First operation in SPIDER and the path to complete MITICA.

The requirements of ITER neutral beam injectors (1 MeV, 40 A negative deuterium ion current for 1 h) have never been simultaneously attained; therefore, a dedicated Neutral Beam Test Facility (NBTF) was set up at Consorzio RFX (Padova, Italy). The NBTF includes two experiments: SPIDER (Source for the Production of Ions of Deuterium Extracted from Rf plasma), the full-scale prototype of the source of ITER injectors, with a 100 keV accelerator, to investigate and optimize the properties of the ion source; and MITICA, the full-scale prototype of the entire injector, devoted to the issues related to the accelerator, including voltage holding at low gas pressure. The present paper gives an account of the status of the procurements, of the timeline, and of the voltage holding tests and experiments for MITICA. As for SPIDER, the first year of operation is described, regarding the solution of some issues connected with the radiofrequency power, the source operation, and the characterization of the first negative ion beam.

A review of giant correlation-length effects via proximity and weak-links coupling in a critical system: 4He near the superfluid transition.

We review measurements of 4He near the superfluid transition in arrangements whereby an array of weak links couple relatively larger, more bulk-like 4He regions. In contrast to experiments which focus on the dependence of the superflow on the chemical potential difference across the links, these studies focus on the specific heat of both the weak links and that of the larger coupled regions, as well as the behavior of the superfluid fraction within the weak links. The data show unexpected results which reflect a very long range coupling as well as modification of the weak link itself due to the proximity to bulk-like helium. One finds that while the three-dimensional correlation length [Formula: see text], where [Formula: see text], is involved in these long-range effects, the distance over which these can be seen is of the order of 100 to 1000 times [Formula: see text]. These results call into question our understanding of the meaning of the correlation length at a critical point as the 'range' over which information can propagate. These studies are the first to measure the thermodynamic properties of weak links for a critical system where fluctuations are important. They differ in essential ways with expectations from mean-field considerations. We compare results with other 4He measurements, with superconductors and the theoretical calculations of the Ising model.

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.

Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.

Significant increase in anxiety during aging in mGlu5 receptor knockout mice.

Glutamatergic mechanisms regulate neuronal circuits implicated in mood and anxiety. Emotional disorders as anxiety and depression are particularly difficult to treat during aging and mechanisms underlying emotional disturbances in the brain of the elderly are poorly understood. This may result from the small number of studies investigating these disorders in aged animals. Among glutamate receptors, metabotropic mGlu5 receptors are thought to play an important role, since their pharmacological blockade induces strong anxiolytic effects. However, the implication of mGlu5 in regulating anxiety is not yet completely understood. Here we analyzed both young adult and aged mice lacking mGlu5 receptors, to clarify, if genetic deletion of the receptor induces similar to pharmacological blockade anxiolytic effects. Unexpectedly, mGlu5 receptor knockout (KO) mice showed increased anxiety accentuating with aging. In contrast, young adult mice displayed an anti-depressive-like phenotype that was no longer detectable in aged animals. Our data support important distinct roles of mGlu5 receptors in modulating anxiety and depression during aging.

Changes of AMPA receptors in MPTP monkeys with levodopa-induced dyskinesias.

Overactivity of glutamate neurotransmission is suspected to be implicated in Parkinson's disease and levodopa-induced dyskinesia. The fast glutamatergic transmission in the striatum from the cortex is mediated mainly by non-n-methyl-d-aspartate (non-NMDA) receptors. Animal models of Parkinson's disease reveal conflicting data concerning striatal glutamate AMPA receptors. The present study thus sought to shed light on the relationship of striatal AMPA receptors to the development of levodopa-induced dyskinesia. [(3)H]Ro 48-8587, a highly potent and selective-specific antagonist ligand for AMPA receptors, was used to investigate, by autoradiography, striatal AMPA receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated for 1 month with levodopa alone, levodopa+CI-1041 (NMDA receptor antagonist) or levodopa+cabergoline (D2 receptor agonist). Levodopa-treated MPTP monkeys developed dyskinesias while those that received levodopa+CI-1041 or levodopa+cabergoline did not. In the anterior caudate nucleus and putamen, specific binding of [(3)H]Ro 48-8587 was reduced in all MPTP-treated monkeys compared to control monkeys, but no significant effect of MPTP was measured in the posterior striatum. In dyskinetic monkeys, specific binding of [(3)H]Ro 48-8587 was elevated in subregions of the posterior caudate nucleus and putamen as compared to saline-treated MPTP monkeys. Levodopa+CI-1041 treatment left unchanged specific binding of [(3)H]Ro 48-8587 whereas levodopa+cabergoline treatment reduced it in subregions of the posterior caudate nucleus and putamen compared to control and levodopa-treated MPTP monkeys. Specific binding of [(3)H]Ro 48-8587 was low in the globus pallidus and remained unchanged following both lesion and treatments. In conclusion, the elevated values of AMPA receptors in dyskinetic monkeys (and their prevention through treatments) were only observed in subregions of the striatum.

Allosteric modulators for mGlu receptors.

The metabotropic glutamate receptor family comprises eight subtypes (mGlu1-8) of G-protein coupled receptors. mGlu receptors have a large extracellular domain which acts as recognition domain for the natural agonist glutamate. In contrast to the ionotropic glutamate receptors which mediate the fast excitatory neurotransmission, mGlu receptors have been shown to play a more modulatory role and have been proposed as alternative targets for pharmacological interventions. The potential use of mGluRs as drug targets for various nervous system pathologies such as anxiety, depression, schizophrenia, pain or Parkinson's disease has triggered an intense search for subtype selective modulators and resulted in the identification of numerous novel pharmacological agents capable to modulate the receptor activity through an interaction at an allosteric site located in the transmembrane domain. The present review presents the most recent developments in the identification and the characterization of allosteric modulators for the mGlu receptors.

[A clinical study of the number processing system: decimal size effects on reading numbers in patients with left parieto-occipital gliomas]. / Effet de la grandeur décimale sur la lecture de chiffres dans les gliomes du carrefour gauche.

An increasing number of studies are focusing on the anatomo-functional organisation of number processing and some cognitive models have been recently developed. Nevertheless, relationships between areas implicated in number processing, and language areas and circuits remain unclear. Recently, Dehaene and Cohen, in their "triple-code model of number processing", (Dehaene and Cohen, 1995) distinguished two alternative number representation and processing systems: one depending on verbal processes, the other representing a quantity manipulation. According to this model, the retrieval of "arithmetical facts" (AF), learned by rote at school and memorised in a verbal form (such as the multiplication table or simple addition problems) can be considered as a verbal automatism; conversely, subtraction problems, which require mental manipulation of the quantities, represent an abstract, semantic elaboration: "Actual Calculation" (AC). The anatomical correlate of the retrieval of AF (depending on automatic verbal associations) seems to correspond to the left-hemispheric perisylvian areas, while impairment of the actual calculation (AC) depends on the intraparietal region, particularly in the left dominant hemisphere. The present study describes the neuropsychological assessment of three patients, tested after surgery for left parieto-occipital tumors. Two of them were affected by an anaplasic glioma, the third by a low-grade glioma. The cognitive evaluation included: words of Rey, numeral (directed and reversed) span, reading of "simple" numbers (from 1 to 10) and of "complex" numbers (many decimals), writing (dictation) and reading a standard text, finger denomination and right-left distinction. All patients showed language disturbances, dysgraphia and severe dyslexia. In reading numbers, we identified two types of errors: lexical and syntactic. "Lexical errors" consisted in a wrong choice among words in the number's lexicon. For instance, all patients made errors in reading "complex" numbers composed by many decimals, switching single numbers but respecting the decimal size and the structure of the whole number (such as 69107 instead of 68107). On the other hand, only one patient committed syntactic errors, misunderstanding the decimal size and the structure of the number. We considered lexical errors as verbal errors, and syntactic errors as semantic errors, affecting the notion of quantity. We tried to explain verbal disturbances as well as lexical errors as a consequence of lesion of the left-hemispheric perisylvian areas, while syntactic errors as a consequence of impairment of the intraparietal region.

Three-dimensional critical behavior with 2D, 1D, and 0D dimensionality crossover: surface and edge specific heats.

The critical behavior at a second order phase transition is characterized by the divergence of the correlation length xi. We have studied the superfluid transition of 4He in a series of experimental cells in which this divergence of xi is modified due to finite-size confinement. In particular, the design of these cells is such that the smallest dimension is kept the same, 1 microm, but the geometry is such that one obtains crossover to dimensionality of 2, 1, and 0. This corresponds to films, channels, and boxes filled with helium. We measure the specific heat and compare these results with theoretical expectations. We identify surface and line specific heat contributions by analyzing the deviation of the specific heat from its behavior in the thermodynamic limit. The design of these cells is made possible by a combination of silicon lithography and direct wafer bonding.

(-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection.

Group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) modulate neurotoxicity of excitatory amino acids and beta-amyloid-peptide (betaAP), as well as epileptic convulsions, most likely via presynaptic inhibition of glutamatergic neurotransmission. Due to the lack of subtype-selective ligands for group-III receptors, we previously utilized knock-out mice to identify mGluR4 as the primary receptor mediating neuroprotection of unselective group-III agonists such as L-AP(4) or (+)-PPG, whereas mGluR7 is critical for anticonvulsive effects. In a recent effort to find group-III subtype-selective drugs we identified (+/-)-PHCCC as a positive allosteric modulator for mGluR4. This compound increases agonist potency and markedly enhances maximum efficacy and, at higher concentrations, directly activates mGluR4 with low efficacy. All the activity of (+/-)-PHCCC resides in the (-)-enantiomer, which is inactive at mGluR2, -3, -5a, -6, -7b and -8a, but shows partial antagonist activity at mGluR1b (30% maximum antagonist efficacy). Chimeric receptor studies showed that the binding site of (-)-PHCCC is localized in the transmembrane region.Finally, (-)-PHCCC showed neuroprotection against betaAP- and NMDA-toxicity in mixed cultures of mouse cortical neurons. This neuroprotection was additive to that induced by the highly efficacious mGluR1 antagonist CPCCOEt and was blocked by MSOP, a group-III mGluR antagonist. Our data provide evidence for a novel pharmacological site on mGluR4, which may be used as a target-site for therapeutics.

Insight into the function of Group I and Group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders.

Following the molecular cloning in the early 1990s of the metabotropic glutamate receptors (mGlu1-8), research that focused on the physiology, pharmacology and function of these receptors revealed their potential role in CNS disorders. Numerous psychiatric and neurological dis-orders are indeed linked to changes in excitatory processes, in which glutamate plays a key role. In contrast to ligand-gated ion channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and kainate], which are responsible for fast excitatory transmission, mGlu receptors have a more modulatory role, by contributing to fine-tuning of synaptic efficacy, and control of the accuracy and sharpness of the transmission. Given the fact that the mGlu receptors are G-protein coupled, they obviously constitute new 'drugable' targets for the treatment of various CNS disorders. Due to the recent emergence of subtype-specific ligands for Group I and II mGlu receptors, this review will concentrate on the molecular characteristics, brain localization, pharmacology and physiological role of these receptors, in order to provide further insights into their therapeutic potential.

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease.

OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postoperative decline in verbal fluency.

Intraoperative mapping of the cortical areas involved in multiplication and subtraction: an electrostimulation study in a patient with a left parietal glioma.

OBJECTIVES: Advances in neuroimaging studies have recently improved the understanding of the functional anatomy of the calculation processes, having in particular underlined the central role of the angular gyrus (AG). In this study, the authors applied this knowledge to the surgical resection of a glioma invading the left AG, by localising and sparing the cortical areas involved in two different components of calculation (multiplication and subtraction), using direct electrical stimulations. METHODS: A calculation mapping was performed in a patient without deficit except a slightly impaired performance for serial arithmetic subtraction, during the resection under local anaesthesia of a left parieto-occipital glioma invading the dominant AG. After somatosensory and language mappings, cortical areas involved in single digit multiplications and subtractions of seven were mapped using the method of electrostimulation, before glioma removal. RESULTS: Distinct sites specifically involved in multiplication or subtraction were detected within the left AG, with a precise spatial distribution and overlapping. All the eloquent (somatosensory, language, and calculation) areas were surgically spared. Postoperatively, the patient had a transient complete deficit for arithmetic subtraction, without either multiplication or language disturbance. The tumour removal was complete. CONCLUSIONS: These findings suggest: firstly, the usefulness of an intraoperative calculation mapping during the removal of a lesion involving the left dominant AG, to avoid permanent postoperative deficit of arithmetic processes while optimising the quality of tumour resection; secondly, the possible existence of a well ordered and dynamic anatomo-functional organisation for different components of calculation within the left AG.

In vitro and in vivo characterization of MPEP, an allosteric modulator of the metabotropic glutamate receptor subtype 5: review article.

There is a need to identify subtype-specific ligands for mGlu receptors to elucidate the potential of these receptors for the treatment of nervous system disorders. To date, most mGlu receptor antagonists are amino acid-like compounds acting as competitive antagonists at the glutamate binding site located in the large extracellular N-terminal domain. We have characterized novel subtype-selective mGlu(5) receptor antagonists which are structurally unrelated to competitive mGlu receptor ligands. Using a series of chimeric receptors and point mutations we demonstrate that these antagonists act as inverse agonists with a novel allosteric binding site in the seven-transmembrane domain. Recent studies in animal models implicate mGlu(5) receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.

Effective monitoring of small river basins.

As the transport of many pollutants occurs during high floods monitoring programs must focus on these intermittent events. In small rivers the pollutants start their travel as short pulses often associated with fine particles, but disperse on their way downstreams. Therefore the chemical data of a flood event are only representative of a small part of the basin adjacent to the monitoring station. This is usually not taken into account by evaluating water quality data.

The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity.

Phencyclidine (PCP), a non-competitive antagonist of ionotropic N-methyl-D-aspartate (NMDA) receptors, produces psychotomimetic effects, such as a disruption in prepulse inhibition (PPI) of the startle response. NMDA antagonists also induce locomotor hyperactivity in rodents. We hypothesized that, like NMDA receptors, metabotropic glutamate receptors (mGluRs) modulate PPI and locomotor activity either alone or, in the case of mGluR5, via interaction with NMDA receptors. Rats treated with the mGluR5 antagonist MPEP (2-methyl-6-phenylethynylpyridine) or the mGluR2/3 agonist LY314582, either alone or in combination with PCP, were tested in PPI and locomotor activity paradigms. Neither MPEP nor LY314582 altered PPI. MPEP, but not LY314582, potentiated the PPI-disruptive effects of PCP. MPEP alone did not alter locomotor or exploratory behavior, but augmented the complex, time-dependent locomotor-stimulating effects of PCP. LY314582 dose-dependently decreased locomotor activity and exploratory holepokes. LY314582 did not alter the PCP-induced increases in locomotor activity, but further decreased the number of holepokes. The effects of MPEP on the response to PCP may reflect the cooperation and co-localization of NMDA and mGlu5 receptors.

Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7.

To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7(-/-)). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7(-/-), but not in mGluR7(+/-), mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7(-/-) mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs.

Design, synthesis and preliminary evaluation of novel 3'-substituted carboxycyclopropylglycines as antagonists at group 2 metabotropic glutamate receptors.

Two novel 3'-substituted carboxycylopropylglycines, (2S,1'S,2'S,3'R)-2-(3'-xanthenylmethyl-2'-carboxycyclopropyl)glycine (8a) and (2S,1'S,2'S,3'R)-2-(3'-xanthenylethyl-2'-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.

Glutamate release inhibiting properties of the novel mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP): complementary in vitro and in vivo evidence.

We have previously demonstrated that neuronal release of the excitatory amino acid glutamate is facilitated by the selective activation of presynaptic Group I metabotropic autoreceptors. Here we report the release inhibiting actions of the novel mGlu(5) receptor-selective antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), both in vitro and in vivo. These data provide compelling evidence for the presence of functional positive modulatory mGlu(5) subtype autoreceptors in the mammalian central nervous system.