[Computerized ranking test in three French universities: Staff experience and students' feedback]. / Épreuves informatisées de type ECNi: retour d'expérience sur un test multiuniversité.

BACKGROUND: The year 2016 will be pivotal for the evaluation of French medical students with the introduction of the first computerized National Ranking Test (ECNi). The SIDES, online electronic system for medical student evaluation, was created for this purpose. All the universities have already organized faculty exams but few a joint computerized ranking test at several universities simultaneously. We report our experience on the organization of a mock ECNi by universities Paris Descartes, Paris Diderot and Paris 13. METHODS: Docimological, administrative and technical working groups were created to organize this ECNi. Students in their fifth year of medical studies, who will be the first students to sit for the official ECNi in 2016, were invited to attend this mock exam that represented more than 50% of what will be proposed in 2016. A final electronic questionnaire allowed a docimological and organizational evaluation by students. An analysis of ratings and rankings and their distribution on a 1000-point scale were performed. RESULTS: Sixty-four percent of enrolled students (i.e., 654) attended the three half-day exams. No difference in total score and ranking between the three universities was observed. Students' feedback was extremely positive. Normalized over 1000 points, 99% of students were scored on 300 points only. Progressive clinical cases were the most discriminating test. CONCLUSION: The organization of a mock ECNi involving multiple universities was a docimological and technical success but required an important administrative, technical and teaching investment.

Evaluation of a novel ECG lead placement method in telemetered freely moving cynomolgus monkeys: assessment of an intravascular biopotential lead.

INTRODUCTION: ECG is considered as a critical biomarker of cardiac safety pharmacology. ECG signal quality is essential for accurate interval quantification and automated arrhythmia detection. METHODS: We evaluated ECG signal quality over a 6 month period from 15 cynomolgus monkeys with radiotelemetry transmitters using biopotential leads where the negative lead was inserted in the jugular vein and advanced to the superior vena cava (intravascular lead) and the positive lead was placed on the diaphragm at the apex of the heart (diaphragmatic lead). Signal noise and signal-to-noise ratio from this implantation methodology were compared with signals obtained from animals with subcutaneous ECG lead. Macroscopic pathology and histopathology associated with the intravascular lead were evaluated at 6 months post-implantation in six monkeys. RESULTS: The ECG morphology obtained with the intravascular/diaphragmatic lead placement was comparable to conventional subcutaneous ECG (emulating Lead II) but presented higher amplitudes (P-wave +50.0%; R-wave +30.0%). Signal noise showed a circadian cycle of changes in magnitude for subcutaneous ECG leads that was not observed with this method. The intravascular/diaphragmatic lead placement presented a higher signal-to-noise ratio than subcutaneous ECG leads. No macroscopic abnormality was observed to be associated with the intravascular lead. Mild thickening of the intima/subintima with mild intimal proliferation of the cranial vena cava surrounding the intravascular lead were noted at histopathological examination. DISCUSSION: The intravascular/diaphragmatic ECG lead placement in cynomolgus monkeys provided reduced signal noise and elevated P-QRS-T amplitudes. The intravascular lead was well tolerated and appeared suitable for chronically instrumented cardiovascular safety pharmacology studies. Further assessments would be warranted to evaluate the potential of this methodology in other species.

Cardiovascular and respiratory safety pharmacology in Göttingen minipigs: Pharmacological characterization.

INTRODUCTION: Similarities between pigs and humans support the relevance of Göttingen minipigs for regulatory safety pharmacology. The minipig is the species of choice for cardiovascular safety pharmacology when pivotal repeat toxicology studies are conducted in this species. METHODS: 4 male Göttingen minipigs with cardiovascular telemetry transmitters received intravenous saline, esmolol (0.5, 1, 2, 4 and 8mg/kg), medetomidine (0.04mg/kg), remifentanil (0.5, 1, 2, 4, 8 and 16µg/kg) and dopamine (2, 8, 10, 20, 30 and 50µg/kg/min) and oral sotalol (3 and 10mg/kg). Respiratory monitoring was conducted in 3 male and 3 female Göttingen minipigs receiving intravenous saline and methacholine (0, 3.4, 13.5 and 68µg/kg). RESULTS: Heart rate (HR) corrected QT was optimal with a method based on analysis of covariance (QTca) followed by Fridericia's standard formula. Esmolol induced a decrease in HR. Medetomidine was associated with an initial hypertension with bradycardia followed by sustained hypotension, bradycadia and prolonged QTc. Remifentanil induced a dose-dependent QTc shortening with an increase in arterial pressures. Sotalol caused a decrease in HR and systolic arterial pressure with an increase in PR and QTc intervals. Dopamine induced an increase in arterial and pulse pressures. Methacholine increased tidal volume, respiratory rate and minute volume. DISCUSSION: The results suggest that the minipig is a valid alternative to other non-rodent species for cardiovascular and respiratory safety pharmacology studies when this species is justified.

A highly flexible system for microstimulation of the visual cortex: design and implementation.

This paper presents the design of a system intended to be used as a prosthesis allowing profoundly visually impaired patients to recover partial vision by means of microstimulation in the primary visual cortex area. The main component of the system is a bio-electronic device to be implanted inside the skull of the user, composed of a plurality of stimulation modules, whose actions are controlled via an interface module. Power and data are transmitted to the implant wirelessly through a bidirectional inductive link, allowing diagnosis of the stimulating device and its environment after implantation, as well as power delivery optimization. A high level of flexibility is supported in terms of stimulation parameters, but a configurable communication protocol allows the device to be used with maximum efficiency. The core of an external controller implemented in a system on a programmable chip is also presented, performing data conversion and timing management such that phosphene intensity can be modulated by any parameter defining stimulation, either at the pulse level or in the time domain. Measured performances achieved with a prototype using two types of custom ASICs implemented in a 0.18-mum CMOS process and commercial components fulfill the requirements for a complete visual prosthesis for humans. When on/off activation is used with predefined parameters, stimuli measured on an electronic test bench could attain a rate in excess of 500 k pulses/s.

The relationship between EAP and EABR thresholds and levels used to program the nucleus 24 speech processor: data from adults.

OBJECTIVE: The objective of this study was to determine the relationship between electrically evoked whole nerve action potential (EAP) and electrical auditory brain stem response (EABR) thresholds and MAP threshold (T-level) and maximum comfort level (C-level) for subjects who use the Nucleus 24 cochlear implant system. DESIGN: Forty-four adult Nucleus 24 cochlear implant users participated in this study. EAP thresholds were recorded using the Neural Response Telemetry System developed by Cochlear Corporation. EABR thresholds were measured for a subset of 14 subjects using standard evoked potential techniques. These physiologic thresholds were collected on a set of five electrodes spaced across the cochlea, and were then compared with behavioral measures of T-level and C-level used to program the speech processor. RESULTS: EAP thresholds were correlated with MAP T- and C-levels; however, the correlation was not strong. A technique for improving the correlation by combining measures of T- and C-levels made on one electrode with the EAP thresholds was presented. Correlations between predicted and measured T- and C-levels using this technique were 0.83 and 0.77, respectively. Similar results were obtained using the EABR thresholds for a smaller set of subjects. In general, EABR thresholds were recorded at levels that were approximately 4.7 programming units lower than EAP thresholds. CONCLUSIONS: Either EAP or EABR thresholds can be used in combination with a limited amount of behavioral information to predict MAP T- and C-levels with reasonable accuracy.

Comparison of EAP thresholds with MAP levels in the nucleus 24 cochlear implant: data from children.

OBJECTIVE: The purpose of this study is to examine the relationship between the electrically evoked compound action potential (EAP) thresholds and the MAP thresholds (T-levels) and maximum comfort levels (C-levels) in children implanted with the Nucleus 24 device. DESIGN: EAP thresholds were measured using the Neural Response Telemetry system of the Nucleus 24 device. Twenty children implanted with the Nucleus 24 cochlear implant participated in this study. EAP thresholds were compared with the behavioral measures of T- and C-level used to construct the MAP these children used on a daily basis. For these subjects, both EAP and MAP T- and C-levels were obtained the same visit, which occurred at 3 to 5 mo postconnection. RESULTS: EAP thresholds were shown to fall between MAP T- and C-level for 18 of 20 subjects tested; however, considerable variability across subjects was noted. On average, EAP thresholds fell at 53% of the MAP dynamic range. Correlations between EAP threshold and MAP T- and C-level improved substantially when combined with behavioral measures obtained from one electrode in the array. CONCLUSIONS: Moderate correlations were found between EAP thresholds and MAP T- and C-levels for the children participating in this study. However, a technique is described for improving the accuracy of predictions of MAP T- and C-levels based on EAP data combined with a small amount of behavioral information.

Dorsal raphe stimulation differentially modulates dopaminergic neurons in the ventral tegmental area and substantia nigra.

The serotoninergic (5-HT) input from the dorsal raphe nucleus (DRN) to midbrain dopamine (DA) neurons is one of the most prominent. In this study, using standard extracellular single cell recording techniques we investigated the effects of electrical stimulation of the DRN on the spontaneous activity of substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) DA neurons in anesthetized rats. Poststimulus time histograms (PSTH) revealed two different types of response in both SNpc and VTA. Some cells exhibited an inhibition-excitation response while in other DA neurons the initial response was an excitation followed by an inhibition. In SNpc, 56% of the DA cells recorded were initially inhibited and 31% of the DA cells were initially excited. In contrast, 63% of VTA DA cells were initially excited and 34% were initially inhibited. Depletion of endogenous 5-HT by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), and the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA), almost completely eliminated the inhibition-excitation response in both SNpc and VTA DA cells, without changing the percentage of DA cells initially excited. Consequently, the proportion of DA neurons that were not affected by DR stimulation increased after 5-HT depletion (from 13% to 60% in SNpc and from 6% to 31% in VTA). In several DA cells, DRN stimulation caused important changes in firing rate and firing pattern. These data strongly suggest that the 5-HT input from the DRN is mainly inhibitory. It also suggests that 5-HT afferences modulate SNpc and VTA DA neurons in an opposite manner. Our results also suggest that non-5-HT inputs from DR can also modulate mesencephalic DA neurons. A differential modulation of VTA and SNpc DA neurons by 5-HT afferences from the DRN could have important implications for the development of drugs to treat schizophrenia or other neurologic and psychiatric diseases in which DA neurons are involved.

Electrically evoked compound action potentials recorded from subjects who use the nucleus CI24M device.

The ability to directly measure the response to a pulse with the NRT opens the possibility of using this system to characterize the responses to more complex stimuli. An example is the responses to constant-amplitude pulse trains. With further changes in the software that controls the implant, it may be possible to characterize the responses to modulated pulse trains or other stimuli that better approximate the type of stimuli that are normally used with a cochlear implant speech processor.

Dopamine and serotonin interactions in the modulation of the expression of the immediate-early transcription factor, nerve growth factor-inducible B, in the striatum.

Nerve growth factor-inducible B is a closely related member of the steroid-thyroid hormone receptor family of ligand-activated transcription factor. Recent evidence suggests a close relationship between nerve growth factor-inducible B and the dopamine system. Basal expression of messenger RNA for nerve growth factor-inducible B is relatively high in the striatum. The aims of the present study were: (i) to study the basal distribution and the modulation of striatal nerve growth factor-inducible B messenger RNA expression by dopamine and serotonin agonists, and (ii) to investigate the effects of combined administration of dopamine (D) and serotonin (5-HT) agonists. First, we investigated the effects of SKF38393 (D1), quinpirole (D2), 8-hydroxy-2-(di-n-propylaminotetralin) (5-HT1A) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (5-HT2A/2C) administered alone on striatal nerve growth factor-inducible B messenger RNA expression. In a second series of experiments, the effects of a combined administration of dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C agonists were studied. The goal of the last series of experiments was to determine the effects of a combined administration of the dopamine D2 agonist and either serotonin 5-HT1A or 5-HT2A/2C agonists. Our results show that: (i) striatal nerve growth factor-inducible B messenger RNA expression exhibited a lateral-medial gradient in drug-naive rats, (ii) quinpirole and 8-hydroxy-2-(di-n-propylaminotetralin) administered alone induced a significant decrease in striatal nerve growth factor-inducible B messenger RNA expression while 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane significantly increased it, (iii) complex interactions were found when dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C agonists were administered in combination, and (iv) combined administration of quinpirole and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane resulted in a significant decrease in nerve growth factor-inducible B expression. Taken together, these results demonstrate that striatal nerve growth factor-inducible B messenger RNA expression can be modulated by both dopamine and serotonin agonists. They also point out the existence of complex interactions between dopamine and serotonin in regard to striatal expression of the immediate-early transcription factor nerve growth factor-inducible B.

Modification of haloperidol-induced pattern of c-fos expression by serotonin agonists.

Acute challenge with clozapine and haloperidol produce different anatomical patterns of c-fos expression in the forebrain. The pharmacological profile of atypical antipsychotics suggests that serotonin might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, we examined the abilities of 5-HT1A and 5-HT2A/2c agonists to modify the pattern of c-fos expression induced by haloperidol and clozapine. Various groups of rats were pretreated with either saline, DOI, 8-OH-DPAT, and 8-OH-DPAT + DOI 30 min prior to haloperidol or clozapine administration. Rats were killed 90 min after antipsychotic administration. In saline-pretreated rats, haloperidol produced intense Fos-LI in all four striatal quadrants while the effect of clozapine was restricted to the medial part of the striatum. Prior administration of 8-OH-DPAT significantly reduced haloperidol-induced Fos-LI in all four striatal quadrants while DOI and 8-OHDPAT + DOI significantly reduced Fos-LI only in dorso- and ventrolateral quadrants. In the nucleus accumbens, haloperidol induced intense Fos-LI in the core and the shell regions whereas clozapine induced c-fos expression only in the shell. Pretreatment with 8-OHDPAT in haloperidol treated rats reduced Fos-LI in the core region yielding to a c-fos pattern similar to that induced by clozapine. In the prefrontal cortex of saline-pretreated rats, haloperidol produced a moderate c-fos expression compared with the intense expression produced by clozapine. Pretreatment with serotonin agonists before haloperidol brought the number of FOS-positive neurons to the same level as in clozapine treated rats. These results show the ability of 5-HT agonists to transform the typical pattern of c-fos expression induced by haloperidol into a pattern resembling that of clozapine.

Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins.

Deregulation of cell proliferation is a hallmark of cancer. In many transformed cells, the cyclin A/CDK2 complex that contains S-phase kinase associated proteins 1 and 2 (SKP1 and SKP2) is highly induced. To determine the roles of this complex in the cell cycle regulation and transformation, we have examined the composition of this complex. We report here that this complex contained an additional protein, human CUL-1, a member of the cullin/CDC53 family. The identification of CUL-1 as a member of the complex raises the possibility that the p19(SKP1)/p45(SKP2)/CUL-1 complex may function as the yeast SKP1-CDC53-F-box (SCF) protein complex that acts as a ubiquitin E3 ligase to regulate the G1/S transition. In mammalian cells, cyclin D, p21(CIP1/WAF1), and p27(KIP1) are short-lived proteins that are controlled by ubiquitin-dependent proteolysis. To determine the potential in vivo targets of the p19(SKP1)/p45(SKP2)/CUL-1 complex, we have used the specific antisense oligodeoxynucleotides against either SKP1, SKP2, or CUL-1 RNA to inhibit their expression. Treatment of cells with these oligonucleotides caused the selective accumulation of p21 and cyclin D proteins. The protein level of p27 was not affected. These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. Aberrant expression of human p19(SKP1)/p45(SKP2)/CUL-1 complex thus may contribute to tumorigenesis by regulating the protein levels of G1 cell cycle regulators.

Cleavage of CDK inhibitor p21(Cip1/Waf1) by caspases is an early event during DNA damage-induced apoptosis.

Activation of the p53-mediated DNA damage response induces either G1 cell cycle arrest or apoptosis. The G1 cell cycle arrest is in part caused by the p53-dependent transcriptional activation of the CDK inhibitor, p21(Cip1/Waf1). We report here that human p21 protein is rapidly induced but selectively cleaved during the apoptotic response to gamma-irradiation. Such an event occurred early, well before the morphological appearance of apoptosis. Ectopical expression of p53 in tumor cells alone could induce p21 expression, followed by p21 cleavage and apoptosis. The cleavage of p21 could be reproduced in extracts prepared from irradiated cells or by recombinant caspase-3, suggesting that a caspase-like activity is responsible for this cleavage. p21 binds independently to both CDK2 and proliferation cell nuclear antigen (PCNA). Our studies indicated that p21 cleavage by the caspase-like activity specifically abolished its interaction with PCNA, suggesting that p21 cleavage may interfere with normal PCNA-dependent repair. Our data suggest that p21 may serve as a critical checkpoint regulator for both cell cycle arrest and apoptosis during the p53-mediated DNA damage response. Manipulation of the checkpoint regulators involved in cell cycle arrest and apoptosis may thus provide a novel strategy to cancer therapy.

Fenfluramine-induced activation of the immediate-early gene c-fos in the striatum: possible interaction between serotonin and dopamine.

DL-Fenfluramine, a serotonin (5-HT) releasing agent, induces rapid expression of Fos-like immunoreactivity (Fos-LI) in the striatum as well as in other brain structures receiving a dense 5-HT innervation. Fenfluramine-induced Fos-LI expression in the striatum may result directly from the activation of 5-HT receptors or may be the result of interactions between dopamine (DA) and 5-HT neurotransmitter systems. To discriminate between these two possibilities, various groups of rats were pretreated with different 5-HT antagonists or a DA D1 antagonist, 20 min before fenfluramine administration. Animals were killed 60 min later. In the striatum, fenfluramine-induced expression of Fos-LI was almost completely blocked by SCH 23390, methysergide and S(-)-propranolol. The immediate-early gene response to fenfluramine was only slightly affected by pretreatment with the 5-HT2A/2C antagonist ritanserin. Fenfluramine was also administered to sham-operated and to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. In the 6-OHDA-lesioned rats, fen-fluramine-induced Fos-LI was decreased by 60% on the DA denervated side compared to the intact side and to sham-operated rats. To further probe the possibility of a direct activation of Fos-LI by 5-HT receptor subtypes, we evaluated the expression of Fos-LI after the administration of different 5-HT agonists. Our results demonstrate that neither 8-OH-DPAT, CGS-12066B, RU 24969 nor phenyl-biguanide was able to reproduce the effects of fenfluramine. Only a high dose of DOI (8.5 mg/kg) produced a moderate expression of Fos-LI in the dorsomedial part of the striatum. This contrasted with the Fos-LI expression in other brain areas where 8-OH-DPAT and DOI (2.5 and 8.5 mg/kg) reproduced the effects of the 5-HT releasing agent. Our results suggest that the release of 5-HT by fenfluramine induced Fos-LI expression predominantly in a striatal region related to associative functions and, that this c-fos response may be under the control of both 5-HT and DA. Moreover, the mechanism by which fenfluramine induces c-fos expression in the striatum differs from other brain regions.

[Rare hemoglobins in Guadeloupe and in the Lesser Antilles (author's transl)]. / Hémoglobines rares en Guadeloupe et aux Petites Antilles.

Screening of abnormal hemoglobins on 25 136 samples allowed us to detect from 1974-1979 rare or uncommon hemoglobins as N Baltimore, Korle Bu, Lepore, K Woolwich, J Broussais and J Baltimore. Hemoglobins N Baltimore, J Broussais, and J Baltimore are detected for the first time in Guadedoupe. The identification of these asymptomatic hemoglobins in this part of the Carribbean region provides information concerning the exact origin of the black population of these islands; e.g., hemoglobin K Woolwich and N Baltimore are found only in specific regions of West Africa.