bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and Functional Cellular Alterations Underlying the Toxicity of Methamphetamine in Rat Retina and Prefrontal Cortex
Authors: PRUDÊNCIO CRISTINA , ABRANTES BRUNO , LOPES ISABEL , TAVARES MARIA AMÉLIA
Published: July 2010

Abstract:The consumption of illicit drugs is an increasing problem in contemporary societies, and is one of the major causes of death and illness all over the world. Methamphetamine is among the drugs more widely used. Although evidence for a role of reactive species—especially reactive oxygen species (ROS) and apoptotic events—has been shown, the mechanism(s) underlying the cellular toxicity induced by this drug is not yet fully identified. In this context the elucidation of the cytotoxic effects induced by methamphetamine in rat frontal cortex and retina, which compromise cell viability and ultimately result in cell death, can further contribute to the understanding of its mechanism of action. This knowledge may provide new insights into the development of new therapeutic approaches to prevent or ameliorate deleterious alterations of the nervous system. The use of epifluorescence microscopy associated with different fluorescent probes, markers of structural and/or functional cell parameters, can be used as a powerful tool to carry out those studies, in particular, the viability probes propidium iodide (PI) to assess plasma membrane integrity and fluorescein diacetate (FDA), which can monitor intracellular esterase activity and/or pH. In a preliminary study, the kinetic assessment of cellular changes induced by different drug concentrations (0, 1.2, 3, and 6 mM) allowed detection of dose‐dependent alterations that are observed earlier in the retina. In fact, in the retina it was possible to monitor alterations (at 4 h of incubation) both in plasma membrane integrity and in esterase activity and/or pH for the lowest drug concentration (1.2 mM). In the prefrontal cortex these changes were only visible for drug concentrations ≥3 mM. This work is a novel approach to the mechanisms of action of illicit drugs in the central nervous system and will provide the foundations and guidelines for further investigations in the context of tolerance, dependence, and addiction.
PPARs: Transcription Factors Controlling Lipid and Lipoprotein Metabolism
Authors: BOCHER VIRGINIE , PINEDA‐TORRA INÉS , FRUCHART JEAN‐CHARLES , STAELS BART
Published: July 2010

Abstract: Nuclear receptors are transcription factors that are activated by ligands and subsequently bind to regulatory regions in target genes, thereby modulating their expression. Nuclear receptors thus allow the organism to integrate signals coming from the environment and to adapt by modifying the expression levels of relevant genes. The peroxisome proliferator‐activated receptors (PPARs) α, β/δ, and γ constitute a subfamily of nuclear receptors. PPARα has been shown to bind and to be activated by leukotriene B4 and the hypolipidemic drugs of the fibrate class; PPARβ/δ ligands are polyunsaturated fatty acids and prostaglandins; while prostaglandin J2 derivatives and the antidiabetic glitazones are, respectively, natural and synthetic ligands for PPARγ. Upon binding and activation by their ligands, they regulate the transcription of numerous genes involved in intracellular lipid metabolism, lipoprotein metabolism, and reverse cholesterol transport in a subtype‐ and tissue‐specific manner. PPARs therefore constitute interesting targets for the development of therapeutic compounds useful in the treatment of disorders of lipid and lipoprotein metabolism.
Hyperglycemia and Insulin Resistance: Possible Mechanisms
Authors: TOMÁS EVA , LIN YEN‐SHOU , DAGHER ZEINA , SAHA ASISH , LUO ZHIJUN , IDO YASUO , RUDERMAN NEIL B.
Published: July 2010

Abstract: Sustained hyperglycemia impairs insulin‐stimulated glucose utilization and glycogen synthesis in human and rat skeletal muscles, a phenomenon referred to clinically as glucose toxicity. In rat extensor digitorum longus (EDL) muscle preparations preincubated for 2‐4 h in a hyperglycemic medium (25 mM vs. 0 mM glucose), we have shown that the ability of insulin to stimulate glucose incorporation into glycogen is impaired. Interestingly, this was associated with a decreased activation of Akt/PKB, but not its upstream regulator, PI3‐kinase. A similar pattern of signaling abnormalities has been observed in adipocytes, L6 muscle cells, C2C12 cells, and (as reported here) EDL incubated with C2‐ceramide. On the other hand, no increase was observed in ceramide mass in EDL incubated with 25 mM glucose. Hyperglycemia‐induced insulin resistance also has been described in adipocytes, where it has been linked to activation of novel and conventional protein kinase C isoforms that phosphorylate the insulin receptor and IRS. In addition, we have recently shown that hyperglycemia causes insulin resistance in cultured human umbilical vein endothelial cells (HUVEC). Here, it was associated with an increased propensity to apoptosis and, as in muscle, with an impaired ability of insulin to activate Akt. Interestingly, these effects of hyperglycemia and an increase in diacylglycerol synthesis, which is also caused, were prevented by adding AICAR, an activator of AMP‐activated protein kinase (AMPK), to the incubation medium. These results suggest that hyperglycemia causes insulin resistance in cells other than those in classic insulin target tissues. Whether AMPK activation can reverse or prevent insulin resistance in all of these cells remains to be determined.
Free Fatty Acid Metabolism in Human Skeletal Muscle Is Regulated by PPARγ and RXR Agonists
Authors: CIARALDI THEODORE P. , CHA BONG‐SOO , PARK KYONG‐SOO , CARTER LESLIE , MUDALIAR SUNDER R. , HENRY ROBERT R.
Published: July 2010

Abstract: Free fatty acid (FFA) oxidation in human skeletal muscle cells can be stimulated, both independently and in a synergistic manner, by agonists for PPARγ and RXR. Increased FFA disposal in muscle through augmented oxidation could reduce intramyocellular lipid accumulation. The abilities of such agents to improve glucose tolerance and insulin action may thus involve effects on both glucose and FFA metabolism.
Genetic and Molecular Analyses of Complex Metabolic Disorders: Genetic Linkage
Authors: MENZEL S.
Published: July 2010

Abstract: Wide efforts have taken place with complex metabolic disorders to emulate the success that linkage analysis has had in explaining the nature of monogenic metabolic diseases such as MODY (maturity‐onset diabetes of the young) and FH (familial hypercholesterolemia). New linkage methods are being specifically developed and tested for complex disorders since some of the basic assumptions of traditional linkage analysis used with Mendelian traits are not valid. The nature of complex diseases precludes the use of extended families under the hypothesis that the same disease allele acts in most affected individuals throughout a pedigree. Rather, a multitude of genes and of rare and common alleles creates an apparently chaotic pattern of heterogeneity within and between families. Therefore, very simple family structures, in many studies even isolated sibling pairs, form the basis of efforts to compare the inheritance of disease with that of the chromosomal regions under investigation. Also, assumptions about how individual loci contribute to the overall disease inheritance used for the models applied in linkage computation have to be kept to a minimum. The overall effect of this, together with the potentially weak influence of many loci, is a heavy toll on the statistical power to detect individual contributing genes. This may be the reason why very few scans so far have yielded disease loci that meet genome‐wide significance criteria. The confirmation of original loci in secondary studies has proven, as predicted, to be very difficult. Nevertheless, the overall emerging picture is very encouraging: one of the genome scans in type 2 diabetes has been carried through to the positional cloning of the underlying genetic variant, namely, the calpain 10‐associated polymorphism in type 2 diabetes. Several other loci have been detected repeatedly throughout studies in various human racial groups, such as the chromosome 1q and 20q diabetes loci, and have become the target of collaborative fine‐mapping efforts. Modifications to present methodology are in development with the goal to increase statistical power: examples are the use of intermediate traits with potentially increased genetic homogeneity, the investigation of admixed populations, and the study of linkage disequilibrium over wide genomic regions.
Type of Dietary Fat and Insulin Resistance
Authors: RIVELLESE ANGELA A. , DE NATALE CLAUDIA , LILLI STEFANIA
Published: July 2010

Abstract: Animal studies have already shown the possibility to modulate insulin action by changing not only the amount of total fat, but also the type of fat. In these studies, saturated fat significantly increased insulin resistance, long‐ and short‐chain ω3 fatty acids significantly improved it, whereas the effects of monounsaturated and ω6 polyunsaturated fatty acids ranged somewhere in between the two. A recent multicenter study (the Kanwu study) on humans has shown that shifting from a diet rich in saturated fatty acids to one rich in monounsaturated fat improved insulin sensitivity in healthy people, while a moderate ω3 supplementation did not affect it; this second finding confirms previous results in type 2 diabetic patients with hypertriglyceridemia. There are also other aspects of the metabolic syndrome that can be influenced by the different type of dietary fat, particularly blood pressure and lipid metabolism. With respect to blood pressure, the majority of studies show that ω3 fatty acids are able to reduce blood pressure in hypertensive patients, but not in normotensive individuals; this result has been confirmed also by the Kanwu study, where no changes in blood pressure were seen after ω3 supplementation in healthy people. On the other hand, in this study, the change from saturated to monounsaturated fatty acids was able to significantly reduce diastolic blood pressure. As to the lipid abnormalities more frequently present in the metabolic syndrome (i.e., hypertriglyceridemia and low HDL cholesterol), the main effects are related to ω3 fatty acids, which surely reduce triglyceride levels, but at the same time increase LDL cholesterol. In conclusion, there is so far sound evidence in humans that the quality of dietary fat is able to influence insulin resistance and some of the related metabolic abnormalities.
Comparison of the Extrapancreatic Action of BRX‐220 and Pioglitazone in the High‐Fat Diet‐Induced Insulin Resistance
Authors: ŠEBÖKOVÁ ELENA , KÜRTHY MARIA , MOGYOROSI T. , NAGY KAROLY , DEMCÁKOVA EDITA , UKROPEC JOZEF , KORANYI LASZLO , KLIMEŠ IWAR
Published: July 2010

Abstract: A new Biorex molecule, BRX‐220, has been shown to be effective in animal models of diabetic neuro‐ and retinopathy. Recent in vitro studies showed that it might also have an insulin‐sensitizing action. Therefore, the effect of BRX‐220 on insulin sensitivity was compared with the action of pioglitazone (PGZ) in high fat (HF) diet‐induced insulin resistance (IR) of rats. Methods—Male Wistar rats were fed for 3 weeks a standard chow (PD) or the HF (70‐cal%) diet. The HF‐fed rats were also given daily BRX‐220 (20 mg/kg BW) or PGZ (6 mg/kg BW) by gavage. In vivo insulin action was assessed by the euglycemic hyperinsulinemic clamp. Glucose, insulin, FFA, triglyceride (TG), and glycerol levels in blood were also measured, as well as tissue TG content. Results—Increased levels of fed TG in circulation after HF diet (PD: 2.0±0.2 vs. HF: 5.0±0.8 mmol/L) were partially corrected by BRX‐220 (HF + BRX: 3.8±0.3) and normalized by PGZ (HF + PGZ: 2.6±0.3). Both molecules prevented the increase in fed serum FFA levels after HF diet (PD: 0.5±0.06; HF: 1.8±0.2 mmol/L), with a more pronounced effect of PGZ (HF + BRX: 1.2±0.1; HF + PGZ: 0.7±0.06). Tissue TG levels increased significantly in response to HF feeding in both liver (HF: 16±3.0; PD: 6.4±1.1 μmol/g) and skeletal muscle (HF: 7.7±1.2; PD: 2.4±0.4). This increase was completely normalized by both agents in the liver (HF + BRX: 8.8±0.8; HF + PGZ: 8.8±1.0), and only partially in the skeletal muscles. HF diet‐induced in vivo IR (PD: 25.4±0.5; HF: 15.7±0.5 mg/kg/min) was significantly reduced by BRX‐220 (HF + BRX: 18.7±0.3) and PGZ (HF + PGZ: 22.8±0.4) treatment. Conclusions—(1) Subchronic administration of BRX‐220 leads to an improvement of in vivo insulin action. (2) This insulin‐sensitizing effect is, however, not as pronounced as that of PGZ. (3) It is accompanied by a decrease of circulating TG and FFA levels in the postprandial state and (4) by lower TG content in liver and skeletal muscle.
Impaired Endothelial Function of Thoracic Aorta in Hereditary Hypertriglyceridemic Rats
Authors: TÖRÖK J. , BABÁL P. , MATUŠKOVÁ J. , LUPTÁK I. , KLIMEŠ I. , ŠIMKO F.
Published: July 2010

Abstract:Objective—Hereditary hypertriglyceridemia (hHTG) in rats was found to be associated with metabolic abnormalities and elevation of blood pressure. There is controversy regarding the relation between hHTG and vascular function. The aim of this study was to determine the reactivity and accompanying structural changes in thoracic aorta from hereditary hypertriglyceridemic rats and hHTG rats that were given, for a long time,NG‐nitro‐l‐arginine methyl ester (L‐NAME) with and without simultaneous captopril treatment.Methods—Isolated rings of thoracic aorta were mounted in organ chambers for isometric tension recording or for measurement of endothelium‐dependent relaxation. Morphological changes of thoracic aorta (wall thickness, diameter) were measured using light microscopy.Results—Endothelium‐dependent relaxation (EDR) to acetylcholine (ACh, 10−5M) was significantly attenuated in the hHTG group compared to control Wistar rats (59.3 ± 8.5% vs. 95.8 ± 6.5%,p< 0.001), but normalized after pretreatment with captopril. EDR to ACh was further inhibited in hHTG rats treated with L‐NAME (36.0 ± 2.3%,p< 0.001). Maximum residual relaxation was only partly restored with captopril treatment (72.4 ± 5.8%,p< 0.001). Hypertriglyceridemia did not significantly alter the sensitivity of the thoracic aorta to exogenous noradrenaline. The diameter/wall thickness (D/W) ratio in aortas of control Wistar rats averaged 16.25 ± 0.57. This ratio was significantly lower in hHTG rats (12.52 ± 0.38,p< 0.01) and was not altered after treatment with captopril. In the hHTG rats treated with L‐NAME, the D/W ratio was further significantly decreased (8.25 ± 0.30,p< 0.001). Simultaneous captopril treatment attenuated the decrement of this ratio (9.80 ± 0.75,p< 0.05).Conclusions—Results showed that hHTG is accompanied by functional and morphological alterations in the rat thoracic aorta. These changes in hHTG and in hHTG rats treated with L‐NAME could be, at least in part, protected by captopril treatment.
Lipids and Insulin Resistance: What We've Learned at the Fourth International Smolenice Symposium
Authors: RAVUSSIN E. , KLIMEŠ I. , ŠEBÖKOVÁ E. , HOWARD B. V.
Published: July 2010

Abstract: A summary of the Fourth International Smolenice Symposium on Lipids and Insulin Resistance focusing on “The Role of Fatty Acid Metabolism and Fuel Partitioning” is provided. Highlights and issues of the conference are mentioned, as well as strategies for the future.
Probing Ion Binding Sites in the Na+/Ca2+ Exchanger
Authors: SHIGEKAWA MUNEKAZU , IWAMOTO TAKAHIRO , UEHARA AKIRA , KITA SATOMI
Published: July 2010

Abstract: The membrane domain of the Na+/Ca2+ exchanger (NCX) contains two conserved internal repeat sequences, designated the α‐1 and α‐2 repeats. We have studied the topological disposition of residues in the α repeats and a neighboring region by substituted cysteine accessibility scanning as well as the functional importance of these residues by kinetically evaluating transport activities of cysteine‐substituted or other site‐directed NCX1 mutants. The results suggest that the α‐1 repeat contains a reentrant loop originating from extracellular side of the membrane, while the α‐2 repeat and its neighboring region contain a complex reentrant loop structure originating from the cytoplasmic side. We identified several residues in the α‐1 repeat loop whose mutation caused significant alterations in the interaction of NCX1 with a transport substrate Ca2+o and inhibitory ions Ni2+ and Co2+. On the other hand, we found residues in the α‐2 repeat loop region whose mutation altered the interaction with an activating ion Li+ and an inhibitory drug KB‐R7943 in addition to the effect on Ca2+o and Ni2+. Collectively, our data suggest that these α‐repeat regions participate in the formation of ion translocation pathway of the exchanger and that the α‐1 repeat loop plays an important role in ion selection.
Stoichiometry of the Na+/Ca2+ Exchanger
Authors: MATSUOKA SATOSHI
Published: July 2010

Abstract: We reevaluated the exchange stoichiometry of the Na+/Ca2+ exchange current by measuring its reversal potential. The exchange current was measured from the inside‐out macropatch excised from intact sarcolemma of guinea pig ventricular myocytes. This method provides more accurate control of extracellular and cytoplasmic ion concentrations and of membrane potential than is possible with a whole‐cell clamped preparation. The exchange current was isolated as exchanger inhibitory peptide (XIP)‐sensitive current or as cytoplasmic Na+‐ and Ca2+‐induced current. The reversal potential of the Na+/Ca2+ exchange current was, for the most part, close to the equilibrium potential of the 4Na+:1Ca2+ exchange, although it tended to get closer to that of 3Na+: 1Ca2+ exchange at lower Na+ concentrations. We concluded that the stoichiometry is 4 or that it may vary depending on the cytoplasmic Na+. The 4Na+:1Ca2+ exchange was further studied with computer modeling. A consecutive 4Na+:1Ca2+ exchange model with two active states and two inactive states (E2 model) could not well reconstruct the current‐voltage relation of the exchanger. However, a consecutive 4Na+:1Ca2+ exchange model with 10 active states and 2 inactive states (E10 model), which included voltage‐dependent Na+ and Ca2+ occlusions, well simulated the current‐voltage relation. Implications of 4Na+:1Ca2+ exchange is also discussed.
Functional Regulation of Alternatively Spliced Na+/Ca2+ Exchanger (NCX1) Isoforms
Authors: SCHULZE D. H. , POLUMURI S. K. , GILLE T. , RUKNUDIN A.
Published: July 2010

Abstract: Alternative splicing of RNA transcripts is a general characteristic for NCX genes in mammals, mollusks, and arthropods. Among the family of three NCX genes in mammals, the NCX1 gene contains six exons, namely, A, B, C, D, E, and F, that make up the alternatively spliced region. Studies of the NCX1 gene transcripts suggested that 16 distinct gene products can be produced from the NCX1 gene. The exons A and B are mutually exclusive when expressed. Generally, exon A‐containing transcripts are predominantly found in excitable cells like cardiomyoctes and neurons, whereas exon B‐containing transcripts are mostly found in nonexcitable cells like astrocytes and kidney cells. Other alternatively spliced exons (C‐F) appear to be cassette‐type exons and are found in various combinations. Interestingly, exon D is present in all characterized transcripts. The alternatively spliced isoforms of NCX1 show tissue‐specific expression patterns, suggesting functional adaptation to tissues. To investigate functional differences among alternatively spliced isoforms of NCX1, we expressed an exon A‐containing transcript present in cardiac tissue (NCX1.1) and an exon B‐containing transcript found in the kidney (NCX1.3) in Xenopus oocytes. We demonstrated that the Na+/Ca2+ exchangers expressed by exon A‐ and exon B‐containing transcripts display differences in activation by PKA and by [Ca2+]i. We also observed that these two isoforms show differences in voltage dependence. Suprisingly, the alternatively spliced isoforms of NCX1 display greater functional differences among themselves than the products of different gene loci, NCX1, NCX2, and NCX3.
Enhanced Sodium‐Calcium Exchange in the Infarcted Heart
Authors: LITWIN SHELDON E. , ZHANG DONGFANG
Published: July 2010

Abstract: Arrhythmias and contractile dysfunction both contribute to the high morbidity and mortality in patients with congestive heart failure. Contractile dysfunction is generally believed to reflect a decrease in the amplitude of intracellular Ca2+ transients, whereas tachyarrythmias are often initiated in the setting of cellular Ca2+ overload. In a rabbit model of left ventricular dysfunction due to myocardial infarction, we found evidence that myocyte sarcoplasmic reticulum Ca2+ content may be normal or even increased at slow stimulation rates. This may occur because prolonged action potential duration promotes Ca2+ influx via the Na+/Ca2+ exchanger. Despite preserved SR Ca2+ content, intracellular Ca2+ transients and contractions may be reduced in amplitude because of impaired synchronization of Ca2+ release events throughout the myocyte.
Modulation of Contractility in Failing Human Myocytes by Reverse‐Mode Na/Ca Exchange
Authors: PIACENTINO VALENTINO , WEBER CHRISTOPHER R. , GAUGHAN JOHN P. , MARGULIES KENNETH B. , BERS DONALD M. , HOUSER STEVEN R.
Published: July 2010

Abstract: A decrease in the peak systolic [Ca]i and slow decay of the Cai transient are common features of the end‐stage failing human ventricular myocyte and may underlie the contractile abnormalities observed in congestive heart failure. The role of the Na/Ca exchanger has been a great area of interest given the changes observed at the molecular level. Results from these experiments have been inconsistent, however, and therefore cellular‐based experiments may be required to characterize the role of the Na/Ca exchanger in failing human myocardium. We review recent data that suggest an increased ability of the Na/Ca exchanger to transport Ca into the cytoplasm in failing human myocytes. We hypothesize that this increased Ca influx can explain the slowed decay and impaired relaxation of failing human ventricular myocytes.
Results of Long‐Term Experimental Studies on the Carcinogenicity of Formaldehyde and Acetaldehyde in Rats
Authors: SOFFRITTI MORANDO , BELPOGGI FIORELLA , LAMBERTIN LUCA , LAURIOLA MICHELINA , PADOVANI MICHELA , MALTONI CESARE
Published: July 2010

Abstract: Formaldehyde was administered for 104 weeks in drinking water supplied ad libitum at concentrations of 1500, 1000, 500, 100, 50, 10, or 0 mg/L to groups of 50 male and 50 female Sprague‐Dawley rats beginning at seven weeks of age. Control animals (100 males and 100 females) received tap water only. Acetaldehyde was administered to 50 male and 50 female Sprague‐Dawley rats beginning at six weeks of age at concentrations of 2,500, 1,500, 500, 250, 50, or 0 mg/L. Animals were kept under observation until spontaneous death. Formaldehyde and acetaldehyde were found to produce an increase in total malignant tumors in the treated groups and showed specific carcinogenic effects on various organs and tissues.
Carcinogenicity of Methyl‐Tertiary Butyl Ether in Gasoline
Authors: MEHLMAN MYRON A.
Published: July 2010

Abstract: Methyl tertiary butyl ether (MTBE) was added to gasoline on a nationwide scale in 1992 without prior testing of adverse, toxic, or carcinogenic effects. Since that time, numerous reports have appeared describing adverse health effects of individuals exposed to MTBE, both from inhalation of fumes in the workplace and while pumping gasoline. Leakage of MTBE, a highly water‐soluble compound, from underground storage tanks has led to contamination of the water supply in many areas of the United States. Legislation has been passed by many states to prohibit the addition of MTBE to gasoline. The addition of MTBE to gasoline has not accomplished its stated goal of decreasing air pollution, and it has posed serious health risks to a large portion of the population, particularly the elderly and those with respiratory problems, asthma, and skin sensitivity. Reports of animal studies of carcinogenicity of MTBE began to appear in the 1990s, prior to the widespread introduction of MTBE into gasoline. These reports were largely ignored. In ensuing years, further studies have shown that MTBE causes various types of malignant tumors in mice and rats. The National Toxicology Program (NTP) Board of Scientific Counselors' Report on Carcinogens Subcommittee met in December 1998 to consider listing MTBE as “reasonably anticipated to be a human carcinogen.” In spite of recommendations from Dr. Bailer, the primary reviewer, and other scientists on the committee, the motion to list MTBE in the report was defeated by a six to five vote, with one abstention. On the basis of animal studies, it is widely accepted that if a chemical is carcinogenic in appropriate laboratory animal test systems, it must be treated as though it were carcinogenic in humans. In the face of compelling evidence, NTP Committee members who voted not to list MTBE as “reasonably anticipated to be a human carcinogen” did a disservice to the general public; this action may cause needless exposure of many to health risks and possibly cancers.
Carcinogenicity and Mechanistic Insights on the Behavior of Epoxides and Epoxide‐Forming Chemicals
Authors: MELNICK RONALD L.
Published: July 2010

Abstract: Many epoxides and their precursors are high production volume chemicals that have major uses in the polymer industry and as intermediates in the manufacture of other chemicals. Several of these chemicals were demonstrated to be carcinogenic in laboratory animal studies conducted by the Ramazzini Foundation (e.g., vinyl chloride, acrylonitrile, styrene, styrene oxide, and benzene) and by the National Toxicology Program (e.g., ethylene oxide, 1,3‐butadiene, isoprene, chloroprene, acrylonitrile, glycidol, and benzene). The most common sites of tumor induction were lung, liver, harderian gland, and circulatory system in mice; Zymbal's gland and brain in rats; and mammary gland and forestomach in both species. Differences in cancer outcome among studies of epoxide chemicals may be related to differences in study design (e.g., dose, duration, and route of exposure; observation period; animal strains), as well as biological factors affecting target organ dosimetry of the DNA‐reactive epoxide (toxicokinetics) and tissue response (toxicodynamics). N7‐Alkylguanine, N1‐alkyladenine, and cyclic etheno adducts, as well as K‐ras and p53 mutations, have been detected in animals and/or workers exposed to several of these chemicals. The classifications of these chemical carcinogens by IARC and NTP are based on animal and human data and results of mechanistic studies. Reducing occupational and environmental exposures to these chemicals will certainly reduce human cancer risks.
Contextual Inhibitory Gating of Impulse Traffic in the Intra‐amygdaloid Network
Authors: PARÉ DENIS , ROYER SÉBASTIEN , SMITH YOLAND , LANG ERIC J.
Published: July 2010

Abstract:New data on the organization of the intra‐amygdaloid circuit is reviewed, beginning with the basolateral (BL) complex, the main input station of the amygdala for sensory afferents, and concluding with the central (CE) nucleus, an important source of projections to brain‐stem structures mediating fear responses. The BL complex is endowed with a highly divergent system of intrinsic glutamatergic connections. Yet, BL projection cells have unusually low firing rates. This apparent contradiction is explained by the presence of powerful inhibitory pressures in the BL amygdala: (1) interneurons that generate large‐amplitude inhibitory synaptic potentials and (2) projection cells that express a Ca2+‐dependent K+current that can be activated by subthreshold synaptic inputs. Likewise, excitatory projections from the BL amygdala to the CE nucleus are controlled by clusters of GABAergic neurons, termed the intercalated (ITC) cell masses. In response to BL inputs, ITC cells generate feedforward inhibition in CE neurons. However, ITC neurons exhibit properties that allow them to modify the amount of inhibition they generate depending on the distribution of BL activity in space and time. Indeed, ITC cell masses can inhibit each other via lateromedial connections. Moreover, they express an unusual K+conductance that modifies their response to BL inputs depending on their recent firing history. Thus, inhibitory mechanisms of the amygdala allow for flexible, context‐dependent gating of BL impulses to the CE nucleus.
Role of the Amygdala in Fear Extinction Measured with Potentiated Startle
Authors: DAVIS MICHAEL , WALKER DAVID L. , MYERS KARYN M.
Published: July 2010

Abstract: Although much is now known about the neural basis of excitatory fear conditioning, much less is known about the neural basis of inhibitory conditioning. One type of inhibitory conditioning is extinction, a process in which stimuli that elicit fear by virtue of previous associations with aversive stimuli such as shock (excitatory fear conditioning) are now presented in the absence of the aversive stimuli (extinction training). As a result, the ability of the conditioned stimulus to elicit fear gradually diminishes. Extinction is different from forgetting and does not reflect an erasure of the original fear memory. Instead, extinction is an active form of inhibitory learning that competes with excitatory fear conditioning. Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA‐receptor‐linked mitogen‐activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist D‐cycloserine facilitates extinction after either systemic administration or intra‐amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because D‐cycloserine is a widely available and safe compound, D‐cycloserine or similar agents might be usefully combined with traditional extinction‐based approaches in the treatment of clinical fear.
Inhibition of the Amygdala: Key to Pathological States?
Authors: QUIRK GREGORY J. , GEHLERT DONALD R.
Published: July 2010

Abstract:The amygdala plays an important role in associating sensory stimuli with aversive or appetitive outcomes. Conditioning procedures potentiate inputs to the amygdala, which facilitate emotional responses via subcortical and cortical outputs. Powerful inhibitory circuits exist that control expression of conditioned responses in the amygdala, including inhibition from prefrontal cortex. Deficient inhibitory tone in the amygdala could lead to overexpression of conditioned responses, producing pathological states such as anxiety disorders and drug‐seeking behavior. Support for this comes from several lines of animal research: (1) GABA antagonist‐induced priming of anxiety states, (2) extinction of conditioned fear, (3) modulation of inhibitory avoidance memory, and (4) cue‐induced reinstatement of drug seeking. Cue‐induced craving in humans is associated with feelings of fear and autonomic arousal, suggesting a link between fear and addiction in the amygdala. Future therapies aimed at increasing inhibitory tone in the amygdala, either locally or via the prefrontal cortex, may prevent anxiety disorders and addiction relapse. Novel neuropeptides, which can either excite or inhibit specific components of anxiety responses, offer promise in this regard.
Brain Imaging Studies in Mood and Anxiety Disorders
Authors: ANAND AMIT , SHEKHAR ANANTHA
Published: July 2010

Abstract: Human studies attempting to elucidate brain functioning in health and disease are crucial for our understanding of neuropsychiatric disorders. In the past, scientists relied heavily on neurological lesion studies to understand the functional roles of brain areas. In the last few decades, brain imaging research has made it possible to investigate the molecular and synaptic neuronal events as well as the functioning of neuronal networks in vivo, in patients with neuropsychiatric illnesses. In this context, the functional role of the amygdala has been a focus of neuroimaging studies by leading researchers. Several of these researchers presented papers at a conference, entitled The Amygdala in Brain Function: Basic and Clinical Approaches, that provided the basis for this volume. These papers follow this review in the current volume. The present paper briefly summarizes the highlights of the different presentations, focusing on the functional diversity of the amygdala and its role in different neuropsychiatric disorders; reviews the various brain imaging technologies currently available; and discusses the major findings on the pathophysiology and treatment of depression, bipolar disorder, and anxiety disorders.
Actuarial Assessment of Risk among Sex Offenders
Authors: HARRIS GRANT T. , RICE MARNIE E.
Published: July 2010

Abstract:The appraisal of risk among sex offenders has seen recent advances through the advent of actuarial assessments. Statistics derived from Relative Operating Characteristics (ROCs) permit the comparison of predictive accuracies achieved by different instruments even among samples that exhibit different base rates of recidivism. Such statistics cannot, however, solve problems introduced when items from actuarial tools are omitted, when reliability is low, or when there is high between‐subject variability in the duration of the follow‐up. We present empirical evidence suggesting that when comprehensive actuarial tools (VRAG and SORAG) are scored with high reliability, without missing items, and when samples of offenders have fixed and equal opportunity for recidivism, predictive accuracies are maximized near ROC areas of 0.90. Although the term ‘dynamic’ has not been consistently defined, such accuracies leave little room for further improvement in long‐term prediction by dynamic risk factors. We address the mistaken idea that long‐term, static risk levels have little relevance for clinical intervention with sex offenders. We conclude that highly accurate prediction of violent criminal recidivism can be achieved by means of highly reliable and thorough scoring of comprehensive multi‐item actuarial tools using historical items (at least until potent therapies are identified). The role of current moods, attitudes, insights, and physiological states in causing contemporaneous behavior notwithstanding, accurate prediction about which sex offenders will commit at least one subsequent violent offense can be accomplished using complete information about past conduct.
Rape‐Law Reform circa June 2002
Authors: SCHULHOFER STEPHEN
Published: July 2010

Abstract:This paper reviews court decisions determining the scope of liability for rape over the period 1998–2002. It finds many troubling signs that some courts, under some circumstances, are still wedded to the traditional (very strict) view of the kind of force necessary to support a charge of rape. There are, however, signs of encouraging progress: convictions in circumstances where even a decision to prosecute would have been unthinkable 20 years ago, and holdings that accept power, authority, or indirect intimidation as sufficient ‘force.’ Is it possible to gotoo farin this direction? And is there any reason to worry that this could actually happen in reality? The research identifies several areas in which this surprising possibility may be about to materialize, for example on the normatively and practically difficult question of the degree of intoxication or alcohol‐induced willingness sufficient to invalidate consent.
Sexual Offender Containment
Authors: ENGLISH KIM , JONES LINDA , PATRICK DIANE , PASINI‐HILL DIANE
Published: July 2010

Abstract: Victims of sexual assault are unlikely to report the crime. For many sexual offenders, then, their sexually deviant behavior remains largely unknown except for crimes that result in arrest or notification to social services. Little is known about the offender's past behavior and little will be known about the offender's future abusive behavior. It is within this context that the containment approach for managing sexual offenders becomes critical to protecting future victimization by known offenders. This paper describes the need to incorporate information learned from the postconviction polygraph examination into intense treatment and criminal justice supervision. Age of onset and frequency and variety of deviant behavior are known risk factors, probably because they reflect the extent to which deviancy is part of the offender's lifestyle. Treatment and supervision plans must incorporate this information, along with the risk presented by these offenders to very specific age and gender groups. This study of data collected on disclosures made by 180 convicted sexual offenders (most were convicted of crimes against children) during the course of four different treatment/polygraph programs found that 39% had a history of sexually assaulting adults, 31% had sexually assaulted both male and female victims, 36% had engaged in bestiality, and two‐thirds of the incest offenders had assaulted victims outside the family. Complete information is necessary for treatment providers and supervising officers to develop meaningful and relevant treatment and supervision plans, and for imminent, situational risk factors to be managed and contained.
Apoptosis Inducing Factor and PARP‐Mediated Injury in the MPTP Mouse Model of Parkinson's Disease
Authors: WANG HONGMIN , SHIMOJI MIKA , YU SEONG‐WOON , DAWSON TED M. , DAWSON VALINA L.
Published: July 2010

Abstract: Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD‐like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP‐induced neurotoxicity are not yet fully understood but involve activation of N‐methyl‐D‐aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage‐sensing enzyme poly (ADP‐ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity‐induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.
Transgenic Models of α‐Synuclein Pathology
Authors: HASHIMOTO MAKOTO , ROCKENSTEIN EDWARD , MASLIAH ELIEZER
Published: July 2010

Abstract: Accumulation and toxic conversion to protofibrils of α‐synuclein has been associated with neurological disorders such as Parkinson's disease (PD), Lewy body disease, multiple system atrophy, neurodegeneration with brain iron accumulation type 1, and Alzheimer's disease. In recent years, modeling these disorders in transgenic (tg) mice and flies has helped improve understanding of the pathogenesis of these diseases and has established the basis for the development of new experimental treatments. Overexpression of α‐synuclein in tg mice in a region‐ and cell‐specific manner results in degeneration of selective circuitries accompanied by motor deficits and inclusion formation similar to what is found in PD and related disorders. Furthermore, studies in singly and doubly tg mice have shown that toxic conversion and accumulation can be accelerated by α‐synuclein mutations associated with familial parkinsonism, by amyloid β peptide 1–42 (Aβ 1–42), and by oxidative stress. In contrast, molecular chaperones such as Hsp70 and close homologues such as α‐synuclein have been shown to suppress toxicity. Similar studies are underway to evaluate the effects of other modifying genes that might play a role in α‐synuclein ubiquitination. Among them considerable interest has been placed on the role of molecules associated with familial parkinsonism (Parkin, UCHL‐1). Furthermore, studying the targeted overexpression of α‐synuclein and other modifier genes in the nigrostriatal and limbic system by using regulatable promoters, lentiviral vectors, and siRNA will help improve understanding of the molecular mechanisms involved in selective neuronal vulnerability, and it will aid the development of new treatments.
Microglial NADPH Oxidase Mediates Leucine Enkephalin Dopaminergic Neuroprotection
Authors: QIN LIYA , LIU YUXIN , QIAN XUN , HONG JAU‐SHYONG , BLOCK MICHELLE L.
Published: July 2010

Abstract:Here, we report that leucine enkephalin (LE) is neuroprotective to dopaminergic (DA) neurons at femtomolar concentrations through anti‐inflammatory properties. Mesencephalic neuron‐glia cultures pretreated with femtomolar concentrations of LE (10−15‐10−13M) protected DA neurons from lipopolysaccharide (LPS)‐induced DA neurotoxicity, as determined by DA uptake assay and tyrosine hydroxylase (TH) immunocytochemistry (ICC). However, des‐tyrosine leucine enkephalin (DTLE), an LE analogue that is missing the tyrosine residue required for binding to the kappa opioid receptor, was also neuroprotective (10−15‐10−13M), as determined by DA uptake assay and TH ICC. Both LE and DTLE (10−15‐10−13M) reduced LPS‐induced superoxide production from microglia‐enriched cultures. Further, both LE and DTLE (10−14, 10−13M) reduced the LPS‐induced tumor necrosis factor‐alpha (TNFα) mRNA and TNFα protein from PHOX+/+microglia, as determined by quantitative real‐time RT‐PCR and ELISA analysis in mesencephalic neuron‐glia cultures, respectively. However, both peptides failed to inhibit TNFα expression in PHOX−/−cultures, which are unable to produce extracellular superoxide in response to LPS. Additionally, LE and DTLE (10−14, 10−13M) failed to show any neuroprotection against LPS in PHOX−/−cultures. Together, these data indicate that LE and DTLE are neuroprotective at femtomolar concentrations through the inhibition of oxidative insult associated with microglial NADPH oxidase and the attenuation of the ROS‐mediated amplification of TNFα gene expression in microglia.
Early Effects of Modulating Nuclear Factor‐κB Activation on Traumatic Spinal Cord Injury in Rats
Authors: JIMÉNEZ‐GARZA OCTAVIO , CAMACHO JAVIER , IBARRA ANTONIO , MARTÍNEZ ANGELINA , GUÍZAR‐SAHAGÚN GABRIEL
Published: July 2010

Abstract: Genes regulated by NF‐κB play an important role on secondary damage and repair after spinal cord injury (SCI). To assess the early effects of the pharmacological inhibition and overactivation of NF‐κB, pyrrolidine dithiocarbamate (PDTC) or lipopolysaccharide were given to rats before or after SC contusion. The amount of spared SC tissue was higher (P < 0.05) at 24 h postinjury in rats posttreated with PDTC; both PDTC‐treated rats showed no significant trend to decrease polymorphonuclear infiltrate. p65 subunit was present in inflammatory cells, neurons, and astrocytes at the injury site. These data support further investigation on functional effects of NF‐κB inhibition in acute SCI.
The Antiapoptotic Actions of Mood Stabilizers
Authors: CHUANG DE‐MAW
Published: July 2010

Abstract:Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate‐induced,N‐methyl‐d‐aspartate (NMDA) receptor‐mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3‐kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain‐derived neurotrophic factor, heat‐shock protein (HSP), and Bcl‐2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase‐3 (GSK‐3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia‐induced brain infarction, caspase‐3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short‐term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl‐2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.
An Old Story with a New Twist: Do NMDAR1 mRNA Binding Proteins Regulate Expression of the NMDAR1 Receptor in the Presence of Alcohol?
Authors: KUMARI MEENA , ANJI ANTJE
Published: July 2010

Abstract:NMDA receptors not only play a pivotal role in normal physiological processes in the central nervous system (CNS), but have been identified as an important target of ethanol. Chronic exposure to ethanol induces a number of adaptive processes in the CNS, including an upregulation of NMDA receptor number and function. The increase in NMDA receptor number in response to chronic ethanol exposure bothin vivoandin vitrois accompanied by an increase in NMDAR1 and NMDAR2B polypeptide levels. It is widely believed that these adaptive changes play an important role in the development of alcohol dependence and withdrawal syndrome. At the molecular level, chronic ethanol exposure of fetal cortical neurons selectively increases expression of NMDAR1 splice variants lacking exon 5 and exon 22. Chronic ethanol exposure of fetal cortical neurons also increases NMDAR1 mRNA half‐life in these neurons. However, when new protein synthesis is inhibited, the half‐life of NR1 mRNA in these neurons returns to control values, strongly suggesting that ethanol induces the synthesis of protein(s) that may regulate the decay of NR1 mRNA. In recent years, it has become apparent that regulation of mRNA stability is an important aspect of regulation of gene expression. Changes in mRNA stability can be accomplished by interaction betweencis‐acting sequences in the 3′ untranslated region (3′UTR) of mRNAs andtrans‐acting proteins expressed in cells. Such interactions may protect RNAs from degradation by ribonucleases, thereby increasing the half‐life of mRNAs.