Showing papers by "University of Cagliari published in 2001"

Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein

Abstract: Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of ∼2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed “SOST.” Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot–containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

Abstract: In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

An anorexic lipid mediator regulated by feeding

Abstract: Oleylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide. Like anandamide, OEA is produced in cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis, suggesting a function in cellular signalling. However, OEA does not activate cannabinoid receptors and its biological functions are still unknown. Here we show that, in rats, food deprivation markedly reduces OEA biosynthesis in the small intestine. Administration of OEA causes a potent and persistent decrease in food intake and gain in body mass. This anorexic effect is behaviourally selective and is associated with the discrete activation of brain regions (the paraventricular hypothalamic nucleus and the nucleus of the solitary tract) involved in the control of satiety. OEA does not affect food intake when injected into the brain ventricles, and its anorexic actions are prevented when peripheral sensory fibres are removed by treatment with capsaicin. These results indicate that OEA is a lipid mediator involved in the peripheral regulation of feeding.

Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan.

Abstract: The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders presenting in infancy with muscle weakness, contractures, and dystrophic changes on skeletal-muscle biopsy. Structural brain defects, with or without mental retardation, are additional features of several CMD syndromes. Approximately 40% of patients with CMD have a primary deficiency (MDC1A) of the laminin α2 chain of merosin (laminin-2) due to mutations in the LAMA2 gene. In addition, a secondary deficiency of laminin α2 is apparent in some CMD syndromes, including MDC1B, which is mapped to chromosome 1q42, and both muscle-eye-brain disease (MEB) and Fukuyama CMD (FCMD), two forms with severe brain involvement. The FCMD gene encodes a protein of unknown function, fukutin, though sequence analysis predicts it to be a phosphoryl-ligand transferase. Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13.3. We report the genomic organization of the FKRP gene and its pattern of tissue expression. Mutations in the FKRP gene have been identified in seven families with CMD characterized by disease onset in the first weeks of life and a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, and normal brain structure and function. Affected individuals had a secondary deficiency of laminin α2 expression. In addition, they had both a marked decrease in immunostaining of muscle α-dystroglycan and a reduction in its molecular weight on western blot analysis. We suggest these abnormalities of α-dystroglycan are caused by its defective glycosylation and are integral to the pathology seen in MDC1C.

Cocaine and Amphetamine Increase Extracellular Dopamine in the Nucleus Accumbens of Mice Lacking the Dopamine Transporter Gene

Abstract: Behavioral and biochemical studies suggest that dopamine (DA) plays a role in the reinforcing and addictive properties of drugs of abuse. Recently, this hypothesis has been challenged on the basis of the observation that, in mice genetically lacking the plasma membrane dopamine transporter [DAT-knock out (DAT-KO)], cocaine maintained its reinforcing properties of being self-administered and inducing place preference, despite the failure to increase extracellular dopamine in the dorsal striatum. Here we report that, in DAT-KO mice, cocaine and amphetamine increase dialysate dopamine in the medial part of the nucleus accumbens. Moreover, reboxetine, a specific blocker of the noradrenaline transporter, increased DA in the nucleus accumbens of DAT-KO but not of wild-type mice; in contrast, GBR 12909, a specific blocker of the dopamine transporter, increased dialysate dopamine in the nucleus accumbens of wild-type but not of DAT-KO mice. These observations provide an explanation for the persistence of cocaine reinforcement in DAT-KO mice and support the hypothesis of a primary role of nucleus accumbens dopamine in drug reinforcement.

Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection.

Abstract: Objectives To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self-reported symptoms or medication side effects are related to adherence. Design Cross-sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods Participants receiving HAART completed a 16-item self-administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV- and HAART-related symptoms experienced during the last 4 weeks. Results From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA Conclusions In addition to patient characteristics, medication-related variables, and reasons for nonadherence, patient-reported symptoms and medication side effects were significantly associated with adherence to HAART.

First-principles prediction of structure, energetics, formation enthalpy, elastic constants, polarization, and piezoelectric constants of AlN, GaN, and InN: Comparison of local and gradient-corrected density-functional theory

Abstract: A number of diverse bulk properties of the zinc-blende and wurtzite III-V nitrides AlN, GaN, and InN, are predicted from first principles within density-functional theory using the plane-wave ultrasoft pseudopotential method, within both the local density approximation (LDA) and generalized gradient approximation (GGA) to the exchange-correlation functional. Besides structure and cohesion, we study formation enthalpies (a key ingredient in predicting defect solubilities and surface stability), spontaneous polarizations and piezoelectric constants (central parameters for nanostructure modeling), and elastic constants. Our study bears out the relative merits of the two density-functional approaches in describing diverse properties of the III-V nitrides (and of the parent species ${\mathrm{N}}_{2},$ Al, Ga, and In). None of the two schemes gives entirely successful results. However, the GGA associated with the multiprojector ultrasoft pseudopotential method slightly outperforms the LDA overall as to lattice parameters, cohesive energies, and formation enthalpies of wurtzite nitrides. This is relevant to the study of properties such as polarization, vibrational frequencies, elastic constants, nonstochiometric substitution, and absorption. A major exception is the formation enthalpy of InN, which is underestimated by the GGA (\ensuremath{\sim}0 vs -0.2 eV).

p63 Gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation

Abstract: p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand–split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3′ splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.

High-temperature ultrafast polariton parametric amplification in semiconductor microcavities.

Abstract: Cavity polaritons, the elementary optical excitations of semiconductor microcavities, may be understood as a superposition of excitons and cavity photons1. Owing to their composite nature, these bosonic particles have a distinct optical response, at the same time very fast and highly nonlinear. Very efficient light amplification due to polariton–polariton parametric scattering has recently been reported in semiconductor microcavities at liquid-helium temperatures2,3,4,5,6,7,8,9,10,11. Here we demonstrate polariton parametric amplification up to 120 K in GaAlAs-based microcavities and up to 220 K in CdTe-based microcavities. We show that the cut-off temperature for the amplification is ultimately determined by the binding energy of the exciton. A 5-µm-thick planar microcavity can amplify a weak light pulse more than 5,000 times. The effective gain coefficient of an equivalent homogeneous medium would be 107 cm-1. The subpicosecond duration and high efficiency of the amplification could be exploited for high-repetition all-optical microscopic switches and amplifiers. 105 polaritons occupy the same quantum state during the amplification, realizing a dynamical condensate of strongly interacting bosons which can be studied at high temperature.

Nonlinear macroscopic polarization in III-V nitride alloys

Abstract: We study the dependence of macroscopic polarization on composition and strain in wurtzite III-V nitride ternary alloys using ab initio density-functional techniques. The spontaneous polarization is characterized by a large bowing, strongly dependent on the alloy microscopic structure. The bowing is due to the different response of the bulk binaries to hydrostatic pressure and to internal strain effects (bond alternation). Disorder effects are instead minor. Deviations from parabolicity (simple bowing) are of order 10% in the most extreme case of AlInN alloys, much less at all other compositions. Piezoelectric polarization is also strongly nonlinear. At variance with the spontaneous component, this behavior is independent of microscopic alloy structure or disorder effects, and due entirely to the nonlinear strain dependence of the bulk piezoelectric response. It is thus possible to predict the piezoelectric polarization for any alloy composition using the piezoelectricity of the parent binaries.

Optimal distributed generation allocation in MV distribution networks

Abstract: The necessity for flexible electric systems, changing regulatory and economic scenarios, energy savings and environmental impact are providing impetus to the development of distributed generation (DG), which is predicted to play an increasing role in the electric power system of the future. With so much new distributed generation being installed, it is critical that the power system impacts be assessed accurately so that DG can be applied in a manner that avoids causing degradation of power quality, reliability and control of the utility system. For these reasons, the paper proposes a new software procedure, based on a genetic algorithm, capable of establishing the optimal distributed generation allocation on an existing MV distribution network, considering all the technical constraints, like feeder capacity limits, feeder voltage profile and three-phase short circuit current in the network nodes.

Agent-based simulation of a financial market

Abstract: This paper introduces an agent-based artificial financial market in which heterogeneous agents trade one single asset through a realistic trading mechanism for price formation. Agents are initially endowed with a finite amount of cash and a given finite portfolio of assets. There is no money-creation process; the total available cash is conserved in time. In each period, agents make random buy and sell decisions that are constrained by available resources, subject to clustering, and dependent on the volatility of previous periods. The model proposed herein is able to reproduce the leptokurtic shape of the probability density of log price returns and the clustering of volatility. Implemented using extreme programming and object-oriented technology, the simulator is a flexible computational experimental facility that can find applications in both academic and industrial research projects.

Stress and neuroactive steroids.

Abstract: The discovery that the endogenous steroid derivatives 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, or 3 alpha,5 alpha-TH PROG) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, or 3 alpha,5 alpha-TH DOC) elicit marked anxiolytic and anti-stress effects and selectively facilitate gamma-aminobutyric acid (GABA)-mediated neurotransmission in the central nervous system (see Chapter 3) has provided new perspectives for our understanding of the physiology and neurobiology of stress and anxiety. Evidence indicating that various stressful conditions that downregulate GABAergic transmission and induce anxiety-like states (Biggio et al., 1990) also induce marked increases in the plasma and brain concentrations of these neuroactive steroids (Biggio et al., 1996, 2000) has led to the view that stress, neurosteroids, and the function of GABAA receptors are intimately related. Changes in the brain concentrations of neurosteroids may play an important role in the modulation of emotional state as well as in the homeostatic mechanisms that counteract the neuronal overexcitation elicited by acute stress. Indeed, neurosteroids not only interact directly with GABAA receptors but also regulate the expression of genes that encode subunits of this receptor complex. This chapter summarizes observations from our laboratories and others, suggesting that neurosteroids and GABAergic transmission are important contributors to the changes in emotional state induced by environmental stress.

Methods for Designing Multiple Classifier Systems

Abstract: In the field of pattern recognition, multiple classifier systems based on the combination of outputs of a set of different classifiers have been proposed as a method for the development of high performance classification systems. In this paper, the problem of design of multiple classifier system is discussed. Six design methods based on the so-called "overproduce and choose" paradigm are described and compared by experiments. Although these design methods exhibited some interesting features, they do not guarantee to design the optimal multiple classifier system for the classification task at hand. Accordingly, the main conclusion of this paper is that the problem of the optimal MCS design still remains open.

An approach to the automatic design of multiple classifier systems

Abstract: Multiple classifier systems (MCSs) based on the combination of outputs of a set of different classifiers have been proposed in the field of pattern recognition as a method for the development of high performance classification systems. Previous work clearly showed that multiple classifier systems are effective only if the classifiers forming them are accurate and make different errors. Therefore, the fundamental need for methods aimed to design “accurate and diverse” classifiers is currently acknowledged. In this paper, an approach to the automatic design of multiple classifier systems is proposed. Given an initial large set of classifiers, our approach is aimed at selecting the subset made up of the most accurate and diverse classifiers. A proof of the optimality of the proposed design approach is given. Reported results on the classification of multisensor remote sensing images show that this approach allows the design of effective multiple classifier systems.

BIHARMONIC SUBMANIFOLDS OF ${\mathbb S}^3$

Abstract: We explicitly classify the nonharmonic biharmonic submanifolds of the unit three-dimensional sphere ${\mathbb S}^3$.

Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity.

Abstract: Interleukin-10 (IL-10) has been shown to reduce neuronal degeneration after CNS injury. However, the molecular mechanisms underlying the neuroprotective properties of this cytokine are still under investigation. Glutamate exacerbates secondary injury caused by trauma. Thus, we examined whether IL-10 prevents glutamate-mediated cell death. We used rat cerebellar granule cells in culture because these neurons undergo apoptosis upon exposure to toxic concentrations of glutamate (100-500 microm) or NMDA (300 microm). Pretreatment of cerebellar granule cells with IL-10 (1-50 ng/ml) elicited a dose- and time-dependent reduction of glutamate-induced excitotoxicity. Most importantly, IL-10 reduced the number of apoptotic cells when added to the cultures together or 1 hr after glutamate. Using patch-clamping and fluorescence Ca(2+) imaging techniques, we examined whether IL-10 prevents glutamate toxicity by blocking the function of NMDA channel. IL-10 failed to affect NMDA channel properties and to reduce NMDA-mediated rise in intracellular Ca(2+). Thus, this cytokine appears to prevent glutamate toxicity by a mechanism unrelated to a blockade of NMDA receptor function. Various proteases, such as caspase-3, and transcription factors, such as nuclear factor kappaB (NF-kappaB), have been proposed to participate in glutamate-mediated apoptosis. Thus, we examined whether IL-10 modulates the activity of these apoptotic markers. IL-10 blocked both the glutamate-mediated induction of caspase-3 as well as NF-kappaB DNA binding activity, suggesting that the neuroprotective properties of IL-10 may rely on its ability to block the activity of proapoptotic proteins.

Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex.

Abstract: The aim of this study was to determine whether extracellular dopamine (DA) in the prefrontal cortex (PFC) might originate other than from DA neurons, also from noradrenergic (NA) ones To this aim, we compared the levels of DA and NA in the dialysates from the PFC, a cortical area innervated by NA and DA neurons, and cortices that receive NA but minor or no DA projections such as the primary motor, the occipital-retrosplenial, and the cerebellar cortex Moreover, the effect of alpha(2)-ligands and D(2)-ligands that distinctly modify NA and DA neuronal activity on extracellular NA and DA in these areas was studied Extracellular NA concentrations were found to be similar in the different cortices, as expected from the homogeneous NA innervation, however, unexpectedly, also DA concentrations in the PFC were not significantly different from those in the other cortices The alpha(2)-adrenoceptor agonist clonidine, intraperitoneally (ip) injected or locally perfused into the PFC, reduced not only extracellular NA levels, as expected from its ability to inhibit NA neuron activity, but also markedly reduced extracellular DA levels Conversely, the alpha(2)-adrenoceptor antagonist idazoxan, ip injected or locally perfused into the PFC, not only increased extracellular NA levels, in line with its ability to activate NA neuron activity, but also increased those of DA Conversely, in contrast to its ability to inhibit DA neuronal activity, the D(2) receptor agonist quinpirole only modestly and transiently reduced extracellular DA levels, while gamma-butyrolactone failed to modify DA levels in the PFC; conversely, haloperidol, at variance from its ability to activate DA neurons, failed to significantly modify extracellular DA levels in the PFC Both haloperidol and quinpirole were totally ineffective after local perfusion into the PFC Systemically injected or locally perfused, clonidine and idazoxan also modified both DA and NA concentrations in dialysates from primary motor, occipital-retrosplenial and cerebellar cortices as observed in the PFC Finally, ip injected or locally perfused, clonidine reduced and idazoxan increased extracellular NA levels in the caudate nucleus, but neither alpha(2)-ligand significantly modified extracellular DA levels Our results suggest that extracellular DA in the PFC, as well as in the other cortices, may depend on NA rather than DA innervation and activity They suggest that dialysate DA reflects the amine released from NA neurons as well, where DA acts not only as NA precursor but also as co-transmitter The co-release of NA and DA seems to be controlled by alpha(2)-receptors located on NA nerve terminals

Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats.

Abstract: Rationale: Δ9-Tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient of marijuana, as well as synthetic cannabinoid (CB1) receptor agonists, has led to negative or equivocal results when tested with the intravenous self-administration procedure, the best validated behavioural model for evaluating abuse liability of drugs in experimental animals. We recently reported, however, that the synthetic CB1 receptor agonist WIN 55,212-2 is intravenously self-administered by drug-naive mice and that its self-administration is blocked by the cannabinoid CB1 receptor antagonist SR 141716A. Objective: To assess a reliable model of cannabinoid intravenous self-administration in rats. Long Evans male rats were allowed the opportunity to self-administer WIN 55,212-2 at doses ranging from 6.25 to 50 µg/kg per injection, under a fixed-ratio 1 (FR1) schedule of reinforcement and nose-pokes as the operant responses. The effect of either a change in the unit drug dose available or a pretreatment with the specific CB1 receptor antagonist SR 141716A were then investigated (maintenance phase). Finally, the extinction of the self-administration behaviour was evaluated. Results: Response rate depended on the drug dose available, with maximum rates occurring at 12.5 µg/kg per injection. Response rate increased following pretreatment with the specific CB1 receptor antagonist, SR 141716A. Moreover, operant behaviour rapidly extinguished following both the substitution of saline or vehicle for cannabinoid and the disconnection of the drug delivery pumps. Conclusion: Rats will intravenously self-administer the synthetic CB1 receptor agonist WIN 55,212-2 under specific experimental conditions, thus allowing further investigation of the neurobiological mechanisms underlying cannabinoid-taking behaviour.

Accurate calculation of polarization-related quantities in semiconductors

Abstract: We demonstrate that polarization-related quantities in semiconductors can be predicted accurately from first-principles calculations using the appropriate approach to the problem, the Berry-phase polarization theory. For III-V nitrides, our test case, we find polarization, piezoelectric constants, and polarization differences between nitride pairs, and piezoelectric constants quite close to their previously established values. Refined data are nevertheless provided for all the relevant quantities.

Methods and compositions for treating flaviviruses and pestiviruses

Abstract: A method and composition for treating a host infected with flavivirus or pestivirus comprising administering an effective flavivirus or pestivirus treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS

Abstract: Background: Autologous hematopoietic stem cell transplantation (ASCT) has been recently utilized with encouraging results in patients with poorly controlled MS. Objective: To determine in severe cases of MS the effect of ASCT on gadolinium (Gd)-enhanced MRI and to obtain information on clinical course and safety. Methods: In a cooperative study, 10 patients with rapidly evolving secondary progressive MS were transplanted, after BEAM conditioning regimen (carmustine, etoposide, cytosine-arabinoside, and melphalan), with unmanipulated autologous peripheral blood SC mobilized with high-dose cyclophosphamide (CY; 4 g/m 2 ) and granulocyte-colony-stimulating factor. Triple-dose Gd-enhanced scans were performed monthly for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI for the following 6 months and then once every 3 months. Results: The median follow-up is now 15 months (range 4 to 30 months). The number of Gd-enhancing lesions decreased immediately after mobilization with CY and finally dropped to zero in all cases after the conditioning regimen. The number of new T2-weighted positive lesions paralleled data obtained for Gd-enhanced MRI. Clinically, patients improved slightly or remained stable. Conclusion: These results demonstrate that the therapeutic sequence CY–BEAM–ASCT has the capacity to completely suppress MR-enhancing activity, an effect that is sustained with time. The final impact of this procedure on disease course remains to be established.

Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia

Abstract: Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine.

Abstract: Rationale: Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids. Objectives: In this study we investigated if repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Δ9-THC and morphine. Methods: Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Δ9-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Δ9-THC (75 and 150 µg/kg i.v.), with a synthetic cannabinoid agonist WIN55212–2 (75 and 150 µg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded. Results: Rats previously administered with Δ9-THC showed a greater behavioural activation compared to controls in response to challenge with Δ9-THC (150 µg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Δ9-THC and WIN55212–2, 75 and 150 µg/kg i.v.). The effect of the challenge with Δ9-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand. Conclusions: The results of the present study demonstrate that repeated exposure to Δ9-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.