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This paper uses a novel micro econometric approach to analyze the impact of social benefits on the individual probabilities of poverty exit and entry in Italy, and their relative importance with respect to other socio-economic determinants of poverty transitions. Year to year transitions are defined as dichotomous variables capturing the changes of the individual poverty status, and are analyzed using random effects probit models estimated on pooled Italian data from 9 longitudinal components of IT-SILC covering the period 2004–2015. Our results show that social benefits strongly counteract the adverse effects of individual characteristics like unemployment, work intensity, inactivity, household size (and composition) and past poverty experience on the individual probabilities of poverty exit and entry. Despite their important effects on the individual probabilities of transitions, however, social benefits have a limited coverage among the vulnerable groups of the population, which strongly limits their aggregate impact on transition rates and poverty rates.

The ASTRI (Astrofisica con Specchi a Tecnologia Replicante Italiana) Project led by the Italian National Institute for Astrophysics (INAF) is developing and will deploy at the Observatorio del Teidea mini-array (ASTRI Mini-Array) composed of nine telescopes similar to the small-size dual-mirror Schwarzschild-Couder telescope (ASTRI-Horn) currently operating on the slopes of Mt. Etna in Sicily. The ASTRI Mini-Array will surpass the current Cherenkov telescope array differential sensitivity above a few tera-electronvolt (TeV), extending the energy band well above hundreds of TeV. This will allow us to explore a new window of the electromagnetic spectrum, by convolving the sensitivity performance with excellent angular and energy resolution figures. In this paper we describe the Core Science that we will address during the first four years of operation, providing examples of the breakthrough results that we will obtain when dealing with current open questions, such as the acceleration of cosmic rays, cosmology and fundamental physics and the new window, for the TeV energy band, of the time-domain astrophysics.

Within the framework of the Cherenkov Telescope Array (CTA) observatory, the Italian National Institute for Astrophysics (INAF) is leading the “Astrofisica con Specchi a Tecnologia Replicante Italiana” (ASTRI) Project mainly devoted to the definition and development of a set of small-size class telescopes with dual-mirror optical design (SST-2M) for the CTA southern site. The prototype of such telescopes, named ASTRI SST-2M, is installed in Italy at the INAF “M.C. Fracastoro” observing station located in Serra La Nave, Mount Etna, Sicily. In addition to the dual-mirror optical design based on the Schwarzschild-Couder configuration, the ASTRI SST-2M telescope adopts a focal plane camera formed by an array of monolithic silicon photomultiplier sensors coupled with a specifically designed front-end electronics and back-end electronics that represent a further innovative solution for the detection of atmospheric Cherenkov light. The ASTRI SST-2M prototype is currently under completion of the overall commissioning phase: structure, mirrors, camera, control software, data archiving and analysis pipeline. This contribution focuses the attention on the software devoted to the control and monitoring operations of the ASTRI camera. We will provide a brief description of the electronic assemblies and of the software architecture designed, according to software engineering modularization, in terms of functional blocks and how they are deployed in the back-end electronics. Then, we will show how all these functionalities are accessible by the user through the graphical user interface developed and currently used for the engineering tests performed on site.

We report on numerical results of energy spectra of photoelectrons emitted by irradiating a hydrogen atom with the superposition of two pulses. The spectra have been obtained by numerical integration of the time dependent Schrödinger equation. The highest frequency component of the pulse has been assumed to have low intensity and such a frequency that a single photon may ionize the atom. Its duration has been assumed to lie in the range of subfemtoseconds. The lowest frequency component that redistribute the energy of the ionized electrons has an higher intensity and duration of few femtoseconds. We find that when the field are aligned, the electron energy spectra strongly depend on the time lag of the fields, on the carrier-envelope relative phase of the lowest frequency pulse, and on the duration of the X-ray pulse. Moreover it has been found that by changing the angle between the direction of the low and high frequency fields significant modifications to the spectra occur that could be used to measure the relative orientation of the fields.

Deposition of maximum laser energy into a small, high-Z enclosure in a short laser pulse creates a hot environment. Such targets were recently included in an experimental campaign using the first four of the 192 beams of the National Ignition Facility [J. A. Paisner, E. M. Campbell, and W. J. Hogan, Fusion Technology 26, 755 (1994)], under construction at the University of California Lawrence Livermore National Laboratory. These targets demonstrate good laser coupling, reaching a radiation temperature of 340 eV. In addition, the Raman backscatter spectrum contains features consistent with Brillouin backscatter of Raman forward scatter [A. B. Langdon and D. E. Hinkel, Physical Review Letters 89, 015003 (2002)]. Also, NIF Early Light diagnostics indicate that 20% of the direct backscatter from these reduced-scale targets is in the polarization orthogonal to that of the incident light.

We present iron abundance analysis for 23 wide binaries with main sequence components in the temperture range 4900–6300 K, taken from the sample of the pairs currently included in the radial velocity planet search on going at the Telescopio Nazionale Galileo (TNG) using the high resolution spectrograph SARG. The use of a line-by-line differential analysis technique between the components of each pair allows us to reach errors of about 0.02 dex in the iron content difference. Most of the pairs have abundance differences lower than 0.02 dex and there are no pairs with differences larger than 0.07 dex. The four cases of differences larger than 0.02 dex may be spurious because of the larger error bars affecting pairs with large temperature difference, cold stars and rotating stars. The pair HD 219542, previously reported by us to have a different composition, here is shown to be normal. For non-rotating stars warmer than 5500 K, characterized by a thinner convective envelope and for which our analyis appears to be of higher accuracy, we are able to exclude in most cases the consumption of more than 1 Earth Mass of iron (about 5 Earth masses of meteoritic material) during the main sequence lifetime of the stars, placing more stringent limits (about 0.4 Earth masses of iron) in five cases of warm stars. This latter limit is similar to the estimates of rocky material accreted by the Sun during its main sequence lifetime. Combining the results of the present analysis with those for the Hyades and Pleiades, we conclude that the hypothesis that pollution by planetary material is the only mechanism responsible for the highest metallicity of the stars with planets may be rejected at more than 99% level of confidence if the incidence of planets in these samples is as high as 8% and similar to the field stars included in current radial velocity surveys. However, the significance of this result drops considerably if the incidence of planets around stars in binary systems and clusters is less than a half of that around normal field stars.

The star HD 219542 B has been reported by us (Desidera et al. 2003) to show low-amplitude radial velocity variations that could be due to the presence of a Saturn-mass planetary companion or to stellar activity phenomena. In this letter we present the results of the continuation of the radial velocity monitoring as well as a discussion of literature determinations of the chromospheric activity of the star (Wright et al. 2004). These new data indicate that the observed radial velocity variations are likely related to stellar activity. In particular, there are indications that HD 219542 B underwent a phase of enhanced stellar activity in 2002 while the activity level has been lower in both 2001 and 2003. Our 2003 radial velocity measurements now deviate from our preliminary orbital solution and the peak in the power spectrum at the proposed planet period is severely reduced by the inclusion of the new data. We therefore dismiss the planet hypothesis as the cause of the radial velocity variations.

We performed a careful differential abundance analysis of individual components of six main sequence binaries with separations of a few hundreds of AU. To reduce analysis concerns, we selected systems with almost equal mass components. We were able to derive differential abundances of several elements with errors down to 0.01 dex in the best cases. We found that in four systems the two components have the same chemical composition, within these very severe limits. However, clear differences were found for the two remaining systems (HD 219542 and HD 200466), in both cases the primaries being more Fe-rich than the secondaries, by $0.091\pm 0.009$and $0.053\pm 0.024$dex respectively. Similar differences were found for most of the elements considered in our analysis; however, we found no appreciable difference for volatile elements and a trend for increasing abundance differences with increasing condensation temperature for individual elements, a result similar to that found for some single stars with planets by Smith et al. ([CITE]). Finally, we note that HD 219542A has a Li-abundance comparable to those of Li-rich stars in old open clusters, while no Li is detected in the slightly cooler HD 219542B. We suggest that the primaries of these two systems have accreted rocky planets or the inner dust-rich part of a protoplanetary disk, likely due to gravitational perturbation caused by the presence of the companion.

A highly and rapidly variable bipolar mass outflow from StHα190 has been discovered, the first time in a yellow symbiotic star. Permitted emission lines are flanked by symmetrical jet features and multi-component P-Cyg profiles, with velocities up to 300 km s-1. Given the high orbital inclination of the binary, if the jets leave the system nearly perpendicular to the orbital plane, the de-projected velocity equals or exceeds the escape velocity (1000 km s-1). StHα190 looks quite peculiar in many other respects: the hot component is an O-type sub-dwarf without an accretion disk or a veiling nebular continuum and the cool component is a G7 III star rotating at a spectacular 105 km s-1, unseen by a large margin in field G giants.

The enzyme indoleamine 2,3-dioxygenase (IDO) regulates immune responses through the capacity to degrade the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favour the differentiation of regulatory T cells. Considerable experimental evidence indicates that IDO can be expressed by dendritic cells, by tumour cells or by surrounding stromal cells, either within proximity of the tumour or at distal sites. Recent advances in the biochemistry of IDO and in our understanding of the biological relevance of IDOmediated tryptophan consumption to the establishment of dominant immune tolerance to cancer will be summarised and discussed. Within the wider context of cancer immunotherapy, this Review also delineates how IDO could be exploited as a molecular target for therapeutic intervention in order to boost anti-cancer immunity.

The ASTRI Mini-Array (MA) is an INAF project to build and operate a facility to study astronomical sources emitting at very high-energy in the TeV spectral band. The ASTRI MA consists of a group of nine innovative Imaging Atmospheric Cherenkov telescopes. The telescopes will be installed at the Teide Astronomical Observatory of the Instituto de Astrofisica de Canarias (IAC) in Tenerife (Canary Islands, Spain) on the basis of a host agreement with INAF. Thanks to its expected overall performance, better than those of current Cherenkov telescopes' arrays for energies above ∼5 TeV and up to 100 TeV and beyond, the ASTRI MA will represent an important instrument to perform deep observations of the Galactic and extra-Galactic sky at these energies.

Context. A new extremely high speed photon-counting photometer, Iqueye, has been installed and tested at the New Technology Telescope, in La Silla.Aims. This instrument is the second prototype of a ?quantum? photometer being developed for future Extremely Large Telescopes of 30?50?m aperture.Methods. Iqueye divides the telescope aperture into four portions, each feeding a single photon avalanche diode. The counts from the four channels are collected by a time-to-digital converter board, where each photon is appropriately time-tagged. Owing to a rubidium oscillator and a GPS receiver, an absolute rms timing accuracy better than 0.5?ns during one-hour observations is achieved. The system can sustain a count rate of up to 8?MHz uninterruptedly for an entire night of observation.Results. During five nights of observations, the system performed smoothly, and the observations of optical pulsar calibration targets provided excellent results.

RiassuntoNel presente lavoro, vengono riportati i risultati di un'indagine sulla vegetazione della foce del Fiume Salso, presso Licata (Sicilia meridionale). In quest'area umida, nonostante l'elevato impatto antropico, è ancora possibile osservare comunità vegetali di apprezzabile valore naturalistico. il sito accoglie anche una ricca avifauna locale e migratoria. La flora è rappresentata da un significativo contingente di psammofite, alofite e igrofite, fra cui Rumex palustris, terofita molto rara in Sicilia. Le comunità vegetali indagate nella suddetta area appartengono a varie classi fitosociologiche come: Cakiletea maritimae, che riunisce associazioni annuali alo-nitrofile legate ai suoli sabbiosi; Ammophiletea, riguardante le associazioni perenni tipiche delle dune costiere; Sarcocornietea fruticosae, che comprende associazioni che vivono in ambienti salmastri; Thero-Suadeteala quale raggruppa associazioni annuali estive caratterizzate da alofite succulente; Saginetea maritimae, che include associazioni primaverili dominate da piccole terofite alofile; Phragmito-Magnocaricetea, riguardante le associazioni igrofile differenziate da elofite perenni di grossa taglia; Stellarietea media, in cui vengono incluse le associazioni nitrofile annuali. L'associazione Rumicetum palustrisappartenente all'alleanza Frankenion pulverulentaedei Saginetea maritimaeviene qui descritta per la prima volta. Si analizzano anche i principali fattori che degradano la vegetazione naturale e vengono fornite linee guida per il restauro e la gestione ambientale.

Background: EUS is highly accurate for staging gastric lymphoma. Because stage correlates to outcome, interobserver agreement is mandatory. However, previous studies suggest that interobserver agreement might vary according to T-stage. A multicenter evaluation of observer agreement with respect to endosonographic staging of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was therefore conducted. Methods: Fifty-four patients were studied; 42 were also evaluated after eradication of Helicobacter pylori infection. EUS was performed at different institutions by 10 experienced endosonographers who collected the best photographs for each examination. Interobserver agreement was estimated with kappa statistics. Results: Overall interobserver agreement for T-stage was fair, both before and after treatment (@k = 0.38 and @k = 0.37, respectively). Overall interobserver agreement for N-stage was substantial before treatment, but only fair after treatment (@k = 0.63 and @k = 0.34, respectively). The lowest values of agreement occurred with T1sm (submucosa) and T2 stage lesions. Conclusions: Interobserver agreement for staging of gastric MALT lymphoma by EUS is suboptimal before as well as after treatment of H pylori infection. This evidence suggests that gastric EUS may be more difficult technically compared with EUS of other organs. Lack of agreement is crucial because it influences the choice of therapy and assessment of response to treatment. Good interobserver agreement would permit better communication concerning the clinical status of patients, comparison of the results of different studies, and stratification of patients within clinical trials. (Gastrointest Endosc 2002;55:662-8.)

SARG is a cross dispersed echelle spectrograph in operation since late spring 2000 at the Italian Telescopio Nazionale Galileo (TNG) 3.5 m telescope, La Palma. SARG offers both single object and long slit (up to 26 arcsec) observing modes covering a spectral range from λ = 0.37 up to1 μm, with resolution ranging from R= 29,000 up to R= 164,000. Cross dispersion is provided by means of a selection of four grisms; interference filters may be used for the long slit mode (up to 26 arcsec). A dioptric camera images the cross dispersed spectra onto a mosaic of two 2048 × 4096 EEV CCDs (pixel size: 13.5 μm) allowing complete spectral coverage at all resolving power for λ < 0.8 μm. In order to reach a high wavelength calibration precision an iodine-absorbing cell is provided. A Distributed Active Temperature Control System (DATCS) maintains constant the temperature of all spectrograph components at a preset value. Early results show that SARG works according to original specifications in terms of wavelength coverage, efficiency (measured peak efficiency is about 13%),resolution (maximum resolution R= 164,000 using a 0.3 arcsec slit, R∼144,000 using an image slicer), and stability (preliminary estimates of radial velocity accuracy is ∼3 m/s using the iodine cell and ±150 m/s without the iodine cell).

The release of cholecystokinin-like immunoreactivity (CCK-LI) in human brain was investigated using synaptosomes prepared from neocortical specimens removed during neurosurgery. CCK-LI basal release from superfused synaptosomes was increased 3 to 4-fold during depolarization with 15 mM KCI. The K(+)-evoked overflow of CCK-LI was strictly Ca(++)-dependent. The gamma-aminobutyric acidB (GABA(B)) receptor agonist (-)baclofen (0.3-100 microM) inhibited CCK-LI overflow in a concentration-dependent manner (EC50 = 2.20 microM; maximal effect: 45%). The novel GABA(B) receptor ligand CGP 47656 mimicked (-)baclofen (EC50 = 2.45 microM; maximal effect: 50%), whereas the GABA(A) agonist muscimol was ineffective up to 100 microM. The inhibitory effect of 10 microM (-)baclofen on the CCK-LI overflow was concentration-dependently prevented by two selective GABA(B) receptor antagonists, CGP 35348 (IC50 = 13.91 microM) and CGP 52432 (IC50 = 0.08 microM). The effect of 10 microM CGP 47656 was abolished by 1 microM CGP 52432. In experiments on [3H]GABA release, CGP 47656 behaved as an antagonist at the GABA(B) autoreceptors: added at 10 microM, it prevented the inhibitory effect of 10 microM (-)baclofen on the K+ (15 mM)-evoked release of [3H]GABA from human synaptosomes. We conclude that 1) the release of CCK-LI evoked from human brain tissue appears of neuronal origin; 2) the CCK-releasing terminal possess inhibitory presynaptic GABA(B) receptors; 3) these receptors differ pharmacologically from human neocortex GABA(B) autoreceptors, which are CGP 35348-insensitive (Fassio et al., 1994) but can be blocked by CGP 47656; 4) because cholecystokinin has been implicated in anxiety, the GABA(B) receptors here characterized may represent targets for novel anxiolytic agents.

The bisdioxopiperazine ICRF 187 is a potent intracellular chelating agent which effectively diminishes Adriamycin cardiotoxicity without compromising its antitumor activity. Our study aimed at verifying whether ICRF 187 can modulate the cytotoxic action of cisplatin (CDDP) on ovarian cancer cells. We used the A2780 ovarian cancer cell line and a subline resistant to CDDP (A2780-CDDP) obtained in our laboratory by continuous exposure of the parental cells to progressively increasing CDDP doses. In both cell lines ICRF 187 (0.1-0.5 μg/ml) used in combination with CDDP (0.01-1 μg/ml) produced a dose-dependent reduction of CDDP IC50(the concentration inhibiting 50% of cell growth). Moreover, when ICRF 187 was used in combination with CDDP, analysis of the data by the isobole method showed that the combination of the two drugs produced a synergistic antiproliferative activity in both cell lines, with a CDDP potentiation up to fivefold. Our in vitrodata show that ICRF 187 can synergize with CDDP. Prospective clinical trials are now needed to verify whether the addition of ICRF 187 to CDDP-containing regimens will result in an improved clinical response in ovarian cancer.

We have previously shown that protein kinase C (PKC) activity is up‐regulated in nerve terminals of animals that have been subjected to targeted cellular ablation of cortical and hippocampal neurons by treatment with methylazoxymethanol (MAM), which results in impaired long‐term potentiation (LTP) and cognitive deficit. In this study we investigated the consequences of increased membrane‐bound PKC in the regulation of release of glutamate, the major excitatory transmitter involved in LTP. We show that nerve terminals of MAM‐treated rats show higher PKC activity, as monitored by the in situphosphorylation of B‐50/GAP‐43, in both basal and phorbol ester‐stimulated conditions. In these animals, hippocampal nerve endings release a greater amount of glutamate than those of controls, both in basal conditions and when synaptosomes are stimulated with KCI or 3,4–diaminopyridine. The potentiation observed in MAM‐treated rats was counteracted by the PKC blocker H‐7 and the clostridial tetanus toxin. On the contrary, GABA release was not significantly up‐regulated, either in basal or in depolarization‐evoked conditions. Therefore our data show that the increase in synaptosomal PKC activity is paralleled by increased glutamate but not GABA release in this animal model. Whether this reflects specific up‐regulation of membrane PKC activity in glutamatergic terminals or an alteration in the regulation of glutamate release remains to be determined.

The possibility of interaction between neurotransmitter uptake mechanisms and presynaptic receptors regulating transmitter release was investigated using rat brain synaptosomes in superfusion. Various conditions were considered including: absence of substrate for the uptake with uptake potentially operative; absence of substrate and presence of uptake inhibitors; and uptake activated by added substrate, with or without uptake inhibitors. The release of [3H]-5-hydroxytryptamine ([3H]-5-HT) evoked by 15 mM KCl from cerebral cortex synaptosomes was inhibited by lysergic acid diethylamide. The 5-HT uptake inhibitors citalopram and chlorimipramine did not affect the inhibitory action of lysergic acid diethylamide. Clonidine decreased both the K+-evoked release of [3H]norepinephrine and that of [3H]-5-HT in cortical synaptosomes through the activation of presynaptic alpha-2 adrenoceptors. In superfusion conditions, the action of clonidine on [3H]norepinephrine release was not antagonized by the norepinephrine uptake inhibitors desipramine or cocaine; similarly, the inhibition of [3H]-5-HT release was unaffected when 5-HT uptake was blocked. The K+-evoked release of [3H]dopamine from striatal nerve terminals was potentiated by acetylcholine (ACh) through the activation of muscarinic presynaptic receptors. The action of ACh was not modified by the presence of nomifensine, a dopamine uptake inhibitor. Finally, in superfused cortical synaptosomes, the block of the high-affinity uptake of choline by hemicholinium-3 had no effect on the muscarinic autoreceptor-mediated inhibition of [3H]ACh release by ACh. Altogether the present results do not support the previously proposed idea that in nerve terminals a functional coupling may exist between uptake mechanisms and presynaptic receptors.

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.

Summary ?-Aminobutyric acid (GABA) increased in a concentration-dependent way (3–300?M) the basal release of tritium from rat cerebral cortex and hippocampus synaptosomes, prelabelled with3H-noradrenaline (3H-NA); however, GABA was ineffective on hypothalamic nerve endings. The effect displayed by low concentrations (<10?M) of GABA was largely bicuculline-sensitive. Muscimol mimicked GABA, while (-)baclofen was inactive.

The design, components, and operation of the CCD camera at the Catania Astrophysical Observatory are described. Consideration is given to the mechanical interface between the spectrograph Schmidt camera and the dewar; the acquisition system, which includes a CCD controller and computer; and the software for data handling and prereduction. The linearity, readout noise, and charge-transfer efficiency for the CCD camera are evaluated. Examples revealing the applicability of the echelle spectrograph with CCD camera are presented.

The aim of this work was the identification of pharmacologically distinct subtypes of gamma-aminobutyric acidB (GABAB) receptors in the central nervous system. Inasmuch as GABAB receptors are often sited on axon terminals where they mediate inhibition of transmitter release, we chose as models the GABAB receptors mediating inhibition of release of 1) endogenous GABA; 2) endogenous glutamate; and 3) somatostatin-like immunoreactivity (SRIF-LI). The experimental set up consisted of rat cerebrocortical synaptosomes depolarized in superfusion with 12 or 15 mM KCl. Endogenous GABA and glutamate were measured by high-performance liquid chromatography and SRIF-LI by radioimmunoassay. The selective GABAB receptor agonist (-)-baclofen inhibited in a concentration-dependent manner the K(+)-evoked release of GABA, glutamate and SRIF-Ll with similar potencies and efficacies [EC50 values, 1.1-1.5 microM; maximal inhibition, 45-50% at about 10 microM (-)-baclofen]. The GABAB receptor antagonist phaclofen concentration-dependently reduced the effects of (-)-baclofen on the release of GABA and SRIF-Ll but not on the release of glutamate, where it was ineffective up to 1000 microM. The rank order of potency (Ki values are shown in parentheses) are: SRIF-Ll (7.8 microM); GABA (10.4 microM); and glutamate (greater than 115 microM). The novel GABAB receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP 35348) displayed a different pattern on the three release systems examined (Ki values are shown in parentheses): SRIF-Ll (0.38 microM); glutamate (0.48 microM); and endogenous GABA (greater than 115 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of gamma-aminobutyric acid (GABA) on the release of somatostatin-like immunoreactivity (SRIF-LI) was studied in synaptosomes prepared from rat cerebral cortex and exposed in superfusion to the amino acid. GABA (1-300 microM) increased the spontaneous outflow of SRIF-LI in a concentration-dependent manner. The effect of GABA was not prevented by the GABAA receptor antagonists bicuculline or picrotoxin. The GABAA receptor agonist muscimol (10-100 microM) did not affect SRIF-LI release. Similarly ineffective was the GABAB receptor agonist (-)-baclofen (100 microM). The GABA-induced SRIF-LI release was counteracted by the GABA uptake inhibitors N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A) and nipecotic acid. When used as a GABA carrier substrate, nipecotic acid mimicked GABA and increased SRIF-LI release; its effect was antagonized by SK&F 89976A. The mechanism involved appears to be selective for GABA inasmuch as neutral amino acids such as leucine, alpha-aminobutyric acid or valine, tested at 100 microM, had little or no effect on the release of SRIF-LI. Neither GABA (100 microM) nor nipecotic acid (300 microM) enhanced the release of cholecystokinin-like immunoreactivity. The GABA-evoked somatostatin release was calcium-dependent and tetrodotoxin-insensitive. It is concluded that a carrier for the uptake of GABA exists on somatostatin-releasing terminals of rat cerebral cortex and that GABA uptake may regulate somatostatin release. This conclusion would be compatible with the reported coexistence of GABA and somatostatin in cerebrocortical neurons.

This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 µM. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3',4',7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 µM Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anticancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.

Studies of molecular cloning predict great heterogeneity for the GABAA receptor; however, evidence for functionally and pharmacologically distinct native GABAA receptors is relatively scarce. In this work we have compared some of the functional and pharmacological properties of two GABAA receptors previously shown to be present in the adult rat central nervous system. In superfused hippocampal synaptosomes activation of GABAA receptors increased the basal release of [3H]noradrenaline (ec50 for GABA = 3.2 μM). In contrast, the overflow evoked by depolarization with high-K+ (12 or 35 mM) was not affected. Conversely, GABAA receptor activation led to potentiation of the K+-evoked overflow of [3H]d-aspartate from cerebellar synaptosomes (ec50 for GABA = 1.3 μM) whereas the basal release remained unchanged. GABA and muscimol also potentiated the K+-evoked overflow of endogenous glutamate in cerebellum.

A new game-form, theset-theoretic form, is introduced and it is shown that a set-theoretic form can be associated with every extensive form. The map from extensive forms to set-theoretic forms is not one-to-one and this fact is used to define a notion of equivalence for extensive games. A transformation for extensive forms is then defined, called theinterchange of contiguous simultaneous moves, and it is shown that it is possible to move from one game to any other game in the same equivalence class by using this transformation a finite number of times and without ever leaving the equivalence class. This transformation is a generalization of Thompson's “interchange of decision nodes”. Thus given an extensive gameG there is a different extensive gameG' that is equivalent toG if and only if there are moves inG that are simultaneous and the difference betweenG andG' lies exactly in the fact that (some of) these moves are taken in a different temporal order in the two games.

The release of endogenous glutamate (GLU) elicited by depolarization of rat cerebellum synaptosomes was inhibited potently (pEC30 = 9.77) by 5-hydroxytryptamine (5-HT). The 5-HT action was antagonized by methiothepin (pA2 = 10.37); ketanserin, methysergide, cinanserin and spiperone were ineffective. Exogenous 5-HT also inhibited the release of [3H]-5-HT from cerebellar synaptosomes (pEC30 = 8.73). Methiothepin, but not ketanserin, methysergide, cinanserin or spiperone counteracted the inhibition (pA2 = 9.28). The receptors involved (presynaptic 5-HT heteroreceptors and autoreceptors) were activated by the 5-HT1 agonist RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole) which showed comparable activity at the two receptor systems. (-)-Propranolol, used as a 5-HT1 antagonist, shifted to the right (pA2 = 8.05) the dose-response curve of 5-HT at the autoreceptors, but was ineffective at the receptors regulating GLU release. On the contrary, the 5-HT1A agonist 8-hydroxy-2-di-N-propylamino)tetralin activated the presynaptic heteroreceptors (pEC30 = 7.98), but was ineffective as a 5-HT autoreceptor agonist. The results allow the following major conclusions: 5-HT receptors are located on GLU terminals in rat cerebellum where they may modulate in an inhibitory way the release of GLU; 5-HT autoreceptors possibly involved in a negative feedback regulation of 5-HT release are present on cerebellar 5-HT nerve endings; 5-HT autoreceptors and heteroreceptors can be pharmacologically differentiated and appear to represent subtypes of the 5-HT1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Slices of the rabbit occipito-parietal cortex were preincubated with 3H-serotonin and then superfused and stimulated electrically (2 min at 3 Hz). In the absence of drugs, the stimulation-evoked overflow of tritium was approximately 3% of the tritium content of the tissue. Unlabelled serotonin and 5-carboxamido-tryptamine, when administered in the presence of 6-nitroquipazine, reduced the evoked overflow of tritium. Their effects were antagonized by metitepin (apparent pA2 value 8.1) and (±)-cyanopindolol (apparent pA2 value 6.4). Metitepin, but not cyanopindolol, increased evoked tritium overflow; the effect of metitepin was greater in the presence than in the absence of nitroquipazine. The evoked overflow of tritium was also depressed by clonidine, an effect antagonized by idazoxan (apparent pA2 value 7.0) but not by prazosin. Phenylephrine caused a decrease only at high concentrations that simultaneously accelerated basal tritium efflux. Prazosin and idazoxan did not change evoked tritium overflow, and phentolamine increased it significantly only when administered in the presence of (+)-oxaprotiline. Rauwolscine produced an inhibition that was prevented by metitepin. It is concluded that the serotonergic axons of the rabbit occipitoparietal cortex possess presynaptic, release-inhibiting serotonin autoreceptors and a2-adrenoceptors. The receptors appear to receive an input of endogenous serotonin and, to a lesser extent, noradrenaline, under the conditions of these in vitro experiments.

It has been demonstrated that the flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone; Q) inhibits the growth of several cancer cell lines. There is evidence suggesting that the antiproliferative activity of this substance is mediated by the so-called type II estrogen-binding, site (type II EBS). We looked for the presence of type II EBS and the effect of Q on the proliferation of an Adriamycinresistant estrogen-receptor-negative human breast-cancer cell line (MCF-7 ADRr). By whole-cell assay using estradiol labelled with 6,7-tritium ([3H]-E2) as a tracer, we demonstrated that MCF-7 ADRr cells contain type II EBSs. Competition analysis revealed that diethylstilbestrol (DES) and Q competed with similar potency for [3H]-Es binding to type II EBSs. The antiestrogen tamoxifen (TAM) competed for type II EBSs, albeit to a lesser extent than either DES or Q. Growth experiments demonstrated that Q and DES exerted a dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 µm, whereas TAM was less effective. Q could also inhibit colony formation in a clonogenic assay. Our results indicate that multidrug-resistant estrogen-receptor-negative MCF-7 cells express, type II EBSs and are sensitive to the inhibitory effect of Q. This substance could be the parent compound of a novel class of anticancer agents.

The anorexigenic drug d-fenfluramine (d-F) increased the in vitro release of [3H]5-hydroxytryptamine ([3H]-5-HT) from rat hypothalamic synaptosomes. The release induced by 5 microM d-F was Ca(++)-independent, insensitive to 5-HT autoreceptor activation and prevented by the 5-HT uptake inhibitor fluoxetine (0.1 microM). The release evoked by 0.5 microM d-F also was blocked by fluoxetine, but it was Ca(++)-dependent and sensitive to autoreceptor activation. Thus, relatively high concentrations of d-F release 5-HT through an outward carrier mediated transport; at 0.5 microM the evoked release seems instead exocytotic, although it probably requires previous uptake of d-F by the 5-HT transporter. During in vivo intrahypothalamus microdialysis, in free-moving rats, local infusion (0.5 or 5 microM) or i.p. administration (0.8 or 2.5 mg/kg) of d-F produced increases of extracellular 5-HT. These effects were prevented completely by local (0.1 microM) or i.p. (1 mg/kg) administration of fluoxetine. Although both 0.8 and 2.5 mg/kg of d-F consistently increased hypothalamic extracellular 5-HT, only the higher dose induced hypophagia. This hypophagia was, however, not significantly modified by fluoxetine, although it was blocked by the 5-HT receptor antagonist metergoline (2 mg/kg i.p.). The results show that d-F is a potent 5-HT releaser also in the hypothalamus, one major site of action of the anorexigenic drug. Depending on the concentration, the release elicited by d-F may occur by a dual mechanism requiring integrity of the 5-HT transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of gamma-aminobutyric acid (GABA) on the basal release of [3H]acetylcholine ([3H]ACh) was investigated using synaptosomes prepared from rat hippocampus and superfused after prelabeling with [3H]choline. Exogenous GABA added to the superfusion medium caused a long-lasting and concentration-dependent enhancement of the basal efflux of [3H]ACh. The effect of GABA was not antagonized by bicuculline or picrotoxin. Muscimol increased slightly but not significantly the release of [3H]ACh, whereas (+/-)-baclofen or (-)-baclofen were ineffective. The effect of GABA was counteracted by SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid], SK&F 100330A [N-(4,4-diphenyl-3-butenyl)-guvacine] and SK&F 100561 [N-(4,4-diphenyl-3-butenyl)-homo-beta-proline], three novel inhibitors of GABA uptake, but was unaffected by hemicholinium-3 or by beta-alanine. Nipecotic acid, a substrate-inhibitor of the GABA transporter, mimicked GABA and enhanced [3H]ACh release. The results indicate that a GABA transport system is present on cholinergic terminals.

We investigated the effect of the flavonoid quercetin (Q) on the proliferation of the ovarian cancer cell line OVCA 433. Growth experiments demonstrated that Q exerted a reversible dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 microM. Two other flavonoids tested, rutin and hesperidin, were ineffective in inhibiting cell growth. Cell cycle analysis showed that the growth inhibitory effect of Q was due to a blocking effect in the GO/G1 phase. Using a whole cell assay with (6.7-3H) oestradiol (3H-E2) as tracer we demonstrated that OVCA 433 cells contain type II oestrogen binding sites (type II EBS). Competition analysis showed that Q competed for 3H-E2 binding to type II EBS while both rutin and hesperidin did not. Appreciable amounts of type II EBS were also detected in seven primary ovarian tumours. Our results suggest that Q may regulate ovarian cancer cell growth through a mechanism involving a binding interaction with type II EBS. This mechanism could also be active in vivo since primary ovarian tumours contain type II EBS.

Rat cerebral cortex slices or synaptosomes were labelled with 3H-5-hydroxytryptamine (3H-5-HT) and subsequently superfused. They were depolarized by electrical stimulation (slices) or with high K+ (slices and synaptosomes). Continuous electrical stimulation (2 Hz, 24 mA, 2 ms) and continuous or discontinuous K+ depolarization (15–25 mM) were used. 1. Continuous electrical stimulation or continuous K+-depolarization of slices evoked a steady overflow of tritium that slowly decayed with time. 2. Exposure to increasing concentrations of 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate (RU 24969) (0.001–0.1 µM) during continuous electrical stimulation produced a concentration-dependent decrease in tritium overflow. Citalopram (1 µM) counteracted the effect of RU 24969. 3. RU 24969 inhibited the evoked 3H-overflow and citalopram reduced the effect of RU 24969 also during continuous depolarization of slices with 20 mM K+. Similar results were obtained by using 5-methoxytryptamine or LSD. 4. In slices 1 µM citalopram increased significantly the tritium overflow evoked by electrical stimulation or by 20 mM K+-depolarization. 5. Increasing the K+ concentration from 20 mM to 25 mM mimicked the effects of 1 µM citalopram both on the RU 24969 activity and on the evoked tritium overflow. 6. RU 24969 (0.001–0.1 µM) decreased in a concentration-dependent way the release of tritium from cortical synaptosomes depolarized with K+ (15–20 mM). The presence of 1 µM citalopram did not modify significantly the effect of the agonist. Citalopram was ineffective also when the serotonin uptake carrier in superfused synaptosomes was activated by tryptamine. In conclusion, in slices of rat cerebral cortex, the action of exogenous 5-HT autoreceptor agonists is inhibited by 5-HT uptake blockers independently of the depolarizing agent (electrical stimulation or high-K+) used to elicit 3H-5-HT release. Increasing K+-concentration, which probably increases serotonin in the biophase, mimics the presence of the reuptake inhibitor. These data together with the finding that, in superfused synaptosomes, 5-HT uptake inhibition did not affect the potency of autoreceptor agonists, favours the idea that, in cerebral cortex slices, inhibitors of 5-HT reuptake prevent activation of autoreceptors by exogenous agonists by increasing the concentration of 5-HT in the autoreceptor biophase.