bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Factors Driving Emerging Infectious Diseases
Authors: Aguirre A. Alonso , Tabor Gary M.
Published: August 2009

The extinction of species across the globe is accelerating directly or indirectly from human activities. Biological impoverishment, habitat fragmentation, climate change, increasing toxification, and the rapid global movement of people and other living organisms have worked synergistically to diminish ecosystem function. This has resulted in unprecedented levels of disease emergence driven by human‐induced environmental degradation, which poses a threat to the survival and health of biodiversity. What is often overlooked in the discussion of the health consequences to humans is that critically endangered wildlife species are at grave risk of extinction by disease outbreaks. As habitat becomes more compressed and with migration routes cut off, gene pools of small species are stranded in isolated habitat fragments. Species now are vulnerable to encroachment, malnutrition, environmental pollutants, and epidemics from domestic animals and humans. Furthermore, the continuous degradation of ecosystems is leading to increased stress, immunosuppression, and greater susceptibility to disease. Disease can be catastrophic to a diminished stressed population, becoming in some instances the leading factor of local, regional, and global extinctions. The strategies of the new field of conservation medicine include long‐term monitoring, health assessment, and interventions to protect species at risk. We particularly must minimize the threat of any potentially catastrophic disease outbreaks resulting from anthropogenic changes to the environment. Current and future diagnostic molecular techniques offer new opportunities to identify tools for the management and possible treatment of diseases in imperiled species.
Study of Bovine Trypanotolerance by Whole Transcriptome Analysis
Authors: Berthier David , Chantal Isabelle , Thevenon Sophie , Sakande Hassane , Maillard Jean‐Charles , Bengaly Zakaria , Piquemal David , Marti Jacques , Cuny Gerard
Published: August 2009

African trypanosomiases are parasitic diseases transmitted by tse‐tse flies, considered as the main sanitary obstacle to animal production development in sub‐Saharan Africa. However, if trypanosomiases have dramatic consequences on zebu (Bos indicus) populations, they have a weaker impact on the western African taurine (Bos taurus), which is known to be naturally tolerant to trypanosome infection. Mechanisms governing this trypanotolerant trait are still poorly understood, but today, recent postgenomic biotechnologies, such as the SAGE technique (serial analysis of gene expression) allow us to explore the full transcriptome. Twelve SAGE libraries were constructed from two trypanotolerant animals (N'Dama and Baoulé) and one susceptible species of cattle (the Sudanese zebu) during an experimental Trypanosoma congolense infection; 43,458 different tags were obtained at several particular points during the infection (before infection, at the maximum of parasitemia, the maximum of anemia, and at the end of the experiment after value normalization). Bioinformatics analyses highlighted some interesting gene variations with respect to the trypanotolerance status of the animal.
First Report of Bovine Anaplasmosis Caused by Anaplasma centrale in Europe
Authors: Carelli Grazia , Decaro Nicola , Lorusso Eleonora , Paradies Paola , Elia Gabriella , Martella Vito , Buonavoglia Canio , Ceci Luigi
Published: August 2009

Anaplasma centrale (Rickettsiales: Anaplasmataceae) is used as a live vaccine for cattle against the pathogenic Anaplasma marginale in tropical and subtropical areas. Herein we report a clinical case of bovine anaplasmosis associated with A. centrale infection in Italy, together with the first molecular identification and phylogenetic analysis of this Anaplasma species or subspecies in Europe.
Infection and Seroconversion of Susceptible Animals Introduced into a Babesiosis Endemic Area
Authors: Lopez Martin , Figueroa Julio V. , Ramos Juan A. , Mosqueda Juan J. , Rojas Edmundo , Vega Carlos A. , Alvarez J. Antonio
Published: August 2009

The study aimed to determine the incubation period of Babesia sp. infection in naive cattle and to monitor the serological response once exposed to natural Boophilus microplus (Rhipicephalus microplus)‐infested paddocks. The study was carried out on a farm located in Veracruz, Mexico. Five groups of five steers were relocated every 3 months from a tick‐free area to a tick‐infested paddock. Animals were introduced in October, January, April, July, and October. Blood samples were taken daily until day 21 to determine packed cell volume (PCV), percentage of parasitized erythrocytes (PPE), and antibody titers to Babesia bigemina and B. bovis by the indirect fluorescent antibody procedure. Detection of Babesia in blood was also performed by species‐specific PCR. The estimated incubation period was 6–14 days post introduction to paddocks (PIP), with fever (41°C) for at least 3 days. PCV decreased by >25% and Babesia parasites were observed during the clinical phase of the disease. The highest individual PPEs (0.44% and 0.22% for B. bovis and B. bigemina, respectively) were observed from animals introduced in October. The four other groups showed a mean PPE ranging from 0.002–0.146% at day 14 PIP. All animals were detected as PCR positive between 8–14 days PIP. The highest antibody titers were 1:3328. The environmental conditions were favorable throughout the year for tick reproduction as the farm showed enzootic stability and hyperendemic conditions for bovine babesiosis. In this type of farm, strategic tick control could be accompanied by babesiosis vaccination, particularly for cattle relocated from tick‐free areas.
Immune Response of Theileria sp.‐infected Sheep to Recombinant Theileria Proteins
Authors: Seitzer Ulrike , Liu Zhijie , Yin Hong , Beyer Doreen , Kullmann Birgit , Miranda Joana , Ahmed Jabbar S.
Published: August 2009

Sheep and goats in northwest China suffer from theileriosis from infection with Theileria sp. (China), resulting in large economic losses. To investigate the immune response to infection with Theileria sp. (China), parameters of cellular and humoral immunity of experimentally infected sheep against two recombinantly expressed Theileria proteins were investigated. The in vitro proliferative response of blood mononuclear cells to a recombinant T. annulata membrane protein and a recombinant Theileria sp. (China) homologue to T. annulata surface protein, both putative membrane proteins, was significantly elevated and significant amounts of specific immunoglobulins were produced against both.
The Poultry Red Mite Dermanyssus gallinae as a Potential Carrier of Vector‐borne Diseases
Authors: De Luna Carlos J. , Arkle Samuel , Harrington David , George David R. , Guy Jonathan H. , Sparagano Olivier A. E.
Published: August 2009

The poultry red mite Dermanyssus gallinae is an obligatory blood‐sucking parasite that is considered to be one of the most important ectoparasites in the poultry industry, mainly because it is responsible for important economic losses, leads to a reduction of welfare of laying hens, and may pose a disease risk to humans. As a result of these problems, much of the current research on this parasite targets new methods of control. Less attention has been paid to the importance of D. gallinae as a carrier of vector‐borne diseases. Some authors have mentioned the possible involvement of D. gallinae in the transmission (both in vitro and directly isolated from the mites) of viral and bacterial agents. Our research group has demonstrated the presence of Mycobacterium spp. within D. gallinae. DNA coding for Mycobacterium spp. was successfully amplified from unfed adult D. gallinae, larvae, and eggs by using reverse transcription‐polymerase chain reaction targeting the 16S rRNA gene. The results have suggested the possible transovarial and transstadial transmission of pathogens by D. gallinae.
Frequency and Type of Renal Lesions in Dogs Naturally Infected withLeptospiraSpecies
Authors: Ortega‐Pacheco A. , Colin‐Flores R. F. , Gutiérrez‐Blanco E. , Jiménez‐Coello M.
Published: August 2009

The aim of this study was to determine the frequency and type of renal lesions associated with positive titers againstLeptospirasp. in a stray dog population. Three hundred fifty pairs of kidneys and an equal number of serum samples were collected from dogs captured by the dog pound of Merida, Yucatan, Mexico. Euthanasia of dogs was performed following the regulations of the Official Mexican Health Ministry (NOM‐033‐ZOO‐1995). Serum samples were evaluated with the microscopic agglutination test, and tissue samples were processed and fixed in paraffin. After staining with hematoxylin and eosin, the frequency of renal lesions was determined and classified. As an additional evaluation, samples with interstitial nephritis were stained by the Warthin–Starry method in order to observe the presence of spirochete forms that could be morphologically compatible withLeptospiraspp. We found that 98% of cases presented at least one type of lesion. The main histological lesions found were mesangial proliferative glomerulonephritis (MPGN) in 63.7% (n= 223), mesangial proliferative glomerulonephritis and interstitial nephritis (MPGN+IN) in 34% (n= 119), nephrosclerosis in 0.57% (n= 2), mesangial glomerulonephritis in 0.28% (n= 1), and interstitial nephritis (IN) in 0.28% (n= 1). Thirty‐four percent (n= 122) of the dogs were seropositive toLeptospirasp., mainly against serovarcanicola. Among dogs with IN (alone or associated with MPGN) (n= 120), 49.1% were seropositive toLeptospirasp., but only 17% of them showed spirochete forms compatible with the bacteria. A statistical association between seropositive dogs and the presence of MPGN+IN was determined (P< 0.0001; odds ratio 2.7, confidence interval 1.7–4.5). We concluded that the frequency of renal lesions found in this study is high andL. canicolais probably the most common circulating serovar in dogs from this area. Dogs that have been in contact withLeptospiraspp. have a higher risk of developing renal lesions of the type MPGN+IN.
Zoonoses and Climate Variability
Authors: Cardenas Rocio , Sandoval Claudia M. , Rodriguez‐Morales Alfonso J. , Vivas Paul
Published: August 2009

Leishmaniasis in the Americas is transmitted by Lutzomyia spp., which have many animal reservoirs. Previous studies indicated potential changes in vectors of climate‐related distribution, but impact outcomes need to be further studied. We report climatic and El Niño events during 1985–2002 that may have had an impact on leishmaniasis in 11 southern departments of Colombia: Amazonas, Caquetá, Cauca (Ca), Huila, Meta (Mt), Nariño, Putumayo (Py), Tolima, Valle (Va), Vaupes (Vp), and Vichada. Climatic data were obtained by satellite and epidemiologic data were obtained from the Health Ministry. NOAA climatic classification and SOI/ONI indexes were used as indicators of global climate variability. Yearly variation comparisons and median trend deviations were made for disease incidence and climatic variability. During this period there was considerable climatic variability, with a strong El Niño for 6 years and a strong La Niña for 8. During this period, 19,212 cases of leishmaniasis were registered, for a mean of 4756.83 cases/year. Disease in the whole region increased (mean of 4.98%) during the El Niño years in comparison to the La Niña years, but there were differences between departments with increases during El Niño (Mt 6.95%, Vp 4.84%), but the rest showed an increase during La Niña (1.61%–64.41%). Differences were significant in Va (P= 0.0092), Py (P= 0.0001), Ca (P= 0.0313), and for the whole region (P= 0.0023), but not in the rest of the departments. The importance of climate change is shown by shifts in insect and animal distributions. These data reflect the importance of climate on transmission of leishmaniasis and open further investigations related to forecasting and monitoring systems, where understanding the relationship between zoonoses and climate variability could help to improve the management of these emerging and reemerging diseases.
Fluorescence‐based Detection of Leishmania infantum DNA in Phlebotomus Vectors
Authors: Reale Stefano , Torina Alessandra , Sole Maria , Calderone Simona , Piazza Maria , Lupo Tiziana , Manna Laura , Gravino Angelo Elio , Currò Vittoria , Vitale Fabrizio
Published: August 2009

The geographical diffusion of leishmaniasis can depend on the factors limiting the distribution of sandfly vectors. In Sicily, as in all Mediterranean areas, sandflies are present almost all year round because the climate permits perpetuation of this vector's life cycle. Transmission can occurs in rural and domestic habitats through the bite of infected female phlebotomine sandflies. In Italy, the visceral form of leishmaniasis is commonly found, which is due exclusively to L. infantum. Two species of sandfly are considered the main vectors: Phlebotomus perniciosus and P. perfiliewi. Fluorescence resonance energy transfer technology was used to determine the parasite load in phlebotomine vectors, and the test was targeted on a 117‐bp fragment of kinetoplast DNA minicircles. The assay was evaluated, focusing on analytical sensitivity, discriminatory power, and reliability of quantification. During 2005, a total of 1686 sandflies were trapped in various Sicilian provinces and in farms randomly selected using black light traps. We found 20, 30, and 16 sandflies positive for Leishmania for each kind of analyzed phlebotomine sandfly, respectively, corresponding to 6.5% for the gravid, 2.7% for the fed, and 6.3% for other groups. Previously the insects were identified on the basis of morphology and the most prevalent sandfly species were P. Sergentomyia minuta, P. perfiliewi, and P. perniciosus.
Extranigral Neurodegeneration in Parkinson's Disease
Authors: Samantaray Supriti , Butler Jonathan T. , Ray Swapan K. , Banik Naren L.
Published: August 2009

It is widely known that the pathophysiology of idiopathic Parkinson's disease (PD) is associated with neurodegeneration and inflammatory responses in the midbrain substantia nigra. However, the possibility of neurodegeneration and inflammatory responses in other areas of the central nervous system (CNS) in course of the pathogenesis of PD remains to be explored. In this investigation, we provide evidence in support of the hypothesis that spinal cord, the final coordinator of movement, is also involved during parkinsonian degeneration using two distinct experimental parkinsonism models induced by the neurotoxin 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine (MPTP) and the environmental toxin rotenone. A key focus of our study is the role that calpain, a Ca2+‐activated neutral protease, plays in disrupting the structural–functional integrity of the spinal cord in the context of spinal cord degeneration in experimental parkinsonism. We examined the mechanisms of calpain‐mediated neuronal death in differentiated spinal cord motoneuron cultures following exposure to the active parkinsonian toxins 1‐methyl‐4‐phenyl‐pyridinium ion (MPP+) and rotenone and also tested the neuroprotective efficacy of calpeptin, a calpain inhibitor, in these cell culture models of experimental parkinsonism. Our results implied that spinal cord motoneurons could be a potential extranigral target of neurodegeneration during pathogenesis of PD in the CNS and that calpain inhibition could provide neuroprotection.
Dextromethorphan
Authors: Banken Joseph A. , Foster Howell
Published: August 2009

Dextromethorphan is reviewed in its role as an emerging drug of abuse, and the effects of dextromethorphan, along with those of co‐ingredients in OTC formulations, are discussed. The Drug Abuse and Warning Network (DAWN) national data in the United States are examined in the context of data from other poison control centers, and possible national trends are postulated. Implications for dextromethorphan as an emerging drug of abuse are explored. Data from the Arkansas Poison Control Center (APCC) show emerging trends in the abuse of dextromethorphan, particularly in this rural area of the United States.
Antagonist of M1 Muscarinic Acetylcholine Receptor Prevents Neurotoxicity Induced by Amphetamine via Nitric Oxide Pathway
Authors: Bashkatova Valentina , Hornick Ariane , Vanin Anatoly , Prast Helmut
Published: August 2009

The psychostimulant amphetamine (AMPH) has been found to induce striatal acetylcholine release and neurotoxic processes via nitric oxide (NO) and lipid peroxidation (LPO). Our purpose was to determine whether blocking striatal muscarinic (M1) receptors by the selective M1 antagonist toxin 7 (MT 7; bilaterally, 2 μg per side) might attenuate the effects of AMPH (4 × 5 mg/kg, i.p.). Systemic AMPH administration increased NO and LPO in the striatal tissue. Stimulation of M1 receptors by i.c.v. injection of M1 agonist McN‐A‐343 (200 μg) caused a similar enhancement of NO and LPO. Pretreatment with the MT7 prevented the AMPH‐induced NO generation and greatly reduced the LPO caused by the psychostimulant. These results show that M1 acetylcholine receptors are critically involved in neurotoxic processes induced by AMPH via NO and LPO.
Short Allele of 5‐HTTLPR as a Risk Factor for the Development of Psychosis in Japanese Methamphetamine Abusers
Authors: Ezaki Norikazu , Nakamura Kazuhiko , Sekine Yoshimoto , Thanseem Ismail , Anitha Ayyappan , Iwata Yasuhide , Kawai Masayoshi , Takebayashi Kiyokazu , Suzuki Katsuaki , Takei Nori , Iyo Masaomi , Inada Toshiya , Iwata Nakao , Harano Mutsuo , Komiyama Tokutaro , Yamada Mitsuhiko , Sora Ichiro , Ujike Hiroshi , Mori Norio
Published: August 2009

Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5‐HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5′ flanking region of the 5‐HTT gene (5‐HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age‐, sex‐, and geographic‐origin‐matched healthy controls. Patients were also subdivided according to the presence (n= 119) or absence (n= 148) of spontaneous relapse. We observed significant genotypic association of the 5‐HTTLPR polymorphism with MAP psychosis (P= 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls (P= 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse (P= 0.004). 5‐HTTLPR has been suggested to regulate the transcriptional activity of 5‐HTT, with S alleles showing lesser transcriptional efficiency and also lower 5‐HT1A receptor‐binding potential. Prolonged MAP use, combined with the high frequency of 5‐HTTLPR S‐alleles, may lead to reduced 5‐HTT levels and 5‐HT1A receptor‐binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5‐HTTLPR polymorphism in MAP psychosis.
Methamphetamine Fails to Alter the Noradrenergic Integrity of the Heart
Authors: Ruffoli Riccardo , Soldani Paola , Pasquali Livia , Ruggieri Stefano , Paparelli Antonio , Fornai Francesco
Published: August 2009

The chronic use of methamphetamine leads to cardiomyopathy and a nigrostriatal dopamine deficiency that partly mimics what occurs in Parkinson's disease. This study examines the cardiac effects occurring after chronic administration of methamphetamine and parkinsonism‐inducing neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Despite the similarities concerning the nigrostriatal dopamine denervation, methamphetamine failed to produce chronic norepinephrine depletion in the heart, thus contrasting with what occurs in Parkinson's disease or after administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. These data suggest that the chronic cardiovascular effects induced by methamphetamine rely on biochemical changes which differ from those activated by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine or during the course of Parkinson's disease.
Differential Response of Neurotensin to Methamphetamine Self‐Administration
Authors: Frankel Paul S. , Hoonakker Amanda J. , Hanson Glen R.
Published: August 2009

Neurotensin (NT) is a tridecapeptide associated with extrapyramidal and limbic pathways and is thought to inhibit dopamine (DA) functions in nigrostriatal, mesocortical, and mesolimbic systems. Because of these effects, NT has been referred to as an endogenous neuroleptic. We previously reported that low, high, and multiple doses of psychostimulants such as methamphetamine (METH) have profound effects on tissue levels, expression of associated mRNA, and release of NT in DA‐linked brain structures via activation of DA D‐1 and D‐2 receptors. In order to investigate the potential clinical significance of responses by NT systems to these stimulants, we have examined METH in a self‐administration paradigm and evaluated changes in tissue levels of NT in limbic and extrapyramidal regions. After food training, adult Sprague‐Dawley rats were allowed to self‐administer (i.v.) METH (0.03 or 0.06 mg/0.01 mL) by lever‐pressing (FR = 5) during 4‐hr sessions until a cumulative total of ∼3–4 mg was infused. Animals were sacrificed 6 hr after the last infusion of drug, and NT tissue levels were determined by established RIA techniques. For comparisons, the treatment sessions also included yoked animals that received identical quantities and/or patterns of either METH or saline solution. The results demonstrated four distinct patterns of NT response including (1) regions of no NT changes in either self‐administering or yoked METH groups; (2) regions of comparably increased NT levels in both METH‐treated groups; (3) regions where self‐administration of METH potentiated the increased NT levels relative to yoked METH groups; and (4) a region of increased NT levels only in self‐administering, and not yoked, METH‐treated groups.
Glutamate Cysteine Ligase Modifier (GCLM) Subunit Gene Is Not Associated with Methamphetamine‐Use Disorder or Schizophrenia in the Japanese Population
Authors: Kishi Taro , Ikeda Masashi , Kitajima Tsuyoshi , Yamanouchi Yoshio , Kinoshita Yoko , Kawashima Kunihiro , Inada Toshiya , Harano Mutsuo , Komiyama Tokutaro , Hori Toru , Yamada Mitsuhiko , Iyo Masaomi , Sora Ichiro , Sekine Yoshimoto , Ozaki Norio , Ujike Hiroshi , Iwata Nakao
Published: August 2009

A recent study showed a significant association between schizophrenia in European samples and the glutamate cysteine ligase modifier (GCLM) subunit gene, which is the key glutathione (GSH)‐synthesizing enzyme. Since the symptoms of methamphetamine (METH)‐induced psychosis are similar to those of schizophrenia, the GCLM gene is thought to be a good candidate gene for METH‐use disorder or related disorders. To evaluate the association between the GCLM gene and METH‐use disorder and schizophrenia, we conducted a case‐control study of Japanese subjects (METH‐use disorder, 185 cases; schizophrenia, 742 cases; and controls, 819). Four SNPs (2 SNPs from an original report and JSNP database, and 2 “tagging SNPs” from HapMap database) in the GCLM gene were examined in this association analysis; one SNP showed an association with both METH‐use disorder and METH‐induced psychosis. After Bonferroni's correction for multiple testing, however, this significance disappeared. No significant association was found with schizophrenia. Our findings suggest that a common genetic variation in the GCLM gene might not contribute to the risk of METH‐use disorder and schizophrenia in the Japanese population.
Alpha4 and Beta2 Subunits of Neuronal Nicotinic Acetylcholine Receptor Genes Are Not Associated with Methamphetamine‐Use Disorder in the Japanese Population
Authors: Kishi Taro , Ikeda Masashi , Kitajima Tsuyoshi , Yamanouchi Yoshio , Kinoshita Yoko , Kawashima Kunihiro , Inada Toshiya , Harano Mutsuo , Komiyama Tokutaro , Hori Toru , Yamada Mitsuhiko , Iyo Masaomi , Sora Ichiro , Sekine Yoshimoto , Ozaki Norio , Ujike Hiroshi , Iwata Nakao
Published: August 2009

The mesolimbic system is thought to be involved in the reinforcing action of many addictive drugs and the release of dopamine modulated by neuronal nicotine cholinergic receptors (nAChRs). Several investigations suggested that nAChRs on dopaminergic terminals play an important role in the development of some long‐lasting adaptations associated with drug abuse. A majority of high‐affinity nicotine binding sites in the brain have been showed in heteropentameric alpha4 (alpha4) and beta2 subunit (beta2) of nAChRs. Therefore, we conducted a genetic association analysis of the alpha4 gene (CHRNA4) and beta2 gene (CHRNB2) with methamphetamine (METH)‐use disorder (191 cases and 753 controls). We first evaluated the linkage disequilibrium (LD) structure of these genes and selected 7 and 5 tagging SNPs (tag SNPs) on CHRNA4 and CHRNB2, respectively. Some tag SNPs were significantly associated with total METH‐use disorder and METH‐induced psychosis; however, these associations were no longer statistically significant after Bonferroni's correction for multiple testing. In conclusion, our results suggest that neither CHRNA4 nor CHRNB2 plays a major role in Japanese METH‐use disorder.
Association Study between Casein Kinase 1 Epsilon Gene and Methamphetamine Dependence
Authors: Kotaka T. , Ujike H. , Morita Y. , Kishimoto M. , Okahisa Y. , Inada T. , Harano M. , Komiyama T. , Hori T. , Yamada M. , Sekine Y. , Iwata N. , Iyo M. , Sora I. , Ozaki N. , Kuroda S.
Published: August 2009

Casein kinase 1 epsilon (CKIɛ) is a component of the DARPP‐32 in second‐messenger pathway. CKIɛ phosphorylates and activates DARPP‐32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. A recent clinical study showed that rs135745, a noncoding single nucleotide polymorphism of the 3′‐untranslated region of the CSNK1E gene, was associated with the intensity of the subjective response to an oral amphetamine dose in normal volunteers. Differences in sensitivity to the drug should affect development of dependence to it. Hence, we genotyped rs135745 of the CSNK1E (MIM 600863) gene in 215 patients with methamphetamine dependence and 274 age‐ and gender‐matched normal controls. No significant differences in genotype and allele frequencies were observed between the patients with methamphetamine dependence and controls. There was also no significant association between rs135745 and the clinical characteristics of methamphetamine dependence and co‐morbid methamphetamine psychosis (e.g., age of first consumption, latency of psychosis, prognosis of psychosis after therapy, spontaneous relapse of psychotic symptoms, and poly‐substance abuse status). The present findings suggest that having a genetic variant of the CSNK1E gene did not affect susceptibility to methamphetamine dependence or psychosis, at least in a Japanese population.
Toluene and TCE Decrease Binding to Mu‐Opioid Receptors, but Not to Benzodiazepine and NMDA Receptors in Mouse Brain
Authors: Páez‐Martínez N. , Ambrosio E. , García‐Lecumberri C. , Rocha L. , Montoya G. L. , Cruz S. L.
Published: August 2009

In vitroandin vivostudies have shown that abused solvents affect different neurotransmitter systems, including the GABAergic, glutamatergic, and opioidergic. The first purpose of this study was to determine in mice whether an acute exposure to 4,000 ppm toluene or 12,000 ppm 1,1,1‐trichloroethane (TCE) modifies receptor binding levels to: (a) DAMGO, a mu‐opioid receptor selective agonist; (b) MK‐801, a noncompetitive selective NMDA‐receptor antagonist; and (c) flunitrazepam, a benzodiazepine binding site selective agonist. In addition, in separate groups of animals, nociceptive effects of toluene alone or co‐administered with morphine were evaluated in the hot‐plate test. Mice were exposed to toluene or TCE in static exposure chambers for 30 min, and their brains were removed 24 h later for autoradiography. Acute toluene inhalation produced a significant decrease in mu‐opioid receptor binding levels in cingulate and piriform cortices, caudate putamen, thalamus, amygdala, and periaqueductal gray, whereas TCE significantly decreased mu‐opioid receptor levels, but only in thalamus and periaqueductal gray. Both toluene and TCE decreased benzodiazepine receptor binding levels in discrete brain areas, but had no effect on NMDA receptor levels. In the hot‐plate test, a single toluene exposure counteracted morphine antinociceptive response when the solvent exposure time was immediately followed by morphine treatment, but not when morphine was administered 24, 48, 72, and 96 h later. However, co‐administration of morphine and toluene 24, 48, 72, and 96 h after the single solvent exposure resulted in morphine‐induced analgesia blockade. Present results suggest that mu‐opioid receptors are an important molecular target for organic solvents, and that the inhalation of these compounds may affect the analgesic properties of opioids.
Defining “Neuroinflammation”
Authors: O'Callaghan James P. , Sriram Krishnan , Miller Diane B.
Published: August 2009

Neuroinflammation is a hot topic in contemporary neuroscience. A relatively new open‐access journal, theJournal of Neuroinflammation, focuses on this field. As another example, abstracts to the 2007 Annual Meeting of the Society for Neuroscience could be submitted in several subcategories of neuroinflammation, a strong signal of growth in this research area. While it is becoming clear that activation of microglia and astroglia and the attendant expression of proinflammatory cytokines and chemokines often are associated with disease‐, trauma‐, and toxicant‐induced damage to the CNS, it is by no means clear that a cause‐and‐effect relationship exists between the presence of a neuroinflammatory process and neural damage. We have explored this issue with two models of dopaminergic neurotoxicity. We used a single low‐dose regimen of MPTP or METH, a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in the substantia nigra. Both compounds increased the expression of the microglia‐associated factors, Il‐1α, Il6, Ccl2, and Tnf‐α, and also elicited morphologic evidence of microglial activation prior to induction of astrogliosis. Pharmacologic antagonism of MPTP and METH neurotoxicity prevented these proinflammatory responses, findings suggestive of a link between neuroinflammation and the observed neurotoxic outcomes. Nevertheless, when we used minocycline to suppress the expression of all these mediators, with the exception of Tnf‐α, we failed to see neuroprotection. Likewise, when we examined the effects of MPTP or METH in transgenic mice lacking Il6, Ccl2, or Tnfr1/2 genes, deficiency of either Il6 or Ccl2 did not alter neurotoxicity, whereas deficiency in Tnfr1/2 was neuroprotective. Although these observations pointed to a role of the proinflammatory cytokine, TNF‐α, in the neurotoxic effects of MPTP and METH, other observations did not support this supposition. For example, activation of NF‐κB or induction of iNOS, known components of inflammatory responses and free radical formation, were not observed. Moreover, immunosuppressive regimens of glucocorticoids failed to suppress TNF‐α or attenuate neurotoxicity. Taken together, our observations suggest that MPTP and METH neurotoxicity are associated with the elaboration of a “neuroinflammatory” response, yet this response lacks key features of inflammation and, with the exception of TNF‐α, neurotoxicity appears to be the cause rather than the consequence of proinflammatory signals.
Methamphetamine‐Induced Early Increase of IL‐6 and TNF‐α mRNA Expression in the Mouse Brain
Authors: Gonçalves Joana , Martins Tânia , Ferreira Raquel , Milhazes Nuno , Borges Fernanda , Ribeiro Carlos Fontes , Malva João O. , Macedo Tice R. , Silva Ana P.
Published: August 2009

The mechanisms by which methamphetamine (METH) causes neurotoxicity are not well understood. Recent studies have suggested that METH‐induced neuropathology may result from a multicellular response in which glial cells play a prominent role, and so it is plausible to suggest that cytokines may participate in the toxic effects of METH. Therefore, in the present work we evaluated the effect of an acute administration of METH (30 mg/kg in a single intraperitoneal injection) on the interleukin (IL)‐1β, IL‐6, and tumor necrosis factor (TNF)‐α mRNA expression levels in the hippocampus, frontal cortex, and striatum of mice. We observed that METH did not induce changes in the IL‐1β mRNA expression levels in both hippocampus and striatum, with immeasurable levels in the frontal cortex. Regarding IL‐6, METH induced an increase in the expression levels of this cytokine in the hippocampus and striatum, 1 h and 30 min post injection, respectively. In the frontal cortex, the increase in IL‐6 mRNA levels was more significant and remained high even after 2 h. Moreover, the expression levels of TNF‐α were increased in both hippocampus and frontal cortex 30 min post METH administration, with immeasurable levels in the striatum. We conclude that the pro‐inflammatory cytokines IL‐6 and TNF‐α rapidly increase after METH administration, providing a new insight for understanding the effect of this drug of abuse in the brain.
Exploratory Behavior in Rats Postnatally Exposed to Cocaine and Housed in an Enriched Environment
Authors: Magalhães Ana , Melo Pedro , Alves Cecília Juliana , Tavares Maria Amélia , De Sousa Liliana , Summavielle Teresa
Published: August 2009

Exposure to cocaine in early periods of postnatal life is usually associated with changes in development of neurotransmitter systems and structure of the central nervous system. Such changes are most likely correlated with behavioral alterations. Environmental enrichment conditions (EC) in early stages is a factor that affects structural and behavioral development. The purpose of this study is to examine the effects of EC on rats postnatally exposed to cocaine on exploratory behavior. Wistar rats were assigned to four groups—Group 1: pups exposed to cocaine hydrochloride (15 mg/kg body weight/day) s.c., in two daily doses, from postnatal day (PND) 1 to 28 and reared in EC; Group 2: pups exposed to cocaine as previously described and reared in a standard environmental conditions (SC); Group 3: pups saline‐injected and reared in EC; and Group 4: pups saline‐injected and reared in SC. On PND 21, 24, and 28, groups of four rats (to reduce anxiety) were placed for 10 minutes into an arena with several objects. The following exploratory behavioral categories were examined: object interaction, exploration, manipulation, approximation, and total time of object contact. Animals from Group 2 showed decreased object interaction and total contact on PND 21. Control offspring reared in EE showed decreases in exploratory behavior at all ages analyzed compared with the control SE group, while cocaine‐exposed animals reared in EC showed decreased object interaction, object approximation, and total exploratory behavior. The results in this group suggest that EC improved information acquisition and memory processes in animals postnatally exposed to cocaine.
Antagonists at Metabotropic Glutamate Receptor Subtype 5
Authors: Carroll F. Ivy
Published: August 2009

As a result of intensive investigation, particularly in the pharmaceutical industry, a number of potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists have been discovered. The structure activity relationship studies that led to the discovery of these mGluR5 antagonists are presented in this review. Results from studies on selected mGluR5 antagonists in animal models that simulate drug reward, reinforcement, and relapse appear promising. The comorbidity between drug abuse and anxiety and depression make drugs active in these disorders of great interest. Clinical studies showed that the mGluR5 antagonist fenobam was an active anxiolytic drug. Several new mGluR5 antagonists produced anxiolytic and antidepressant‐like effects in animal models of these disorders. The results from the clinical and animal studies provide information for new approaches to finding mechanistically distinct pharmacotherapies to help patients achieve and maintain abstinence from cocaine, methamphetamine, opiates, ethanol, and nicotine (smoking).
Substance Abuse Vaccines
Authors: Orson Frank M. , Kinsey Berma M. , Singh Rana A.K. , Wu Yan , Gardner Tracie , Kosten Thomas R.
Published: August 2009

Conventional substance‐abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine. New approaches, including vaccination to block the effects of these drugs on the brain, are in advanced stages of development. Although several potential mechanisms for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism involves binding of the drug by antibodies in the bloodstream, thereby blocking entry and/or reducing the rate of entry of the drug into the central nervous system. The benefits of such antibodies on drug pharmacodynamics will be influenced by both the quantitative and the qualitative properties of the antibodies. The sum of these effects will determine the success of the clinical applications of antidrug vaccines in addiction medicine. This review will discuss these issues and present the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine, and morphine.
Molecular Mechanisms of Fat Preference and Overeating
Authors: Gaillard Dany , Passilly‐Degrace Patricia , Besnard Philippe
Published: August 2009

Obesity is recognized as a worldwide health problem. Overconsumption of fatty foods contributes significantly to this phenomenon. Rodents, like humans, display preferences for lipid‐rich foods. Rodents thus provide useful models to explore the mechanisms responsible for this complex feeding behavior resulting from the integration of multiple oral and postoral signals. Over the last decades, the lipid‐mediated regulation of food intake has received considerable attention. By contrast, orosensory lipid perception was long thought to involve only textural and olfactory cues. Recent findings have challenged this limited viewpoint. These recent data strongly suggest that the sense of taste also plays significant roles in the spontaneous preference for fatty foods. This paper provides a brief overview of postoral regulation of food intake by lipids and then highlights recent data suggesting the existence of a “fatty taste” which might contribute to lipid overeating and hence to the risk of obesity.
Implication of Activated Astrocytes in the Development of Drug Dependence
Authors: Narita Minoru , Suzuki Masami , Kuzumaki Naoko , Miyatake Mayumi , Suzuki Tsutomu
Published: August 2009

Astrocytes are a subpopulation of glial cells that directly affect neuronal function. This review focuses on the potential functional roles of astrocytes in the development of behavioral sensitization and rewarding effects induced by chronic treatment with drugs of abuse.In vitrotreatment of cortical neuron/glia cocultures with either methamphetamine or morphine caused activation of astrocytes via protein kinase C (PKC). Purified cortical astrocytes were markedly activated by methamphetamine, whereas morphine had no such effect. Methamphetamine, but not morphine, caused a long‐lasting astrocytic activation in cortical neuron/glia cocultures. Morphine‐induced behavioral sensitization, assessed as hyperlocomotion, was reversed by 2 months of withdrawal from intermittent morphine administration, whereas behavioral sensitization to methamphetamine‐induced hyperlocomotion was maintained even after 2 months of withdrawal.In vivotreatment with methamphetamine, which was associated with behavioral sensitization, caused PKC‐dependent astrocytic activation in the mouse cingulate cortex and nucleus accumbens. Furthermore, the glial modulator propentofylline dramatically diminished the activation of astrocytes and the rewarding effect induced by methamphetamine and morphine. On the other hand, intra–nucleus accumbens and intra–cingulate cortex administration of astrocyte‐conditioned medium aggravated the development of rewarding effects induced by methamphetamine and morphine. Furthermore, astrocyte‐conditioned medium, but not methamphetamine itself, clearly induced differentiation of neural stem cells into astrocytes. These findings provide direct evidence that astrocytes may, at least in part, contribute to the development of the rewarding effects induced by drugs of abuse in the nucleus accumbens and cingulate cortex.
Anti‐CCP Antibody, a Marker for the Early Detection of Rheumatoid Arthritis
Authors: Van Venrooij Walther J. , Van Beers Joyce J.B.C. , Pruijn Ger J.M.
Published: August 2009

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of synovial joints. In most cases this will lead to the formation of pannus tissue, ultimately leading to joint destruction. Early diagnosis, coupled with aggressive use of disease‐modifying antirheumatic drugs, has been shown to have a favorable effect on the course of the disease. Therefore, early and accurate diagnosis has become increasingly important. Several sets of criteria have been published to achieve such an early diagnosis, and all of them include measurement of antibodies directed to citrullinated peptides or proteins. This review summarizes our present knowledge about the most well‐known and established test to measure these antibodies, the anti‐CCP test, which measures antibodies directed to cyclic citrullinated peptides. We describe the current views on how these antibodies are generated and how genetic and environmental parameters are important in this process. The anti‐CCP test is more specific than the commonly used RF test (95% versus less than 90%) and has a comparable sensitivity (more than 70%). These antibodies are detectable very early in the disease and are reported to predict the development of erosive RA. Increasing evidence supports a role for these antibodies in the pathology of the disease. In conclusion, testing for anti‐CCP autoantibodies is widely accepted as an indispensable tool for diagnosis and early treatment in the management of rheumatoid arthritis patients.
Functional Analysis of FOXP3
Authors: Buckner Jane H. , Ziegler Steven F.
Published: August 2009

Tolerance to self antigens is established in two ways: first in the thymus through the deletion of thymocytes expressing self‐reactive T cell receptors; and second, in the periphery through multiple mechanisms involving deletion, anergy, and suppression. Dominant tolerance to self antigens in the periphery is primarily the function of the CD4+CD25+FOXP3+ subset of T cells, which have the capability of suppressing autoreactive T cells that have escaped deletion during thymic selection. The essential role of the transcription factor FOXP3 in the development and function of these cells has been well documented. However, the underlying mechanisms by which FOXP3 controls this process are less well understood. This review will focus on the role of FOXP3 in regulating CD4 T cell function in both humans and mice, with an emphasis on recent work in human systems.
RANK/RANKL: Regulators of Immune Responses and Bone Physiology
Authors: Leibbrandt Andreas , Penninger Josef M.
Published: August 2009

Bone‐related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF‐κB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK‐RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine‐tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.
Toll‐like Receptor and RIG‐1‐like Receptor Signaling
Authors: Kawai Taro , Akira Shizuo
Published: August 2009

Toll‐like receptors (TLRs) and RIG‐I‐like receptors (RLRs) constitute distinct families of pattern‐recognition receptors that sense nucleic acids derived from viruses and trigger antiviral innate immune responses. TLR3, TLR7, and TLR9 are membrane proteins localized to the endosome that recognize viral double‐stranded RNA, single‐stranded RNA, and DNA, respectively, while RLRs, including RIG‐I, Mda5, and LGP2, are cytoplasmic proteins that recognize viral RNA. Upon recognition of these nucleic acid species, TLRs and RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in activation of NF‐κB, MAP kinases, and IRFs that control the transcription of genes encoding type I interferon and other inflammatory cytokines, which are important for eliminating viruses. Here, we review recent insights into the signaling pathways initiated by TLR and RLR and their roles in innate and adaptive immune responses.
Regulation and Function of Proinflammatory TH17 Cells
Authors: Martinez Gustavo J. , Nurieva Roza I. , Yang Xuexian O. , Dong Chen
Published: August 2009

Naïve CD4+ helper T (TH) cells, upon activation by antigen‐presenting cells (APC), differentiate into different types of effector cells that are characterized by their distinct cytokine production profiles and immune regulatory functions. In addition to TH1 and TH2 cells, a third subset of effector TH cells has recently been described and termed TH17. Since their identification, TH17 cells have emerged as crucial players in infectious, inflammatory, and autoimmune diseases, and cancer. In this review, we summarize the latest discoveries on the cytokine‐mediated regulation and transcriptional programming of TH17 cells and their roles in different immune responses and diseases.