Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase.

T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti-interleukin (IL)-6R (tocilizumab) immunoglobulin (Ig)G has been used as disease-modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL-6 on NMO-derived CD4(+) T cell behaviour. High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients. Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities. The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells. In contrast, the production of IL-10 was amplified in those cell cultures. Further, anti-IL-6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in-vivo and in-vitro IL-6 levels were significantly higher among those patients who experienced clinical relapse during 2-year follow-up. In summary, our results suggest a deleterious role of IL-6 in NMO by favouring, at least in part, the expansion of corticoid-resistant Th17 cells.

Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.

Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.

Data available on the extent of cocaine use and dependence: biochemistry, pharmacologic effects and global burden of disease of cocaine abusers.

Drug use is seen more as an individualistic behaviour and is therefore not readily conceived of from a population perspective. There is general recognition of several phases and degrees of drug abuse, from initiation and early-use patterns to long-term chronic use. Cocaine and its derivative "crack" cocaine provide an example of both the globalization of substance use and the cyclical nature of drug epidemics. Cocaine is a powerful CNS (Central Nervous System) stimulant but exerts its action in a several types of adverse health effects, including acute toxic effects (i.e. overdose, accidental injury and violence), dependence, cardiovascular disease, cirrhosis, bloodborne bacterial and viral infections, and mental disorders. Of interest, many people who use Cocaine will use also other drugs; therefore, ascribing adverse health effect to a certain drug might be difficult. Any mucous membrane can act as a port of entry for cocaine and the systemic effect is greatly influenced by the route and speed of administration. The effects of Cocaine mainly depend on the user's addiction, the dose received and the mode of assumption. Laws restricting the availability of cocaine saw a decrease in consumption in these countries until the 1960s. The number of cocaine users worldwide ranged from 14 million to 21 million (0.3-0.5% of the population aged 15-64 years). The largest market was North America, then western and central Europe and South America.

Compromised decision-making and increased gambling proneness following dietary serotonin depletion in rats.

Psycho-genetic studies have revealed a role for the brain serotonin system in gambling proneness and poor decision-making. We assessed whether manipulation of brain serotonin levels in rats affected performance in operant-based tasks for decision-making and gambling proneness. Male Wistar rats were exposed to an l-tryptophan (TRP) deficient diet (0.0 g/kg; T- group) or to a control, l-tryptophan containing diet (2.8 g/kg; T+ group). The same rats were tested for decision-making performance in the rodent Iowa Gambling Task (rIGT) using home-cage operant panels, and subsequently for gambling proneness in a Probabilistic Delivery Task (rPDT) using classic Skinnerboxes. At sacrifice, monoamines and metabolites were evaluated with HPLC analysis, confirming a drastically reduced serotonin synthesis, as well as altered dopamine turnover in the prefrontal cortex of T- rats. As expected, control rats (T+) progressively chose the option with the best long-term payoff in the rIGT, and also shifted from "Large & Luck-Linked" (LLL) to "Small & Sure" (SS) reinforcers in the rPDT. In contrast, depleted animals (T-) exhibited a weaker improvement of performance in the rIGT and maintained a sub-optimal attraction for LLL reinforcer in the rPDT. Comparing individual performances in both tests, we found a significant correlation between the two tasks in control (T+) but not in depleted (T-) rats. The present study revealed that (1) brain 5-HT depletion leads to poor decision-making and to gambling proneness; (2) the relationship between these two traits, shown in the control group, was disrupted in 5-HT depleted rats. The data are discussed in terms of changes within forebrain loops involved in cognitive and motivational/affective processes.

Short- and long-term consequences of prenatal exposure to the cannabinoid agonist WIN55,212-2 on rat glutamate transmission and cognitive functions.

The aim of the present review is to summarize integrated neurochemical, morphological and neurobehavioral evidence, in particular from our laboratory, which emphasize the short- and long-term consequences of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. The results obtained provide evidence that maternal exposure to WIN55,212-2 induces an impairment of cognitive capacities in the offspring. This impairment is associated with alterations of cortical and hippocampal glutamate outflow, cortical neuron morphology and hippocampal long-term potentiation. These findings are in line with clinical data showing that the consumption of marijuana by women during pregnancy has negative consequences on the cognitive functions of their children. Thus, although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of glutamate transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.

Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2.

Chronic use of levodopa, the most effective treatment for Parkinson's disease, causes abnormal involuntary movements named dyskinesias, which are linked to maladaptive changes in plasticity and disturbances of dopamine and glutamate neurotransmission in the basal ganglia. Dyskinesias can be modeled in rats with unilateral 6-hydroxydopamine lesions by repeated administration of low doses of levodopa (6 mg/kg, s.c.). Previous studies from our lab showed that sub-chronic treatment with the cannabinoid agonist WIN55,212-2 attenuates levodopa-induced dyskinesias at doses that do not interfere with physiological motor function. To investigate the neurochemical changes underlying WIN55,212-2 anti-dyskinetic effects, we used in vivo microdialysis to monitor extracellular dopamine and glutamate in the dorsal striatum of both the hemispheres of freely moving 6-hydroxydopamine-treated, SHAM-operated and intact rats receiving levodopa acutely or chronically (11 days), and studied how sub-chronic WIN55,212-2 (1 injection x 3 days, 20 min before levodopa) affected these neurochemical outputs. Our data indicate that: (1) the 6-hydroxydopamine lesion decreases dopamine turnover in the denervated striatum; (2) levodopa injection reduces extracellular glutamate in the side ipsilateral to the lesion of dyskinetic rats; (3) sub-chronic WIN55,212-2 prevents levodopa-induced glutamate volume transmission unbalances across the two hemispheres; and (4) levodopa-induced dyskinesias are inversely correlated with glutamate levels in the denervated striatum. These data indicate that the anti-dyskinetic properties of WIN55,212-2 are accompanied by changes of dopamine and glutamate outputs in the two brain hemispheres of 6-hydroxydopamine-treated rats.

TiO(2) nanorods/PMMA copolymer-based nanocomposites: highly homogeneous linear and nonlinear optical material.

Original nanocomposites have been obtained by direct incorporation of pre-synthesized oleic acid capped TiO(2) nanorods into properly functionalized poly(methyl methacrylate) copolymers, carrying carboxylic acid groups on the repeating polymer unit. The presence of carboxylic groups on the alkyl chain of the host functionalized copolymer allows an highly homogeneous dispersion of the nanorods in the organic matrix. The prepared TiO(2)/PMMA-co-MA nanocomposites show high optical transparency in the visible region, even at high TiO(2) nanorod content, and tunable linear refractive index depending on the nanoparticle concentration. Finally measurements of nonlinear optical properties of TiO(2) polymer nanocomposites demonstrate a negligible two-photon absorption and a negative value of nonlinear refractive index, highlighting the potential of the nanocomposite for efficient optical devices operating in the visible region.

Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures.

The effects of prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 (0.5 mg/kg s.c.), alone or in combination with carbon monoxide, on extracellular glutamate levels in primary rat cerebral cortical neuronal cultures, were investigated. Dam weight gain, pregnancy length and litter size at birth were not affected by prenatal treatment with WIN 55,212-2 and carbon monoxide alone or in combination. Basal and K(+)-evoked extracellular glutamate levels were reduced in cortical cultures from pups born to mothers exposed to WIN 55,212-2 and carbon monoxide alone or in combination compared to cultures from rats born to vehicle-treated mothers. In cultures obtained from rats exposed to vehicle or carbon monoxide alone during gestation, WIN 55,212-2 (0.01-100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. In cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide the WIN 55,212-2 ( 1 nM)-induced increase in extracellular glutamate levels was lower than that observed in cultures from rats born to vehicle-treated mothers and similar at those observed at 10 and 100 nM concentrations. The selective CB1 receptor antagonist SR141716A (10 nM) counteracted the WIN 55,212-2-induced increase in extracellular glutamate levels in cultures exposed to vehicle or carbon monoxide during gestation, but failed to antagonise it in cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide. These findings provide evidence that prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide, alone or in combination, is associated with an impairment in cortical glutamatergic transmission. It could be speculated that such detrimental effects might be involved in the reported deficit in learning and memory associated with prenatal marijuana exposure.

Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis.

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.

Antinutritional effects of fumonisin B1 and pathophysiological consequences.

Due to its structural similarity with sphingosine, fumonisin B(1) (FB(1)) inhibits ceramide synthase (a key enzyme of sphingolipid biosynthesis) leading to an intracellular accumulation of sphingoid bases with a consequent increase of sphinganine/sphingosine (SA/SO) ratio. In adult male rats, dietary exposure to fumonisin induces a significant increase in both SA concentrations and SA/SO ratio in kidney, but not in liver and brain, as well as a significant reduction of body weight gain. Regarding the brain, the developing rat is more sensitive to FB(1) than the adult rat. FB(1) treatment produces in the forebrain and brainstem: (i) an increase in SA levels and SA/SO ratio, (ii) a reduction in myelin deposition, and (iii) an impairment of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity. FB(1) effects on myelin are similar to those produced by starvation (temporary removal of pups from dam during postnatal period), thus suggesting that hypomyelination could be due, at least partly, to a nutritional deficiency. Finally, FB(1) reduces the uptake of folate in different cell lines. The resulting folate deficiency could explain the association of FB(1) exposure with neural tube defects.

High third-order nonlinear optical susceptibility in new fluorinated poly(p-phenylenevinylene) copolymers measured with the Z-scan technique.

The third-order nonlinear optical properties of a series of copoly(2, 3, 5, 6-tetrafluoro-1, 4-phenylenevinylene-2, 5-dioctyloxy-1, 4-phenylenevinylene) that contain variable ratios of two differently substituted monomers have been studied in chloroform solutions at l=1064 nm by the picosecond Z-scan technique. Nonlinear refractive index n(2) of the samples investigated has been found to be negative, and a strong dependence of its magnitude on the copolymer's composition has been observed. The highest third-order nonlinear optical susceptibility, |x((3))|=(6 +/- 2)x 10(-10) esu, was measured for a copolymer obtained by reaction of equimolar quantitites of the parent monomers.

Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate gamma-aminobutyric acid levels.

The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana.

[Helical CT without contrast media as alternative to other methods in urolithiasis]. / La Tc spirale senza mdc in alternativa alle altre metodiche nella urolitiasi.

PURPOSE: During the last five years the use of unenhanced helical CT (HTC) has been proposed as a preliminary diagnostic approach in patients with typical renal colics or with nonspecific flank pain. The aim of this study was to describe our experience in this field. MATERIAL AND METHODS: 130 consecutive patients (82 men and 48 women, with an average age of 54 years) were studied; 94 of them presented typical renal colics, while 36 presented acute flank pain. The parameters used were: 5-mm-thick sections, a pitch of 1.6, a reconstruction interscan spacing at 3 mm, an examination area extending from the kidneys to the base of the bladder. Depending on the case, examinations were carried out using urography in the instrumental or surgical pretreatment phase, ultrasonography to check urinary dilatation and juxtavesical calculi, pyeloMR, ureteroscopic extraction, surgical operation, extracorporeal lithotripsy, and finally the expulsion of the calculi was checked. RESULTS: 81 cases of urolithiasis, 6 cases of renal abnormalities and other renal pathologies, 23 cases of extraurinary pathologies correlated to the symptoms, 5 cases of extraurinary pathologies not correlated to the symptoms and 15 normal cases, were diagnosed. The results obtained were a) a sensitivity of 96.8%, a specificity of 98.4% and a diagnostic accuracy of 97.6% in identifying ureteral calculi; b) a diagnostic accuracy of 100% in identifying urinary tract dilatation; c) a sensitivity of 100% and a specificity of 96.7% in determining the level of obstruction; d) a sensitivity of 92.9% and a specificity of 100% in determining the cause of obstruction. CONCLUSIONS: Confirming the data in the medical literature, helical CT has yielded for more reliable results than the other procedures in identifying the following: calculi, acute obstruction of the urinary tract and other urinary and extraurinary pathologies correlated to the symptoms. Therefore helical CT, where available, must be accepted as the method of preliminary evaluation in all patients with typical renal colics or with nonspecific flank pain.

Effects of ENA713 and CHF2819, two anti-Alzheimer's disease drugs, on rat amino acid levels.

The effects of oral ENA713 and CHF2819 (0.5, 1.5 and 4.5 mg/kg), two novel acetylcholinesterase inhibitors, on extracellular concentrations of amino acids in rat hippocampus, were evaluated using in vivo microdialysis. ENA713, at 4.5 mg/kg, but not CHF2819, significantly decreased glutamate, taurine, arginine and citrulline levels, without affecting aspartate concentrations. These results suggest that the modulation of amino acidergic transmission could represent an additional mechanism of action in Alzheimer's disease for some acetylcholinesterase inhibitors.

Biochemical and neurobehavioral profile of CHF2819, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease.

1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo¿2,3-bindol-5-ol 2-ethylphenylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, and 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals, which show a significant decrease in basal acetylcholine levels with respect to young adult rats, also exhibit a marked increase in the hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine levels and a significant elevation of extracellular concentrations of 5-hydroxytryptamine, whereas it does not modify norepinephrine and gamma-aminobutyric acid levels in the hippocampus of young adult rats. Functional observational battery screening demonstrates that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological end points (body weight and temperature). However, this compound induces involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. These findings suggest that the anti-amnestic properties of CHF2819, together with its stimulatory effect on cholinergic and serotonergic functions, might have a therapeutic potential mainly for the symptomatic treatment of Alzheimer's disease patients in which the cognitive impairment is accompanied by a depressive syndrome.

Prenatal exposure to low concentrations of carbon monoxide alters habituation and non-spatial working memory in rat offspring.

Inhalation of low concentrations (75 and 150 ppm) of carbon monoxide (CO) by pregnant rats from days 0 to 20 of gestation leads to alterations in habituation and working memory in young adult male offspring subjected to the novel exploration object test. In particular, lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and the familiar object were found in CO (75 and 150 ppm)-exposed offspring. These alterations were not accompanied by changes in spontaneous motor activity (open field test). The subtle behavioral deficits observed in the present study have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin (HbCO) concentrations equivalent to those observed in human cigarette smokers.

Effects of early postnatal exposure to low concentrations of carbon monoxide on cognitive functions in rats.

Male Wistar rats were exposed to 75 and 150 ppm of carbon monoxide (CO) from day 1 after birth until postnatal day 10 and their cognitive functions were evaluated at 3 and 18 months of age. The results show that early postnatal exposure to CO does not affect the acquisition and reacquisition of an active avoidance task in both adult and aged rats. Conversely, our previous findings indicate that prenatal exposure to CO (75 and 150 ppm), resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those found in human cigarette smokers, induces long-lasting learning and memory deficits. These findings suggest that neurofunctional sequelae of prenatal CO exposure are notably different from those occurring in response to early postnatal exposure and that the vulnerability of the developing brain to prolonged, relatively mild, decrease in oxygen availability induced by CO critically depends on the particular period of developmental exposure.

Effects of prenatal exposure to low concentrations of carbon monoxide on sexual behaviour and mesolimbic dopaminergic function in rat offspring.

1. Inhalation of low concentrations of carbon monoxide (CO) by pregnant rats (75 and 150 p.p.m. from day 0 to day 20 of gestation) leads to changes in mesolimbic dopaminergic transmission associated with an impairment of sexual behaviour in male offspring. 2. Eighty day old males exposed in utero to CO (150 p.p.m.) exhibited a significant increase in mount/ intromission latency as well as a significant decrease in mount/intromission frequency. A significant decrease in ejaculation frequency was also found in CO (150 p.p.m.)-exposed animals. 3. The acute administration of amphetamine, at a dose (0.5 mg kg(-1) s.c.) stimulating copulatory activity in control rats, failed to reduce mount/intromission latency and did not increase mount frequency in 80-day offspring exposed to CO (150 p.p.m.) during gestation. 4. These behavioural alterations were paralleled by neurochemical changes (in vivo microdialysis) showing that prenatal CO exposure, at concentrations (150 p.p.m.) that did not affect basal extracellular levels of dopamine in the nucleus accumbens, blunted the amphetamine (0.5 mg kg(-1) s.c.)-induced increase in dopamine release in 80-day old male rats. 5. No significant changes in either behavioural or neurochemical parameters were observed in 10-month old rats exposed prenatally to CO. 6. Since the alterations in sexual behaviour and dopaminergic transmission have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those maintained by human cigarette smokers, the present data further point out the large risk that the smoking mother poses for her offspring.

[Prognostic factors of local recurrence after conservative surgery in breast carcinoma. Our experience]. / Fattori prognostici della recidiva locale dopo chirurgia conservativa per carcinoma della mammella. Nostra esperienza.

One of the most important problems linked to the conservative surgery of breast cancer consists of local recurrences (LR), even if it has now been proven that the appearance of LR has no influence on overall survival of the patients operated for breast cancer. We have considered 108 patients suffering from breast cancer and treated with quadrantectomy plus axillary dissection. In these patients were found 4 LR (3.7%), that in two cases appeared in the residual mammary gland and in other two cases were found on the skin scar. The mean time of occurrence of the LR was of 43 month (range 18-90 month). The authors have correlated the appearance of LR with some characteristics of the tumor, as the pT, the histologic type, the histologic Grading, the estrogen receptor status and the extensive intraductal component of the tumor (EIC). No particular correlations were found between the pT, histologic type, histologic Grading, estrogen receptor status of the tumor and the onset of LR. Instead a significant correlation was found between the LR appearance and the EIC of the tumor. In fact, for the tumors with a rich EIC there was found a 11.5% incidence of LR against a 1.2% impact of LR for the tumors with a low EIC. The authors conclude that is impossible now to assert that exist really some prognostic factor but is most important to note that there are many data in the literature that seems ever more to point at the rich EIC of the tumor as an important prognostic factor of LR.