des effets locaux au niveau des sous bassins. En outre, deux dents de requin exceptionnelles présentent des valeurs extrêmement basses de δ18O. Ces données suggèrent que ces deux dents se sont formées alors que les requins fréquentaient un environnement d'eau douce avec de faibles valeurs de 18O. Le calcul de la composition isotopique de l'oxygène de cette eau douce permet d'obtenir une estimation de la paléoélévatian moyenne des Alpes du Miocène (~2300m). La tendance 87Sr/86Sr pour ces échantillons concorde approximativement avec un environnement d'océan ouvert au cours du Miocène. Toutefois un nombre d'échantillons dévie des compositions d'océan ouvert typiques, avec des rapports élevés suggérant des modifications de l'eau de mer par des sources locales et terrestres. Les effets locaux sont aussi reflétés au niveau des valeurs en εNd des fossiles paratéthysiens. Ceci est cohérent avec un apport d'anciennes roches cristallines et de sédiments mésozoïques, tandis que d'autres échantillons avec des valeurs hautes de εNd indiquent une influence d'un volcanisme néogène dans le budget marin. En excluant les échantillons dont les compositions isotopiques confirment une influence locale, une valeur moyenne de εNd de 7.9 t 0.5 peut être déduite pour l'eau de la Parathétys. Cette valeur est semblable à la valeur correspondant à l'Océan Indien durant le Miocène, confirmant un rôle dominant de cet océan dans la Paratéthys. Au niveau de la Méditerranée, les compositions en isotopes stables du Carbone et de l'Oxygène de foraminifères planctoniques et benthique de la région Umbria-Marche présentent un offset typique à leurs habitats. De plus les changements dans leurs compositions suivent les changements globaux, suggérant ainsi que les conditions climatiques régionales et le cycle du carbone étaient contrôlés par des phénomènes globaux. La composition en isotopes radiogéniques d'assemblages fossiles permet une reconnaissance sur trois périodes distinctes. De 25 à 19 millions d'années (Ma), des valeurs élevées de εNd et un faible rapport 87Sr/86Sr dans les sédiments soutiennent l'idée d'une activité tectonique et volcanique intense, liée à l'ouverture de la Méditerranée occidentale. Entre 19 et 13 Ma, la Méditerranée montre des valeurs de εNd qui sont largement contrôlées par une incursion d'eau provenant de l'Océan Indien. En effet, aux alentours de 15,2 Ma, des pics dans l'enregistrement des valeurs de εNd, coïncidant avec des événements volcaniques et de brèves diminutions du niveau marin. Enfin, de 13 à 7 Ma, les fossiles ont des rapports ß7Sr/8fiSr similaires à ceux de l'eau de mer au Miocène. Leurs valeurs de εNd indiquent une influence changeante de l'océan Atlantique, et de l'océan Indien ou des sources d'eau de merde la Parathétys qui entrent dans les bassins méditerranéens. Ce changement est guidé par des modifications globales du niveau marin et par la tectonique locale. RÉSUMÉ DE LA THÈSE (POUR LE GRAND PUBLIC) Les analyses des compositions en éléments traces et isotopiques des fossiles marins sont un outil très utile pour reconstruire les conditions océaniques et climatiques anciennes. Ce travail de thèse se concentre sur les sédiments déposés dans un environnement marin proches des Alpes au cours du Miocène, entre 23 et 7 millions d'années (Ma). Cette période est caractérisée par une tectonique alpine active, ainsi que par des changements climatiques et océanographiques globaux importants. Dans le but de tracer ces changements, les compositions isotopiques du Strontium, du Néodyme, de l'Oxygène et du Carbone ont été analysées dans des fossiles bien préservés ainsi que les sédiments contemporains. Les échantillons proviennent de deux provinces océaniques distinctes, la première est la Mer Méditerranée, et l'autre est une mer épicontinentale appelée Parathétys, qui existait au nord et à l'est des Alpes durant le Miocène. Au niveau de la Parathétys Occidentale et Orientale, les compositions isotopiques d'oxygène de dents de requins confirment un dépôt sous un climat subtropical à tempéré chaud avec des températures d'eau entre 14 et 28°C au Miocène. En outre, deux dents de requins exceptionnelles ont enregistré des compositions isotopiques d'oxygène extrêmement basses. Cela suggère que ces deux dents se sont formées alors que les requins entraient dans un système d'eau douce. Le calcul de la composition isotopique de l'oxygène de cette eau douce permet d'obtenir une estimation de la paléoélévation des Alpes au Miocène qui est aussi élevée que celle d'aujourd'hui. La tendance isotopique du Strontium pour ces échantillons concorde approximativement avec un environnement d'océan ouvert. Cependant un certain nombre d'échantillons indique des modifications de l'eau de mer par des sources terrestres locales. Les effets locaux sont aussi visibles au niveau des compositions isotopiques du Néodyme, qui sont en accord avec un apport provenant de roches cristallines anciennes et de sédiments du Mésozoïque, alors que d'autres échantillons indiquent une influence volcanique néogène dans le budget marin. A l'exclusion des échantillons dont les compositions correspondent à une influence locale, les compositions isotopiques du Néodyme de la Parathétys sont très similaires aux valeurs de l'Océan Indien, montrant ainsi un rôle important des masses d'eau IndoPacifiques dans cette région. Au niveau de la Méditerranée, les compositions en isotopes stables du Carbone et de l'Oxygène de foraminifères planctoniques et benthique de la région Umbria-Marche présentent un offset typique à leurs habitats. De plus, les changements dans leurs compositions suivent les changements globaux, suggérant ainsi que les conditions climatiques régionales et le cycle du carbone étaient contrôlés par des phénomènes globaux. La composition en isotopes radiogéniques d'assemblages fossiles permet une reconnaissance sur trois périodes distinctes. De 25 à 19 Ma, des rapport isotopiques élevés pour le Néodyme et faibles pour le Strontium dans les sédiments et les fossiles soutiennent l'idée d'une activité tectonique et volcanique intense, liée à l'ouverture de la Méditerranée occidentale. Entre 19 et 13 Ma, la Méditerranée présente des rapports isotopiques du Néodyme qui sont largement contrôlés par une incursion d'eau provenant de l'Océan Indien. En effet, aux alentours de 15,2 Ma, des pics dans l'enregistrement des valeurs des isotopes du Néodyme coïncident avec des événements volcaniques et de brèves diminutions du niveau marin. Finalement, de 13 à 7 Ma, les fossiles ont des rapports isotope Strontium similaires à ceux de l'eau de mer au Miocène. Les rapports isotopiques du Néodyme indiquent une influence changeante de l'océan Atlantique, et de l'océan Indien ou des sources d'eau de mer de la Parathétys qui entrent dans les bassins méditerranéens. Ce changement est guidé par des modifications globales du niveau marin et par la tectonique locale.

Il desiderio materno nei casi di maltrattamento infantile

The work of this thesis would like to investigate two particular questions about the care of underage: on the one hand, the maltreatment, and the mother's desire on the other hand. About the first, this proposal try to underscore the elaborate irregularity and disparity related to this phenomenon and his historical evolution. The objective's thesis propose to underline that the abuse crosses the crisis of educational dimension inside and outside the family. We are talking about a type of crisi that places at the origin of a specific clinic and that it is about the maltreatment designated, at the same time, to cope with the educational void and with the ill-treated under age's hardships. The so-called clinic of the maltreatment horns, therefore, with the purpose to join and to set in order the normative and educational aspects. However, the prescriptive requirement is intended to measure against the same one crisis in a paradoxical way; the laws and the juveniles court must make up for the lack absence of the rules that characterized the maltreatment, getting around to use the typical reference that traditionally were been at the base of the educational way's construction. The same crimes on underage often found in the father the responsibility. The requirements and the therapeutic needs has utilized the theoretical construct of the trauma as the key line of clinical practice. On the one hand, the trauma was been paired controversially to the psychoanalytical concepts as the notion of the phantom, in the same manner that the objective truth is been opposed to the notion of the imagination and fantasy; on the other hand, the trauma was gotten to be the mark and the characteristic that defined the individual identity of the mistreated persons, regardless of the person's clinical structure or, generally, regardless of the their individual position. Both the normative demand and therapeutic converge on the idealization of the imaginary figure that is able to supply to every type of maltreatment: the mother. This position is connected on theoretical construct well-established in the mythology, that associated the mother figure to a natural dimension; this is related to the second point at issue: the mother's desire. The awareness of the mother figure in natural and idealized terms describes accusingly and negatively the trauma, without seeing the difference between trauma that helps to give a structure to the individual position from the trauma solely devastating. The mother's mythology, therefore, is in an evident antagonism with the female figure and woman's sexuality. In these way the maltreatment's clinic suggests that a woman is able to be a mother only when she doesn't appreciate the rule of female. This situation preclusives a comparison with own sexuality and gives to the women a complex of castration. The clinic cases reported highlight as these difficulties are the expression of the familiarity's heredity that wasn't been sufficiently elaborated. This condition (into the relation between mother and his child) turn the infant in the incapacity to symbolized and it doesn't help him to accede to the positive trauma, to the language and to the edipic rule; this is the reason why the child toils difficulties to approach to own personality and to orient himself in the relation with his body, with the body of the adults and the same age children.

Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: an immunohistochemical study

The monocarboxylate transporter MCT2 belongs to a large family of membrane proteins involved in the transport of lactate, pyruvate and ketone bodies. Although its expression in rodent brain has been well documented, the presence of MCT2 in the human brain has been questioned on the basis of low mRNA abundance. In this study, the distribution of the monocarboxylate transporter MCT2 has been investigated in the cortex of normal adult human brain using an immunohistochemical approach. Widespread neuropil staining in all cortical layers was observed by light microscopy. Such a distribution was very similar in three different cortical areas investigated. At the cellular level, the expression of MCT2 could be observed in a large number of neurons, in fibers both in grey and white matter, as well as in some astrocytes, mostly localized in layer I and in the white matter. Double staining experiments combined with confocal microscopy confirmed the neuronal expression but also suggested a preferential postsynaptic localization of synaptic MCT2 expression. A few astrocytes in the grey matter appeared to exhibit MCT2 labelling but at low levels. Electron microscopy revealed strong MCT2 expression at asymmetric synapses in the postsynaptic density and also within the spine head but not in the presynaptic terminal. These data not only demonstrate neuronal MCT2 expression in human, but since a portion of it exhibits a distinct synaptic localization, it further supports a putative role for MCT2 in adjustment of energy supply to levels of activity.

Tethyan margins in space and time

Rifting processes, leading to sea-floor spreading, are characterized by a sequence of events: transtensive phase of extension with syn-rift volcanism; simple shear extension accompanied by lithospheric thinning and asthenospheric up-welling and thermal uplift of the rift shoulder and asymmetric volcanism. The simple shear model of extension leads to an asymmetric model of passive margin: a lower plate tilted block margin and an upper plate flexural, ramp-like margin- Both will be affected by thermal contraction and subsidence, starting soon after sea-floor spreading. Based on these actualistic models Tethyan margins are classified as one type or the other. Their evolution from the first transtensional phase of extension to the passive margin stage are analyzed. Four main rifting events are recognized in the Tethyan realm: an episode of lower Paleozoic events leading to the formation of the Paleotethys; a Late Paleozoic event leading to the opening of the Permotethys and East Mediterranean basin: an early Mesozoic event leading to the opening of the Pindos Neotethys and a Jurassic event related to the opening of the Alpine/Atlantic Neotethys. Type margins are given as example of each rifting event: -Northern Iran (Alborz) as a type area for the Late Ordovician to Silurian rifting of Paleotethys. -Northern India and Oman for the Late Carboniferous to early Permian rifting of Permotethys. -The East Mediterranean (Levant, Tunisia) as a Late Carboniferous rifting event. -The Neotethyan rifting phases are separated in two types: an eastern Pindos system found in Turkey and Greece is genetically linked to the Permotethys with a sea-floor spreading delayed until middle Triassic: a western Alpine system directly linked to the opening of the central Atlantic is characterized by a Late Triassic transtensive phase, an early to Middle Liassic break-away phase and. following sea-floor spreading, a thermal subsidence phase starting in Dogger. Problems related to the closure of the Paleozoic oceanic domains are reviewed. A Late Permian, early Triassic phase of `'docking'' between an European accretionary prism (Chios) and a Paleotethyan margin is supported by recent findings in the Mediterranean area. Back-arc rifting within the European active margin led to the formation of marginal seas during Permian and Triassic times and will contribute to the closure of the Paleozoic oceans.

Effects of dopamine on total oxygen consumption and oxygen delivery in healthy men.

The effect of acute intravenous dopamine (DA) administration at three sequential (but randomized) infusion rates was studied in eight young male volunteers. DA was infused at 2.5, 5, and 10 micrograms.kg-1.min-1. O2 consumption (VO2) and CO2 production (VCO2) were measured continuously by means of a computerized indirect calorimeter (blood system). In response to the 5- and 10-micrograms.kg-1.min-1 DA infusion rates, a significant increase (P less than 0.01) in VO2 corresponding to a 6% (range, 3-10) and 15% (range, 12-23) increase, respectively, of preinfusion values was observed. In contrast, at the low dose (2.5 micrograms.kg-1.min-1), DA induced no significant change in VO2. Cardiac output (Qc) increased significantly after the three DA administration rates [19% (range, 0-42), 34% (range, 17-71), and 25% (range, -3 to +47)] for the doses 2.5, 5, and 10 micrograms.-kg-1.min-1, respectively. The increase in O2 delivery (QO2) outweighed VO2 at all administration rates despite the relative drop in QO2 at the maximal DA administration rate. These results indicate that in humans DA improves net O2 supply to tissues proportionally more than it increases VO2 at all doses used in the present study.

Neuroprotection in cerebral ischemia with XG-102, a new peptide inhibitor of JNK

Abstract Stroke or cerebrovascular accident, whose great majority is of ischemic nature, is the third leading cause of mortality and long lasting disability in industrialised countries. Resulting from the loss of blood supply to the brain depriving cerebral tissues of oxygen and glucose, it induces irreversible neuronal damages. Despite the large amount of research carried out into the causes and pathogenic features of cerebral ischemia the progress toward effective treatments has been poor. Apart the clot-busting drug tissue-type plasminogen activator (tPA) as effective therapy for acute stroke (reperfusion by thrombolysis) but limited to a low percentage of patients, there are currently no other approved medical treatments. The need for new therapy strategies is therefore imperative. Neuronal death in cerebral ischemia is among others due to excitotoxic mechanisms very early after stroke onset. One of the main involved molecular pathways leading to excitotoxic cell death is the c-Jun NH2-terminal kinase (JNK) pathway. Several studies have already shown the efficacy of a neuroprotective agent of a new type, a dextrogyre peptide synthesized in the retro inverso form (XG102, formerly D-JNKI1), which is protease-resistant and cell-penetrating and that selectively and strongly blocks the access of JNK to many of its targets. A powerful protection was observed with this compound in several models of ischemia (Borsello et al. 2003;Hirt et al. 2004). This chimeric compound, made up of a 10 amino acid TAT transporter sequence followed by a 20 amino acids JNK binding domain (JBD) sequence from JNK inhibitor protein (JIP) molecule, induced both a major reduction in lesion size and improved functional outcome. Moreover it presents a wide therapeutic window. XG-102 has proved its powerful efficacy in an occlusion model of middle cerebral artery in mice with intracérebroventricular (i.c.v.) injection but in order to be able to consider the development of this drug for human ischemic stroke it was therefore necessary to determine the feasibility of its systemic administration. The studies being the subject of this thesis made it possible to show a successful neuroprotection with XG-102 administered systemically after transient mouse middle cerebral artery occlusion (MCAo). Moreover our data. provided information about the feasibility to combine XG-102 with tPA without detrimental action on cell survival. By combining the benefits from a reperfusion treatment with the effects of a neuroprotective compound, it would represent the advantage of bringing better chances to protect the cerebral tissue. Résumé L'attaque cérébrale ou accident vasculaire cérébral, dont la grande majorité est de nature ischémique, constitue la troisième cause de mortalité et d'infirmité dans les pays industrialisés. Résultant de la perte d'approvisionnement de sang au cerveau privant les tissus cérébraux d'oxygène et de glucose, elle induit des dommages neuronaux irréversibles. En dépit du nombre élevé de recherches effectuées pour caractériser les mécanismes pathogènes de l'ischémie. cérébrale, les progrès vers des traitements efficaces restent pauvres. Excepté l'activateur tissulaire du plasminogène (tPA) dont le rôle est de désagréger les caillots sanguins et employé comme thérapie efficace contre l'attaque cérébrale aiguë (reperfusion par thrombolyse) mais limité à un faible pourcentage de patients, il n'y a actuellement aucun autre traitement médical approuvé. Le besoin de nouvelles stratégies thérapeutiques est par conséquent impératif. La mort neuronale dans l'ischémie cérébrale est entre autres due à des mécanismes excitotoxiques survenant rapidement après le début de l'attaque cérébrale. Une des principales voies moléculaires impliquée conduisant à la mort excitotoxique des cellules est la voie de la c-Jun NH2terminal kinase (JNK). Plusieurs études ont déjà montré l'efficacité d'un agent neuroprotecteur d'un nouveau type, un peptide dextrogyre synthétisé sous la forme retro inverso (XG-102, précédemment D-JNKI1) résistant aux protéases, capable de pénétrer dans les cellules et de bloquer sélectivement et fortement l'accès de JNK à plusieurs de ses cibles. Une puissante protection a été observée avec ce composé dans plusieurs modèles d'ischémie (Borsello et al. 2003;Hirt et al. 2004). Ce composé chimérique, construit à partir d'une séquence TAT de 10 acides aminés suivie par une séquence de 20 acides aminés d'un domaine liant JNK (JBD) issu de la molécule JNK protéine inhibitrice. (JIP), induit à la fois une réduction importante de la taille de lésion et un comportement fonctionnel amélioré. De plus il présente une fenêtre thérapeutique étendue. XG-102 a prouvé sa puissante efficacité dans un modèle d'occlusion de l'artère cérébrale moyenne chez la souris avec injection intracerebroventriculaire (i.c.v.) mais afin de pouvoir envisager le développement de ce composé pour l'attaque cérébrale chez l'homme, il était donc nécessaire de déterminer la faisabilité de son administration systémique. Les études faisant l'objet de cette thèse ont permis de montrer une neuroprotection importante avec XG-102 administré de façon systémique après l'occlusion transitoire de l'artère cérébrale moyenne chez la souris (MCAo). De plus nos données ont fourni des informations quant à la faisabilité de combiner XG-102 et tPA, démontrant une protection efficace par XG-102 malgré l'action nuisible du tPA sur la survie des cellules. En combinant les bénéfices de la reperfusion avec les effets d'un composé neurooprotecteur, cela représenterait l'avantage d'apporter des meilleures chances de protéger le tissu cérébral.

Critical role for the lactate transporter, monocarboxylate transporter 1 (mct1), in the regeneration of peripheral nerves

Axons, and particularly regenerating axons, have high metabolic needs in order to maintain critical functions such as axon transport and membrane depolarization. Though some of the required energy likely comes form extracellular glucose and ATP generated in the soma, we and others hypothesize that some of the energy may be supplied by lactate. Unlike glucose that requires glycolytic enzymes to produce pyruvate, lactate can be converted directly to pyruvate by lactate dehydrogenase and transported into mitochondria for oxidative metabolism. In order to be transported into or out of cells, lactate requires specific monocarboxylate transporters (MCTs), the most abundant of which is MCT1. If MCT1 and lactate are critical for nerve function and regeneration, we hypothesize that MCT1 heterozygote null mice, which appear phenotypically normal despite having approximately 40% MCT1 as compared to wildtype littermate mice, would have reduced capacity for repair following nerve injury. To investigate this, adult MCT1 heterozygote null mice or wild-type mice underwent unilateral sciatic nerve crush in the proximal thigh. We found that regeneration of the sciatic nerve, as measured by recovery of compound muscle action potentials (CMAP) in the lateral plantar muscles following proximal sciatic nerve stimulation, was delayed from a median of 21 days in wildtype mice to 38.5 days in MCT1 heterozygote mice. In fact, half of the MCT1 heterozygote null mice had no recovery of CMAP by the endpoint of the study at 42 days, while all of the wild-type mice had recovered. In addition, the maximal amplitude of CMAP recovery in MCT1 heterozygote mull mice was reduced from a mean of 3 mV to 0.5 mV. As would be expected, the denervated gastrocnemius muscle of MCT1 heterozygote null mice remained atrophic at 42 days compared to wild-type mice. Our experiments show that lactate supplied through MCT1 is necessary for nerve regeneration. Experiments are underway to determine whether loss of MCT1 prevents nerve regrowth directly due to reduced energy supply to axons or indirectly by dysfunctional Schwann cells normally dependent on lactate supply through MCT1.

Late Pliensbachian-Early Toarcian (Early Jurassic) environmental changes in an epicontinental basin of NW Europe (Causses area, central France): A micropaleontological and geochemical approach

We present an integrated work based on calcareous nannofossil and benthic foraminiferal assemblages, and geochemical analyses of two Upper Pliensbachian-Lower Toarcian sections located in the central-South France. The studied sections, Tournadous and Saint-Paul-des-Fonts, represent the proximal and the distal part, respectively, of the Jurassic Causses Basin, one of the small, partly enclosed basins belonging to the epicontinental shelf of the NW Tethys. At the transition from Late Pliensbachian to Early Toarcian, the Causses Basin recorded an emersion in response to the global sea-level fall. Our data indicate severe environmental conditions of marine waters, including salinity decrease and anoxia development, occurring in the Early Toarcian. The acme of this deterioration coincides with the Early Toarcian Anoxic Event (T-OAE) but, due to the restricted nature of the basin. anoxia persisted until the end of the Early Toarcian. mainly in the deeper parts of the basin. The micronutrients and organic organic-matter fluxes were probably high during the entire studied time interval, as shown by nannofossil and foraminiferal assemblages. However, nannoplankton production drastically decreased during the T-OAE, as demonstrated by very low nannofossil fluxes, and only taxa tolerant to low-saline surface waters could thrive. At the same time, benthic foraminifers temporarily disappeared in response to sea-bottom anoxia. Our study demonstrates that environmental changes related to the T-OAE are well-recorded even in small, partly enclosed basins of NW Europe, like the Causses Basin. Within this area, the effects of global changes. like sea sea-level and temperature fluctuations, are modulated by local conditions mainly controlled by the morphology of the basin. (C) 2008 Elsevier B.V. All rights reserved.

Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014;62:1125-1141.