bluuebunny/crossref_metadata_2025 huggingface dataset:
Rat Heart NCX1.1 Stoichiometry Measured in a Transfected Cell System
Authors: LYTTON JONATHAN , DONG HUI
Published: July 2010

Abstract: Expression of cDNA encoding the rat heart NCX1.1 protein in HEK‐293 cells provides a simple system in which properties of the expressed protein can be determined in the absence of contaminating ionic conductances or parallel transport pathways. Using this system, we have determined that NCX1.1 transports 4 Na+ in exchange for 1 Ca2+ and accompanied by the movement of 2 positive charges. The measured stoichiometry is constant over a range of different intracellular Na+ and Ca2+ concentrations, independent of the nature of the Ca2+ buffer used and not affected by the direction of the applied voltage ramp. We conclude that our measurements are unlikely to be confounded by poor control over ionic conditions close to the intracellular surface of the membrane. A stoichiometry of 4:1 for NCX1 has important implications for models of the role of NCX1 in cellular Ca2+ handling and suggests that in the heart the exchanger will be cardioprotective over a wider range of conditions and have a greater contribution to action potential shape than previously appreciated.
Cellular Regulation of Sodium‐Calcium Exchange
Authors: CONDRESCU MADALINA , OPUNI KWABENA , HANTASH BASIL M. , REEVES JOHN P.
Published: July 2010

Abstract: Na+/Ca2+ exchange activity was studied in transfected Chinese hamster ovary (CHO) cells expressing the wild‐type cardiac exchanger (NCX1.1) or mutants created by site‐directed mutagenesis. The activity of the wild‐type exchanger, but not exchanger mutants deficient in Ca2+‐dependent activation, was inhibited by sphingolipids such as ceramide and sphingosine. We propose that sphingolipids interfere with the regulatory activation of exchange activity by Ca2+ and suggest that this interaction provides a means for monitoring and regulating diastolic Ca2+ levels in beating cardiac myocytes. Exchange activity in CHO cells was also linked, through a poorly understood feedback mechanism, to Ca2+ accumulation within internal stores such as the endoplasmic reticulum and the mitochondria. Finally, the F‐actin cytoskeleton was shown to modulate exchange activity through interactions involving the exchanger's central hydrophilic domain. We conclude that regulation of exchange activity in intact cells involves multiple interactions with various lipid species, cytosolic Ca2+, organellar Ca2+ stores, and the cytoskeleton.
Na/Ca Exchange in Function, Growth, and Demise of β‐Cells
Authors: HERCHUELZ ANDRÉ , DIAZ‐HORTA OSCAR , Van EYLEN FRANÇOISE
Published: July 2010

Abstract: Recent knowledge concerning the Na/Ca exchanger (NCX) in the pancreatic β‐cell is reviewed. The β‐cell expresses various NCX1 splice variants in a species‐specific pattern (NCX1.3 and 1.7 in the rat; NCX1.2, 1.3, and 1.7 in the mouse) and in variable and different proportions. In the rat β‐cell, the exchanger displays a high capacity, accounts for about 70% of Ca2+ extrusion, and participates in Ca2+ inflow during membrane depolarization. In the mouse, however, the contribution of the exchanger to Ca2+ extrusion is more modest, and to Ca2+ inflow, less evident. The exchanger has a stoichiometry of 3 Na+ for 1 Ca2+, is electrogenic, and displays a reversal potential at −20 mV. Although being of low magnitude, the current generated by the exchanger shapes glucose‐induced β‐cell electrical activity and intracellular Ca2+ oscillations. Intracellular Ca2+ may also trigger apoptosis. For instance, overexpression of the exchanger increases Ca2+‐dependent and Ca2+‐independent β‐cell death by apoptosis, a phenomenon resulting from the depletion of ER Ca2+ stores with subsequent activation of caspase‐12. Na/Ca exchange overexpression also reduces β‐cell growth. Hence, the Na/Ca exchanger is a versatile system that appears to play an important role in the function, growth, and demise of the β‐cell.
Brain Distribution of the Na+/Ca2+Exchanger‐Encoding Genes NCX1, NCX2, and NCX3 and Their Related Proteins in the Central Nervous System
Authors: CANITANO ADRIANA , PAPA MICHELE , BOSCIA FRANCESCA , CASTALDO PASQUALINA , SELLITTI STEFANIA , TAGLIALATELA MAURIZIO , ANNUNZIATO LUCIO
Published: July 2010

Abstract:In the central nervous system, the Na+/Ca2+exchanger plays a fundamental role in controlling changes in the intracellular concentrations of Na+and Ca2+ions that occur in physiologic conditions such as neurotransmitter release, cell migration and differentiation, gene expression, as well as neuro‐degenerative processes. Three genes, NCX1, NCX2, and NCX3, encoding for Na+/Ca2+exchanger isoforms have been cloned. In this review, by using non‐radioactivein situhybridization and light immunohistochemistry with NCX isoform‐specific riboprobes and antibodies, respectively, a systematic brain mapping for both transcripts and proteins encoded by all three NCX genes is described. Intense expression of NCX transcripts and proteins was detected in the cerebral cortex, hippocampus, thalamus, metathalamus, hypothalamus, brainstem, spinal cord, and cerebellum. In these areas, NCX transcripts and proteins were often found with an overlapping distribution pattern, although specific brain areas displaying a peculiar expression of each exchanger isoform were also found. Furthermore, immunoelectron and confocal microscopy revealed the expression of the NCX1 isoform of the exchanger at both pre‐ and postsynaptic sites as well as in association with membranes of the endoplasmic reticulum. Collectively, these data suggest that the different isoforms of the Na+/Ca2+exchanger appear to be selectively expressed in several CNS regions where they might underlie different functional roles.
Simulation of Na/Ca Exchange Activity during Ischemia
Authors: NOBLE DENIS
Published: July 2010

Abstract: Simulation of sodium‐calcium exchange activity during the rise of intracellular sodium that occurs during ischemia suggests that the exchanger may not reverse direction except transiently during calcium oscillations. This conclusion depends on the presence of a small resting leak of calcium into the cell, consistent with radioactive calcium flux measurements. The conditions for intracellular calcium to rise to around 3 μM were explored. A combination of extracellular potassium accumulation and extracellular sodium depletion is sufficient to explain this result. The computations also show a counterintuitive result concerning the role of the exchanger in the mechanism of calcium oscillations. Reducing its activity would be expected to enhance these oscillations, whereas increasing it can reduce or suppress oscillations. If such oscillations play a role in acute ischemic arrhythmias, then block of Na/Ca exchange may not be therapeutic.
Functional Consequences of Na/Ca Exchanger Overexpression in Cardiac Myocytes
Authors: TERRACCIANO CESARE
Published: July 2010

Abstract: Several factors are important in the relationship between Na/Ca exchanger overexpression and Ca cycling in physiological and pathophysiological situations. First, there are species differences. Transgenic mouse cardiac myocytes overexpressing Na/Ca exchanger showed a faster Ca transient associated with increased sarcoplasmic reticulum (SR) Ca content compared with wild‐type myocytes. Cultured rabbit cardiac myocytes overexpressing Na/Ca exchanger showed reduced amplitude of the Ca transient and reduced SR Ca content. Second, the activity of other Ca regulatory proteins have to be considered. When Ca uptake via SR Ca ATPase (SERCA) was reduced by thapsigargin in transgenic mouse myocytes overexpressing Na/Ca exchanger, the time course of the Ca transient was slowed, and the SR Ca content was reduced to wild‐type mouse myocyte levels, suggesting a potential compensatory role of Na/Ca exchanger overexpression when SERCA function is reduced. Finally, there are confounding factors related to the pathophysiological conditions. Our results suggest that Na/Ca exchanger overexpression can compensate for defects in SR Ca uptake in mouse myocytes. The consequences of Na/Ca exchanger overexpression in other species and conditions is unpredictable and require further investigation.
Developmental Robustness
Authors: KELLER EVELYN FOX
Published: July 2010

Abstract: Developmental robustness, the capacity to stay “on track” despite the myriad vicissitudes that inevitably plague a developing organism, is, I argue, a prerequisite for natural selection and key to our understanding of the evolution of developmental processes. But how is such robustness achieved? And how can we reconcile this property with the delicate precision that seems to characterize so many developmental mechanisms, with what Michael Behe calls “irreducible complexity”? By looking at context, I argue. Developmental mechanisms must be robust with respect to the kinds of insults they are most likely to face, but with respect to less likely vicissitudes, they can be fragile. More specifically, I examine the relative absence of reaction‐diffusion mechanisms in development and suggest that such mechanisms, theoretically attractive though they may be, have been judged by evolution to be ill suited for providing protection against the kinds of vicissitudes developing organisms are most likely to face, and have been supplanted by more intricate mechanisms that are protected from insult by structural design.
From Representational Preformationism to the Epigenesis of Openness to the World?
Authors: MOSS LENNY
Published: July 2010

Abstract:The problem of how to reconcile the apparent “purposiveness” of the living organism with nonteleological, mechanist modes of explanation was given a certain form through most of the 20th century by a relatively decontextualized understanding of the gene as the heritable determinant of phenotypic traits. As instrumentally preformationist presuppositions about genes give way to the burgeoning elucidation of cell and molecular mechanisms of epigenesis, basic questions about the nature of complex living systems and their evolutionary origins once again come into consideration. Some suggestions are offered for a vision of the genetically recontextualized organism.
Results of Long‐Term Experimental Studies on the Carcinogenicity of Ethylene‐bis‐Dithiocarbamate (Mancozeb) in Rats
Authors: BELPOGGI FIORELLA , SOFFRITTI MORANDO , GUARINO MARINA , LAMBERTINI LUCA , CEVOLANI DANIELA , MALTONI CESARE
Published: July 2010

Abstract: Mancozeb, an ethylene‐bis‐dithiocarbamate (EBDC), has been one of the most commonly used fungicides in commercial use for several decades. Nevertheless, up to now, no adequate published experimental studies on the carcinogenicity of Mancozeb have been published. Because of the importance of the compound and of the number of people potentially exposed (workers engaged in the production and use of the fungicide, people living in agricultural areas where the compound is sprayed, and people consuming polluted products), a long‐term experimental study of Mancozeb was begun at the Cancer Research Center of the Ramazzini Foundation. Groups of 150 male and female Sprague‐Dawley rats, 8 weeks old at the start of the treatment, were administered Mancozeb at the concentration of 1000, 500, 100, 10, and 0 ppm in feed supplied ad libitum for 104 weeks. At the end of the treatment, animals were kept under controlled conditions until spontaneous death. Mancozeb caused an increase in (1) total malignant tumors, (2) malignant mammary tumors, (3) Zymbal gland and ear duct carcinomas, (4) hepatocarcinomas, (5) malignant tumors of the pancreas, (6) malignant tumors of the thyroid gland, (7) osteosarcomas of the bones of the head, and (8) hemolymphoreticular neoplasias. On the basis of these data, Mancozeb must be considered a multipotent carcinogenic agent.
The National Toxicology Program Rodent Bioassay
Authors: BUCHER JOHN R.
Published: July 2010

Abstract: The National Toxicology Program rodent cancer bioassay program design evolved from that of the National Cancer Institute in the 1970s. Groups of 50 or more mice are assigned to control or treatment groups. Test substances are given at three dose levels by intubation, dietary or drinking water consumption, or dermal or inhalation exposure. Dosing starts at age 5–6 weeks and lasts for 2 years, when surviving animals receive a complete histopathologic examination. Statistical approaches accommodate survival differences and no longer require differentiation between fatal and incidental tumors. Photocarcinogenicity studies, employing SKH‐1 hairless mice, evaluate onset of skin papillomas and incidences at 1 year. Top doses are chosen to expose animals to a minimally toxic challenge and lower doses to operate within the linear range of kinetics. This dosing allows comparison of results across studies. Bioassay and ancillary studies successfully identify tumor‐causing agents in rodents, provide information on dose‐response, and characterize other chemical‐related toxicities. NTP and Ramazzini Foundation bioassay designs differ in several aspects, but bioassays at both institutions provide chemical‐specific information for predicting human carcinogens, thus providing for protection of public health. Bioassays constitute an essential information reference set for new assay development and further investigations into mechanisms of action. The scientific community and the public owe a huge debt of gratitude to Dr. Cesare Maltoni of the European Foundation of Oncology and Environmental Sciences and to Dr. David P. Rall of the National Institute of Environmental Health Sciences for their foresight and wisdom in creating and nurturing these bioassay programs.
Synaptic Plasticity in the Amygdala
Authors: CHAPMAN PAUL F. , RAMSAY MARK F. , KREZEL WOJCIECH , KNEVETT SIMON G.
Published: July 2010

Abstract:Long‐term potentiation (LTP) is a widely studied form of synaptic plasticity, and a considerable amount of evidence indicates that it could be involved in learning and memory. Intensive investigation of this phenomenon in the hippocampus has yielded tremendous insight into the workings of synapses in the mammalian central nervous system, but important questions remain to be answered. The most important of these are: (1) whether LTP is the basis of learning and memory, and (2) how similar are the induction, maintenance, and expression mechanisms in the rest of the brain to those in the hippocampus. Because the most important strategy for linking LTP to learning involves disrupting the mechanisms of LTP and examining the consequences on behavior, it is likely that the first question cannot be answered until the second has been addressed. Recent evidence indicates that although the general processes have much in common, significant differences exist among forebrain structures, including the hippocampus, basolateral amygdala, and ventral striatum. It is clear that the roles of receptors and calcium channels, kinases, and transcription factors vary within these structures, reflecting the different functions of these brain regions.
The Amygdala, Fear, and Memory
Authors: FANSELOW MICHAEL S. , GALE GREG D.
Published: July 2010

Abstract: Lesions of the frontotemporal region of the amygdala, which includes lateral and basal nuclei, cause a loss of conditional fear responses, such as freezing, even when the lesions are made over a year and a half from the original training. These amygdala‐damaged animals are not hyperactive and show normal reactivity to strong stimuli such as bright lights. After receiving tone‐mild shock pairings rats normally display an appropriately weak response when exposed to the tone. Rats' fear of the tone can be inflated by giving them exposure to strong shocks in the absence of the tone between training and testing. This inflation of fear memory is abolished if the frontotemporal amygdala is inactivated by muscimol only during the inflation treatment with strong shocks. Based on such findings we suggest that the frontotemporal amygdala permanently encodes a memory for the hedonic value of the aversive stimulus used to condition fear.
GluR5 Kainate Receptors, Seizures, and the Amygdala
Authors: ROGAWSKI MICHAEL A. , GRYDER DIVINA , CASTANEDA DORA , YONEKAWA WAYNE , BANKS MELISSA K. , LI H.E.
Published: July 2010

Abstract:The amygdala is a critical brain region for limbic seizure activity, but the mechanisms underlying its epileptic susceptibility are obscure. Several lines of evidence implicate GluR5 (GLUK5) kainate receptors, a type of ionotropic glutamate receptor, in the amygdala's vulnerability to seizures and epileptogenesis. GluR5 mRNA is abundant in temporal lobe structures including the amygdala. Brain slice recordings indicate that GluR5 kainate receptors mediate a portion of the synaptic excitation of neurons in the rat basolateral amygdala. Whole‐cell voltage‐clamp studies demonstrate that GluR5 kainate receptor‐mediated synaptic currents are inwardly rectifying and are likely to be calcium permeable. Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium‐dependent process. The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558. Intra‐amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment. Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long‐term plasticity mechanisms that underlie some forms of epileptogenesis. Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments. Most antiepileptic drugs do not act through effects on glutamate receptors. However, topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor‐mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses.
Consideration of a Unified Model of Amygdalar Associative Functions
Authors: GABRIEL MICHAEL , BURHANS LAUREN , KASHEF ALIREZA
Published: July 2010

Abstract:This paper considers issues arising from presentations by Barry Everitt and Gorica Petrovich concerning amygdalar involvement in appetitive conditioning. Studies reported by these researchers are beginning to unravel the distribution of associative functions among amygdalar nuclei and their efferent targets. The main issue addressed here concerns how to integrate the information from studies of appetitive conditioning with conclusions from studies of other forms of associative learning, including pavlovian fear conditioning and instrumental conditioning. Most students of this issue will agree that no prima facie integration is readily apparent in current scholarship. Although we do not here provide the definitive integration, we do attempt to take some preliminary, broad‐brush steps towards that goal.
Drug Addiction, Relapse, and the Amygdala
Authors: SEE RONALD E. , FUCHS RITA A. , LEDFORD CHRISTOPHER C. , McLAUGHLIN JOSELYN
Published: July 2010

Abstract:Evidence has extensively implicated the amygdala in the associative learning process for appetitive reinforcers. Recent interest has focused on the role of the amygdala in the learned associations that occur during the process of drug addiction and relapse. Using an animal model of relapse after chronic cocaine self‐administration, we found that rats reinstate extinguished lever responding for conditioned stimuli (tone + light) previously paired with cocaine or heroin (‘conditioned‐cued reinstatement’). The basolateral amygdala (BLA) complex plays a critical role in this behavior, because permanent lesions or reversible pharmacologic inactivation of the BLA attenuates conditioned‐cued reinstatement without affecting cocaine self‐administration or cocaine‐primed reinstatement. Conditioned‐cued reinstatement appears to be mediated in part by dopamine inputs to the BLA, as intra‐BLA infusion of a dopamine D1 receptor antagonist blocks reinstatement, whereas intra‐BLA infusion of amphetamine potentiates reinstatement. Furthermore, the BLA is also necessary for acquisition of associative learning with cocaine‐paired stimuli. Disruption of neural activity within the BLA by sodium channel blockade or muscarinic receptor blockade just before acquisition of stimulus‐cocaine associations blocks the ability of conditioned stimuli to elicit conditioned‐cued reinstatement after extinction. Together, these results reveal the importance of the amygdala as part of a corticolimbic circuit mediating both the acquisition and the expression of conditioning that plays a critical role in relapse to drug‐seeking behavior.
Is the Human Amygdala Specialized for Processing Social Information?
Authors: ADOLPHS RALPH
Published: July 2010

Abstract:A number of studies in humans and other animals has confirmed the amygdala's role in modulating cognition and behavior on the basis of a stimulus' motivational, emotional, and social atttributes. This raises the question of how these attributes are related: is social information processing reducible to motivational processing? Some recent data suggest the possibility that the amygdala's primitive function may be motivational processing that is domain‐general, but that its function in primates, and especially humans, may have evolved to process social information specifically. While the issue is unresolved, future experiments could provide additional support.
Criminal and Noncriminal Sexual Aggressors
Authors: MALAMUTH NEIL M.
Published: July 2010

Abstract:In contrast to widely held beliefs, I suggest that research conducted with either criminal or noncriminal samples of sexually aggressive men actually reveals many similar characteristics shared by both groups. The Hierarchical‐Mediational Confluence (HMC) model is presented here to integrate these findings. As relatively distal risk factors, it includes personality and behavioral characteristics associated with psychopaths and predictive of antisocial behavior generally. As more proximate risk factors, it includes personality and behavioral characteristics specifically associated with sexual aggression, such as attitudes condoning sexual aggression, dominance for sexual arousal, and heavy pornography consumption. In addition, the model predicts that the interactive combination of the various risk factors results in higher sexual aggression than expected by the additive combination of these risk factors, a prediction similar to the distinction between ‘primary’ and ‘secondary’ psychopaths. A series of studies supporting the HMC model is presented. Finally, some differences between criminal and noncriminal sexual aggressors are also noted. In particular, criminal sexual aggressors have often committed various other antisocial acts in addition to sexual aggression. In contrast, noncriminals primarily reveal only some elevation in personality characteristics potentiating such nonsexual antisocial behaviors, but report having committed only sexual aggression.
The Developmental Antecedents of Sexual Coercion against Women: Testing Alternative Hypotheses with Structural Equation Modeling
Authors: KNIGHT RAYMOND A. , SIMS‐KNIGHT JUDITH E.
Published: July 2010

Abstract: A unified model of the origin of sexual aggression against women on both adult and juvenile sexual offender samples has been developed and successfully tested. This model proposed three major causal paths to sexual coercion against women. In the first path, physical and verbal abuse was hypothesized to produce callousness and lack of emotionality, which disinhibited sexual drive and sexual fantasies. These in turn disinhibited hostile sexual fantasies, and led to sexual coercion. In the second causal path, sexual abuse contributed directly to the disinhibition of sexual drive and sexual fantasies, which through hostile sexual fantasies led to sexual coercion. The third path operated through early antisocial behavior, including aggressive acts. It developed as a result of both physical/verbal abuse and callousness/lack of emotion. It in turn directly affected sexual coercion and worked indirectly through the hostile sexual fantasies path. In the present study, the anonymous responses of a group of 168 blue‐collar, community males to an inventory (the Multidimensional Assessment of Sex and Aggression) were used in a structural equation model to test the validity of this model. Moreover, this model was pitted against Malamuth's (1998) two‐path model. Whereas the three‐path model had an excellent fit with the data (CFI = .951, RMSEA = .047), the two‐path model fit less well (CFI = .857, RMSEA = .079). These results indicate the superiority of the three‐path model and suggest that it constitutes a solid, empirically disconfirmable heuristic for the etiology of sexual coercion against women.
Detecting Anomalous Sexual Interests in Juvenile Sex Offenders
Authors: SETO MICHAEL C. , MURPHY WILLIAM D. , PAGE JACQUELINE , ENNIS LIAM
Published: July 2010

Abstract: Phallometric studies suggest that some adolescent sex offenders exhibit anomalous sexual interests. However, there have been ethical and practical objections to the phallometric testing of adolescents. Alternative measures may be needed if we are to understand the role of anomalous sexual interests in adolescent sexual offending. The Screening Scale for Pedophilic Interests (SSPI) was designed as a brief measure of pedophilic interests based on sexual offense history variables: any male victims, more than one victim, any victims under age 12, and any unrelated victims. Score on the SSPI is significantly and positively correlated with phallometrically measured pedophilic interests among adult offenders against children. In this study, the SSPI was scored in three samples of adolescent sex offenders who underwent phallometric testing for pedophilic interests. Scores on the SSPI were positively correlated with a phallometric index of relative sexual arousal to children in all three samples. This relationship was strongest using visual stimuli. The positive relationship between SSPI scores and pedophilic responding held up despite the use of different penile measures, stimulus sets, procedures, and scoring methods. The usefulness of the SSPI as a proxy measure among adolescents is discussed.
Distinguishing and Combining Risks for Sexual and Violent Recidivism
Authors: THORNTON DAVID , MANN RUTH , WEBSTER STEVE , BLUD LINDA , TRAVERS ROSIE , FRIENDSHIP CAROLINE , ERIKSON MATT
Published: July 2010

Abstract: A two‐dimensional risk assessment system for sexual offenders was created that can classify them for risk of sexual recidivism, risk of nonsexual violent recidivism, and the composite risk of reconviction for sexual or nonsexual assaults. Receiver operating characteristic (ROC) analyses of separate follow‐up samples were used for cross‐validation. The system is easier to score than Static‐99, and substantially easier to score than the VRAG or SORAG, while yielding comparable predictive accuracy in cross‐validation samples with follow‐ups from 2 years to 19 years. ROC AUC coefficients between .74 and .81 were found for the different scales and samples.
A Sex Equality Approach to Sexual Assault
Authors: MacKINNON CATHARINE A.
Published: July 2010

Abstract: Sexual assault is a practice of sex inequality. It is not generally addressed as such by law, including criminal law, and should be.
Sex Offender Reentry Courts
Authors: La FOND JOHN Q. , WINICK BRUCE J.
Published: July 2010

Abstract: Recently enacted legal strategies to protect society from dangerous sex offenders generally use two very different approaches: Long‐term incapacitation or outright release. The first strategy relies on harsh criminal sentences or indeterminate sexual predator commitment laws. The second relies primarily on registration and notification laws. Both strategies rely on prediction models of dangerousness. Authorities determine at a single moment the likelihood that an offender will sexually ‘recidivate’ and then choose the appropriate type of control for an extended period. This paper reviews the problems of predicting sexual recidivism in the context of both strategies. It then proposes special sex offender reentry courts to manage the risk that sexual offenders will reoffend. Risk management allows decision makers to adjust calculations of individual risk on an ongoing basis in light of new information and to adjust the level of control. Drawing on Therapeutic Jurisprudence—a belief that legal rules, procedures, and legal roles can have positive or negative psychological impact on participants in the legal system—these courts can impose, and then adjust control over sex ofenders in the community. In a sex offender reentry court, the judge is a member of an interdisciplinary team that uses a community containment approach; the offender, as a condition for release, enters into a behavioral contract to engage in treatment and submit to periodic polygraph testing. This therapeutic jurisprudence approach creates incentives for offenders to change their behavior and attitudes, thereby reducing their recidivism risk and earning more freedom. It can also monitor compliance and manage risk more effectively.
Sex Offender Registration and Community Notification: Emerging Legal and Research Issues
Authors: LOGAN WAYNE A.
Published: July 2010

Abstract:Sex offender registration and community notification laws, now in effect nationwide, have inspired considerable controversy. This article examines the variety of legal challenges brought against the laws since the mid‐1990s and surveys issues likely to receive judicial attention in the immediate future. The article also provides an overview of the limited empirical work done to date on registration and notification, and the major areas that warrant additional research, including, most notably, inquiry into efficacy, costs, and consequences.
Victim and Citizen Perspectives on Sexual Offender Policy
Authors: BERLINER LUCY
Published: July 2010

Abstract: At any point, the ‘best practices’ for managing sexual offenders typically derive from the prevailing social policy regarding such offenders. Social policy perspectives held by victims, citizens in the community, and sexual offender experts often are quite different, with victims, their advocates, and citizens supporting management strategies that are more harsh and restrictive than the strategies recommended by the experts. In this paper, these varying perspectives are discussed, and recommendations are made for ways in which sexual offender experts can be influential in shaping social policy.
Physiology and Pathophysiology of Parkinson's Disease
Authors: HAMANI CLEMENT , LOZANO ANDRES M.
Published: July 2010

Abstract: The behavior of neurons in the basal ganglia is severely disrupted in Parkinson's disease (PD). In nonhuman parkinsonian primate models, the disturbance in neurons in basal ganglia output structures include increased firing, bursting, an augmented synchrony, correlated activity, and a tendency towards loss of specificity in their receptive fields. This abnormal neuronal behavior, transmitted to the thalamus, cortex and brainstem, is thought to disrupt the functioning of the motor system and underlie the major motor manifestations of PD—tremor, rigidity, akinesia, gait, and postural disturbances. The mainstay of treatment has been to replace the missing dopamine with medication. With time and disease progression, however, dopamine replacement becomes less efficacious and new adverse effects, including the development of motor fluctuations and drug‐induced involuntary movements or dyskinesias, emerge. When the patients reach this stage, surgical therapy becomes an option. Most surgical interventions are performed at the level of the thalamus, globus pallidus, and subthalamic nucleus, aiming at the disruption of the pathological activity that accompanies the Parkinson's deficiency state. With this abnormal neuronal activity neutralized, normal movements can in many cases be restored.
Midbrain Dopaminergic Neurons
Authors: SIMON HORST H. , BHATT LAVINIA , GHERBASSI DANIEL , SGADÓ PAOLA , ALBERÍ LAVINIA
Published: July 2010

Abstract: Midbrain dopaminergic neurons are the main source of dopamine in the mammalian central nervous system and are associated with one of the most prominent human neurological disorders, Parkinson's disease. During development, they are induced in the ventral midbrain by an interaction between two diffusible factors, SHH and FGF8. The local identity of this part of the midbrain is probably determined by the combinatorial expression of three transcription factors, Otx2, Pax2, and Pax5. After the last cell division, the neurons start to express transcription factors that control further differentiation and the manifestation of cellular properties characteristic for adult dopaminergic neurons of the substantia nigra compacta and the ventral tegmentum. The first to appear is the LIM‐homeodomain transcription factor, Lmx1b. It is essential for the survival of these neurons, and it regulates the expression of another transcription factor, Pitx3, an activator of tyrosine hydroxylase. Lmx1b is followed by the orphan steroid receptor Nurr1. It is essential for the expression of the dopaminergic phenotype. Several genes involved in dopamine synthesis, transport, release, and reuptake are regulated by Nurr1. This requirement is specific to the midbrain dopaminergic neurons, since other populations of the same neurotransmitter phenotype develop normally in absence of the gene. A day after Nurr1, two homeodomain transcription factors, engrailed‐1 and ‐2, are expressed. In animals deficient in the two genes, the midbrain dopaminergic neurons are generated, but then fail to differentiate and disappear very rapidly. Interestingly, α‐synuclein, a gene recently linked to familial forms of Parkinson's disease, is regulated by engrailed‐1 and ‐2.
Transcription Factors in the Development of Midbrain Dopamine Neurons
Authors: BURBACH J. PETER H. , SMITS SIMONE , SMIDT MARTEN P.
Published: July 2010

Abstract: The development of midbrain dopamine (DA) neurons follows a number of stages marked by distinct events. After preparation of the region by signals that provide induction and patterning, at least two cascades of transcription factors contribute to the fully matured midbrain DA systems. One cascade involving the nuclear receptor Nurr1 is required to synthesize the neurotransmitter DA; the enzyme tyrosine hydroxylase (TH) depends on it. The other cascade involves homeobox genes. Lmx1b and engrailed genes are expressed before the genesis of DA neurons and maintain their expression in these neurons. Lmx1b drives Ptx3, which is the latest transcription factor known to be induced. Its induction coincides with that of TH. Disruption of the function of Ptx3 affects the formation of the substantia nigra (SN) and alters the anatomical organization of the midbrain DA systems. While each cascade contributes to a specific aspect of DA neurons, both cascades are required for survival during development, indicating that the maintenance of DA neurons is delicately dependent on the appropriate activity of multiple transcriptional cascades.
Mitochondrial Mechanisms of Neural Cell Death and Neuroprotective Interventions in Parkinson's Disease
Authors: FISKUM GARY , STARKOV ANATOLY , POLSTER BRIAN M. , CHINOPOULOS CHRISTOS
Published: July 2010

Abstract: Mitochondrial dysfunction, due to either environmental or genetic factors, can result in excessive production of reactive oxygen species, triggering the apoptotic death of dopaminergic cells in Parkinson's disease. Mitochondrial free radical production is promoted by the inhibition of electron transport at any point distal to the sites of superoxide production. Neurotoxins that induce parkinsonian neuropathology, such as MPP+ and rotenone, stimulate superoxide production at complex I of the electron transport chain and also stimulate free radical production at proximal redox sites including mitochondrial matrix dehydrogenases. The oxidative stress caused by elevated mitochondrial production of reactive oxygen species promotes the expression and (or) intracellular distribution of the proapoptotic protein Bax to the mitochondrial outer membrane. Interactions between Bax and BH3 death domain proteins such as tBid result in Bax membrane integration, oligomerization, and permeabilization of the outer membrane to intermembrane proteins such as cytochrome c. Once released into the cytosol, cytochrome c together with other proteins activates the caspase cascade of protease activities that mediate the biochemical and morphological alterations characteristic of apoptosis. In addition, loss of mitochondrial cytochrome c stimulates mitochondrial free radical production, further promoting cell death pathways. Excessive mitochondrial Ca2+ accumulation can also release cytochrome c and promote superoxide production through a mechanism distinctly different from that of Bax. Ca2+ activates a mitochondrial inner membrane permeability transition causing osmotic swelling, rupture of the outer membrane, and complete loss of mitochondrial structural and functional integrity. While amphiphilic cations, such as dibucaine and propranolol, inhibit Bax‐mediated cytochrome c release, transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition. These advances in the knowledge of mitochondrial cell death mechanisms and their inhibitors may lead to neuroprotective interventions applicable to Parkinsons's disease.
Pathophysiology of Parkinson's Disease: The MPTP Primate Model of the Human Disorder
Authors: WICHMANN THOMAS , DeLONG MAHLON R.
Published: July 2010

Abstract: The striatum is viewed as the principal input structure of the basal ganglia, while the internal pallidal segment (GPi) and the substantia nigra pars reticulata (SNr) are output structures. Input and output structures are linked via a monosynaptic “direct” pathway and a polysynaptic “indirect” pathway involving the external pallidal segment (GPe) and the subthalamic nucleus (STN). According to current schemes, striatal dopamine (DA) enhances transmission along the direct pathway (via D1 receptors), and reduces transmission over the indirect pathway (via D2 receptors). DA also acts on receptors in GPe, GPi, SNr, and STN. Electrophysiologic and other studies in primates rendered parkinsonian by treatment with the dopaminergic neurotoxin MPTP have demonstrated a reduction of neuronal activity of GPe and an increase of neuronal discharge in STN, GPi. and SNr. These findings are compatible with the view that striatal DA loss results in increased activity over the indirect pathway. Prominent bursting, oscillatory discharge patterns, and increased synchronization of neighboring neurons are found throughout the basal ganglia. These may result from changes in the activity of local circuits (e.g., the GPe‐STN “pacemaker”) or from more global abnormalities of the basal ganglia‐thalamocortical network. These findings have been replicated in human patients undergoing microelectrode‐guided stereotactic procedures targeted at GPi or STN. PET studies in patients with Parkinson's disease have lent further support to the proposed circuit abnormalities. The current models of basal ganglia function have recently been criticized. For instance, the strict separation of direct and indirect pathways and the segregation of D1 and D2 receptors have been questioned, and the almost complete absence of motor side effects of pallidal or thalamic lesions in human patients and animals is inconsistent. These results suggest that changes in discharge patterns and synchronization between basal ganglia neurons, abnormal network interactions, and compensatory mechanisms are at least as important in the pathopohysiology of parkinsonism as changes in discharge rates in individual basal ganglia nuclei. Lesions of GPi or STN are effective in treating parkinsonism, because they reduce or abolish abnormal basal ganglia output, enabling remaining circuits to function more normally.
Antiapoptotic and Anti‐inflammatory Mechanisms of Heat‐Shock Protein Protection
Authors: YENARI MIDORI A. , LIU JIALING , ZHENG ZHEN , VEXLER ZINAIDA S. , LEE JONG EUN , GIFFARD RONA G.
Published: July 2010

Abstract: We and others have previously shown that heat‐shock proteins (HSPs) are involved in protecting the brain from a variety of insults including stroke, epilepsy, and other related insults. While the mechanism of this protection has largely been thought to be due to their chaperone functions (i.e., preventing abnormal protein folding or aggregation), recent work has shown that HSPs may also directly interfere with other cell death pathways such as apoptosis and inflammation. Using models of cerebral ischemic and ischemia‐like injury, we overexpressed the 70‐kDa heat‐shock protein (HSP70) using gene transfer or by studying a transgenic mouse model. HSP70 protected neurons and astrocytes from experimental stroke and stroke‐like insults. HSP70 transgenic mice also had better neurological scores following experimental stroke compared to their wild‐type littermates. Overexpressing HSP70 was associated with less apoptotic cell death and increased expression of the antiapoptotic protein, Bcl‐2. Furthermore, HSP70 suppressed microglial/monocyte activation following experimental stroke. HSP70 overexpression also led to the reduction of matrix metalloproteinases. We suggest that HSPs are capable of protecting brain cells from lethal insults through a variety of mechanisms and should be explored as a potential therapy against stroke and other neurodegenerative diseases.
Effect of Neuroprotective Drugs on Gene Expression in G93A/SOD1 Mice
Authors: IGNACIO SHEILA , MOORE DAN H. , SMITH ANDREW P. , LEE NANCY M.
Published: July 2010

Abstract:Gene expression analysis is a powerful tool that has been used to define the pathological processes underlying many diseases. Several laboratories, including our own, have used this approach to identify molecular abnormalities in the G93A/SOD1 mouse, an animal model of amyotrophic lateral sclerosis (ALS). Here, we report the results of analysis of an expanded panel of genes throughout the entire lifetime in the spinal cord of these animals. In addition to upregulation of microglia/neuroinflammatory genes identified previously, we observed upregulation of metallothionein‐I and ‐II (MT‐I, MT‐II). MT‐I and MT‐II play an important role in disposition of zinc ion, and other studies have also indicated their levels are altered in development of motor neuron disease in these animals. We also analyzed the effect on these expression profiles of several candidate drugs that have been shown to have neuroprotective effectsin vivoorin vitro. That is, we asked whether administration to the G93A/SOD1 mice of any of these drugs could reverse the alterations in gene expression patterns that occur as the animals develop. The mice were given daily doses of these drugs when they were 9‐11 weeks old, at a stage early in development of motor neuron disease, continuing for 5 weeks, at which time they were sacrificed. Treatment of the mice with l‐carnosine, a dipeptide that scavenges free radicals and chelates zinc, did not affect expression of any of the genes altered in these animals. However, it did upregulate 3 genes unaffected by the presence of the G93A/SOD1 mutation: glial fibrillary acidic protein (GFAP), stroma‐derived factor‐1 (SDF‐1), and excitatory amino acid transporter‐2 (EAAT2). In contrast, metallothionein‐III (MT‐III) was downregulated. Treatment of the animals with baicalein, an herbal extract with anti‐inflammatory and numerous other effects, downregulated the microglia markers CD68, CD80, and CD86, all of which were upregulated in untreated mutant animals. Baicalein treatment also downregulated tumor necrosis factor receptor (TNFRp55) and upregulated noninducible nitric oxide synthase (nNOS) and glutamine synthase (GS). These 3 genes were unaffected by the presence of the G93A mutation. We discuss the implication of these results for testing the effects of these and other candidate drugs in mutant SOD1 mice.
Brain Response to Injury and Neurodegeneration
Authors: BAZAN NICOLAS G. , MARCHESELLI VICTOR L. , COLE‐EDWARDS KASIE
Published: July 2010

Abstract: Synaptic activity and ischemia/injury promote lipid messenger formation through phospholipase‐mediated cleavage of specific phospholipids from membrane reservoirs. Lipid messengers modulate signaling cascades, contributing to development, differentiation, function (e.g., memory), protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. Oxidative stress disrupts lipid signaling and promotes lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the microvasculature) is altered in early cerebrovascular and neurodegenerative disease. We discuss how lipid signaling regulates critical events in neuronal survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to show how gene expression may drive synaptic circuitry formation in the “wrong” direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell biogenesis and function, and neuroprotection. Free docosahexaenoic acid released in the brain during experimental stroke leads to the synthesis of stereospecific messengers through oxygenation pathways. One messenger, 10,17S‐docosatriene (neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory gene expression in brain ischemia‐reperfusion. In retina, photoreceptor survival depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized in RPE cells undergoing oxidative stress, potently counteracts oxidative stress‐triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins Bcl‐2 and Bcl‐xL, and decreases proapoptotic Bax and Bad expression. These findings expand our understanding of how the nervous system counteracts redox disturbances, mitochondrial dysfunction, and proinflammatory conditions. The specificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age‐related macular degeneration, spinal cord injury, and other neuroinflammatory or neurodegenerative diseases.
Identification of Rat Hippocampal mRNAs Altered by the Mitochondrial Toxicant, 3‐NPA
Authors: PRZYBYLA‐ZAWISLAK BEATA D. , THORN BRETT T. , ALI SYED F. , DENNIS RICHARD A. , AMATO ANTONINO , VIRMANI ASHRAF , BINIENDA ZBIGNIEW K.
Published: July 2010

Abstract:3‐Nitropropionic acid (3‐NPA) is a model mitochondrial inhibitor that causes selective neurodegeneration in brain. 3‐NPA‐induced neurodegeneration occurs via a secondary neurotoxicity, caused initially by ATP depletion and redox changes in the cell. It is known that the hippocampal degeneration caused by mitochondrial dysfunction affects learning and memory, cognitive functions commonly disturbed in neurodegenerative diseases. The 3‐NPA‐ treated animal model can be used to study molecular mechanisms underlying selective degeneration in the brain. In this study, a microarray approach was utilized to define changes in the expression of 530 genes in the rat hippocampus after acute exposure to 3‐NPA at 30 mg/kg, sc. The microarray data were collected at 30 min, 2 h, and 4 h post‐3‐NPA. Statistical modeling using an ANOVA mixed model applied to Van der Waerden scores of rank‐transformed intensity data was used to assign statistical significance to 44 transcripts. These transcripts represent genes associated with energy metabolism, calcium homeostasis, the cytoskeleton, neurotransmitter metabolism, and other cellular functions. Changes in the transcripts of genes encoding 2 transporters [blood‐brain specific anion transporter (Slco1c1) and sodium‐dependent inorganic phosphate cotransporter (Slc17a7)] were confirmed by real‐time RT‐PCR. In conclusion, this study identified 2 new potential targets for enhancement of neuroprotection or inhibition of neurodegeneration associated with ATP depletion in the hippocampus.