Traitement de la dépression résistante par l'association citalopram-lithium. Méthodologie d'une étude multicentrique en double aveugle et résultats préliminaires [Treatment of resistant depression with the citalopram-lithium combination. Methodology of a double-blind multicenter study and preliminary results].

Citalopram, a new bicyclic antidepressant, is the most selective serotonin reuptake inhibitor. In a number of double-blind controlled studies, citalopram was compared to placebo and to known tricyclic antidepressants. These studies have shown their efficacy and good safety. The inefficacy of a psychotropic treatment in at least 20% of depressives has led a number of authors to propose original drug combinations and associations, like antidepressant/lithium (Li), antidepressant/sleep deprivation (agrypnia), antidepressant/ECT, or antidepressant/LT3. The aim of this investigation is to evaluate the clinical effectiveness and safety of a combined citalopram/lithium treatment in therapy-resistant patients, taking account of serotonergic functions, as tested by the fenfluramine/prolactin test, and of drug pharmacokinetics and pharmacogenetics of metabolism. DESIGN OF THE STUDY: A washout period of 3 days before initiating the treatment is included. After an open treatment phase of 28 days (D) with citalopram (20 mg D1-D3; 40 mg D4-D14; 40 or 60 mg D15-D28; concomitant medication allowed: chloral, chlorazepate), the nonresponding patients [less than 50% improvement in the total score on the 21 item-Hamilton Depression Rating Scale (HDRS)] are selected and treated with or without Li (randomized in double-blind conditions: citalopram/Li or citalopram/placebo) during the treatment (D29-D35). Thereafter, all patients included in the double-blind phase subsequently receive an open treatment with citalopram/Li for 7 days (D36-D42). The hypothesis of a relationship between serotoninergic functions in patients using the fenfluramine/prolactin test (D1) and the clinical response to citalopram (and Li) is assessed. Moreover, it is evaluated whether the pharmacogenetic status of the patients, as determined by the mephenytoin/dextromethorphan test (D0-D28), is related to the metabolism of fenfluramine and citalopram, and also to the clinical response. CLINICAL ASSESSMENT: Patients with a diagnosis of major depressive disorders according to DSM III are submitted to a clinical assessment of D1, D7, D14, D28, D35, D42: HDRS, CGI (clinical global impression), VAS (visual analog scales for self-rating of depression), HDRS (Hamilton depression rating scale, 21 items), UKU (side effects scale), and to clinical laboratory examens, as well as ECG, control of weight, pulse, blood pressure at D1, D28, D35. Fenfluramine/prolactin test: A butterfly needle is inserted in a forearm vein at 7 h 45 and is kept patent with liquemine. Samples for plasma prolactin, and d- and l-fenfluramine determinations are drawn at 8 h 15 (base line). Patients are given 60 mg fenfluramine (as a racemate) at 8 h 30. Kinetic points are determined at 9 h 30, 10 h 30, 11 h 30, 12 h 30, 13 h 30. Plasma levels of d- and l-fenfluramine are determined by gas chromatography and prolactin by IRNA. Mephenytoin/dextromethorphan test: Patients empty their bladders before the test; they are then given 25 mg dextropethorphan and 100 mg mephenytoin (as a racemate) at 8 h 00. They collect all urines during the following 8 hours. The metabolic ratio is determined by gas chromatography (metabolic ratio dextromethorphan/dextrorphan greater than 0.3 = PM (poor metabolizer); mephenytoin/4-OH-mephenytoin greater than 5.6, or mephenytoin S/R greater than 0.8 = PM). Citalopram plasma levels: Plasma levels of citalopram, desmethylcitalopram and didesmethylcitalopram are determined by gas chromatography--mass spectrometry. RESULTS OF THE PILOT STUDY. The investigation has been preceded by a pilot study including 14 patients, using the abovementioned protocol, except that all nonresponders were medicated with citalopram/Li on D28 to D42. The mean total score (n = 14) on the 21 item Hamilton scale was significantly reduced after the treatment, ie from 26.93 +/- 5.80 on D1 to 8.57 +/- 6.90 on D35 (p less than 0.001). A similar patCitalopram, a new bicyclic antidepressant, is the most selective serotonin reu

N-myc controls proliferation, morphogenesis, and patterning of the inner ear

Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis.

OBJECTIVE: To analyze the expression of estrogen receptors α and β as well as their target genes implicated in proliferation, c-myc, cyclin D1, and GREB1, in the endometrium of women with or without endometriosis. DESIGN: Expression analysis in human tissue. SETTING: University hospitals and a clinic. PATIENT(S): Ninety-one premenopausal women (59 patients with endometriosis and 32 controls) undergoing laparoscopic surgery. INTERVENTION(S): Biopsies were obtained at time of surgery, performed during the proliferative phase of the cycle. MAIN OUTCOME MEASURE(S): Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Tissue localization of these estrogen-regulated genes was analyzed by immunohistochemistry. RESULT(S): Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were increased in ectopic tissue in comparison with both normal and eutopic endometrium. Estrogen receptor mRNA levels also were upregulated in the eutopic peritoneal tissue of patients with endometriosis. Cyclin D1 and GREB1 expression was augmented in eutopic endometrium. c-myc, cyclin D1, and GREB1 proteins exhibited a nuclear localization in ectopic endometrial tissue. CONCLUSION(S): This constitutes the first report of increased expression of GREB1, as well as cyclin D1 and c-myc, in peritoneal endometriotic lesions, implicating these proteins in estrogen-dependent growth in this context.

The effect of virtual reality on visual vertigo symptoms in patients with peripheral vestibular dysfunction: a pilot study.

Individuals with vestibular dysfunction may experience visual vertigo (VV), in which symptoms are provoked or exacerbated by excessive or disorientating visual stimuli (e.g. supermarkets). VV can significantly improve when customized vestibular rehabilitation exercises are combined with exposure to optokinetic stimuli. Virtual reality (VR), which immerses patients in realistic, visually challenging environments, has also been suggested as an adjunct to VR to improve VV symptoms. This pilot study compared the responses of sixteen patients with unilateral peripheral vestibular disorder randomly allocated to a VR regime incorporating exposure to a static (Group S) or dynamic (Group D) VR environment. Participants practiced vestibular exercises, twice weekly for four weeks, inside a static (Group S) or dynamic (Group D) virtual crowded square environment, presented in an immersive projection theatre (IPT), and received a vestibular exercise program to practice on days not attending clinic. A third Group D1 completed both the static and dynamic VR training. Treatment response was assessed with the Dynamic Gait Index and questionnaires concerning symptom triggers and psychological state. At final assessment, significant betweengroup differences were noted between Groups D (p = 0.001) and D1 (p = 0.03) compared to Group S for VV symptoms with the former two showing a significant 59.2% and 25.8% improvement respectively compared to 1.6% for the latter. Depression scores improved only for Group S (p = 0.01) while a trend towards significance was noted for Group D regarding anxiety scores (p = 0.07). Conclusion: Exposure to dynamic VR environments should be considered as a useful adjunct to vestibular rehabilitation programs for patients with peripheral vestibular disorders and VV symptoms.

Dietas artificiais para a criação de larvas e adultos da mosca-das-frutas sul-americana

O objetivo deste trabalho foi adequar as dietas artificiais para o desenvolvimento dos estágios de larva e adulto da mosca-das-frutas sul-americana (Anastrepha fraterculus). Para o estágio larval, foram testadas as seguintes dietas: D1, original, com 10 g de ágar; D2, modificada, com 3,6 g de ágar; e, D3, modificada, com bagaço seco de cana-de-açúcar. Para os adultos, foram testadas quatro dietas: A, levedura de cerveja + mel (2:1); B, açúcar refinado + extrato de levedura + gérmen de trigo cru (3:1:1); C, extrato de soja + açúcar mascavo + gérmen de trigo cru (3:1:1); e D, levedura seca de cervejaria + mel (2:1). Avaliaram-se os parâmetros biológicos de duração do período ovo-pupa, duração e viabilidade do estágio de pupa, massa média de pupas, razão sexual e duração e viabilidade do período ovo-adulto. O desenvolvimento larval em D1 e D2 foi semelhante e indicou que a criação de larvas pode ser realizada com 1/3 da quantidade de ágar da utilizada em D1. A utilização do bagaço seco de cana-de-açúcar, na dieta artificial, afetou negativamente o desenvolvimento larval. As dietas artificiais com levedura de cerveja + mel e com açúcar refinado + extrato de levedura + gérmen de trigo cru são as mais adequadas para a criação de adultos.

A pilot study of the efficacy of IL1 blockade by anakinra in acute calcific periarthritis of the rotator cuff

Background/Purpose: Calcific periarthritis of rotator cuff can induce acute and severe shoulder pain and is accompnied by signs of acute inflammation. The calcific deposits are composed of calcium phosphate crystals such as hydroxyapatite or basic calcium phosphate. These crystals stimulate the production and release of IL1b from macrophages, in an analogous manner to MSU and CPPD crystals. As IL1 blockade is effective in reducing signs and symptoms of inflammation in acute gout, we performed a pilot study to study if it is also effective in calcific periarthritis Methods: 5 consecutive patients were included (mean age: 62, 3 females, 2 males) between March 2011 and March 2012. Symptoms of acute shoulder pain at rest had to be present for _7 days before inclusion, associated with limitation of shoulder mobility and the presence on calcification in the rotator cuff by conventional radiography. None of the patients had responded to at least 48 hours of high doses of NSAIDs. Exclusion criteria included no corticosteroid therapy in the last 2 weeks and the exclusion of other rheumatologic or infectious diseases- .Clinical evaluation consisted of patient assessment of pain (total, rest and activity) by VAS (100mm scale) at days 0, 1, 3, 15, 42 and clinical examination of shoulder mobility at days 0, 3, 15. ESR and CRP were measured at days 0, 3. Plain radiographs were performed at days 0 and 15 and an ultrasound examination (including Doppler) was performed at days 0, 3, 15. Anakinra 100mg daily was administered for 3 consecutive days after the first evaluation (day 0). Rescue analgesics were allowed and recorded. Results: At inclusion, all patients had severe shoulder pain: mean (SD) VAS day pain of 72mm (_25mm), mean VAS night pain of 96 (_ 5) and impaired shoulder mobility. CRP was elevated in all of them (mean of 3X). Treatment with anakinra lead to rapid relief of pain in all patients, starting already on the first night following the first injection. The reduction of VAS pain was particularly striking for rest pain: mean (SD) VAS of 4mm (_ 5) at day 1 and this response was maintained for the 5 patients at the end of the three injections without any need of rescue medication. Mean rest VAS was 6 (_8) at day 3. The effect on day pain was less spectacular: mean (SD) VAS at D1 of 30 (_ 18), at D3 of 27 (_ 11). Shoulder mobility also improved and the CRP normalized in 4 of 5 patients at day 3. At day 42, 4 of 5 the patients were still totally asymptomatic. On X rays and US, the calcifications were reduced in size: mean maximal diameter of 21 mm at day 0 to 12 mm at day 15, but did not disappear in any patient. The main change on US was a significant and rapid (at day 3) reduction of Doppler activity around the calcification. Conclusion: This pilot open study suggests that IL-1_ inhibition may be an interesting therapeutic approach in acute calcific periarthritis, especially in patients who have not responded adequately to NSAIDs. The effect on pain seems to be more rapid (within a few hours) than steroid injection although a randomized controlled study needs to be performed to confirm this observation.

Respostas ecofisiológicas de cafeeiros submetidos ao deficit hídrico para concentração da florada no Cerrado de Minas Gerais

O objetivo deste trabalho foi avaliar o efeito de diferentes períodos de imposição do deficit hídrico sobre a concentração da florada do cafeeiro (Coffea arabica), bem como sobre as trocas gasosas, a produtividade, a maturação e a qualidade dos grãos. As cultivares Catuaí Vermelho IAC 144 e Bourbon Amarelo J9 foram avaliadas conforme os seguintes tratamentos: não irrigado (NI), irrigado continuamente (IC), e suspensão da irrigação em 1/7/2010 (D1) e em 1/8/2010 (D2), com retorno desta em 24/9/2010. Cerca de três dias após a retomada da irrigação, registrou-se a ocorrência de uma "chuva de florada", com precipitação de 69 mm. O potencial hídrico foliar de antemanhã (Ψam) nas cultivares Catuaí Vermelho IAC 144 e Bourbon Amarelo J9, em 22/9, foi de -0,59 e -0,82 MPa, -0,53 e -0,79 MPa, e -0,34 e -0,49 MPa, para os tratamentos NI, D1 e D2, respectivamente. O percentual máximo de botões florais no estádio E4, imediatamente antes da ocorrência da chuva, não foi afetado pelos níveis de deficit impostos durante o inverno, independentemente das cultivares. Os níveis moderados de deficit hídrico impostos pelos tratamentos (Ψam ~ -0,80 MPa) produziram pouco ou nenhum efeito sobre as trocas gasosas, a taxa de florescimento ou a uniformidade de maturação - percentagem de cerejas de 66% -, e a produtividade e a classificação dos grãos, de ambas as cultivares. O efeito dos diferentes tratamentos sobre o status hídrico dos botões florais não se sobrepõe ao efeito da chuva de florada, que foi determinante para sua abertura.

The effect of virtual reality on visual vertigo symptoms in patients with peripheral vestibular dysfunction: a pilot study

Individuals with vestibular dysfunction may experience visual vertigo (VV), in which symptoms are provoked or exacerbated by excessive or disorientating visual stimuli (e.g. supermarkets). VV can significantly improve when customized vestibular rehabilitation exercises are combined with exposure to optokinetic stimuli. Virtual reality (VR), which immerses patients in realistic, visually challenging environments, has also been suggested as an adjunct to VR to improve VV symptoms. This pilot study compared the responses of sixteen patients with unilateral peripheral vestibular disorder randomly allocated to a VR regime incorporating exposure to a static (Group S) or dynamic (Group D) VR environment. Participants practiced vestibular exercises, twice weekly for four weeks, inside a static (Group S) or dynamic (Group D) virtual crowded square environment, presented in an immersive projection theatre (IPT), and received a vestibular exercise program to practice on days not attending clinic. A third Group D1 completed both the static and dynamic VR training. Treatment response was assessed with the Dynamic Gait Index and questionnaires concerning symptom triggers and psychological state. At final assessment, significant betweengroup differences were noted between Groups D (p = 0.001) and D1 (p = 0.03) compared to Group S for VV symptoms with the former two showing a significant 59.2% and 25.8% improvement respectively compared to 1.6% for the latter. Depression scores improved only for Group S (p = 0.01) while a trend towards significance was noted for Group D regarding anxiety scores (p = 0.07). Conclusion: Exposure to dynamic VR environments should be considered as a useful adjunct to vestibular rehabilitation programs for patients with peripheral vestibular disorders and VV symptoms.

The role of Receptor Activator of NFKB Ligand (RANKL) in mammary gland development

Abstract : The female reproductive hormones estrogen, progesterone and prolactin control postnatal breast development and are important to breast carcinogenesis. The mechanisms by which they elicit proliferation and morphogenesis remain poorly understood. Using the mouse as a model to study the molecular mechanisms through which hormones elicit morphogenetic changes in the mammary gland in vivo, we found the Receptor Activator of NFκB Ligand, a Tumor Necrosis Factor family member, to be strongly induced by progesterone. Recent publications suggested that hormone dependant RANKURANK signals are involved in the terminal differentiation of mammary gland alveolar buds into lobulo-alveolar structures competent for lactation. I show that in the absence of epithelial RANKL a distinct earlier stage of mammary gland development, side branch formation, is blocked. RANKL acts as a major mediator downstream of progesterone; it is required for progesterone-induced paracrine proliferation and completely rescues the mutant phenotype when ectopically expressed in progesterone receptor (PR) KO mammary epithelia. RANKL is not required for cell autonomous division of estrogen receptor alpha (ERa) /PR positive cells. Cyclin D1, previously implicated as a mediator of RANKL, is not affected by ablation of RANKL and is not required for RANKL-induced paracrine proliferation but for the cell autonomous proliferation. Gene expression arrays to find specific RANKL downstream targets have identified Id4, ElfS and one secreted metalloprotease (Adamtsl8) as potential candidates validated by Q-RT-PCR. Interestingly, Id4 and Adamtsl8 are expressed by the myoepithelial cells. Their expression additionally coincides with RANKL mRNA expression at mid pregnancy, possibly implying a functional contribution of both genes to RANKL mediated sidebranch formation. ElfS in contrast, is found to be strongly expressed by the end of pregnancy supporting recent findings of a prolactin mediated regulation. As for RANKL, this gene was in particular induced in luminal cells. Taken together, I report that progesterone is the major proliferative stimulus in the adult mammary gland eliciting proliferation of ERaJPR positive cells by a cell autonomous, cyclin D1-dependent and a paracrine RANKL-dependent mechanism. My work moreover suggests, that RANKL acts as a major orchestrator affecting different downstream mediators, through which progesterone exerts its effects concomitantly on different cellular compartments. Résumé : Les hormones sexuelles telles que l'oestrogène, la progestérone et la prolactine contrôlent le développement postnatal du sein et sont impliquées dans la cazcinogenèse. Les mécanismes par lesquels elles induisent la prolifération et la morphogénèse demeurent incompris. En utilisant la souris comme modèle, J'ai trouvé que le ligand activateur du récepteur de NFκB, une protéine de la famille du facteur de nécrose des tumeurs, peut être fortement induit par la progestérone. Les publications récentes ont suggéré que cette protéine est nécessaire à la fin de la grossesse, quand les cellules sécrétrices du lait apparaissent. Par des techniques de transplantation d'épithélium, je montre contrairement aux études précédentes, qu'en l'absence de RANKL dans l'épithélium une partie distincte du développement mammaire, la formation de branches latérales, est bloquée. La progestérone agit de manière pazacrine par l'intermédiaire de 12ANKL pour induire la prolifération tandis que la mort cellulaire n'est pas affectée. De plus, l'injection d'une protéine recombinante RANKL dans une souris mutante pour le récepteur à la progestérone induit la prolifération des cellules épithéliales en l'absence de grossesse ; la surexpression de RANKL dans ces mêmes mutants mène à une réversion complète du phénotype. Mes expériences démontrent que la progestérone induit deux types distincts de prolifération. Un premier type direct dans laquelle les cellules positives au récepteur à la progestérone prolifèrent. Cette division cellulaire est alors indépendante de RANKL mais dépendante de la cycline D1. Le second type de prolifération est induit par un mécanisme pazacrine et dépend de RANKL mais pas de la cycline D1. Ici, les cellules négatives au récepteur à la progestérone prolifèrent. Pour détecter des gènes cibles de la voie de signalisation du RANKL, un profil d'expression des gènes a été généré. Les facteurs de transcription Id4, EIf5 et une métalloprotéase sécrétée (Adamtsl8) ont été identifiés en tant que cibles potentielles. D'autres analyses de validation démontrent qu'Id4, Adamtsl8, RANKL mais pas E1f5 sont fortement exprimés au cours de la grossesse, coïncidant avec la formation de branchements latéraux induit par progestérone. EIf5 s'est avéré être exprimé vers la fin de la grossesse appuyant des résultats récents proposant une régulation par la prolactine. Le système canalaire mammaire se compose de couches cellulaires: une couche interne de cellules luminales et une externe de cellules myoépithéliale. Les expériences génétiques d'expression ont révélé que RANKL. et E1f5 sont exprimés dans la partie luminale tandis qu'Id4 et Adamtsl8 sont dans les cellules myoépithéliales. En conclusion, je prouve que la progestérone est le stimulus principal induisant la prolifération dans la glande mammaire d'adulte. Deux mécanismes de prolifération sont impliqués: l'un direct dépendant de la cycline Dl et l'autre paracrine dépendant de RANKI.. Mon travail suggère par ailleurs que RANKL agit en tant que médiateur important, par lequel la progestérone exerce ses effets sur différents compartiments cellulaires tels que la coordination de la prolifération des cellules épithéliales avec la réorganisation de la matrice extracellulaire et de la membrane basale exigées pour la morphogénèse du système canalaire latéral.

Dopamine affects parvalbumin expression during cortical development in vitro.

This study was undertaken to determine how dopamine influences cortical development. It focused on morphogenesis of GABAergic neurons that contained the calcium-binding protein parvalbumin (PV). Organotypic slices of frontoparietal cortex were taken from neonatal rats, cultured with or without dopamine, harvested daily (4-30 d), and immunostained for parvalbumin. Expression of parvalbumin occurred in the same regional and laminar sequence as in vivo. Expression in cingulate and entorhinal preceded that in lateral frontoparietal cortices. Laminar expression progressed from layer V to VI and finally II-IV. Somal labeling preceded fiber labeling by 2 d. Dopamine accelerated PV expression. In treated slices, a dense band of PV-immunoreactive neurons appeared in layer V at 7 d in vitro (DIV), and in all layers of frontoparietal cortex at 14 DIV, whereas in control slices such labeling did not appear until 14 and 21 DIV, respectively. The laminar distribution and dendritic branching of PV-immunoreactive neurons were quantified. More labeled neurons were in the superficial layers, and their dendritic arborizations were significantly increased by dopamine. Treatment with a D1 receptor agonist had little effect, whereas a D2 agonist mimicked dopamine's effects. Likewise, the D2 but not the D1 antagonist blocked dopamine-induced changes, indicating that they were mediated primarily by D2 receptors. Parvalbumin expression was accelerated by dopaminergic reinnervation of cortical slices that were cocultured with mesencephalic slices. Coapplication of the glutamate NMDA receptor antagonist MK801 or AP5 blocked dopamine-induced increases in dendritic branching, suggesting that changes were mediated partly by interaction with glutamate to alter cortical excitability.

Investigation of interaction between native and impurity defects in ZnSe

Zinc selenide is a prospective material for optoelectronics. The fabrication of ZnSe­based light-emitting diodes is hindered by complexity of p-type doping of the component materials. The interaction between native and impurity defects, the tendency of doping impurity to form associative centres with native defects and the tendency to self-compensation are the main factors impeding effective control of the value and type of conductivity. The thesis is devoted to the study of the processes of interaction between native and impurity defects in zinc selenide. It is established that the Au impurity has the most prominent amphoteric properties in ZnSe among Cu, Ag and Au impurities, as it forms a great number of both Au; donors and Auz„ acceptors. Electrical measurements show that Ag and Au ions introduced into vacant sites of the Zn sublattice form simple single-charged Agz„+ and Auzn+ states with d1° electron configuration, while Cu ions can form both single-charged Cuz„ (d1) and double-charged Cuzr`+ (d`o) centres. Amphoteric properties of Ag and Au transition metals stimulated by time are found for the first time from both electrical and luminescent measurements. A model that explains the changes in electrical and luminescent parameters by displacement of Ag ions into interstitial sites due to lattice deformation forces is proposed. Formation of an Ag;-donor impurity band in ZnSe samples doped with Ag and stored at room temperature is also studied. Thus, the properties of the doped samples are modified due to large lattice relaxation during aging. This fact should be taken into account in optoelectronic applications of doped ZnSe and related compounds.

Yverdon-les-Bains et Sermuz à la fin de l'âge du fer

La première partie de cette étude est consacrée à l'étude des vestiges découverts entre 1990 et 1994 à Yverdon-les-Bains (VD) en quatre points de la rue des Philosophes (n°s 7, 13, 21 et 27). L'étude des secteurs fouillés permet de retracer l'histoire d'une zone périphérique de l'agglomération depuis la fin du IVe s. av. J.-C. jusqu'au haut Moyen Age, où une nécropole s'est développée sur trois des parcelles étudiées {cf. CAR 75). L'accès oriental de l'agglomération est barré dès la fin du IVe s. par une palissade peut-être associée à un fossé. Le secteur sud n'a pas livré de vestige contemporain de cet aménagement, mais a été fréquenté depuis le début du IIe s. av. notre ère. Par la suite, un réseau de fossés de petites dimensions a été mis en place, qui d'un point de vue topographique se situe en aval du cordon littoral III, dans une zone anciennement marécageuse. Une fonction drainante a ainsi été postulée pour ces aménagements, qui ont peut-être été réalisés en vue de la construction du rempart. Celui-ci a été dégagé sur trois des parcelles fouillées. Un niveau de démolition repéré au n° 7 de la rue des Philosophes indique qu'il se prolongeait probablement en direction du lac, de l'autre côté de la voie d'accès conduisant à Voppidum partiellement dégagée en 1982 .Le rempart d'Yverdon se rattache au groupe des remparts à poteaux frontaux (Pfostenschlitzmauer) caractérisé par un parement en pierres sèches interrompu à intervalles réguliers (en moyenne 1.40 m) par des pieux de grandes dimensions (section: 50/60 x 30/40 cm) qui étaient reliés à une seconde rangée de pieux, distante d'environ 4 m du front de l'ouvrage; une rampe située à l'arrière de ce dispositif devait assurer la stabilité de l'ensemble. L'excellente conservation de plusieurs dizaines de ces pieux a permis de dater de manière absolue la construction de l'ouvrage vers 80 av. J.-C. Le rempart yverdonnois présente une particularité technique inédite des plus intéressante du point de vue constructif : les pieux des deux rangées ne sont pas implantés verticalement comme cela est généralement le cas, mais de manière oblique. Ce mode opératoire présente un progrès important, car il améliore notablement le comportement statique de l'ouvrage tout en facilitant sa mise en oeuvre (étude du Prof. L. Pflug). La fortification est précédée, dans le secteur sud, par plusieurs aménagements en bois, dont une palissade construite quelques années avant le rempart lui-même et une série de pieux qui pourrait appartenir à une ligne de défense avancée. Trois fossés précèdent le rempart dans le secteur oriental. Le premier, situé à moins d'un mètre de la base de la fortification, est probablement antérieur à cette dernière. Hormis les structures à caractère défensif, plusieurs aménagements de La Tène finale ont été dégagés sur les différentes parcelles, dont une cabane semi-enterrée de plan rectangulaire au n° 7 de la rue des Philosophes. En raison de sa situation extra muros et de son plan, une vocation artisanale a été proposée pour ce bâtiment. Une tombe datée de La Tène D1 par ses offrandes a été découverte au nord du chantier des Philosophes 21 parmi un groupe de sépultures de la nécropole tardo-antique du Pré de la Cure. La transgression lacustre mise en évidence au Parc Piguet paraît également avoir affecté la partie orientale de l'oppidum. Cet événement est survenu avant la démolition de la fortification, qui est datée vers le milieu du Ier s. avant notre ère. Les vestiges du vicus d'époque romaine, dégagés uniquement sur de petites surfaces, comprennent plusieurs constructions en terre et bois, une cave et un bâtiment maçonnés ainsi que plusieurs puits. L'étude du mobilier associé aux aménagements les plus récents situe l'abandon de l'agglomération dans la seconde moitié du IIIe s. ap. J.-C. pour trois des parcelles fouillées, alors que la zone des Philosophes 27 était peut-être encore occupée au siècle suivant.Les fouilles ont livré un abondant mobilier dont la majeure partie remonte à La Tène finale. La céramique de cette époque a été classée en fonction de critères technologique, formel et esthétique précis afin de mettre en évidence des marqueurs significatifs en termes chronologiques. Six horizons principaux ont été distingués, qui s'échelonnent entre le IIe s. av. J.-C. et le début de l'époque tibérienne. On retiendra pour la fin de l'âge du Fer que la première partie de La Tène finale est caractérisée par un vaisselier comprenant une majorité de formes basses en pâte sombre fine, alors que la période suivante voit une nette augmentation des récipients en pâte grossière, dont la plupart sont des pots à cuire à large lèvre déversée. Le registre décoratif évolue également: certains motifs ne sont attestés que durant une période, alors que d'autres se distinguent uniquement par leur fréquence. D'un point de vue économique, Yverdon, à l'image des sites du Plateau suisse, se situe durant la première partie de La Tène finale en dehors des voies commerciales. Les produits méditerranéens sont en effet extrêmement rares durant cette période, alors que leur nombre augmente sensiblement vers la fin de l'âge du Fer. La seconde partie de cette étude est dévolue à l'étude du murus gallicus de Sermuz (Ph. Curdy) et à la comparaison des divers modes constructifs mis en oeuvre pour les fortifications de la région des Trois-Lacs. La partie conclusive récapitule de manière chronologique l'évolution des occupations à Yverdon-les-Bains depuis l'âge du Bronze jusqu'au haut Moyen Âge et propose d'intégrer les nouveaux résultats dans une perspective historique. Diverses hypothèses évoquent les raisons qui conduirent les Yverdonnois à se retrancher vers 80 av. J.-C. et les relations qu'ils entretenaient avec le site voisin de Sermuz. Pour terminer, la fonction de ce dernier est discutée dans ce cadre, notamment l'hypothèse d'une occupation du territoire helvète par des troupes romaines antérieure à l'Alpenfeldzug .

Intravoxel incoherent motion diffusion-weighted imaging in the liver: comparison of mono-, bi- and tri-exponential modelling at 3.0-T.

PURPOSE: To determine whether a mono-, bi- or tri-exponential model best fits the intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) signal of normal livers. MATERIALS AND METHODS: The pilot and validation studies were conducted in 38 and 36 patients with normal livers, respectively. The DWI sequence was performed using single-shot echoplanar imaging with 11 (pilot study) and 16 (validation study) b values. In each study, data from all patients were used to model the IVIM signal of normal liver. Diffusion coefficients (Di ± standard deviations) and their fractions (fi ± standard deviations) were determined from each model. The models were compared using the extra sum-of-squares test and information criteria. RESULTS: The tri-exponential model provided a better fit than both the bi- and mono-exponential models. The tri-exponential IVIM model determined three diffusion compartments: a slow (D1 = 1.35 ± 0.03 × 10(-3) mm(2)/s; f1 = 72.7 ± 0.9 %), a fast (D2 = 26.50 ± 2.49 × 10(-3) mm(2)/s; f2 = 13.7 ± 0.6 %) and a very fast (D3 = 404.00 ± 43.7 × 10(-3) mm(2)/s; f3 = 13.5 ± 0.8 %) diffusion compartment [results from the validation study]. The very fast compartment contributed to the IVIM signal only for b values ≤15 s/mm(2) CONCLUSION: The tri-exponential model provided the best fit for IVIM signal decay in the liver over the 0-800 s/mm(2) range. In IVIM analysis of normal liver, a third very fast (pseudo)diffusion component might be relevant. KEY POINTS: ? For normal liver, tri-exponential IVIM model might be superior to bi-exponential ? A very fast compartment (D = 404.00 ± 43.7 × 10 (-3)  mm (2) /s; f = 13.5 ± 0.8 %) is determined from the tri-exponential model ? The compartment contributes to the IVIM signal only for b ≤ 15 s/mm (2.)

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome.

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.

Nutrição do porta-enxerto 'Flying Dragon'

No Brasil, o uso do trifoliata 'Flying Dragon', como porta-enxerto em citros, tem crescido quando se buscam pomares com altas densidades, devido, principalmente, a induzir nanismo à maioria das variedades de copa compatíveis. No entanto, por possuir desenvolvimento lento, existe a necessidade de se estudar melhor o crescimento desse porta-enxerto. A nutrição é uma importante ferramenta que visa a acelerar o crescimento e a melhorar o vigor e a qualidade das plantas. Diante disso, foi avaliada a aplicação de nutrientes no crescimento do porta-enxerto em três experimentos. No primeiro experimento, utilizaram-se seis doses de N parceladas; no segundo, seis doses de P (aplicadas em dose total, misturadas diretamente no substrato); e no terceiro, seis doses de K parceladas. As seis doses foram constituídas por: D0 = testemunha sem adubação; D1= metade da dose-padrão; D2 = a dose-padrão (920 mg dm-3 de N, 790 mg dm-3 de K e 100 mg dm-3 de P); D3 = uma vez e meia a dose-padrão; D4 = duas vezes a dose-padrão; e D5 = duas vezes e meia a dose-padrão. Assim, coletaram-se dados biométricos da planta de diâmetro e altura, quinzenalmente, e dados de massa seca da parte aérea e da raiz, mensalmente. O delineamento utilizado foi o inteiramente casualizado, com parcela subdividida. O nitrogênio teve papel fundamental no incremento das massas secas de raiz e da parte aérea.