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Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. The in vivo effects of a chronic expression of exogenous ApN restricted to adipose tissue are unclear. Moreover, the regulatory effects of ApN on its own expression and on that of its receptors are still unknown. In this study, we generated transgenic (Tg) mice with moderate expression of exogenous ApN targeted to adipose tissue (native full-length ApN being placed under control of the adipocyte promoter aP2). After a transient overexpression of ApN in young pups, we intriguingly observed a reduction of ApN mRNA levels and protein content in fat depots, together with a decrease of circulating ApN in adult mice. As a result, the phenotype of these adult mice included glucose intolerance, insulin resistance, and increased adiposity. Reduced expression of ApN in fat tissue was associated with diminished expression of uncoupling protein 2 involved in energy dissipation, and higher expression of fatty acid synthase, a key enzyme of lipogenesis, and of TNFalpha implicated in insulin resistance. Concomitantly, the expression of the ApN receptor AdipoR2 that mediates action of full-length ApN was downregulated, while that of AdipoR1 was unaffected. In agreement with the in vivo studies, recombinant ApN added to the culture medium of 3T3-F442A adipocytes caused a decrease in AdipoR2 and ApN mRNA levels. This treatment did not affect the expression of AdipoR1. Eventually, we demonstrated a contrario that AdipoR2 (but not R1) was specifically upregulated in fat of ApN(-/-) mice. Our in vivo and in vitro data provide evidence for a novel regulatory feedback loop by which ApN downregulates its own production and the expression of its AdipoR2 receptor.

Human faces look more similar to each other when they are presented upside-down, leading to an increase of error rates and response times during individual face discrimination tasks. Here we used functional magnetic resonance imaging (fMRI) to test the hypothesis that this perceived similarity leads to a lower recovery from identity adaptation for inverted faces than for upright faces in face-sensitive areas of the occipito-temporal cortex. Ten subjects were presented with blocks of upright and inverted faces, with the same face identity repeated consecutively in half of the blocks, and different facial identities repeated in the other blocks. When face stimuli were presented upright, the percent signal change in the bilateral middle fusiform gyrus (MFG) was larger for different faces as compared to same faces, replicating previous observations of a recovery from facial identity adaptation in this region. However, there was no significant recovery from adaptation when different inverted faces were presented. Most interestingly, the difference in activation between upright and inverted faces increased progressively during a block when different facial identities were presented. A similar pattern of activation was found in the left middle fusiform gyrus, but was less clear-cut in bilateral face-sensitive areas of the inferior occipital cortex. These findings show that the differential level of activation to upright and inverted faces in the fusiform gyrus is mainly due to a difference in recovery from adaptation, and they explain the discrepancies in the results reported in previous fMRI studies which compared the processing of upright and inverted faces. The lack of recovery from adaptation for inverted faces in the fusiform gyrus may underlie the face inversion effect (FIE), which takes place during perceptual encoding of individual face representations.

Glucose induces insulin secretion (IS) and also potentiates the insulin-releasing action of secretagogues such as arginine and sulfonylureas. This potentiating effect is known to be impaired in type 2 diabetic patients, but its cellular mechanisms are unclear. IS and cytosolic Ca(2+) concentration ([Ca(2+)](i)) were measured in mouse islets during perifusion with 3-15 mmol/l glucose (G3-G15, respectively) and pulse or stepwise stimulation with 1-10 mmol/l arginine or 5-250 micromol/l tolbutamide. In G3, arginine induced small increases in [Ca(2+)](i) but no IS. G7 alone only slightly increased [Ca(2+)](i) and IS but markedly potentiated arginine effects on [Ca(2+)](i), which resulted in significant IS (already at 1 mmol/l). For each arginine concentration, both responses further increased at G10 and G15, but the relative change was distinctly larger for IS than [Ca(2+)](i). At all glucose concentrations, tolbutamide dose dependently increased [Ca(2+)](i) and IS with thresholds of 25 micromol/l for [Ca(2+)](i) and 100 micromol/l for IS at G3 and of 5 micromol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on [Ca(2+)](i) increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and [Ca(2+)](i) at increasing arginine or tolbutamide concentrations became steeper as the glucose concentration was raised. Thus glucose augmented more the effect of each agent on IS than that on [Ca(2+)](i). In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of [Ca(2+)](i) and the action of Ca(2+) on exocytosis. This dual mechanism must be borne in mind to interpret the alterations of the potentiating action of glucose in type 2 diabetic patients.

The middle fusiform gyrus (MFG) and the inferior occipital gyrus (IOG) are activated by both detection and identification of faces. Paradoxically, patients with acquired prosopagnosia following lesions to either of these regions in the right hemisphere cannot identify faces, but can still detect faces. Here we acquired functional magnetic resonance imaging (fMRI) data during face processing in a patient presenting a specific deficit in individual face recognition, following lesions encompassing the right IOG. Using an adaptation paradigm we show that the fMRI signal in the rMFG of the patient, while being larger in response to faces as compared to objects, does not differ between conditions presenting identical and distinct faces, in contrast to the larger response to distinct faces observed in controls. These results suggest that individual discrimination of faces critically depends on the integrity of both the rMFG and the rIOG, which may interact through re-entrant cortical connections in the normal brain.

AIMS/HYPOTHESIS: Adiponectin is an adipokine that exhibits insulin-sensitising, fat-burning and anti-inflammatory properties as well as modulatory effects on oxidative stress. We examined whether adiponectin could be induced in a non-adipose tissue, skeletal muscle, in response to metabolic or oxidative aggression both in vivo (in a murine model of type 2 diabetes) and in vitro. METHODS: Obese and diabetic ob/ob mice were used and compared with lean littermates. Some obese mice were treated with the antioxidant probucol for 3 weeks. At the end of the experiment, blood was sampled and tibialis anterior muscles were collected for mRNA measurement and immunohistochemistry. Additional in vitro experiments were performed on C2C12 myotubes cultured for up to 48 h. RESULTS: In spite of hypoadiponectinaemia, Adipoq mRNA levels were markedly increased in the skeletal muscle of ob/ob mice and correlated with systemic oxidative stress. Adipoq upregulation was shown in laser-microdissected myocytes of obese mice. Concomitantly, immunoreactivity for adiponectin was enhanced in obese muscle fibres together with lipid infiltration and local markers of oxidative stress. In cultured C2C12 myotubes, a triglyceride mix and reactive oxygen species producers (H2O2 or a lipoperoxidation end-product) upregulated Adipoq expression and adiponectin production. This effect was reversed by an antioxidant. Finally, treatment of obese mice with probucol also attenuated upregulation in muscle. CONCLUSIONS/INTERPRETATION: The paradoxical upregulation of adiponectin in muscle of obese and diabetic mice may result from lipotoxicity and related oxidative stress. This unexpected finding could be viewed as a local protection to counteract ectopic fat deposition and oxidative damage.

The instant blood-mediated inflammatory reaction (IBMIR) is triggered in clinical islet transplantation when human pancreatic islets come in contact with blood and may explain the initial tissue loss associated with this procedure. Low molecular weight dextran sulfate (LMW-DS; MM 5000), today available for clinical use, inhibits both complement and coagulation activation. In a tubing loop model, LMW-DS at concentrations ranging from 0.01 to 1 g/L showed a dose-dependent inhibition of IBMIR with an inhibition of coagulation and complement activation and less consumption of platelets and other blood cells. In blood or plasma APTT was demonstrated to be an excellent method for monitoring the LMW-DS concentration both in vitro and in vivo in a nonhuman primate model. The toxicity was assessed using a glucose challenge test and the pharmacokinetics was tested in the nonhuman primate model. Here, we present a tentative protocol for using LMW-DS in clinical islet transplantation.

Stimulatory concentrations of glucose induce two patterns of cytosolic Ca2+ concentration ([Ca2+]c) oscillations in mouse islets: simple or mixed. In the mixed pattern, rapid oscillations are superimposed on slow ones. In the present study, we examined the role of the membrane potential in the mixed pattern and the impact of this pattern on insulin release. Simultaneous measurement of [Ca2+]c and insulin release from single islets revealed that mixed [Ca2+]c oscillations triggered synchronous oscillations of insulin secretion. Simultaneous recordings of membrane potential in a single beta-cell within an islet and of [Ca2+]c in the whole islet demonstrated that the mixed pattern resulted from compound bursting (i.e., clusters of membrane potential oscillations separated by prolonged silent intervals) that was synchronized in most beta-cells of the islet. Each slow [Ca2+]c increase during mixed oscillations was due to a progressive summation of rapid oscillations. Digital image analysis confirmed the good synchrony between subregions of an islet. By contrast, islets from sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3 (SERCA3)-knockout mice did not display typical mixed [Ca2+]c oscillations in response to glucose. This results from a lack of progressive summation of rapid oscillations and from altered spontaneous electrical activity, i.e., lack of compound bursting, and membrane potential oscillations characterized by lower-frequency but larger-depolarization phases than observed in SERCA3+/+ beta-cells. We conclude that glucose-induced mixed [Ca2+]c oscillations result from compound bursting in all beta-cells of the islet. Disruption of SERCA3 abolishes mixed [Ca2+]c oscillations and augments beta-cell depolarization. This latter observation indicates that the endoplasmic reticulum participates in the control of the beta-cell membrane potential during glucose stimulation.

OBJECTIVE AND DESIGN: The resistance of macroprolactinomas to dopamine agonist (DA) therapy, whether defined as an absence of PRL normalization or the lack of significant tumour shrinkage after prolonged treatment at high doses, is usually regarded as unpredictable. The aim of this retrospective study, conducted in a teaching hospital, was to determine whether cavernous sinus (CS) invasion assessed by magnetic resonance imaging (MRI) is associated with a higher rate of resistance to DA therapy. METHODS: Forty-nine patients with a macroprolactinoma were included in this study and classified into four groups according to the percentage of encasement of the intracavernous internal carotid artery (ICA) by the tumour. All patients received DA as the primary treatment, mainly cabergoline (CAB). PRL normalization and tumour shrinkage during treatment were evaluated as a function of CS invasion. RESULTS: Tumours encasing more than three-quarters of the intracavernous ICA (group 4) were less responsive to DA therapy, exhibiting a lower rate of early (< or = 3 months) PRL normalization (8%vs. 69% in the others groups; P < 0.01) under a higher dose of CAB (median: 3.5 mg vs. 1.0 mg per week; P < 0.01). CS invasion was a strongly significant and independent predictor of hormonal resistance to CAB (P < 0.01). This hormonal resistance occurred in eight patients (16%), all but one belonging to group 4. Significant tumour shrinkage was observed in 31 out of 45 assessable cases (69%) and was more likely to occur in the case of PRL normalization (P < 0.01). CONCLUSIONS: Parasellar extension of macroprolactinomas, assessed on the basis of strict MRI criteria, may predict a negative response to DA. The responsiveness of noninvasive macroprolactinomas (over 90%) is similar to that reported in microprolactinomas, whereas invasive tumours are resistant to treatment in more than 50% of cases.

Seizures starting in patients over 60 years old are frequent. Diagnosis is sometimes difficult and frequently under- or overrated. Cerebrovascular disorders are the main cause of a first seizure. Because of more frequent comorbidities, physiologic changes, and a higher sensitivity to drugs, treatment has some specificity in elderly people. The aim of this paper is to present the result of a consensus meeting held in October 2004 by a Belgian French-speaking group of epileptologists and to propose guidelines for the management and the treatment of epilepsy in elderly people.

GOALS: To give an overview on the theoretical and practical applications of chemosensory event-related potentials. METHODS: Chemosensory event-related potentials (ERPs) may be elicited by brief and precisely defined odorous stimuli. Based on the principles of air-dilution olfactometry, a stimulator was developed in the late 1970s, which allows stimulation of the olfactory neuroepithelium and the nasal mucosa with no concomitant mechanical stimulation. Chemosensory ERPs were obtained after stimulation of the olfactory nerve (olfactory ERPs) or the trigeminal nerve (somatosensory or trigeminal ERPs). The characteristics of the stimulator for chemosensory research as well as the variables influencing the responses are discussed in this paper. RESULTS: Implementation and normative data from our department are reported with different clinical examples from otorhinolaryngologic clinic. The bulk of the evoked response consists of a large negative component (often referred to as N1), which occurs between 320 and 450 ms after stimulus onset. This component is followed by a large positive component, often referred to as P2, occurring between 530 and 800 ms after stimulus onset. Absence of olfactory ERPs and presence (even with subtle changes) of somatosensory ERPs is a strong indicator of the presence of an olfactory dysfunction. CONCLUSIONS: This review examines and discusses the methods of chemosensory stimulation as well as the electrophysiological correlates elicited by such stimuli. The clinical applications of chemosensory ERPs in neurology and otorhinolaryngology are outlined.

OBJECTIVE: To investigate whether differences in olfactory function between healthy individuals and patients with olfactory loss could be detected by various diagnostic tests. DESIGN: Psychophysical testing of orthonasal and retronasal olfactory functions, magnetic resonance imaging of olfactory bulb (OB) volume, and chemosensory event-related potential (ERP) measurement performed between January 1, 2005, and October 31, 2005. SETTING: Academic tertiary referral medical center. PATIENTS: Eleven healthy individuals with normal olfactory function (NL) and 11 patients with nasal polyposis (NP), 11 with posttraumatic olfactory loss (PT), and 11 with postinfectious olfactory loss (PI) were included in this study. MAIN OUTCOME MEASURES: Orthonasal and retronasal olfactory test results, magnetic resonance imaging-based OB volume, and ERPs to both olfactory and intranasal trigeminal stimulation. RESULTS: Orthonasal and retronasal testing revealed that NL individuals had higher scores than patients with NP, PT, or PI. Retronasal scores were higher in NP patients compared with PT and PI patients. The OB volumes were higher in NL individuals compared with NP, PT, and PI patients. The OB volumes in PT patients were significantly lower than those from NP and PI patients. Olfactory ERPs were different between NL individuals and NP, PT, and PI patients, and trigeminal ERPs were significantly different when comparing NL individuals with NP patients. For the entire cohort, a significant correlation was found between orthonasal testing and OB volume, between retronasal testing and OB volume, and between both orthonasal and retronasal testing and olfactory ERP amplitudes. Olfactory ERPs were recorded in the 11 NL individuals and in 3 NP, 3 PT, and 4 PI patients, defined as responders. Orthonasal and retronasal test scores, OB volume, and olfactory ERPs were significantly larger in responders compared with nonresponders. CONCLUSIONS: Significant differences in various tests that evalua

There is behavioral evidence that different visual categorization tasks on various types of stimuli (e.g., faces) are sensitive to distinct visual characteristics of the same image, for example, spatial frequencies. However, it has been more difficult to address the question of how early in the processing stream this sensitivity to the information relevant to the categorization task emerges. The current study uses scalp event-related potentials recorded in humans to examine how and when information diagnostic to a particular task is processed during that task versus during a task for which it is not diagnostic. Subjects were shown diagnostic and anti-diagnostic face images for both expression and gender decisions (created using Gosselin and Schyns' Bubbles technique), and asked to perform both tasks on all stimuli. Behaviorally, there was a larger advantage of diagnostic over anti-diagnostic facial images when images designed to be diagnostic for a particular task were shown when performing that task, as compared to performing the other task. Most importantly, this interaction was seen in the amplitude of the occipito-temporal N170, a visual component reflecting a perceptual stage of processing associated with the categorization of faces. When participants performed the gender categorization task, the N170 amplitude was larger when they were presented with gender diagnostic images than with expression-diagnostic images, relative to their respective non-diagnostic stimuli. However, categorizing faces according to their facial expression was not significantly associated with a larger N170 when subjects categorized expression diagnostic cues relative to gender-diagnostic cues. These results show that the influence of higher-level task-oriented processing may take place at the level of visual categorization stages for faces, at least for processes relying on shared diagnostic features with facial identity judgments, such as gender cues.

The ability to identify conspecifics from the face is of primary interest for human social behavior. Newborns' visual preference for schematic face-like stimuli has been recently related to a sensitivity for visual patterns with a greater number of elements in the upper compared to the lower part. At the adult level, neuroimaging studies have identified a network of cortical areas devoted to the detection and identification of faces. However, whether and how low-level structural properties of face stimuli contribute to the preferential response to faces in these areas remain to be clarified. Using functional magnetic resonance imaging (fMRI), here we investigated whether the adults' face-sensitive cortical areas show a preference for top-heavy patterns, similarly to newborns' preference. Twelve participants were presented with head-shaped and square patterns with either more elements in the upper or the lower vertical part. In the right fusiform gyrus ('fusiform face area', FFA), an area showing a preference for faces over other visual object categories, there was a larger activation for curvilinear patterns with more high-contrast elements in the upper part, even though these patterns were not perceived as face stimuli. These findings provide direct evidence that the FFA is tuned for geometrical properties fitting best with the structure of faces, a computational mechanism that might drive the automatic detection of faces in the visual world.

OBJECTIVE: The study aimed to investigate whether the degree of postinfectious olfactory loss is reflected in volume of the olfactory bulb (OB). STUDY DESIGN: Retrospective study of 26 patients with postinfectious olfactory loss. MATERIALS AND METHODS: Olfactory function was assessed with the "Sniffin' Sticks" test kit, and the magnetic resonance imaging study focused on OB volume and the olfactory sulcus. RESULTS: The study revealed that 1) OB volume varies with regard to olfactory function, 2) OB volume decreases with duration of olfactory loss, and 3) patients with parosmia had smaller OB volumes than patients who did not report such smell distortions, although their overall olfactory function was not significantly different from each other. CONCLUSION: The study emphasizes that OB volume is a gauge of olfactory function.

OBJECTIVE: The aims of this study were to evaluate olfactory function with orthonasal and retronasal testing in patients with posttraumatic olfactory loss and to investigate the relation between residual olfactory function and olfactory bulb (OB) volume. METHOD: A retrospective study of 25 patients with posttraumatic olfactory loss was performed. Orthonasal olfactory function was assessed with the Sniffin' Sticks test kit; retronasal olfactory function was assessed with intraorally applied odors. Magnetic resonance imaging was used to determine OB volume and cortical damage in the frontal and temporal areas. RESULTS: The main outcomes of the present study were the demonstration of a correlation between olfactory function and OB volume, which was more pronounced for retronasal than for orthonasal olfactory function; retronasal olfactory function was most affected in the patients with the most extensive cerebral damage and was least compromised in patients without such damage; OB volumes were smaller in patients with parosmia compared with those without; and the presence of parosmia was clearly associated with the presence of cerebral damage. CONCLUSION: The data confirm that OB volume is an indicator of olfactory function but, interestingly, in this study, it is largely determined by retronasal olfactory sensitivity. In addition, these results emphasize the role of higher cortical centers in olfactory function, and especially in parosmia, which may, at least in some cases, be related to lesions in the fronto-orbital and anterior temporal cortices. It would be of interest to investigate OB volume further in relation to the prognosis of the disorder.

2-Chloro-2 '-deoxyadenosine (CdA, cladribine) is a nucleoside analogue (NA) used for the treatment of lymphoproliferative disorders. Phosphorylation of the drug to CdAMP by deoxycytidine kinase (dCK) and its subsequent conversion to CdATP is essential for its efficacy. DCK deficiency is a common mechanism of resistance to NA, which could be overcome by the pronucleotide approach. The latter consists of using the nucleoside monophosphate conjugated to a lipophilic group enabling CdAMP to enter the cells by passive diffusion. In this study, we show that cycloSaligenyl-2-chloro-2 '-deoxyadenosine monophosphate (cycloSal-CdAMP) is 10-fold more potent that CdA in a dCK-deficient lymphoma cell line. These results suggest that the use of cycloSal-nucleotides could be a strategy to counteract resistance caused by dCK deficiency.

AIMS: To assess the prevalence and severity of bone disease in type 1 diabetic patients and to determine serum markers of bone remodeling as well as their relationship with bone mineral density (BMD). METHODS: BMD [by dual energy x-ray absorptiometry (DXA)] and serum markers of bone remodeling [osteocalcin, c-terminal telopeptide of type I collagen (CTX)], leptin and osteoprotegerin (OPG) were measured in 42 adult males with type 1 diabetes. Twenty-four non-diabetic subjects served as controls. RESULTS: In 40% of the patients, osteopenia at the lumbar spine (L1-L4) and/or at the left hip was found, and 7% met criteria for osteoporosis. L1-L4 BMD z-score was correlated with age (r=0.365, P=0.018) and a similar trend was observed at left hip. L1-L4 BMD z-score was negatively correlated with CTX and osteocalcin (r=-0.343, P=0.028; r=-0.376, P=0.024, respectively). A significant correlation was evidenced between BMD z-score at both lumbar spine and left hip and leptin values (r=0.343, P=0.03; r=0.395, P=0.012, respectively) but after adjustment for weight this correlation was no longer significant. Osteocalcin, CTX and leptin concentrations were comparable between patients and controls, while OPG concentrations tend to be higher in diabetic subjects (P=0.08). CTX was negatively correlated with age (r=-0.390, P=0.012) and positively correlated with osteocalcin (r=0.696, P<0.001). OPG was positively correlated with age (r=0.507, P=0.001). CONCLUSION: Our results suggest that in diabetic subjects osteopenia is a relatively frequent complication but bone loss is attenuated with age progression. Whether this is also mediated by OPG and/or leptin remains to be confirmed., [Densité osseuse et marqueurs biologiques du métabolisme osseux chez des hommes diabétiques de type 1] Objectif : Le but de l'étude était d'une part d'analyser la fréquence et la gravité de l'ostéopénie chez des patients diabétiques de type 1 et d'autre part, de mesurer les marqueurs biologiques de formation osseuse et de les corréler avec la densité minérale. Méthodes : Nous avons mesuré la densité osseuse (BMD) ainsi que les valeurs d'ostéocalcine, du télopeptide-C terminal du collagène de type 1 (CTX), de leptine et d'ostéoprotégérine (OPG) chez 42 patients masculins atteints de diabète de type 1. 24 sujets non diabétiques ont servi de témoins. Résultats : Une ostéopénie du rachis lombaire (L1-L4) et/ou de la hanche gauche fut objectivée chez 40 % des patients. Une ostéoporose fut identifiée chez 7 %. Il existait une corrélation entre BMD (Z Score) et l'âge (r = 0,365 ; P = 0,018) en L1-L4. Une même tendance était trouvée au niveau de la hanche. La densité osseuse était inversement corrélée avec le CTX et l'ostéocalcine (r = -0.343 ; P = 0,028 ; r = -0,376, P = 0,024). Par ailleurs, une relation a aussi été mise en évidence entre BMD et la leptine, qui ne restait cependant pas significative après ajustement pour le poids. Les taux d'ostéocalcine, CTX et leptine étaient comparables chez les diabétiques et les témoins, alors que ceux d'OPG tendaient à être plus élevés chez les sujets diabétiques (P = 0,08). CTX était corrélée significativement avec l'âge (r = -0,390, P = 0,012) et positivement avec l'ostéocalcine (r = 0,696, P ≪ 0,001). OPG était également corrélée à l'âge (r = 0,507, P = 0,001). Conclusion : Nos données montrent que si l'ostéopénie est une complication relativement fréquente du diabète de type 1, la perte osseuse tend à s'atténuer avec l'âge. Il reste à confirmer que ce processus est modulé par l'OPG et/ou la leptine.

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have anti-epileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory : changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.

The frontal eye field ( FEF) has long been regarded as a cortical area critically involved in the execution of voluntary saccadic eye movements. However, recent studies have suggested that the FEF may also play a role in orienting attention. To address this issue, we reversibly inactivated the FEF using multiple microinjections of muscimol, a GABA(A) agonist, in two macaque monkeys performing visually guided saccades to a single target. The effects of FEF inactivation were also studied in a covert visual search task that required monkeys to search for a target presented among several distractors without making any eye movements. As expected, inactivating the FEF caused spatially selective deficits in executing visually guided saccades, but it also altered the ability to detect a visual target presented among distractors when no eye movements were permitted. These results allow us to conclude definitively to an involvement of the FEF in both oculomotor and attentional functions. Comparison of the present results with a similar experiment conducted in the lateral intraparietal cortex area revealed qualitatively different deficits, suggesting that the two areas may make distinct contributions to selective attention processes.

Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy. Using a seizure-prone Fast-kindling rat strain with known comorbid behavioral features, we investigated the effects of VNS on spatial memory, epileptogenesis, kindled seizures and body weight. Electrodes were implanted in both amygdalae and around the left vagus nerve of 17 rats. Following recovery, rats were tested in the Morris water-maze utilizing a fixed platform paradigm. The VNS group received 2 h of stimulation prior to entering the Morris water-maze. Rats were then tested in the kindling paradigm wherein the VNS group received 2 h of stimulation prior to daily kindling stimulation. Finally, the abortive effects of acute VNS against kindling-induced seizures were determined in fully kindled rats by applying VNS immediately after the kindling pulse. Body weight, water consumption and food intake were measured throughout. Memory performance in the Morris water-maze was not different between control and vagus nerve stimulation rats. Similarly, kindling rate was unaffected by antecedent VNS. However, pro-convulsive effects (P < 0.05) were noted, when VNS was administered prior to the kindling pulse in fully kindled rats. Yet, paradoxically, VNS showed anticonvulsant effects (P < 0.01) in those rats when applied immediately after the kindling stimulus. Body weight was significantly lower throughout kindling (P < 0.01) in VNS-treated rats compared with controls, which was associated with reduced food intake (P < 0.05), but without difference in water consumption. VNS appears to be devoid of significant cognitive side effects in the Morris water-maze in Fast rats. Although VNS exhibited no prophylactic effect on epileptogenesis or seizure severity when applied prior to the kindling stimulus, it showed significant anti-convulsant effects in fully kindled rats when applied after seizure initiation. Lastly, VNS prevented the weight gain associated with kindling through reduced food intake

Objectives: Due to the increased diagnosis of prostate cancer at earlier stages and the overall increased use of hormone therapy, also in earlier disease stages, many patients will receive long-term hormone therapy. Therefore, the timing of initiating hormone therapy and the type of hormone therapy have become crucial items in the appropriate management of patients with prostate cancer. in addition, as patients receiving long-term hormone therapy are at an increased risk of acute and chronic side effects, the monitoring of these patients deserves attention. The timing and type of hormone therapy and the monitoring of patients receiving hormone therapy are reviewed in this paper. Methods: A literature review was performed in Medline. Results: The prostate specific antigen doubling time (PSA DT) has been evaluated to determine the risk of disease progression in patients having a relapse after radical therapy. Patients with a PSA DT of < 12 mo have a high risk for disease progression and should probably receive hormone therapy rapidly. In case of a diagnosis of advanced prostate cancer, there is not yet a consensus on when to start hormone therapy. During an interactive voting session, over 200 urologists indicated that the preferred luteinizing hormone releasing hormone (LHRH) agonist should be able to achieve a castrate level of <= 20 ng/dl, as well as to maintain these low testosterone levels without inducing acute-on-chronic or breakthrough responses. Eligard, a novel depot formulation of leuprolide acetate, appears to be the only LHRH agonist currently available able to achieve and maintain serum testosterone levels below the castrate level of 20 ng/dl. Patients receiving long-term hormone therapy should be adequately monitored during follow-up visits. Besides frequent assessment of the PSA level and other recommended assessments, serum testosterone levels should also be determined. In this way, response to therapy can be evaluated, relevant testosterone rises aft

Recent advances in new technologies offer a large range of innovative instruments for designing and processing sounds. This paper reports on the results of a project that took place during the eNTERFACE06 summer workshop in Dubrovnik, Croatia. During four weeks, researchers from the fields of brain-computer interfaces and sound synthesis worked together to explore multiple ways of mapping analysed physiological signals to sound and image synthesis parameters in order to build biologically-driven musical instruments. A reusable flexible framework for bio-musical applications has been developed and validated using three experimental prototypes, from whence emerged some worthwhile perspectives on future research

The ability of motor training to encode a motor memory is reduced in older adults. Here, we tested the hypothesis that training-dependent memory encoding, an issue of relevance in neurorehabilitation, is enhanced in elder individuals by action observation which alone can contribute to learning processes. A group of 11 healthy older adults participated in this study, which consisted of three randomized counterbalanced sessions on different days testing the effects of motor training (MT) alone, action observation (AO) alone, and a combination of both (MT + AO) on motor memory encoding. The combination of MT + AO formed a motor memory in the primary motor cortex and differentially modulated motor cortical excitability in muscles that were agonist and antagonist with respect to the training task, but MT or AO alone did not. These results suggest that action observation can enhance the effects of motor training on memory encoding protocols in the older adult, possibly through Hebbian modulation of intracortical excitatory mechanisms.

People are better at recognizing same-than other-race faces but the theoretical explanation of this phenomenon is still controversial. Here we tested the hypothesis that the "other-race effect'' is related to a reduced ability to encode configural information on other-race faces. Caucasian and Asian participants had to match whole faces to isolated facial features, or onto whole faces differing by a single feature, on both Caucasian and Asian faces. Participants performed better with whole faces as compared to isolated features, demonstrating a "holistic processing'' of faces (Tanaka & Farah, 1993). For Caucasian participants, this "whole/part advantage" was observed only for Caucasian faces. Asian participants who had been living for about a year among Caucasians had a comparable whole/part advantage regardless the race of the faces. These results indicate that same-race faces are processed more holistically than other-race faces, as a result of experience. However, despite processing Caucasian faces as holistically as Asian faces in this paradigm, Asian subjects still presented a large other-race effect. This observation suggests that holistic encoding may be a necessary step in order to be able to recognize other-race faces efficiently, but that it is by no means sufficient to overcome the other-race face effect.

Dans le cadre de : European Signal Processing Conference (EUSIPCO) Autres auteurs : D. Zosso, Q. Noirhomme, M. Davare, B. Macq, JP. Thirian, M. De Craene

Background and Aims: Obesity, and more particularly central obesity, is strongly associated with chronic disorders such as type 2 diabetes, cardiovascular disease and cancer. Adipokines are involved in the pathogenesis of these obesity-linked disorders. However, adipokines secreted by visceral adipose tissue (AT), unlike those secreted by other fat depots, are still poorly characterised. In this study, we searched for novel adipokines secreted by visceral AT, compared their production in lean versus obese subjects and examined the relative contribution of the different cell types to this production [...]

[Treatment diabetes by transplantation of insulin secreting cells. Part I]Treatment of diabetes mellitus poses a huge medical problem. Both the transplantation of pancreas and insulin treatment is connected with numerous complications. The method of treatment which would entirely relieve patients from the necessity of insulin applications and complications of diabetes mellitus has yet not been found. The paper addresses to the issues related to procurement, preservation and culture of pancreatic islets. In this review, the current state of knowledge as well as perspectives of treatment of diabetes through the transplantation of insulin secreting cells was presented.

[Treatment diabetes by transplantation of insulin secreting cells. Part II--prevention of rejection of the transplanted cells].Transplantation of pancreatic islets is the treatment method for type 1 diabetes mellitus permitting maintenance of stable glycemia. Due to the progress of immunosuppression, the results of transplantation of the pancreatic islets are better. Although applied immunosuppression drugs prevent graft rejection, they have many side effects. The latest methods of modulation of the immunological tolerance, an alternative for immunosuppression, were introduced in this paper. The methods of pancreatic islets encapsulation and induction of allogenic chimerism were described.

Les objectifs de la simulation électrique fonctionnelle comprennent la restauration de fonctions déficientes et l’amélioration de la qualité de vie des patients. Les progrès de la recherche biomédicale et des micro-technologies ont permis d’augmenter le nombre de pathologies pouvant tirer bénéfice de cette technique. Dans le domaine des systèmes implantés, les électrodes à manchon spiral sont couramment utilisées. En effet, non invasives pour le nerf, elles permettent un confinement et un meilleur contrôle du courant. Cependant, deux désavantages en limitent l’usage. Premièrement, l’implantation de l’électrode provoque une réaction tissulaire. La fibrose qui apparaît au niveau de l’interface matériaux – tissu augmente la distance fibres nerveuses – contacts réduisant d’autant l’efficacité des électrodes. Deuxièmement, au cours des premières semaines qui suivent l’implantation, les paramètres électrophysiologiques sont instables. La reproductibilité des stimulations et/ou des enregistrements effectués peut ainsi en être altérée. La séquence des événements biologiques déclenchés dans le décours de l’implantation d’un tel système est en fait assez mal connue. Le but de cette thèse est d’acquérir une meilleure connaissance des processus impliqués dans ces deux phénomènes. Dans cette optique, un petit stimulateur implantable a été développé afin de permettre d’évaluer les changements affectant l’interface tissu-électrode au cours d’implantations chroniques. La littérature nous apprend que différents facteurs ou cytokines sont susceptibles d’intervenir. Les deux facteurs considérés dans cette thèse, l’oxyde nitrique (NO) et le ‘vascular endothelial growth factor’ (VEGF), exercent des rôles en partie connus dans la régulation du système vasculaire et dans les mécanismes de neuroprotection. L’implantation d’une électrode à manchon spiral, passive ou active, stimule leur expression dans l’épinèvre et dans l’endonèvre. Leur présence dans l’épinèvre est vraisemblablement, The goal of functional electrical stimulation (FES) is to restore function, improve health or counteract physiological disturbances and neurological damages. New developments in this field have increased the number of pathological conditions that might benefit from a neural prosthesis. Spiral cuff electrodes are currently used for such purpose because they allow a close contact between electrode and nerve. The electrical current is thus confined to the nerve and can be accurately controlled. However, the cuff implantation has two major drawbacks. First, the device implantation induces an inflammatory reaction which evolves towards fibrosis at the nerve-cuff interface. As a result, the electrode efficiency is reduced. Secondly, the first weeks after implantation are characterised by an electrophysiological instability resulting in a significant lack of reproducibility. The sequence of biological events and control mechanisms triggered by an electrode implantation are poorly known. The aim of this study is to gain more knowledge about the biological events leading to these phenomena. For this purpose, a fully implantable stimulator was developed in order to allow monitoring the electrode-tissue interface status during chronic experiments. Various cytokines can be suspected to play a role. The two factors, nitric oxide (NO) and vascular endothelial growth factor (VEGF), observed in this study have both partially known vasoactive and neuroprotective properties. They are up-regulated in the epineurial and in the endoneurial compartments in response to either passive or active cuff electrode implantation. Their presence in the epineurium is likely to be associated with the post-surgical vascular remodelling (oedema, vasodilation and angiogenesis). It is at least partially through these factors that the surgical procedure and the acute inflammatory reaction induce an oedema. This oedema is associated with low electrode impedance and high rheobase values. Gradually the init, Thèse de doctorat en sciences biomédicales (neuroscience) (SBIM3) -- UCL, 2006

Preferentially expressed antigen of melanoma (PRAME) is expressed in wide variety of tumors, but in contrast with most other tumor-associated antigens, it is also expressed in leukaemias. The physiological role of PRAME remains elusive. Interestingly, PRAME expression is correlated with a favorable prognosis in childhood acute leukaemias. Moreover, a high expression of PRAME seems to be predominantly found in acute leukaemias carrying a favorable prognosis. In this study, we confirmed in a series of 26 pediatric acute myelogenous leukaemia patients that PRAME expression is associated with an increased disease-free survival. Upon these clinical observations, we assumed that PRAME could be involved in the regulation of cell death or cell cycle. We observed that transient overexpression of PRAME induced a caspase-independent cell death in cultured cell lines (CHO-K1 and HeLa). Cells stably transfected with PRAME also exhibited a decreased proliferation rate due, at least partially, to an elevated basal rate of cell death. Immunocytochemistry of a FLAG-tagged PRAME, in vivo imaging of an EGFP-tagged PRAME and Western blotting after cell fractionation revealed a nuclear localization of the protein. Using a micro-array based approach, we showed that KG-1 leukaemic cells stably transfected with PRAME presented a significant decrease of expression of the heat-shock protein Hsp27, the cyclin dependent kinase inhibitor p21 and the calcium-binding protein S100A4. Moreover, PRAME-positive leukaemic bone marrow samples expressed lower amounts of Hsp27, p21 and S100A4 than PRAME-negative samples. The expression of those three proteins is known to inhibit apoptosis and has been associated with an unfavorable prognosis in a series of cancers. Finally, repression of PRAME expression by a siRNA strategy increased tumorigenicity of K562 leukaemic cells in nude mice. We suggest that the favorable prognosis of PRAME could be mediated, at least in part, by the repression of these genes., Thèse de doctorat en sciences biomédicales (SBIM 3) (orientation : physiologie cellulaire) -- UCL, 2006

L'élévation de la concentration cytosolique de Ca2+ ([Ca2+]c) est le mécanisme déclenchant de la sécrétion d'insuline stimulée par le glucose dans les cellules beta pancréatiques. Cette élévation résulte essentiellement de l'influx de Ca2+ par les canaux calciques voltage-dépendants, mais de nombreuses études suggèrent qu'une mobilisation de Ca2+ intracellulaire y contribue ou l'amplifie. Dans plusieurs types cellulaires, il existe trois mécanismes de mobilisation de Ca2+ du réticulum endoplasmique (RE): le Ca2+-induced Ca2+-release (CICR), qui peut être médié par les recepteurs à la ryanodine (RyRs) ou les récepteurs à l'IP3 (IP3Rs), le depolarization-induced Ca2+-release (DICR), médié par le RyR1, et l'IP3-induced Ca2+-release (IICR), médié par les IP3Rs. Le but de ma première étude a été d'évaluer la contribution éventuelle du RE dans l'élévation de la [Ca2+]c induite par une dépolarisation ou par le glucose dans les cellules beta. Pour cela, j'ai mesuré les changements de la [Ca2+]c en réponse à la dépolarisation dans des cellules beta de souris. Dans le cas d'une dépolarisation forte et soutenue, une majorité de cellules présente une élévation transitoire superposée à l'élévation soutenue de la [Ca2+]c, qui reflète une mobilisation de Ca2+ intracellulaire puisqu'elle ne s'accompagne pas d'une accélération de l'influx de Ca2+. Cette mobilisation est abolie par l'inhibition des Sarco-endoplasmic Ca2+-ATPases (SERCA) par la thapsigargine, ce qui montre qu'elle provient du RE. La mobilisation n'apparaît pas dans les cellules de souris knock-out pour la SERCA3, ce qui montre qu'elle nécessite la capture du Ca2+ par la SERCA3, une des deux isoformes de la Ca2+-ATPase du RE, qui pompe le Ca2+ dans le RE, exprimées dans les cellules beta. La mobilisation est activée de façon répétitive par des cycles de dépolarisation et repolarisation, et apparaît toujours après le même délai dans une même cellule. Comme elle nécessite un influx de Ca2+, il s'agit d'un CICR. Mais ce C, Thèse de doctorat en sciences biomédicales (SBIM 3) (orientation : physiologie) -- UCL, 2006

AIMS/HYPOTHESIS: Hyperglycaemia and the pro-inflammatory cytokine IL-1beta induce similar alterations of beta cell gene expression, including up-regulation of c-Myc and haeme-oxygenase 1. These effects of hyperglycaemia may result from nuclear factor-kappa B (NFkappaB) activation by oxidative stress. To test this hypothesis, we compared the effects of IL-1beta, high glucose, and hydrogen peroxide, on NFkappaB DNA binding activity and target gene mRNA levels in cultured rat islets. METHODS: Rat islets were pre-cultured for 1 week in serum-free RPMI medium containing 10 mmol/l glucose, and further cultured in glucose concentrations of 5-30 mmol/l plus various test substances. Islet NFkappaB activity was measured by ELISA and gene mRNA expression was measured by RT-PCR. RESULTS: IL-1beta consistently increased islet NFkappaB activity and c-Myc, haeme-oxygenase 1, inducible nitric oxide synthase (iNOS), Fas, and inhibitor of NFkappaB alpha (IkappaBalpha) mRNA levels. In comparison, 1- to 7-day culture in 30 mmol/l instead of 10 mmol/l glucose stimulated islet c-Myc and haeme-oxygenase 1 expression without affecting NFkappaB activity or iNOS and IkappaBalpha mRNA levels. Fas mRNA levels only increased after 1 week in 30 mmol/l glucose. Overnight exposure to hydrogen peroxide mimicked the effects of 30 mmol/l glucose on haeme-oxygenase 1 and c-Myc mRNA levels without activating NFkappaB. On the other hand, the antioxidant N-acetyl-L-cysteine inhibited the stimulation of haeme-oxygenase 1 and c-Myc expression by 30 mmol/l glucose and/or hydrogen peroxide. CONCLUSIONS/INTERPRETATION: In contrast to IL-1beta, high glucose and hydrogen peroxide do not activate NFkappaB in cultured rat islets. It is suggested that the stimulation of islet c-Myc and haeme-oxygenase 1 expression by 30 mmol/l glucose results from activation of a distinct, probably oxidative-stress-dependent signalling pathway.

The role played by sensory information in maintaining motor cortical representations is still incompletely understood. We investigated the effect of digital anaesthesia of the index finger and thumb on the amplitude of motor evoked potentials to transcranial magnetic stimulation (TMS) recorded from the first dorsal interosseus, F-wave response probability and maximal key pinch force. Whereas digital anaesthesia led to a 29% decrease in maximal force, both motor evoked potential amplitudes and F-wave probability remained unchanged. This dramatic decrease in maximal voluntary contraction following digital anaesthesia may result from a lack of proper sensory feedback during the task.

In vitro culture of astroglial progenitors can be obtained from early post-natal brain tissues and several methods have been reported for promoting their maturation into differentiated astrocytes. Hence, a combination of several nutriments/growth factors -- the G5 supplement (insulin, transferrin, selenite, biotin, hydrocortisone, fibroblast growth factor and epidermal growth factor) -- is widely used as a culture additive favouring the growth, differentiation and maturation of primary cultured astrocytes. Considering the key role played by glial cells in the clearance of glutamate in the synapses, cultured astrocytes are frequently used as a model for the study of glutamate transporters. Indeed, it has been shown that when tested separately, growth factors influence the expression and activity of the GLAST and GLT-1. The present study aimed at characterising the functional expression of these transporters during the time course of differentiation of cultured cortical astrocytes exposed to the supplement G5. After a few days, the vast majority of cells exposed to this supplement adopted a typical stellate morphology (fibrous or type II astrocytes) and showed intense expression of the glial fibrillary acidic protein. Both RT-PCR and immunoblotting studies revealed that the expression of both GLAST and GLT-1 rapidly increased in these cells. While this was correlated with a significant increase in specific uptake of radiolabelled aspartate, fluorescence monitoring of the Na+ influx associated with glutamate transporters activity revealed that the exposure to the G5 supplement considerably increased the percentage of cells participating in the uptake. Biochemical and pharmacological studies revealed that this activity did not involve GLT-1 but most likely reflected an increase in GLAST-mediated uptake. Together, these data indicate that the addition of this classical combination of growth factors and nutriments drives the rapid differentiation toward a homogenous cultu

Laser heat stimulators selectively activate Adelta and C-nociceptors in the superficial layers of the skin. Their high power output produces steep heating ramps, which improve synchronization of afferent volleys and therefore allow the recording of time-locked events, such as laser-evoked brain potentials. Study of the electrical brain activity evoked by Adelta- and C-nociceptor afferent volleys revealed the existence of an extensive, sequentially activated, cortical network. These electrophysiological responses are modulated by stimulus-driven and, even more extensively, top-down processes. The specificity and validity of these components for pain research are currently under intense scrutiny.

Epineurial fibrosis, fiber loss, limited reproducibility of recordings and variability of stimulation conditions have been documented after extraneural cuff electrode implantation. These morphological and electrophysiological modifications could be due to the local release of cytokines. We report the expression of two cytokines, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in the rat sciatic nerve after 'cuff' implantation for 18 h, 7 days and 1 month. Immunohistochemical and Western blot analyses showed a transient upregulation of TNF-alpha, during the first week, and a prolonged increase of TGF-beta1, over the 1-month period duration of this study. Considering the known pro-inflammatory roles of TNF-alpha and the pro-fibrotic action of TGF-beta, our results strongly suggest that these cytokines may contribute to nerve alterations occurring within the acute and sub-acute phases after cuff electrode implantation.

Extraneural cuff electrodes have been extensively used to investigate the nervous system. Their implantation is, however, associated with epineurial fibrosis, fiber loss, limited reproducibility of recordings and variability in stimulating conditions. It has recently been shown that TNF-alpha is involved in nerve alterations after electrode implantation. This study investigated whether a peri-operative anti-TNF-alpha treatment could modify the inflammation and fibrosis associated with cuff electrode implantation. Morphometrical and immunohistochemical methods were used to show that a single systemic injection of TNF-alpha neutralizing antibodies is sufficient to reduce the early inflammatory events, but not the long lasting fibrotic reaction.

Glycogen synthase kinase 3 (GSK3) is able to phosphorylate tau at many sites that are found to be phosphorylated in paired helical filaments in Alzheimer disease. Lithium chloride (LiCl) efficiently inhibits GSK3 and was recently reported to also decrease the production of amyloid-beta peptide (Abeta) from its precursor, the amyloid precursor protein. Therefore, lithium has been proposed as a combined therapeutic agent, inhibiting both the hyperphosphorylation of tau and the production of Abeta. Here, we demonstrate that the inhibition of GSK3 by LiCl induced the nuclear translocation of beta-catenin in Chinese hamster ovary cells and rat cultured neurons, in which a decrease in tau phosphorylation was observed. In both cellular models, a nontoxic concentration of LiCl increased the production of Abeta by increasing the beta-cleavage of amyloid precursor protein, generating more substrate for an unmodified gamma-secretase activity. SB415286, another GSK3 inhibitor, induced the nuclear translocation of beta-catenin and slightly decreased Abeta production. It is concluded that the LiCl-mediated increase in Abeta production is not related to GSK3 inhibition.

In order to clarify the respective contribution of the right and left posterior parietal cortex (PPC) to number comparison, transcranial magnetic stimulation (TMS) was used to disrupt PPC processing in subjects instructed to determine whether a digit was smaller or larger than 5. Single pulse TMS was applied over the PPC, either unilaterally or bilaterally, 150, 200, or 250 ms after digit presentation. Sham TMS was used as a control condition to take into account the unspecific effects of TMS on reaction time (RT). The main finding of the present study is a significant increase in RTs when comparing digits close to 5 following a disruption either of the left PPC alone or of both PPC simultaneously. The comparison of digits far from 5 was unaltered by disrupting only one PPC but RTs were found increased after bilateral PPC stimulation. These disruptive effects were observed irrespective of the TMS delay. We concluded that coding precise numerical values requires the integrity of the left PPC, as suggested by the deficit in discriminating close digits consequent to its disruption. In contrast, approximate comparisons can be processed either by the left or right PPC, since simultaneous bilateral TMS was needed to alter the comparison of digits far from 5.

Preferentially expressed antigen of melanoma (PRAME) is expressed in a wide variety of tumors, but in contrast with most other tumor associated antigens, it is also expressed in leukemias. The physiologic role of PRAME remains elusive. Interestingly, PRAME expression is correlated with a favorable prognosis in childhood acute leukemias. Moreover, a high expression of PRAME seems to be predominantly found in acute leukemias carrying a favorable prognosis. On these clinical observations, we assumed that PRAME could be involved in the regulation of cell death or cell cycle. In this study, we show that transient overexpression of PRAME induces a caspase-independent cell death in cultured cell lines (CHO-K1 and HeLa). Cells stably transfected with PRAME also exhibit a decreased proliferation rate due, at least partially, to an elevated basal rate of cell death. Immunocytochemistry of a FLAG-tagged PRAME, in vivo imaging of an enhanced green fluorescent protein-tagged PRAME, and Western blotting after cell fractionation reveal a nuclear localization of the protein. Using a microarray-based approach, we show that KG-1 leukemic cells stably transfected with PRAME present a significant decrease of expression of the heat-shock protein Hsp27, the cyclin-dependent kinase inhibitor p21, and the calcium-binding protein S100A4. The expression of these three proteins is known to inhibit apoptosis and has been associated with an unfavorable prognosis in a series of cancers. Finally, repression of PRAME expression by a short interfering RNA strategy increases tumorigenicity of K562 leukemic cells in nude mice. We suggest that all these observations might explain the favorable prognosis of the leukemias expressing high levels of PRAME.

Implantable stimulators are needed for chronic electrical stimulation of nerves and muscles in experimental studies. The device described exploits the versatility of current microcontrollers for stimulation and communication in a miniature implant. Their standard outputs can provide the required selectable constant-current sources. In this device, pre-programmed stimulation paradigms were selected by transcutaneous light pulses. The potential of a programmable integrated circuit (PIC) was thus exploited. Implantable devices must be biocompatible. A novel encapsulation method that require no specialised equipment and that used two classical encapsulants, silicone and Teflon was developed. It was tested for implantation periods of up to four weeks. A novel way to estimate electrode impedance in awake animals is also presented. It was thus possible to follow the evolution of the nerve-electrode interface and, if necessary, to adjust the stimulation parameters. In practice, the electrode voltage at the end of a known constant-current pulse was measured by the PIC. The binary coded value was then indicated to the user as a series of muscle twitches that represented the binary value of the impedance measurement. This neurostimulator has been successfully tested in vitro and in vivo. Thresholds and impedance values were chronically monitored following implantation of a self-sizing spiral cuff electrode. Impedance variations in the first weeks could reflect morphological changes usually observed after the implantation of such electrodes.

OBJECTIVE: The detection of a lateralized visual target is faster when preceded by a face gazing to the location of this stimulus. Here we aimed to clarify the time-course of the visual processing modulated by these reflexive shifts of attention. METHODS: ERPs were measured on 16 subjects performing a speeded location task on a circular checkerboard. The checkerboard target appeared either on the left or right of the upper or lower visual field, and was preceded by a central face orienting its gaze obliquely to one of the four possible corner locations for the target to appear. RESULTS: Congruently cued targets were located faster than incongruently cued targets and were associated with larger and earlier occipital P1 (approximately 110 ms) and occipito-parieto-temporal N1 (approximately 150 ms) components. However, no such attentional modulations were found on the earlier C1 visual component, best observed with a negative polarity for upper visual field stimulations, and thought to originate largely from primary visual cortex. CONCLUSIONS AND SIGNIFICANCE: These results show that reflexive shifts of attention following oblique eye gaze to upper and lower visual fields increase and speed up the processing of visual information beyond the feedforward flow of information in primary visual cortex.

We tested the effects of using a prosthesis for substitution of vision with audition (PSVA) on sensitivity to the Ponzo illusion. The effects of visual experience on the susceptibility to this illusion were also assessed. In one experiment, both early-blind and blindfolded sighted volunteers used the PSVA to explore several variants of the Ponzo illusion as well as control stimuli. No effects of the illusion were observed. The results indicate that subjects focused their attention on the two central horizontal bars of the stimuli, without processing the contextual cues that convey perspective in the Ponzo figure. In a second experiment, we required subjects to use the PSVA to consider the two converging oblique lines of the stimuli before comparing the length of the two horizontal bars. Here we were able to observe susceptibility to the Ponzo illusion in the sighted group, but to a lesser extent than in a sighted non-PSVA control group. No clear effect of the ilusion was obtained in early-blind subjects. These results suggest that, at least in sighted subjects, perception obtained with the PSVA shares perceptual processes with vision. Visual experience appears mandatory for a Ponzo illusion to occur with the PSVA.