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Modelling shape memory alloys is based on choosing state quantities Ewhich involve the phase volume fractions, on defining the free energy $\Psi(E)$and the pseudo-potential of dissipation $\Phi(E,dE/dt,grad\,T)$depending on the thermal heterogeneity characterised by the temperature gradient $grad\,T$. The derivatives of Ψand Φgive the constitutive laws which are used in the momentum and energy conservation laws. It results a set of partial differential equations: we call it the model. It allows to predict the evolution of the state quantities in a structure made of shape memory alloys. It is of paramount importance to measure the physical parameters of the constitutive laws and to prove that the partial differential equations are coherent and have solutions. Thus modelling involves experiments, theory, and mechanics, engineering and mathematics.

A description of the nanocrystallization process of the amorphous Fe73.5Cu1Nb3Si13.5B9alloy as deduced by a study of the anelastic and magnetoelastic behavior is reported. ΔE effect measurements were performed on the as-prepared alloy and on samples previously submitted to heating treatments in furnace at selected temperatures. The results were coupled to internal friction and dynamic Young's modulus vs. temperature measurements performed both in saturating magnetic field and in zero field. Different stages of the structural evolution towards the final crystalline state have been distinguished and their strict relationship with the observed changes in the magnetoelastic response has been pointed out. In particular a strong ΔE effect was observed in samples annealed at temperatures very close to the one at which the crystallization process starts.

The elastic energy dissipation coefficient and dynamic elasticity modulus were measured in the 3-4000 Hz frequency range by an inverted torsion pendulum and a vibrating reed technique on nanocrystalline aluminium samples obtained by mechanical attrition. The anelasticity spectra in the 300-700 K range on as-prepared samples with average grain size in the 20-40 nm range strongly depends on low temperature annealing treatments. A relaxational damping peak P1 at 460 K (3Hz) is observed in samples after thermal annealing without appreciable grain growth. A second peak P2 located at higher temperatures occurs when the grain size exceeds 100 nm.

the YBa2Cu3O6+x, system exhibits internal friction peaks above room temperature. These peaks are thermally activated. When the system is fully oxygenated (x=l), one peak only is detected. At a lower oxygen content, x<0.8, this peak change in shape and position and a new one can be contemporarily detected. These peaks are reasonably linked with the crystal phases of the system. We present a sequence of measures taken on the same sample, where the evolution of these peaks is shown.

Mechanical spectroscopy, room temperature Mössbauer spectroscopy and magnetisation measurements have been employed to get insight into the structural relaxation process of the grain boundaries in 10 nm-grain sized iron powders produced by ball milling. In particular, by performing the Mössbauer analysis on milled powders previously subjected to proper thermal treatments in the 570-670 K range, the structural evolution of the grain boundaries has been followed through the changes int the hyperfine magnetic field distribution associated to the interfacial region. The results are consistent with a decrease of the magnetic moment of the atoms at the interface, following the relaxation process.

Measurements of the elastic energy dissipation coefficient and of the dynamic Young's modulus were performed on polycrystalline YBa2Cu3O7-xby the vibrating reed technique and torsional pendulum, in the frequency range 1-5000 Hz. The stoichiometry of the samples was varied in the range x = 0.02 - 0.7. From the isothermal modulus measurements a strong softening stage characterizing the onset of the ortho-tetragonal transformation was observed. The long time isotherms give an activation energy of 0.9 = 0.1 eV. Two relaxational damping peaks have been observed and attributed to the short range oxygen dynamics in the well oxygenated and oxygen deficient superconducting phases. On the basis of these results models for the structural transformation linked to oxygen out diffusion and for the oxygen dynamics in different stoichiometric conditions are discussed.

This work describes the anelastic behaviour of human dentin in the temperature range from 100 K to 673 K. Human molars, extracted from individuals (males 55-70 years old) as part of their dental treatment, were cut to obtain bar-shaped samples for mechanical spectroscopy (MS) experiments. The results are presented and discussed in two parts referring to experiments above and below room temperature.

Endothelial progenitor cells (EPCs) have recently been employed in cell-based therapy (CBT) to promote neovascularization and regeneration of ischemic organs, such as heart and limbs. Furthermore, EPCs may be recruited from bone marrow by growing tumors to drive the angiogenic switch through physical engrafting into the lumen of nascent vessels or paracrine release of pro-angiogenic factors. CBT is hampered by the paucity of EPCs harvested from peripheral blood and suffered from several pitfalls, including the differentiation outcome of transplanted cells and low percentage of engrafted cells. Therefore, CBT will benefit from a better understanding of the signal transduction pathway(s) which govern(s) EPC homing, proliferation and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to combat tumoral neovascularization. We have recently found that storeoperated Ca2 entry, a Ca2-permeable membrane pathway that is activated upon depletion of the inositol-1,4,5-trisphosphate-sensitive Ca2 pool, is recruited by vascular endothelial growth factor to support proliferation and tubulogenesis in human circulating endothelial colony forming cells (ECFCs). ECFCs are a subgroup of EPCs that circulate in the peripheral blood of adult individuals and are able to proliferate and differentiate into endothelial cells and form capillary networks in vitro and contribute to neovessel formation in vivo. The present review will discuss the relevance of SOCE to ECFC-based cell therapy and will address the pharmacological inhibition of storedependent Ca2+ channels as a promising target for anti-angiogenic treatments.

The work describes the anelastic behaviour of human dentin below room temperature. Human molars, extracted from individuals as part of their dental treatment, were cut to obtain bar-shaped samples for mechanical spectroscopy (MS) experiments. Repeated cooling-heating cycles in the range 300-100 K have been carried out on the same samples. In the cooling stage of the first cycle Q-1 exhibits a very broad maximum due to a series of phase transformations involving water present in the pores, in the interstices between fibres, between fibrils and inside collagen triple helix. The formation of ice Ih produces permanent damages to the dentin structure (rupture of fibres and fibrils) leading to a decrease of maximum intensity in the following cycles. In the heating stage of all the cycles two maxima, M1 and M2, have been observed around 155 K and 178 K. M1 is due to the transformation of low-density amorphous (LDA) ice into ice IC while M2 to that of ice IC to ice Ih. Above 200 K, Q-1 progressively increases with lower damping values in the cycles after the first one. Dehydrated samples do not exhibit the aforesaid anelastic phenomena confirming that their origin is connected to water and its transformations.

The magnetization state of ball-milled nanocrystalline Fe particles is studied by electron holography. The flux lines of the stray field leaking out from free magnetic poles in the particles are visualized in a wide temperature range. The variations of the exchange length, brought about by temperature changes, are discussed taking into account the random anisotropy model, microstructural characterization data and the known magnetic properties. A correlation between the intensity of the stray field and the value of the exchange length is observed. We suggest that a transition between two different kinds of magnetization patterns takes place depending on the ratio between exchange length and particle size.

Abstract: Nanocrystalline aluminum and nickel were prepared by mechanical attrition in a planetary ball-milling apparatus working under a 10−4 Pa vacuum in the 150–300 K range. A detailed investigation of the mechanical behavior in the anelastic regime was accomplished by employing different mechanical spectroscopy apparatuses in the 0.01–103 Hz range. Measurements of the elastic energy dissipation coefficient and of the dynamic elasticity modulus as a function of temperature and frequency have shown an enhanced damping at low temperatures and an anelastic relaxation peak tentatively assigned to the short range dynamics at the interfaces. Moreover the magnetic field dependence of the dynamic elastic modulus in nickel revealed a strict correlation between the microstrains confined at the interfaces and the magnitude of the magnetoelastic coupling.

Pure iron and aluminium powders and a mixture of composition Fe75Al25 were treated mechanically in a high-energy mill for up to 40 h. X-ray diffraction and analytical transmission electron microscopy were coupled to elastic energy dissipation and dynamic Young's modulus measurements to study the structural transformation of the specimens induced by the mechanical treatment. A quantitative comparison between the structural behaviour of the pure elements and of the mixture was carried out. The role of the parameters such as the composition, the grain size and the activation energy during the process was examined in relation to the competing mechanisms of plastic deformation and recovery.

Single crystals or macrocrystalline sheets of 99.6% pure Al showQ−1instabilities in the temperature range of the Kê peak. Slight deformations of these specimens cause the Kê peak to appear. The possibility is considered that the Kê peak depends on free or polygonized dislocations inside the grains. Campioni mono e macrocristallini di Al (purezza 99.6%) mostrano instabilità nel coefficiente di dissipazione interna, nell'intervallo di temperatura del picco di Kê. Piccole deformazioni di questi campioni provocano la comparsa del picco di Kê. Si considera la possibilità che il picco di Kê dipenda da dislocazioni libere o poligonizzate all'interno dei grani.

Ge specimens having prevalence of screw dislocations introduced at 600 °C and at 350 °C show two specificQ−1peaks. These peaks are interpreted as an intrinsic screw dislocation effect: the corresponding activation energies are nearly one-half those for kink pair generation. Screw dislocations have no effect on the low-temperature Mecs peak, which is present also in nondeformed specimens. Campioni di Ge con prevalenza di dislocazioni a vite introdotte a 600 °C e 350 °C mostrano due picchi specifici di dissipazione interna. Si interpretano questi picchi sulla base di un effetto intrinseco delle dislocazioni a vite. Le energie di attivazione relative sono circa la metà di quelle corrispondenti alla generazione di coppie di «kinks». Le dislocazioni a vite non hanno effetto sul picco a bassa temperatura di Mecs, che è presente anche nei campioni non deformati.

AbstractThe microstructural evolution from the amorphous to nanocrystalline phase in the Fe73·5Cu1Nb3Si13·5B9alloy produced by planar flow casting was studied by performing Young's modulus, internal friction and initial susceptibility measurements against temperature on as-cast ribbons and on samples submitted to selected furnace heating treatments. Moreover, the room-temperature magnetoelastic behaviour in the as-prepared ribbons and in samples annealed in the 570–850 K range was investigated through the analysis of the ΛEeffect. The results indicate that a structural relaxation process of the amorphous phase occurs starting from 450-500 K. In particular, a strong magnetoelastic response observed in samples annealed in the 710–745 K range, namely at temperatures very close to the nanocrystallization temperature (760–770 K), suggests an increase in the saturation magnetostriction with respect to the as-cast alloy, connected with atomic rearrangements causing a compositional fluctuation in the amorphous phase.

The novel antidepressant moclobemide is a reversible inhibitor of monoamine oxidase (MAO), preferentially of type A. Moclomide was active in three animal models considered predictive for antidepressant activity: 1) it prevented dose-dependently akinesia and blepharospasm induced in mice and rats by Ro 4-1284, a short-acting amine releasing agent. Prevention of akinesia by moclobemide also depended upon the dose of Ro 4-1284. For comparison also, effects of cimoxatone, harmaline, tranylcypromine and clorgyline are presented: 2) in cats, it selectively and dose-dependently suppressed rapid eye movement sleep without disturbing the sleep-wakefulness cycle; and 3) in the behavioral despair test in mice, it decreased the immobility score to a similar degree as amitriptyline or imipramine. In addition, moclobemide potentiated 5-hydroxytryptophan-induced stereotypies in rats with a potency similar to cimoxatone and with a duration of action of less than 24 hr. Moclobemide had almost no effect on the spontaneous behavior in mice, rats, cats and monkeys. Only in higher doses, marginal sedation and slight impairment in motor performance were seen. Moclobemide did not prevent pilcarpine-induced salivation in mice, demonstrating the absence of anticholinergic activity. Blood pressure and heart rate of freely moving, spontaneously hypertensive rats were only slightly decreased for less than 3 hr. Moclobemide moderately potentiated the pressor effect of p.o. tyramine in rats. In conclusion, the reversible MAO inhibitor moclobemide is active in animal models sensitive to all major drugs used in the treatment of depression. In contrast to imipramine-like antidepressants, it lacks anticholinergic activity and it differs from classic MAO inhibitors by potentiating only weakly the pressor effect of p.o. tyramine.

The amount of amanitine able to cause the specific nuclear lesions in mouse hepatocytes is 10 times lower when amanitine is administered conjugated to albumin instead of being injected as free toxin.

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.

Agonists at the benzodiazepine receptor (BZR) produce their effects through potentiation of the inhibitory alpha-aminobutyric acid-mediated neurotransmission in the central nervous system via positive allosteric modulation of the gamma-aminobutyric acidA receptor. Agonists with high intrinsic efficacy are anticonvulsant, anxiolytic, muscle relaxant and sedative, whereas agonists with low intrinsic efficacy (partial agonists) are predominantly anticonvulsant and anxiolytic, but antagonize muscle relaxant and sedative effects of full agonists. The four BZR ligands triazolam, diazepam, Ro 19-8022 (a benzoquinolizinone) and bretazenil (Ro 16-6028, an imidazobenzodiazepinone) were pharmacologically characterized in various neurological and behavioral paradigms in mice: two anticonvulsant tests (prevention of audiogenic and pentylenetetrazol-induced seizures), a conflict test which reveals both anxiolytic and sedative properties and two tests which mainly measure motor impairment (rotarod and horizontal wire test). Although triazolam and diazepam elicited an effect in all tests, Ro 19-8022 and bretazenil exhibited anticonvulsant and anxiolytic properties, but virtually failed to induce motor impairment and severe sedation. In separate experiments, fractional BZR occupancy in vivo was assessed by inhibition of [3H]flumazenil binding and correlated with the pharmacological effects. Although diazepam and triazolam produced effects beginning at low to intermediate fractional BZR occupancy, Ro 19-8022 and bretazenil required a higher BZR occupancy to do so, in accordance with their partial agonistic character. With the two full agonists, anticonvulsant and anticonflict activities were elicited at a lower fractional BZR occupancy than muscle relaxant and sedative effects.(ABSTRACT TRUNCATED AT 250 WORDS)

The microstructural evolution during mechanical alloying of Ti and Al powders has been investigated by X-ray diffraction, scanning electron microscopy (SEM)–energy dispersive spectroscopy, and transmission electron microscopy (TEM). Observations by SEM showed a progressive change of the powders’ morphology as a function of milling time. Observations by TEM, performed on a sample milled for 20 h, revealed the simultaneous occurrence of amorphous zones and nanocrystalline domains. The observed amorphous phase is not the final milling product. After 34 h of milling it was possible to identify by TEM fcc (a=0·41 nm) nanocrystalline zones, with a mean size of about 10 nm. By irradiating the powder milled for 20 h with high density electron beams, a sudden in situcrystallisation took place. The crystallite (fcc with a=0·41 nm) size was between 0·1 and 0·5 µm.MST/1281

Ge specimens with either twist or tilt boundaries have been obtained by thermal treatments of polygonization, following the introduction of either screw or edge character dislocations. It was thus possible to follow separately the formation kinetics of the boundaries of one type or the other. Tilt and twist boundaries form in comparable times. The phenomenon has been related to the presence of dissociated dislocations of the «glide set». A seguito dell’introduzione di dislocazioni a vite o di taglio sono stati ottenuti, mediante trattamenti termici di poligonizzazione, campioni di Ge con giunti di torsione o di piegamento. È stato quindi possibile seguire separatamente le cinetiche di formazione dei giunti dell’uno e dell’altro tipo. Giunti di piegamento e di torsione si formano in tempi comparabili, probabilmente perché sono presenti dislocazioni dissociate del «glide set». Были получены образцы Ge с наклонными или скрученными границами с помощью тепловой обработки полигонизации, следуя введению дислокаций, имеющих либо винтовой либо краевой характер. При этом возможно проследить образование границ одного или другого типа. Наклонные и скрученные границы образуются за сравнимые времена. Рассмотренное явление связано с наличием диссоциативных дислокаций «скользящей системы».

Rats were fed a 5 or 20% casein diet that causes liver necrosis unless supplemented with vitamin E or selenite. The following activities were studied in liver subcellular fractions: enzymic formation of lipid peroxides, NADPH-cytochrome creductase, oxidative demethylation of aminopyrine, and incorporation of [14C]leucine into protein (with microsomes); xanthine oxidase (with soluble supernatant); and RNA polymerases I and II (with nuclei). Formation of lipid peroxides was higher in rats fed diets without vitamin E and was not reduced significantly by dietary selenite. The activity of xanthine oxidase was higher in animals fed the 20% casein than in those fed the 5% casein diet; however, a higher activity was observed in the rats fed the latter diet without vitamin E or selenite than in those receiving these supplements. The activity of RNA polymerase I was higher in rats fed the low casein diet. Other activities examined were not affected significantly by the level of dietary casein or by vitamin E or selenite.

Idiopathic recurring stupor (IRS) is a disease of unknown pathogenesis presenting with recurrent stuporous states. We describe three IRS patients in whom there were no metabolic, toxic, or structural brain dysfunctions. Ictal EEGs were characterized by fast (14- to 16-Hz), unreactive background activity. Flumazenil, a benzodiazepine receptor antagonist, promptly resolved the clinical and EEG picture. In all patients, ictal plasma determination showed a marked increase in benzodiazepine-like activity identified as endozepine-4. IRS may be due to an unexplained excess of endozepine-4.

Rats treated with ricin, an inhibitor of protein synthesis, at the dose of 1 μg/100 g body weight, developed within 72 hours a severe liver necrosis. Protein synthesis was practically unchanged. The ultrastructural changes that ricin induces in rat liver were investigated. The earliest changes were observed in sinusoidal cells which were progressively damaged until they became necrotic. Only after the development of these lesions hepatocytes appeared to be damaged. The hypothesis is formulated that hepatocyte necrosis is a consequence of the disappearance of sinusoidal cells. This might explain why protein synthesis was unaffected in liver: since ricin exerted its toxic effect on the sinusoidal cells the inhibition was not detectable, these cells being “diluted” by the mass of parenchymal cells. Ricin at the dose of 10 μg/100 g body weight did not affect protein synthesis in the liver, but exerted a marked and precocious inhibition of protein synthesis in the spleen, which is very rich in reticuloendothelial cells. Moreover, a severe necrosis of the red pulp of the spleen was observed in rats poisoned with this dose of ricin.

The administration of an amanitin-albumin conjugate produces lesions typical of α-amanitin in the cells of the proximal convoluted tubules of rat kidney which are not damaged by the free toxin. Since the cells of the proximal convoluted tubules of rat kidney take up protein by pinocytosis, this finding indicates that these cells are susceptible to the action of amanitin but that the toxin is unable to penetrate into them unless it is coupled to albumin and so forced to enter by pinocytosis.

1. Modeccin, the toxin of Adenia digitata (Modecca digitata), was purified from the roots of this plant by affinity chromatography on Sepharose 4B. 2. This toxin is a protein with mol.wt. 57000, which on treatment with 2-mercaptoethanol can be dissociated into two subunits of mol.wts. 25000 and 32000. 3. Modeccin inhibits protein synthesis in vitro in a lysate of rabbit reticulocytes and in Ehrlich ascites cells; the effect on cells is decreased in the presence of lactose. 4. Dissociation of modeccin into subunits decreases the toxicity to animals and the inhibition of protein synthesis in cells, but enhances the inhibition of protein synthesis in the lysate system.

Some experimental results obtained on metallic glasses of different compositions by means of internal friction and dynamic Young's modulus measurements, carried out between room temperature and the glass-transition temperature, are reported and discussed qualitatively. The results are examined with particular reference to structural relaxation phenomena and plastic deformation, paying particular attention to the specific role of the free volume and internal-stress distribution in determining the anelastic spectra.

Elastic energy dissipation coefficient and dynamic elasticity moduli measurements have been performed by a vibrating reed technique on nanocrystalline aluminium prepared by mechanical attrition through ball milling and cold consolidation. Thermal analysis of the aluminium powders was made with differential scanning calorimetry (DSC). A strong dependence of the anelastic parameters and of the DSC spectra on the sample grain sizes was experienced. A maximum in the stored enthalpy occurs at grain sizes of 25-30 nm. An anomalous modulus behaviour in the 40-600 K region depending on grain size with a corresponding small exotherm in the DSC spectra are observed and attributed to structural relaxation in the nanophase. Anelastic relaxation with an activation energy of about 0.8 eV occurs before extensive grain growth set-up.

Mechanical spectroscopy of a quasi-static or dynamic type has been employed to study some aspects of structural stability in amorphous metals. Experimental results were obtained by internal friction and stress relaxation measurements on various alloys, both on different metastable states and submitted to specific mechanical treatments. The mobility, interaction, generation and annihilation of structural defects are at the origin of the permanent and reversible microstructural transformation observed. Reversible ordering phenomena associated with shear-type defects, irreversible mechanically induced defect annihilation and a transition between different amorphous structures are reported.

Administration of sodium selenite reduced the severity of muscular dystrophy in rats fed Vit. E-free diets, with adequate or low protein content. The effect of selenite was more evident when dystrophic lesions were not severe. Selenite was without effect on muscular dystrophy in Vit. E-deficient guinea pigs.

The capacity to oxidize succinate was studied with liver mitochondria, homogenates or slices from rats maintained with commercial diets or with semipurified diets with or without addition of vitamin E or sodium selenite. A decline in the oxidation rate was observed with all systems in vitamin E-deficient, selenium-deficient animals, and in some instances in rats fed commercial diets. The decline was prevented by administration of large amounts of vitamin E. Dietary selenite prevented decline in mitochondria, but not in homogenates or slices. The significance of respiratory decline as a possible specific lesion of the latent phase of dietary liver necrosis is discussed.

1Rats were fed diets with 20 and 5% of crude or fat-extracted casein as protein source, with or without added methionine, cystine, vitamin E and Factor 3-active sodium selenite. The growth, mortality from hepatic necrosis and liver regeneration after partial hepatectomy were studied.2The adequate dietary protein level given by the 20% of casein, as well as dietary addition of sulfur amino acids did not afford complete protection against liver necrosis. Vitamin E or selenite protected completely when added in sufficient amount to either rations. It may be concluded that the mortality observed in rats fed the 20% casein diet is due to lack of Factor 3-active selenium in the casein used.3The mortality from liver necrosis was higher in male than in female rats. Seasonal variations in the incidence of necrosis were noted.4The regeneration of the liver was slightly impaired in rats fed the 5% casein diets as compared with those fed the 20% casein ones; it was not affected by dietary addition of methionine, cystine or vitamin E.

1. The activity of l-asparaginase was very low in the liver of newborn rats and mice, and increased within a few days of birth. 2. In rats, but not in mice, the enzyme activity was higher in females than in males, was enhanced by administration of oestradiol, and was decreased by gonadectomy. 3. The enzyme activity decreased in mice starved or fed on a low-protein diet; in rats it was enhanced by starvation, by feeding them on a high-protein diet, or by administration of l-asparagine. 4. The asparaginase activity was decreased in regenerating liver, and was almost absent in the Morris hepatoma 5123.

Benzodiazepines produce most, if not all, of their numerous effects on the central nervous system (CNS) primarily by increasing the function of those chemical synapses that use γ-amino butyric acid (GABA) as transmitter1,2. This specific enhancing effect on GABAergic synaptic inhibition is initiated by the interaction of benzodiazepines with membrane proteins of certain central neurones, to which drugs of this chemical class bind with high affinity and specificity3,4. The molecular processes triggered by the interaction of these drugs with central benzodiazepine receptors, and which result in facilitation of GABAergic transmission, are still incompletely understood. Theoretically, benzodiazepines could mimic the effect of hypothetical endogenous ligands for the benzodiazepine receptors, although there is no convincing evidence for their existence5; in vitro studies indicate that benzodiazepines might compete with a modulatory peptide which is present in the supramolecular assembly formed by GABA receptor, chloride ionophore and benzodiazepine receptor and which reduces the affinity of the GABA receptor for its physiological ligand6. The mechanisms of action of benzodiazepines at the molecular level are likely to be better understood following our recent discovery of benzodiazepine derivatives, whose unique pharmacological activity is to prevent or abolish in a highly selective manner at the receptor level all the characteristic centrally mediated effects of active benzodiazepines. Here, we describe the main properties of a representative of this novel class of specific benzodiazepine antagonists.

ABSTRACTMethicillin-resistant Staphylococcus aureus(MRSA) resistant to decolonization agents such as mupirocin and chlorhexidine increases the need for development of alternative decolonization molecules. The absence of reported severe adverse reactions and bacterial resistance to polyhexanide makes it an excellent choice as a topical antiseptic. In the present study, we evaluated the in vitroand in vivocapacity to generate strains with reduced polyhexanide susceptibility and cross-resistance with chlorhexidine and/or antibiotics currently used in clinic. Here we report the in vitroemergence of reduced susceptibility to polyhexanide by prolonged stepwise exposure to low concentrations in broth culture. Reduced susceptibility to polyhexanide was associated with genomic changes in the mprFand purRgenes and with concomitant decreased susceptibility to daptomycin and other cell wall-active antibiotics. However, the in vitroemergence of reduced susceptibility to polyhexanide did not result in cross-resistance to chlorhexidine. During in vivopolyhexanide clinical decolonization treatment, neither reduced polyhexanide susceptibility nor chlorhexidine cross-resistance was observed. Together, these observations suggest that polyhexanide could be used safely for decolonization of carriers of chlorhexidine-resistant S. aureusstrains; they also highlight the need for careful use of polyhexanide at low antiseptic concentrations.