Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions

A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

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

A double role of sperm in scorpions: the mating plug of Euscorpius italicus (Scorpiones: Euscorpiidae) consists of sperm.

Mating plugs occluding the female gonopore after mating are a widespread phenomenon. In scorpions, two main types of mating plugs are found: sclerotized mating plugs being parts of the spermatophore that break off during mating, and gel-like mating plugs being gelatinous fluids that harden in the female genital tract. In this study, the gel-like mating plug of Euscorpius italicus was investigated with respect to its composition, fine structure, and changes over time. Sperm forms the major component of the mating plug, a phenomenon previously unknown in arachnids. Three parts of the mating plug can be distinguished. The part facing the outside of the female (outer part) contains sperm packages containing inactive spermatozoa. In this state, sperm is transferred. In the median part, the sperm packages get uncoiled to single spermatozoa. In the inner part, free sperm is embedded in a large amount of secretions. Fresh mating plugs are soft gelatinous, later they harden from outside toward inside. This process is completed after 3-5 days. Sperm from artificially triggered spermatophores could be activated by immersion in insect Ringer's solution indicating that the fluid condition in the females' genital tract or females' secretions causes sperm activation. Because of the male origin of the mating plug, it has likely evolved under sperm competition or sexual conflict. As females refused to remate irrespective of the presence or absence of a mating plug, females may have changed their mating behavior in the course of evolution from polyandry to monandry.

Gene transfer of the Ly-3 chain gene of the mouse CD8 molecular complex: co-transfer with the Ly-2 polypeptide gene results in detectable cell surface expression of the Ly-3 antigenic determinants.

The CD8 molecule is a glycoprotein expressed on a subset of mature T lymphocytes. It has been postulated to be a receptor for class I major histocompatibility complex molecules. In the mouse, CD8 is a heterodimer composed of Ly-2 and Ly-3 chains. We have isolated and analyzed cDNA and cosmid clones corresponding to the Ly-3 subunit. One of the isolated, cosmid clones was subsequently transfected, alone or in combination with the Ly-2 gene, into mouse Ltk- cells. Analysis of the Ly-2,3 molecules expressed at the surface of the double transfectants indicated that they are serologically and biochemically indistinguishable from their normal counterparts expressed on lymphoid cells. Ltk- cells transfected with the Ly-2 gene alone were shown to react with a subset of anti-CD8 monoclonal antibodies whereas Ly-3 transfectants did not stain with any of the anti-Ly-3 antibodies employed in this study. Since at least one of these antibodies (53-5.8) has been previously shown to recognize an epitope which is retained on the Ly-3 subunit after dissociation of the heterodimeric Ly-2,3 complex, these observations suggest that the expression of the Ly-2 polypeptide is required to permit the detectable cell surface expression of the antigenic determinants carried by the Ly-3 subunit.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Modelling of crowded polymers elucidate effects of double-strand breaks in topological domains of bacterial chromosomes.

Using numerical simulations of pairs of long polymeric chains confined in microscopic cylinders, we investigate consequences of double-strand DNA breaks occurring in independent topological domains, such as these constituting bacterial chromosomes. Our simulations show a transition between segregated and mixed state upon linearization of one of the modelled topological domains. Our results explain how chromosomal organization into topological domains can fulfil two opposite conditions: (i) effectively repulse various loops from each other thus promoting chromosome separation and (ii) permit local DNA intermingling when one or more loops are broken and need to be repaired in a process that requires homology search between broken ends and their homologous sequences in closely positioned sister chromatid.

Phosphorylation by casein kinase 2 facilitates rRNA gene transcription by promoting dissociation of TIF-IA from elongating RNA polymerase I.

The protein kinase casein kinase 2 (CK2) phosphorylates different components of the RNA polymerase I (Pol I) transcription machinery and exerts a positive effect on rRNA gene (rDNA) transcription. Here we show that CK2 phosphorylates the transcription initiation factor TIF-IA at serines 170 and 172 (Ser170/172), and this phosphorylation triggers the release of TIF-IA from Pol I after transcription initiation. Inhibition of Ser170/172 phosphorylation or covalent tethering of TIF-IA to the RPA43 subunit of Pol I inhibits rDNA transcription, leading to perturbation of nucleolar structure and cell cycle arrest. Fluorescence recovery after photobleaching and chromatin immunoprecipitation experiments demonstrate that dissociation of TIF-IA from Pol I is a prerequisite for proper transcription elongation. In support of phosphorylation of TIF-IA switching from the initiation into the elongation phase, dephosphorylation of Ser170/172 by FCP1 facilitates the reassociation of TIF-IA with Pol I, allowing a new round of rDNA transcription. The results reveal a mechanism by which the functional interplay between CK2 and FCP1 sustains multiple rounds of Pol I transcription.

Hybrid model of a double-fed induction machine and back-to-back converter

This report details the port interconnection of two subsystems: a power electronics subsystem (a back-to-back AC/AC converter (B2B), coupled to a phase of the power grid), and an electromechanical subsystem (a doubly-fed induction machine (DFIM), coupled mechanically to a flywheel and electrically to the power grid and to a local varying load). Both subsystems have been essentially described in previous reports (deliverables D 0.5 and D 4.3.1), although some previously unpublished details are presented here. The B2B is a variable structure system (VSS), due to the presence of control-actuated switches: however from a modelling and simulation, as well as a control-design, point of view, it is sensible to consider modulated transformers (MTF in the bond-graph language) instead of the pairs of complementary switches. The port-Hamiltonian models of both subsystems are presents and coupled through a power-preserving interconnection, and the Hamiltonian description of the whole system is obtained; detailed bond-graphs of all the subsystems and the complete system are provided.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Cefuroxime prophylaxis is effective in noninstrumented spine surgery : a double-blind, placebo-controlled study

Rapport de synthèse : Plusieurs investigateurs ont démontré que l'utilisation d'une antibiothérapie prophylactique lors d'interventions neurochirurgicales en terrain non infecté (chirurgie propre) réduisait le taux d'infection. Toutefois, ces taux d'infections sont très variables en fonction des types de chirurgie et de la durée des interventions. Les craniotomies, la mise en place ou le remplacement de shunt ventriculo-cardiaque, l'extirpation de méningiomes intracrâniens et les interventions d'une durée de plus de quatre heures sont grevées d'un taux d'infections post-opératoires plus élevé. Si une prophylaxie antibiotique est maintenant reconnue et utilisée dans ce type de chirurgie, il n'a jamais été démontré que cette pratique amène un bénéfice dans les cas de chirurgie pour hernie discale. Des études ont montré que de nombreux organismes potentiellement pathogènes pouvaient être collectés et cultivés à proximité voire dans le champ opératoire. Malgré ces observations, le taux d'infections post-opératoires reste peu important (entre 1-4% selon les centres). Il n'est actuellement pas possible de distinguer le rôle respectif d'une antibiothérapie prophylactique et des pratiques d'asepsie habituelles (y compris l'usage de solutions de rinçage antiseptiques) dans la faible incidence des infections post-opératoires en ce qui concerne la chirurgie des hernies discales. Lorsque des opérations de chirurgie dite «propre » sont grevées d'un taux de complications aussi bas, une prophylaxie antibiotique n'est généralement pas recommandée, en raison d'un rapport coût-bénéfice défavorable. Le but de cette étude est d'évaluer la nécessité d'une antibiothérapie prophylactique par une céphalosporine de seconde génération (cefuroxime 1,5 g intraveineuse) dans la prévention des infections post-opératoires au cours d'une chirurgie pour hernie discale. Il s'agit d'un essai clinique prospectif, contrôlé contre placebo en insu réciproque, à répartition aléatoire. L'étude a été conduite dans les services de neurochirurgie de l'Hôpital Universitaire de Genève et du Centre Hospitalier Universitaire Vaudois de Lausanne. L'ensemble des patients admis dans ces deux services pour une opération de hernie discale et ayant donné leur consentement ont été inclus dans l'étude qui s'est déroulé sur une période de 6 ans. Mille trois cent soixante-neuf patients opérés pour une hernie discale ont été inclus dans cet essai et 132 patients ont été exclus de l'analyse pour diverses raisons. Au total 1'237 patients ont été analysés, respectivement 613 et 624 patients dans le groupe cefuroxime et le groupe placebo. Les patients des deux groupes présentaient des caractéristiques identiques. Nous n'avons objectivé aucun effet secondaire indésirable attribuable à la cefuroxime ou au placebo. Huit (1.3%) patients du groupe cefuroxime et 18 patients (2.8%) du groupe placebo ont développé une infection du site opératoire (P=0.073). Neuf des patients infectés dans le groupe placebo présentaient une infection profonde du site opératoire (spondylodiscite, abcès épidural) et aucun dans le groupe cefuroxime (P<0.01). Tous les patients avec infection profonde du site opératoire ont été traités par antibiothérapie par voie intraveineuse pour au moins 4 semaines et il a été procédé à une reprise chirurgicale chez deux patients. Ces résultats montrent qu'il faut traiter 69 patients avec une antibiothérapie prophylactique de cefuroxime pour prévenir une infection du site opératoire. En conclusion, l'administration d'une dose de cefuroxime 1.5 g intraveineuse comme prophylaxie lors d'opération de hernie discale, permet de réduire significativement le risque d'infection profonde du site opératoire.

The double-edged sword of social capital: Three essays on entrepreneurship in developing nations

ABSTRACT My study seeks to answer the main question: "how does entrepreneurs' social capital positively and negatively affect their resource mobilization efforts, and exploitation of entrepreneurial opportunity?" To answer this question, I develop a model for examining positive and negative effects of social capital on resource accumulation by entrepreneurs, and the subsequent effect of resource accumulation on the exploitation of entrepreneurial opportunity, and utilize data from Africa to ëmpirically test the relationships in this model. Developing nations are a suitable context because: a) They require entrepreneurship for economic development, b) They have received less attention in management and entrepreneurship research, c) Because of inadequately-developed institutions, entrepreneurs from developing nations face major resource mobilization challenges hence they often turn to their social ties for resources, and d) The communalistic and collectivistic nature of most developing nations -encouraging support and sharing of resources- may help us better understand how society's values and structures may contribute and also deduct firm resources. My study reveals that social capital contributes resources to entrepreneurs in developing nations at a cost that takes away resources, and that more resources but lower costs facilitate entrepreneurial opportunity exploitation. For entrepreneurs in developing nations, large networks, greater shared identity, and more trust are beneficial. To increase chances of raising more resources, entrepreneurs from communalistic societies should include network members from outside their communities. Besides providing financial support, policy-makers should develop training programs and advisory services on configuration of entrepreneurs' networks so as to achieve more resources at a low cost. My study insights can help improve entrepreneurs' resource accumulation efforts and the subsequent growth of their firms, leading to the overall economic growth of developing nations.