Studies in health technology and informatics, 2014
Distance education has grown in importance with the advent of the internet. An adequate evaluatio... more Distance education has grown in importance with the advent of the internet. An adequate evaluation of students in this mode is still difficult. Distance tests or occasional on-site exams do not meet the needs of evaluation of the learning process for distance education. Bayesian networks are adequate for simulating several aspects of clinical reasoning. The possibility of integrating them in distance education student evaluation has not yet been explored much. The present work describes a Simulator based on probabilistic networks built to represent knowledge of clinical practice guidelines in Family and Community Medicine. The Bayesian Network, the basis of the simulator, was modeled to playable by the student, to give immediate feedback according to pedagogical strategies adapted to the student according to past performance, and to give a broad evaluation of performance at the end of the game. Simulators structured by Bayesian Networks may become alternatives in the evaluation of s...
Lecture Notes in Business Information Processing, 2012
Clinical decision making faces relevant uncertainties, outcomes and trade-offs. It has to deal wi... more Clinical decision making faces relevant uncertainties, outcomes and trade-offs. It has to deal with diagnosis uncertainties, the choice of diagnostic tests, the selection of prescriptions and procedures, and the treatment follow up, many times facing severe budget limitations and lack of sophisticated equipment. This paper presents a multi-agent learning system for health care practitioners: SimDeCS (Simulation for Decision Making in the Health Care Service). This system relies on simulations of complex clinical cases integrated in a virtual learning environment, and has been developed within a program offering continuous education, training and qualification to professionals in the Brazilian health care service. SimDeCS will be made available on the Internet, thus providing access to professionals working throughout the country. The main contribution is the system architecture and the model knowledge.The learning environment has been designed as a multi-agent system where three intelligent agents are included: Domain Agent, Learner Agent, and Mediator Agent. The knowledge model is implemented by the Domain Agent through probabilistic reasoning, relying on expert human knowledge encoded in Bayesian networks. A clinical case is presented and discussed.
Mounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes t... more Mounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes to the full symptomatology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), an endogenous neuropeptide, blocks NMDA receptors and inhibits glutamate release by activating metabotropic mGluR3 receptors. NAAG is catabolized to glutamate and N-acetyl-aspartate by the astrocytic enzyme glutamate carboxypeptidase II (GCP II). Changes in GCP II activity may be critically linked to changes in glutamatergic neurotransmission especially at NMDA receptors. We examined whether GCP II function is altered by treatment with the noncompetitive antagonist and psychotomimetic drug phencyclidine (PCP) and with the neuroleptics haloperidol (HAL) and clozapine (CLOZ), in corticolimbic brain regions of the adult rat. Chronic exposure to PCP produced significant increases in GCP II protein expression and activity in the prefrontal cortex (PFC) and hippocampus (HIPP). This effect may be explained by a compensatory response to persistent blockade of NMDA receptors. In addition, chronic treatment with neuroleptics upregulated GCP II activity, but not protein expression, in the PFC. In contrast, GCP II activity was decreased after acute exposure to HAL or CLOZ and was not changed after acute PCP treatment. These findings provide support for a role of GCP II function in the control of glutamatergic neurotransmission and suggest that some of the therapeutic actions of neuroleptic drugs may be mediated through their effects on GCP II activity. These results demonstrate that psychotomimetic and neuroleptic drugs modulate GCP II function in brain regions that are widely involved in the neuropathology of schizophrenia.
Netrins are guidance cues that play a fundamental role in organizing the developing brain. The ne... more Netrins are guidance cues that play a fundamental role in organizing the developing brain. The netrin receptor, DCC (deleted in colorectal cancer), is highly expressed by dopaminergic (DA) neurons. DCC may therefore participate in the organization of DA circuitry during development and also influence DA function in the adult. Here we show that adult dcc heterozygous mice exhibit a blunted behavioral response to the indirect DA agonist amphetamine and do not develop sensitization to its effects when treated repeatedly. These behavioral alterations are associated with profound changes in DA function. In the medial prefrontal cortex, dcc heterozygotes exhibit increased tyrosine hydroxylase (TH) protein levels and dramatic increases in basal concentrations of DA and DA metabolites. In contrast, in the nucleus accumbens, dcc heterozygotes show no changes in either TH or DA levels, but exhibit decreased concentrations of DA metabolites, suggesting reduced DA activity. In addition, dcc heterozygous mice exhibit a small, but significant reduction in total number of TH-positive neurons in midbrain DA cell body regions. These results demonstrate for the first time that alterations in dcc expression lead to selective changes in DA function and, in turn, to differences in DA-related behaviors in adulthood. These findings raise the possibility that changes in dcc function early in life are implicated in the development of DA dysregulation observed in certain psychiatric disorders, such as schizophrenia, or following chronic use of drugs of abuse.
Netrin-1 is a guidance cue molecule fundamental to the organization of neuronal connectivity duri... more Netrin-1 is a guidance cue molecule fundamental to the organization of neuronal connectivity during development. Netrin-1 and its receptors, deleted in colorectal cancer (DCC) and UNC-5 homologues (UNC-5), continue to be expressed in the adult brain, although neither their function nor the kinds of events that activate their expression are known. Two lines of evidence suggest a role for netrin-1 in amphetamine-induced dopamine plasticity in the adult. First, DCC is highly expressed by adult dopamine neurons. Second, adult mice with reduced DCC levels do not develop amphetamine-induced behavioral sensitization. To explore the role of netrin-1 in amphetamine-induced plasticity, we examined the effects of sensitizing treatment regimens of amphetamine on DCC and/or UNC-5 protein expression in the adult rat. These treatments produced striking and enduring increases in DCC and UNC-5 expression in the cell body, but not terminal regions, of the mesocorticolimbic dopamine system. Notably, neuroadaptations in the cell body region of mesocorticolimbic dopamine neurons underlie the development of sensitization to the effects of amphetamine. Furthermore, these localized amphetamine-induced changes were prevented by co-treatment with an N-methyl-D-aspartate receptor antagonist, a treatment known to block the development of amphetamine-induced sensitization of behavioral activation, dopamine release and motivated behavior. Using immunohistochemistry, we showed that both DCC and UNC-5 receptors are highly expressed by adult mesocorticolimbic dopamine neurons. These results provide the first evidence that repeated exposure to a stimulant drug such as amphetamine affects netrin-1 receptor expression in the adult brain. Taken together, our findings suggest that changes in netrin-1 receptor expression may play a role in the lasting effects of exposure to amphetamine and other stimulant drugs.
Rationale Signaling through the netrin-1 receptor, deleted in colorectal cancer (DCC), in dopamin... more Rationale Signaling through the netrin-1 receptor, deleted in colorectal cancer (DCC), in dopamine neurons controls the extent of their innervation to the medial prefrontal cortex (mPFC) during adolescence. In mice, dcc haploinsufficiency results in increased mPFC dopamine innervation and concentrations in adulthood. In turn, dcc haploinsufficiency leads to resilience to the effects of stimulant drugs of abuse on dopamine release in the nucleus accumbens and behavior. Objectives First, we set out to determine whether increased mPFC dopamine innervation causes blunted behavioral responses to amphetamine in adult dcc haploinsufficient mice. Second, we investigated whether unc5c, another netrin-1 receptor expressed by dopamine neurons, is involved in these effects. Third, we assessed whether haploinsufficiency of netrin-1 itself leads to blunted behavioral responding to amphetamine, whether this phenotype emerges before or after adolescence and whether increased mPFC dopamine input is the underlying mechanism. Results Adult, but not adolescent, dcc, unc5c and netrin-1 haploinsufficient mice exhibit blunted behavioral responses to amphetamine. Furthermore, adult dcc, unc5c, and netrin-1 haploinsufficient mice have exaggerated mPFC dopamine concentrations in comparison to their wild-type littermates. Importantly, resilience to amphetamine-induced behavioral activation in all the three mouse models is abolished by selective dopamine depletion in the medial prefrontal cortex. Conclusions dcc, unc5c, or netrin-1 haploinsufficiency leads to increased dopamine content in the mPFC and to resilience against amphetamine-induced behavioral activation. Our findings raise the hypothesis that DCC, UNC5C, and netrin-1 act in concert to organize the adolescent development of mesocortical dopamine innervation and, in turn, determine behavioral responses to drugs of abuse.
Chronic phencyclidine treatment increases dendritic spine density in prefrontal cortex and nucleus accumbens neurons
Synapse, 2007
We examined whether repeated exposure to the noncompetitive NMDA receptor antagonist phencyclidin... more We examined whether repeated exposure to the noncompetitive NMDA receptor antagonist phencyclidine (PCP) produces enduring changes in dendritic structure in a manner similar to the stimulants cocaine and amphetamine. Adult rats were treated with i.p. injections of PCP (5 mg/kg) or saline, twice a day, for 5 consecutive days, for a total of 4 weeks. One month after the last injection, their brains were removed and processed for Golgi-Cox staining. Prior exposure to PCP increased dendritic spine density in the mPFC and NAcc core, but not in the parietal cortex. These findings, which are similar to those observed after chronic treatment with cocaine and amphetamine, raise the possibility that, despite differences in their mechanisms of action, PCP and stimulant drugs may induce some of their enduring effects via common processes.
Altered netrin-1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat
Synapse, 2009
Neonatal ventral hippocampal (nVH) lesions in rats, which model certain features of schizophrenia... more Neonatal ventral hippocampal (nVH) lesions in rats, which model certain features of schizophrenia, alter dopamine (DA)-mediated behaviors in adulthood. The precise mechanisms underlying these effects remain elusive; however, neuronal reorganization within the medial prefrontal cortex (mPFC) has been suggested. Netrins are developmental cues that organize brain wiring, including the mesocorticolimbic DA circuitry. We showed recently that the netrin-1 receptors DCC and UNC5H are highly expressed by DA neurons and that variation in DCC levels during development lead to profound changes in mesocorticolimbic DA function and behavior in adulthood. We hypothesized that changes in netrin-1 receptor function could be one of the mechanisms producing enduring changes in DA function in nVH-lesioned animals. To begin to explore this idea, we examined the effects of nVH lesions on DCC and UNC5H expression in brain regions receiving robust DA innervation; the mPFC, striatum, and nucleus accumbens (NAcc) at three developmental time points; 3 days after lesion, before puberty and during early adulthood. Expression was also examined in the cerebellar simple lobule; a brain region deprived of DA innervation. Neonatal VH lesions produced dynamic changes in DCC expression in the mPFC and NAcc. The direction and magnitude of these changes depended on the developmental age and brain region examined and were specific to regions receiving DA innervation. Although further studies are required to understand the functional significance of these changes, these results raise the interesting possibility that nVH lesions, and perinatal insults in general, may exert their neuronal reorganizational effects by modulating netrin-1 function.
Rationale Stark differences exist between adult (>PND 70) and juvenile (∼PND 21-34) rodents in ho... more Rationale Stark differences exist between adult (>PND 70) and juvenile (∼PND 21-34) rodents in how DCC (deleted in colorectal cancer) receptors and sensitization to amphetamine interact. In adults, repeated amphetamine upregulates DCC receptor expression selectively in the ventral tegmental area (VTA), an effect that is critical for sensitization. In contrast, amphetamine administered to juveniles downregulates VTA DCC expression. Moreover, whereas adult dcc heterozygous mice fail to sensitize when repeatedly treated with amphetamine, drug treatment during the juvenile period actually abolishes this adult "protective" phenotype. Objectives We set out to determine whether adolescence (PND ∼35-55) is a period during which: (1) amphetamineinduced alterations in VTA DCC expression switch from downregulation to upregulation; (2) the "protective" phenotype of adult dcc heterozygotes against sensitization becomes evident; and (3) the adult "protective" phenotype of dcc heterozygotes can still be abolished by repeated amphetamine treatment. Results Repeated amphetamine did not significantly alter VTA DCC expression in adolescent rodents when assessed 1 week later. Both wild-type and dcc heterozygous mice exhibited sensitization at this time. Remarkably, wild-type mice, but not dcc heterozygotes, exhibited sensitization when tested during adulthood. Conclusions Adolescence is a time of transition for dcc heterozygotes as related to sensitization. Our results support the hypothesis that DCC may be a key factor in determining age-dependent individual differences in vulnerability to sensitization. Given that exposure to drugs of abuse during adolescence can have profound consequences for adulthood, the resilience of adult dcc heterozygous mice against adolescent exposure to amphetamine is particularly salient.
Maternal infection during pregnancy has been associated with increased incidence of schizophrenia... more Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokineinduced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.
The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disord... more The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders including schizophrenia but it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function of DCC (deleted in colorectal cancer), a netrin‐1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reduced DCC on several indicators of DA function. Using in‐vivo microdialysis, we showed that adult mice that develop with reduced DCC display increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In ...
Fundamental to neural organization during development, the netrin‐1 guidance cue and its receptor... more Fundamental to neural organization during development, the netrin‐1 guidance cue and its receptor, deleted in colorectal cancer (DCC), continue to be expressed in the adult brain. We have shown recently that adult dcc heterozygous mice do not develop sensitization to the stimulant drug of abuse amphetamine (AMPH) and that repeated exposure to AMPH upregulates DCC expression in adult rats. This upregulation is selective to the ventral tegmental area (VTA), a site critical for the initiation of behavioral plasticity induced by stimulant drugs, and is glutamate‐dependent. Here we demonstrate that the lack of AMPH‐induced sensitization in dcc heterozygotes is associated with a failure of AMPH to upregulate DCC receptor expression in the VTA. Further, we show that, in wild‐type mice, repeated AMPH induces increases in VTA expression of the dendritic spine‐associated protein, spinophilin. Significantly, however, this effect is not observed in dcc heterozygotes. In parallel experiments con...
The 28th Annual Meeting of the Canadian College of Neuropsychopharmacology
J Psychiatry …, 2005
... Casey Department of Neurology and Neurosurgery; Srivastava, Flores, Leyton Department of ... more ... Casey Department of Neurology and Neurosurgery; Srivastava, Flores, Leyton Department of Psychiatry, McGill Univer-sity, Montréal, Que. ... Dr. Sheena Josselyn (University of Toronto, Toronto) talked about potential Molecular mechanisms involved in fear learning by ...
Fos immunohistochemistry was used to stain neurons in the caudal diencephalon, midbrain and hindb... more Fos immunohistochemistry was used to stain neurons in the caudal diencephalon, midbrain and hindbrain driven by rewarding stimulation of the lateral hypothalamus (LH). Increases in Fos-like immunoreactivity were most pronounced ipsilateral to the site of stimulation and tended to be confined within discrete structures such as the posterior LH, arcuate nucleus, ventral tegmental area (VTA), central gray, dorsal raphé, pedunculopontine area (PPTg), parabrachial nucleus, and locus coeruleus. At least two of these structures, the VTA and PPTg, have been implicated in medial forebrain bundle self-stimulation.
This paper describes a software prototype based on computer graphics resources, created to suppor... more This paper describes a software prototype based on computer graphics resources, created to support the teaching of medicine. Designed primarily to meet a need from AMPLIA software, offers an interactive approach to the specialist and the student, where both have the possibility to extract information about the images using them to illustrate the lessons. Resumo. Este artigo descreve um protótipo de software baseado em recursos de computação gráfica, criado para apoiar o ensino de medicina. Desenvolvido principalmente para suprir uma necessidade do software AMPLIA, oferece uma abordagem de interatividade para o especialista e para o aluno, onde ambos têm a possibilidade de extrair informações a respeito das imagens utilizando-as para ilustrar os casos clínicos apresentados em aula.
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