bluuebunny/crossref_metadata_2025 huggingface dataset:
Hormonal, Neurochemical, and Behavioral Response to a Forced Swim Test in Adolescent Rats throughout Cocaine Withdrawal
Authors: Alves Cecília Juliana , Magalhães Ana , Summavielle Teresa , Melo Pedro , De Sousa Liliana , Tavares Maria Amélia , Monteiro Pedro R.R.
Published: August 2009

The use of cocaine in adults has been linked to depression and/or anxiety. Several studies have shown an association between cocaine‐primed craving and depressive symptoms. In animal models, the forced swim test (FST) is frequently used for screening depressive‐like behavior. This study aimed to verify the presence of depression‐like symptoms in adolescent rats after chronic cocaine exposure by analyzing behavior in a FST. The subsequent alterations in neurotransmitters and hypothalamus‐pituitary‐adrenal axis activity induced by this test were also analyzed. Both male and female adolescent Wistar rats were submitted to a chronic “binge” pattern of administration of cocaine hydrochloride, and subjects were tested in a forced swim test 2 days after cocaine's last administration. At the end of the behavioral test, trunk blood was collected for quantification of corticosterone plasma levels, and hypothalamus, prefrontal cortex, amygdala, and hippocampus were dissected for neurochemical determinations. No significant differences were found in the behavior on the FST of both males and females after withdrawal from chronic cocaine administration. Nevertheless, plasma levels of corticosterone were increased in cocaine‐treated males, although not significantly (P= 0.065). In females cocaine failed to affect corticosterone levels. Of interest, neurochemical analyses showed that dopamine turnover was decreased in amygdala in cocaine‐treated males (not significantly,P= 0.055). No significant differences were found on neurotransmitter levels in the other brain regions analyzed. Withdrawal from chronic cocaine administration during adolescence did not have a significant effect on stress‐induced behavioral alterations, although the neurochemical response to the stressful situation provided by FTS seemed to be affected.
Characterization and Pharmacology of the GHB Receptor
Authors: Ticku Maharaj K. , Mehta Ashok K.
Published: August 2009

Radioligand binding using [3H]NCS‐382, an antagonist of the GHB receptor, revealed specific binding sites in the rat cerebrocortical and hippocampal membranes. Scatchard analysis of saturation isotherms revealed two different populations of binding sites. NCS‐382 was about 10 times more potent than GHB in inhibiting [3H]NCS‐382 binding. A variety of ligands for other receptors did not affect [3H]NCS‐382 binding. Quantitative autoradiographic analysis of [3H]NCS‐382 binding revealed similar characteristics. Thus [3H]NCS‐382, being more potent and selective, offers advantage over [3H]GHB as a radioligand. Unlike GHB, several analogues of GHB such as UMB68 (a tertiary alcohol analogue of GHB), UMB86 (4‐hydroxy‐4‐napthylbutanoic acid, sodium salt), UMB72 [4‐(3‐phenylpropyloxy)butyric acid, sodium salt], UMB73 (4‐benzyloxybutyric acid, sodium salt), UMB66 (3‐chloropropanoic acid), gamma‐hydroxyvaleric acid (that is, GHV, a 4‐methyl‐substituted analogue of GHB), 3‐HPA (3‐hydroxyphenylacetic acid), and ethers of 3‐hydroxyphenylacetic acid (UMB108, UMB109, and UMB119) displaced [3H]NCS‐382 without affecting [3H]GABA binding to GABABreceptor. Thus these compounds offer an advantage over GHB as an experimental tool. Our study, aimed at exploring the potential involvement of the GHB receptor in the pharmacology of ethanol, indicated that ethanol does not affect [3H]NCS‐382 binding in the rat brain, thereby suggesting that ethanol does not interact directly with the GHB receptor. Our study, aimed at exploring the involvement of the GHB receptor in the pathology of succinate semialdehyde dehydrogenase deficiency, which is known to cause elevation of GHB levels, revealed no change in the affinity, receptor density or displacement potency as determined by using [3H]NCS‐382 as a radioligand inAldh5a1−/−vs.Aldh5a1+/+mouse brain.
c‐Fos Is an Intracellular Regulator of Cocaine‐Induced Long‐Term Changes
Authors: Xu Ming
Published: August 2009

Development of drug addiction is accompanied by the induction of long‐lasting neurobiological changes. Dopamine D1 receptors are involved in mediating cocaine‐induced neuroadaptation, yet the underlying intracellular mechanisms remain less clear. Using a genetically modified mouse in whichFosis primarily mutated in D1 receptor‐bearing neurons in the brain, we examined a potential role of the immediate early geneFos,which is rapidly induced by cocaine via D1 receptors, in mediating cocaine‐induced persistent neurobiological changes. We found that the composition of AP‐1 transcription complexes and expression levels of AP‐1 complexes, and several transcription factors, neurotransmitter receptors as well as intracellular signaling molecules following repeated cocaine administration are altered inFos‐deficient brains. Moreover, dendritic reorganization of medium spiny neurons induced by repeated exposure to cocaine is attenuated in the mutant brains. The mutant mice also exhibit reduced behavioral sensitization after repeated cocaine administration. These findings suggest that c‐Fos expressed in D1 receptor‐bearing neurons mediates cocaine‐induced persistent changes.
Role of the NMDA Receptor and Nitric Oxide in Memory Reconsolidation of Cocaine‐Induced Conditioned Place Preference in Mice
Authors: Itzhak Yossef
Published: August 2009

Classical pavlovian conditioning has a major role in the development and persistence of drug addiction. Appetitive conditioning by drug reward, as measured by the conditioned place preference (CPP) paradigm, is an exemplar of classical pavlovian conditioning. Aversive conditioning by footshock involves learning and memory processes similar to those involved in appetitive conditioning. Studies on fear conditioning have shown that long‐term fear memory can be extinguished by disruption of reconsolidation of specific memories associated with the fear response. Hence disruption of memory reconsolidation may hold promise for the extinction of maladaptive conditioned behavior. In the present study the effects of the NMDA receptor antagonist, MK‐801, and the nNOS inhibitor 7‐nitroindazole (7‐NI) on memory reconsolidation of cocaine‐induced CPP in mice were investigated. We report that, following the acquisition of cocaine CPP, a single acute administration of either MK‐801 or 7‐NI immediately after retrieval of place preference extinguished subsequent place preference. Moreover, a priming dose of cocaine did not reinstate place preference in the drug‐treated groups compared to controls. Male nNOS knockout (KO) mice acquired short‐lived cocaine CPP compared to wild‐type (WT) mice. A single acute administration of the NO‐donor molsidomine to nNOS KO mice immediately after retrieval of CPP prolonged the expression of place preference compared to controls that received saline, suggesting partial strengthening of memory reconsolidation. Taken together, these findings support the role of the NMDAR/NO signaling pathway in memory reconsolidation of cocaine CPP, and suggest that disruption of this pathway during memory reconsolidation may afford resistance to drug‐seeking behavior.
Acute Administration of 3,4‐Methylenedioxymethamphetamine Induces Profound Hyperthermia, Blood–Brain Barrier Disruption, Brain Edema Formation, and Cell Injury
Authors: Sharma Hari Shanker , Ali Syed F.
Published: August 2009

The psychostimulant 3,4‐,ethylenedioxymethamphetamine (MDMA, “ecstasy”) is known to induce hyperthermia and alterations in neurochemical metabolism in the CNS. However, the detailed cellular or molecular mechanisms behind MDMA‐induced neurotoxicity are still not well known. Since MDMA induces profound hyperthermia that could lead to intense cellular stress and cause disruption of the blood–brain barrier (BBB), this investigation examined the effects of acute MDMA on BBB dysfunction, brain edema, and cell injury in rats and mice. When MDMA (40 mg/kg, i.p.) was administered to rats or mice, these animals exhibited profound behavioral disturbances (hyperactivity and hyperlocomotion) and hyperthermia (>40 to 41°C) at 4 h. At this time, the leakage of Evans blue dye was evident, particularly in the cerebellum, hippocampus, cortex, thalamus, and hypothalamus. This effect was most pronounced in mice compared to rats. Marked increase in brain water along with Na+, K+, and Cl– content was also seen in the aforementioned brain regions. Presence of distorted neuronal and glial cells in brain regions associated with leakage of Evans blue is quite common in MDMA‐treated animals. Increased albumin immunoreactivity, indicating breakdown of the BBB, and upregulation of glial fibrillary acidic protein (GFAP), suggesting activation of astrocytes, were seen in most brain regions showing edematous changes. Upregulation of heat‐shock protein (HSP72) immunoreactivity in the nuclei and cell cytoplasm of the neurons located in the edematous brain regions are quite common. Taken together, these observations are the first to show that MDMA has the capacity to disrupt BBB permeability to proteins and to induce the formation of edema, probably by inducing hyperthermia and cellular stress, as evident with HSP overexpression leading to cell injury.
The Expression of NMDA Receptor Subunit mRNA in Human Chronic Alcoholics
Authors: Ridge Justin P. , Ho Ada M.‐C. , Innes David J. , Dodd Peter R.
Published: August 2009

Ethanol is a modulator at theN‐methyl‐d‐aspartate class of glutamate receptors in the brain. In animal studies the receptor adapts to sustained ethanol exposure through altered expression of the subunits that make up the receptor complex. We used real‐time RT‐PCR normalized to GAPDH to assay NR1, NR2A, and NR2B subunit mRNA in superior frontal and primary motor cortex tissue obtained at autopsy from chronic alcoholics with and without co‐morbid cirrhosis of the liver, and from matched controls. The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in the corresponding areas in both controls and alcoholics without co‐morbid disease, who did not differ significantly from each other. The decrease was area‐dependent when cases were partitioned by the 5‐HTTLPR allele. Thus, polymorphisms in one gene can have a significant effect on the expression of a second, unrelated, gene. The expression of theN‐methyl‐d‐aspartate glutamate receptor complex is under multifactorial control.
Dopamine Receptor D4 Gene −521C/T Polymorphism Is Associated with Opioid Dependence through Cold‐Pain Responses
Authors: Ho Ada M.‐C. , Tang Nelson L.‐S. , Cheung Ben K.‐L. , Stadlin Alfreda
Published: August 2009

Heroin users exhibit abnormal pain sensitivity called opioid‐induced hyperalgesia that may weaken their determination to abstain. The dopamine receptor D4 gene (DRD4) is associated with heroin dependence; one of its polymorphisms is a C/T variation 521 bp upstream to the gene (−521C/T). We investigated whether this polymorphism was related to opioid dependence through modulation of cold‐pain responses. We recruited 84 heroin‐dependent Chinese male subjects and 168 healthy male Chinese controls. Genotyping was performed by PCR‐RFLP. A significantly higher T allele frequency was observed in the heroin group (P= 0.041). Of the cohort recruited, 43 current heroin users and 66 controls were further subjected to a cold‐pressor test (CPT) to determine their pain threshold and tolerance. TT controls demonstrated a significantly lower pain threshold than did their CC/CT counterparts (P= 0.022) and TT opioid users (P= 0.006). Moreover, CC/CT controls had a significantly higher pain tolerance than TT controls (P= 0.042) and CC/CT opioid users (P= 0.010). The data suggest that DRD4−521C/T plays an important role in opioid dependence through modulating cold‐pain responses. TT individuals might have a higher tendency to use opioids because they experience pain less strongly after chronic opioid use.
Predicting Treatment Outcome in Stimulant Dependence
Authors: Reske Martina , Paulus Martin P.
Published: August 2009

The purpose of this review is to highlight some of the issues that need to be addressed to optimally use functional neuroimaging as a clinical tool to predict outcomes in substance use disorders. First, the importance of recognizing the clinical heterogeneity of the substance use disorders population is highlighted. We also emphasize that empirical and theoretical analyses support the idea that the courses of substance use disorders are relatively independent of the types of substance being used. Second, various approaches to the measurement and characterization of the longitudinal courses of substance use disorders are summarized. Third, predictors of outcomes are reviewed and their limitations are discussed. Within this context, we describe aspects of our work that focus on using functional magnetic resonance imaging to predict outcomes. Fourth, we discuss future directions, critical experiments, and the utility of functional neuroimaging as a clinical tool.
ADHD and Smoking
Authors: McClernon Francis Joseph , Kollins Scott Haden
Published: August 2009

Attention‐deficit/hyperactivity disorder (ADHD) and tobacco smoking are among the most common and costly psychiatric and behavioral problems. The rates of co‐occurrence of these two common problems are larger than expected by chance. Despite progress in identifying the neural and genetic substrates of each, the mechanisms underlying the high rates of comorbidity between ADHD and smoking remain largely unknown. We propose that ADHD and smoking involve dysregulation of dopaminergic and nicotinic‐acetylcholinergic circuits and that these aberrations are likely to arise, at least in part, from genetic variations. This review describes an integrative model of the ADHD–smoking comorbidity, with an emphasis on shared neuropharmacological mechanisms. We first describe the prevalence of smoking among ADHD patients. We then describe how ADHD influences stages of smoking behavior (e.g., initiation, maintenance, and relapse). We review common potential genetic substrates of ADHD and smoking, focusing on genes that regulate monoaminergic neurotransmission. We review the behavioral and neuropharmacological bases of smoking and ADHD, focusing on the modulatory roles of nicotine on attention and behavioral control. Finally, we discuss the implications of this model for prevention and clinical outcomes.
Molecular Genetics of Addiction and Related Heritable Phenotypes
Authors: Uhl George R. , Drgon Tomas , Johnson Catherine , Li Chuan‐Yun , Contoreggi Carlo , Hess Judith , Naiman Daniel , Liu Qing‐Rong
Published: August 2009

Genome‐wide association (GWA) can elucidate molecular genetic bases for human individual differences in complex phenotypes that include vulnerability to addiction. Here, we review (a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; (b) technical and ethical aspects of importance for understanding GWA data, including genotyping in individual samples versus DNA pools, analytic approaches, power estimation, and ethical issues in genotyping individuals with illegal behaviors; (c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; (d) overlaps between GWA data sets for dependence on different substances; and (e) overlaps between GWA data for addictions versus other heritable, brain‐based phenotypes that include bipolar disorder, cognitive ability, frontal lobe brain volume, the ability to successfully quit smoking, neuroticism, and Alzheimer's disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A “connectivity constellation” of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.
Drug Addiction and the Memory Systems of the Brain
Authors: Robbins T.W. , Ersche K.D. , Everitt B.J.
Published: August 2009

We review drug addiction from the perspective of the hypothesis that drugs of abuse interact with distinct brain memory systems. We focus on emotional and procedural forms of memory, encompassing Pavlovian and instrumental conditioning, both for action–outcome and for stimulus–response associations. Neural structures encompassed by these systems include the amygdala, hippocampus, nucleus accumbens, and dorsal striatum. Additional influences emanate from the anterior cingulate and prefrontal cortex, which are implicated in the encoding and retrieval of drug‐related memories that lead to drug craving and drug use. Finally, we consider the ancillary point that chronic abuse of many drugs may impact directly on neural memory systems via neuroadaptive and neurotoxic effects that lead to cognitive impairments in which memory dysfunction is prominent.
Protein Kinases and Addiction
Authors: Lee Anna M. , Messing Robert O.
Published: August 2009

Although drugs of abuse have different chemical structures and interact with different protein targets, all appear to usurp common neuronal systems that regulate reward and motivation. Addiction is a complex disease that is thought to involve drug‐induced changes in synaptic plasticity due to alterations in cell signaling, gene transcription, and protein synthesis. Recent evidence suggests that drugs of abuse interact with and change a common network of signaling pathways that include a subset of specific protein kinases. The best studied of these kinases are reviewed here and include extracellular signal‐regulated kinase, cAMP‐dependent protein kinase, cyclin‐dependent protein kinase 5, protein kinase C, calcium/calmodulin‐dependent protein kinase II, and Fyn tyrosine kinase. These kinases have been implicated in various aspects of drug addiction including acute drug effects, drug self‐administration, withdrawal, reinforcement, sensitization, and tolerance. Identifying protein kinase substrates and signaling pathways that contribute to the addicted state may provide novel approaches for new pharmacotherapies to treat drug addiction.
Genes and Molecules That Can Potentiate or Attenuate Psychostimulant Dependence
Authors: Niwa Minae , Yan Yijin , Nabeshima Toshitaka
Published: August 2009

Recent evidence suggests that a variety of molecule products play critical roles in the transitions from recreational drug use to drug abuse, and then to drug dependence. Elucidation of the roles of specific molecules in the development of drug dependence can come from preclinical animal models and/or from clinical data. Among animal models, behavioral sensitization, conditioned place preference, drug discrimination, drug self‐administration, and extensions of these basic procedures have been widely used to identify molecule products that might be involved in psychostimulant dependence. Repeated exposure to psychostimulants causes cellular adaptations in specific neuronal populations that are likely to contribute to dependence in some humans. In animal models, molecules that include shati, piccolo, tumor necrosis factor‐α, and glial cell line‐derived neurotrophic factor can act as antiaddictive factors. In some of these models, other molecules including matrix metalloproteinase and tissue plasminogen activator can act as proaddictive factors. We review evidence that the balance between levels of anti‐ and proaddictive factors induced by addictive drugs could play important roles in developing drug dependence. We focus on potential risk molecules in animal models for the development of methamphetamine dependence and their relevance to abusers. We propose that dynamic changes in the balance between levels of antiaddictive and proaddictive factors in the brain provide some of the determinants of susceptibility to drug dependence. Exploration of the roles that candidate molecules play in an appropriate repertoire of animal behavioral models, especially drug self‐administration and extensions thereof, should thus help us to understand human stimulant dependence.
Drug Addiction in China
Authors: Lu Lin , Wang Xi
Published: August 2009

Drug addiction in China began with the importation of Indian opium by the British in the 16th century and brought severe social and health problems. While drug abuse abated following the establishment of People's Republic of China, modernization and Westernization in the 1980s led to the reemergence of this problem. Drug abuse in China became epidemic, facilitating the spread of HIV/AIDS. The Chinese government has made great efforts to address these problems, focusing both on treatments of drug addiction and on harm‐reduction programs. Although the new trends of drug addiction in China pose great public health challenges, these government interventions are likely to successfully stem the problem of drug abuse in the future.
Risk Evaluation and Mitigation Strategies for Drugs with Abuse Liability
Authors: Wright IV Curtis , Schnoll Sidney , Bernstein David
Published: August 2009

Risk evaluation and mitigation strategies (REMS) formerly known as Risk Minimization Action Plans (RiskMAPs) are a regulatory technique for dealing with anticipated risks of new medications and are especially important for new drugs with abuse potential. This paper describes the origin and history of risk‐management plans for drugs that might be abused, the proper use of these plans in minimizing the risk to the public, and the special difficulties inherent in managing risks for drugs with abuse potential. Drugs with abuse liability are distinctive since the risks inherent in manufacture and distribution include not only risks to patients prescribed the medications, but also risks to the general public including subgroups in the population not intended to get the drug and who receive no medical benefit from the medication. The crafting of risk‐management plans intended to protect nonpatient populations is unique for these products. The content, extent, and level of intensity of these plans affect areas of medical ethics, civil liability, and criminal prosecution. The need for risk‐management plans for drugs with abuse liability can potentially act as a deterrent to investment and is a factor in decisions concerning the development of new medications for the treatments of pain, ADHD, anxiety disorders, and addictions. This paper provides a framework for moving the process of REMS development forward and criteria for evaluating the probity and adequacy of such programs.
Abuse of Amphetamines and Structural Abnormalities in the Brain
Authors: Berman Steven , O'Neill Joseph , Fears Scott , Bartzokis George , London Edythe D.
Published: August 2009

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetaminesin utero. Evidence comes from studies that used a variety of techniques including manual tracing, pattern matching, voxel‐based, tensor‐based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3–4‐methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine‐rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occurin utero.Several forms of white matter abnormality are also common and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross‐sectional designs, which cannot infer causality. Potential confounding influences include effects of pre existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure.
Toll‐like Receptors in Autoimmunity
Authors: Fischer Maria , Ehlers Marc
Published: August 2009

Both genetic predispositions and environmental factors contribute to the development of autoimmunity. Toll‐like receptors (TLR) are a family of pattern recognition receptors (PRRs), and their stimulus by pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs) is an important prerequisite for the induction of various autoimmune diseases. However, activation of specific TLRs can not only induce but also inhibit autoimmune diseases in certain mouse models. The contribution of individual TLRs to the induction of autoimmunity or tolerance involves hematopoietic as well as nonhematopoietic cells expressing combinations of different TLRs. The intercellular and intracellular orchestration of signals from different TLRs, other PRRs, and membrane‐standing receptors dictates activating or inhibitory responses. Here, we summarize TLR‐dependent tolerance mechanisms in B cells and intestinal epithelial cells and TLR‐mediated activation mechanisms leading to the induction of Th17 T cell differentiation in different autoimmune diseases and in inflammatory bowel diseases. Understanding the opposing mechanisms of TLRs for the induction and suppression of autoimmune processes in specific diseases will help to develop novel therapies to treat autoimmunity.
Recalling the Year in Memory T Cells
Authors: Bushar Nicholas D. , Farber Donna L.
Published: August 2009

The memory immune response forms the basis for protective immunity and is orchestrated by long‐lived memory T lymphocytes. Memory T cells mediate potent and rapid effector function upon secondary challenge, and migrate to diverse peripheral sites, resulting in efficacious clearance of pathogens before the onset of disease. However, these robust memory T cell functions and diverse homing capacities can also lead to immunopathology in viral infections, autoimmunity, and transplantation. Elucidating mechanisms controlling memory T cell generation and recall responses therefore has broad clinical and immunological relevance. In this review, we highlight advances in the past year on dissecting the processes of memory generation, recall capacity, and regulation of memory T cell responses. We discuss the past year's studies focused on identifying pathways and precursors for memory development at both the priming and effector stage, and how the earliest events in T cell activation may have far‐ranging influences on the resultant memory T cell population. We also describe results on the biochemical and molecular control of the distinct and immediate effector functions of memory T cells and their implications for immunotherapies. Finally, we present recent technological advances in T cell tracking and imagery and how they may be applied to provide new insight into the complex nature of the memory immune response.
β‐Glucans and Dectin‐1
Authors: Tsoni S. Vicky , Brown Gordon D.
Published: August 2009

β‐Glucans are naturally occurring carbohydrates that possess immune‐modulating activities, but their mechanisms of action are largely unknown. Recent discoveries, however, including identification of β‐glucan receptors, such as dectin‐1, have started to shed some light on the mechanisms underlying the properties of these carbohydrates. The characterization of dectin‐1, in particular, has revealed some of the processes involved in β‐glucan sensing, intracellular signaling, and induction of cellular responses and has provided new insights into the role of β‐glucans in immunity and disease. Here we review both β‐glucans and their receptor, dectin‐1.
Immunology of Mercury
Authors: Vas Jaya , Monestier Marc
Published: August 2009

The heavy metal mercury is ubiquitously distributed in the environment resulting in permanent low‐level exposure in human populations. Mercury can be encountered in three main chemical forms (elemental, inorganic, and organic) which can affect the immune system in different ways. In this review, we describe the effects of these various forms of mercury exposure on immune cells in humans and animals. In genetically susceptible mice or rats, subtoxic doses of mercury induce the production of highly specific autoantibodies as well as a generalized activation of the immune system. We review studies performed in this model and discuss their implications for the role of environmental chemicals in human autoimmunity.
Impulse Control and Related Disorders in Parkinson's Disease
Authors: Lim Shen‐Yang , Evans Andrew H. , Miyasaki Janis M.
Published: August 2009

In the past decade, impulse control disorders, punding, and dopamine dysregulation syndrome (which we refer to collectively as disinhibitory psychopathologies) have been increasingly recognized in treated patients with Parkinson's disease. Practicing neurologists must understand these problems to limit potential harm. In this article, we summarize current knowledge regarding these behavioral disorders, including phenomenology, epidemiology, pathophysiology, and treatment.
Spatial Neglect: Clinical and Neuroscience Review
Authors: Adair John C. , Barrett Anna M.
Published: August 2009

Hemispatial neglect (HSN) is a frequent, conspicuous neurobehavioral accompaniment of brain injury. Patients with HSN share several superficial similarities, leading earlier clinical neuroscientists to view neglect as a unitary condition associated with brain structures that mediate relatively discrete spatial cognitive mechanisms. Over the last two decades, research largely deconstructed the neglect syndrome, revealing a remarkable heterogeneity of behaviors and providing insight into multiple component processes, both spatial and nonspatial, that contribute to hemispatial neglect. This review surveys visual HSN, presenting first the means for detection and diagnosis in its manifold variations. We summarize cognitive operations relevant to spatial attention and evidence for their role in neglect behaviors and then briefly consider neural systems that may subserve the component processes. Finally, we propose several methods for rehabilitating HSN, including the challenges facing remediation of such a heterogeneous cognitive disorder.
Designer Therapies for Glioblastoma Multiforme
Authors: Sathornsumetee Sith , Rich Jeremy N.
Published: August 2009

Primary brain tumors account for less than 2% of all cancers in adults; however, they are often associated with neurologic morbidity and high mortality. Glioblastoma multiforme (GBM) has been a focus of new therapy development in neurooncology because it is the most common primary brain tumor in adults. Standard‐of‐care therapy for newly diagnosed GBM includes surgical resection, radiotherapy, and temozolomide, administered both during and after radiotherapy. However, most patients develop tumor recurrence or progression after this multimodality treatment. Repeat resection and stereotactic radiosurgery upon recurrence may improve outcome only in selected patients. Most salvage chemotherapies offer only palliation. Recent advances in our understanding of the molecular abnormalities of GBM have generated new therapeutic venues of molecularly targeted agents (designer drugs) against key components of cellular pathways critical for cancer initiation and maintenance. Such drugs may offer the potential advantage to increase therapeutic efficacy and decrease systemic toxicity compared with traditional cytotoxic agents. Nonetheless, first‐generation targeted agents have failed to demonstrate survival benefits in unselected GBM patient populations. Several mechanisms of treatment failure of the first‐generation designer drugs have been proposed, whereas new strategies have been developed to increase effectiveness of these agents. Here we will discuss the recent development and the strategies to optimize the effectiveness of designer therapy for GBM.
Cerebral White Matter
Authors: Schmahmann Jeremy D. , Smith Eric E. , Eichler Florian S. , Filley Christopher M.
Published: August 2009

Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico‐cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico‐subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains—WM dementia—occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders.
Hashimoto's Encephalopathy
Authors: Schiess Nicoline , Pardo Carlos A.
Published: August 2009

Hashimoto's encephalopathy (HE) is a controversial neurological disorder that comprises a heterogenous group of neurological symptoms that manifest in patients with high titers of antithyroid antibodies. Clinical manifestations of HE may include encephalopathic features such as seizures, behavioral and psychiatric manifestations, movement disorders, and coma. Although it has been linked to cases of Hashimoto's thyroiditis or thyroid dysfunction, the most common immunological feature of HE is the presence of high titers of antithyroglobulin or anti‐TPO (antimicrosomal) antibodies. At present, it is unclear whether antithyroid antibodies represent an immune epiphenomenon in a subset of patients with encephalopathic processes or they are really associated with pathogenic mechanisms of the disorder. The significance of classifying encephalopathies under the term HE will be determined in the future once the relevance of the role of antithyroid antibodies is demonstrated or dismissed by more detailed experimental and immunopathological studies. The responsiveness of HE to steroids or other therapies such as plasmapheresis supports the hypothesis that this is a disorder that involves immune pathogenic mechanisms. Further controlled studies of the use of steroids, plasmapheresis, or immunosuppressant medications are needed in the future to prove the concept of the pathogenic role of antithyroid antibodies in HE.
The Role of Stochastic Forcing on the Behavior of Thermohaline Circulation
Authors: Lorenzo M. N. , Taboada J. J. , Iglesias I. , Álvarez I.
Published: August 2009

The nonlinear nature of the climate system suggests that its reactions to unexpected perturbations could be different from the expected ones. In nonlinear science it is recognized as a promising paradigm that stochastic fluctuations can generate order or other counterintuitive effects. Thus, noise sources, adequately coupled to a nonlinear system, may give rise to a rich new phenomenology not present in a deterministic noiseless scenario. In this review we focus attention on thermohaline circulation (THC). THC presents two modes of operation; one state shows active THC and the other inactive. Previous episodes of transitions between both states of THC observed in paleoclimatic records and the influence of this circulation on climate have resulted in detailed investigations on the dynamics of the THC. A weakening or a collapse of this current could trigger the onset of a new Younger Dryas. In this review the introduction of stochastic forcing in key parameters, both in a simple box model and in an earth model of intermediate complexity, provokes a weakening and even a shutdown of the THC. The consequences of this weakening are observed in different variables. The surface air temperature and the sea surface temperature are dominated by cooling of the Northern Hemisphere. Changes in the position of the Intertropical Convergence Zone and in precipitation are observed. There is also an intensification of the North Atlantic Oscillation values during winter. These results reinforce the necessity to consider stochastic sources in climate models to improve our understanding of the climate.
Spatio‐temporal Upwelling Trends along the Canary Upwelling System (1967–2006)
Authors: Gómez‐Gesteira M. , De Castro M. , Álvarez I. , Lorenzo M. N. , Gesteira J. L. G. , Crespo A. J. C.
Published: August 2009

Spatio‐temporal trends in upwelling patterns were studied along the Canary Upwelling System for the period 1967–2006. The northwestern coast of African from lat 20°N to 32°N is observed to be under a permanent upwelling regime characterized by coastal sea surface temperatures (SST) colder than the oceanic ones at the same latitude. The temperature difference is termed the temperature upwelling index (UISST). This regime is consistent with the wind‐derived Ekman transport (UIW), which is observed near the coast and is directed offshore. This index shows the existence of upwelling‐favorable conditions all year but has an annual cycle characterized by more upwelling‐favorable conditions from April to September, with a maximum in July, and less upwelling‐favorable conditions from October to March, with a minimum in December to January. Although both indices can be used to characterize the phenomenon, only UIW values were used to quantify upwelling change during the four decades under review because this index is less sensitive to external factors compared to UISST. A strong decrease in upwelling intensity has been observed in all seasons. In particular, the summer (winter) decrease is on the order of 45% (20%) of the mean amplitude of the upwelling cycle.
Ships' Logbooks in Climatological Research
Authors: Wheeler Dennis , García‐Herrera Ricardo
Published: August 2009

This paper traces the history of the use of ships' logbooks in climatological studies from the earliest days of the 17th century to the present day. Although early theories concerning global air circulations by Halley and Hadley were based on information gathered by mariners and recorded in their logbooks, it has only been in the last two decades that interest has returned to this important, but long‐overlooked, source of climatic information. Attention is drawn to the many advantages offered by logbooks, in particular the long period of time that they collectively cover, their near‐global geographic range, the large number of such documents that have survived, and the degree of detailed and reliable record that they provide. Before the mid‐19th century, much of the recorded information is noninstrumental in character but its scientific potential is reflected in the variety of approaches and methods that have been used in its analysis and in the equally wide range of outcomes, from databases to synoptic charts and long‐time series indices that have emerged from the most recent research. Attention is also drawn to the benefits to be derived from old and more recent instrumental logbook data. As only a small percentage of the tens of thousands of logbooks that have been preserved have thus far been examined, the potential for yet further development is enormous.
The ENSO Signal in the Stratosphere
Authors: Calvo Natalia , García‐Herrera Ricardo , Garcia Rolando R.
Published: August 2009

Although the El Niño–Southern Oscillation (ENSO) is a tropospheric phenomenon, its effects are also observed in the stratosphere. Traditionally, the study of ENSO above the troposphere has been difficult because of the lack of global observations at high altitudes and also because of the presence of other sources of variability whose signals are difficult to disentangle from ENSO effects. Recent work with general circulation models that isolate the ENSO signal have demonstrated its upward propagation into the stratosphere. Here we review the literature in this field and show results from the most recent version of the Whole Atmosphere Community Climate Model to illustrate the propagation and the mechanisms whereby the signal manifests itself in the stratosphere. The ENSO signal propagates upward to about 40 km by means of large‐scale Rossby waves. The propagation is strongly influenced by the zonal mean zonal winds. Most of the strong ENSO events tend to peak in the boreal winter and so the ENSO signal is observed mainly at high latitudes during the Northern Hemisphere winter where the winds are westerly and allow Rossby wave propagation. The ENSO signal is also identified at polar latitudes in the Northern Hemisphere winter in the form of warmer temperatures and weaker winds during a strong El Niño event. This signal shows a zonally homogeneous behavior from the intensification of the stratospheric meridional circulation (in which air rises in the tropics and moves toward the winter pole where it descends) forced by anomalous propagation and dissipation of Rossby waves at middle latitudes during strong ENSO events.
The Impact of North Atlantic Wind and Cyclone Trends on European Precipitation and Significant Wave Height in the Atlantic
Authors: Trigo Ricardo M. , Valente Maria A. , Trigo Isabel F. , Miranda Pedro M. A. , Ramos Alexandre M. , Paredes Daniel , García‐Herrera Ricardo
Published: August 2009

An analysis of the frequency of cyclones and surface wind velocity for the Euro–Atlantic sector is performed by means of an objective methodology. Monthly and seasonal trends of cyclones and wind speed magnitude are computed and trends between 1960 and 2000 evaluated. Results reveal a significant frequency decrease (increase) in the western Mediterranean (Greenland and Scandinavia), particularly in December, February, and March. Seasonal and monthly analysis of wind magnitude trends shows similar spatial patterns. We show that these changes in the frequency of low‐pressure centers and the associated wind patterns are partially responsible for trends in the significant height of waves. Throughout the extended winter months (October–March), regions with positive (negative) wind magnitude trends, of up to 5 cm/s/year, often correspond to regions of positive (negative) significant wave height trends. The cyclone and wind speed trends computed for January–March are well matched by the corresponding trends in significant wave height, with February being the month with the highest trends (negative south of lat 50°N up to −3 cm/year, and positive up to 5 cm/year just north of Scotland). Trends in European precipitation are assessed using the Climatic Research Unit data set. The results of the assessment emphasize the link with the corresponding tendencies of cyclone frequencies. Finally, it is shown that these changes are associated, to a large extent, with the preferred phases of major large‐scale atmospheric circulation modes, particularly with the North Atlantic Oscillation, the eastern Atlantic pattern, and the Scandinavian pattern.
A Climatology Based on Reanalysis of Baroclinic Developmental Regions in the Extratropical Northern Hemisphere
Authors: De La Torre Laura , Nieto Raquel , Noguerol Marta , Añel Juan Antonio , Gimeno Luis
Published: August 2009

Regions of the occurrence of different phenomena related to the development of baroclinic disturbances are reviewed for the Northern Hemisphere extratropics, using National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis data. The occurrence of height lows appears to be related to the orography near the earth's surface and with surface‐ and upper‐air cyclogenesis in the upper troposphere. Over the cyclone tracks, the surface maxima appear to be trapped by land masses, whereas over the Mediterranean Sea they are located on the lee side of mountain ranges. The forcing terms of the geopotential tendency and omega equations mark the genesis (and, by the vorticity advection terms, the path) of the extratropical cyclones on the storm track. They occur mostly over the western coast of the oceans, beginning and having maxima on the lee side of the Rocky Mountains and the Tibetan Plateau. Their associated fronts form from the cold air coming from the continents and converging with the warm air over the Gulf and Kuroshio currents. Evident trends are found only for the Atlantic cyclone track (positive) and the Pacific cyclone track (negative) until the last decade when the tendency reverses. Over the southern Pacific, the number of fronts is lower during 1978–1997, coinciding with a period of strong El Niño Southern Oscillation episodes. This information is important for validating numerical models in order to predict changes associated with climate change and to study the behavior of extratropical cyclones and fronts.