bluuebunny/crossref_metadata_2025 huggingface dataset:
Clouds and Shortwave Fluxes at Nauru. Part II: Shortwave Flux Closure
Authors: McFarlane Sally A. , Evans K. Franklin
Published: November 2004

The datasets currently being collected by the Atmospheric Radiation Measurement (ARM) program on the islands of Nauru and Manus represent the longest time series of ground-based cloud measurements in the tropical western Pacific region. In this series of papers, a shortwave flux closure study is presented using observations collected at the Nauru site between June 1999 and May 2000. The first paper presented frequency of occurrence of nonprecipitating clouds detected by the millimeter-wavelength cloud radar (MMCR) at Nauru and statistics of their retrieved microphysical properties. This paper presents estimates of the cloud radiative effect over the study period and results from a closure study in which retrieved cloud properties are input to a radiative transfer model and the modeled surface fluxes are compared to observations.

The average surface shortwave cloud radiative forcing is 48.2 W m−2, which is significantly smaller than the cloud radiative forcing estimates found during the Tropical Ocean Global Atmosphere Coupled Ocean–Atmosphere Response Experiment (TOGA COARE) field project. The difference in the estimates during the two periods is due to the variability in cloud amount over Nauru during different phases of the El Niño–Southern Oscillation (ENSO). In the closure study, modeled and observed surface fluxes show large differences at short time scales, due to the temporal and spatial variability of the clouds observed at Nauru. Averaging over 60 min reduces the average root-mean-square difference in total flux to 10% of the observed flux. Modeled total downwelling fluxes are unbiased with respect to the observed fluxes while direct fluxes are underestimated and diffuse fluxes are overestimated. Examination of the differences indicates that cloud amount derived from the ground-based measurements is an overestimate of the radiatively important cloud amount due to the anisotropy of the cloud field at Nauru, interpolation of the radar data, uncertainty in the microwave brightness temperature measurements for thin clouds, and the uncertainty in relating the sixth moment of the droplet size distribution observed by the radar to the more radiatively important moments.
Predicted Twenty-First-Century Changes in Seasonal Extreme Precipitation Events in the Parallel Climate Model
Authors: Wehner Michael F.
Published: November 2004

Twenty-year return values of annual and seasonal maxima of daily precipitation are calculated from a set of transiently forced coupled general circulation model simulations. The magnitude and pattern of return values are found to be highly dependent on the seasonal cycle. A similar dependence is found for projected future changes in return values.

The correlation between the spatial pattern of return value changes and mean precipitation changes is found to be low. Hence, the changes in mean precipitation do not provide significant information about changes in precipitation extreme values.
Using First Differences to Reduce Inhomogeneity in Radiosonde Temperature Datasets
Authors: Free Melissa , Angell James K. , Durre Imke , Lanzante John , Peterson Thomas C. , Seidel Dian J.
Published: November 2004

The utility of a “first difference” method for producing temporally homogeneous large-scale mean time series is assessed. Starting with monthly averages, the method involves dropping data around the time of suspected discontinuities and then calculating differences in temperature from one year to the next, resulting in a time series of year-to-year differences for each month at each station. These first difference time series are then combined to form large-scale means, and mean temperature time series are constructed from the first difference series. When applied to radiosonde temperature data, the method introduces random errors that decrease with the number of station time series used to create the large-scale time series and increase with the number of temporal gaps in the station time series. Root-mean-square errors for annual means of datasets produced with this method using over 500 stations are estimated at no more than 0.03 K, with errors in trends less than 0.02 K decade−1 for 1960–97 at 500 mb. For a 50-station dataset, errors in trends in annual global means introduced by the first differencing procedure may be as large as 0.06 K decade−1 (for six breaks per series), which is greater than the standard error of the trend. Although the first difference method offers significant resource and labor advantages over methods that attempt to adjust the data, it introduces an error in large-scale mean time series that may be unacceptable in some cases.
The Role of Coupled Sea Surface Temperatures in the Simulation of the Tropical Intraseasonal Oscillation
Authors: Zheng Y. , Waliser D. E. , Stern W. F. , Jones C.
Published: November 2004

This study compares the tropical intraseasonal oscillation (TISO) variability in the Geophysical Fluid Dynamics Laboratory (GFDL) coupled general circulation model (CGCM) and the stand-alone atmospheric general circulation model (AGCM). For the AGCM simulation, the sea surface temperatures (SSTs) were specified using those from the CGCM simulation. This was done so that any differences in the TISO that emerged from the two simulations could be attributed to the coupling process and not to a difference in the mean background state. The comparison focused on analysis of the rainfall, 200-mb velocity potential, and 850-mb zonal wind data from the two simulations, for both summer and winter periods, and included comparisons to analogous diagnostics using NCEP–NCAR reanalysis and Climate Prediction Center (CPC) Merged Analysis of Precipitation (CMAP) rainfall data.

The results of the analysis showed three principal differences in the TISO variability between the coupled and uncoupled simulations. The first was that the CGCM showed an improvement in the spatial variability associated with the TISO mode, particularly for boreal summer. Specifically, the AGCM exhibited almost no TISO variability in the Indian Ocean during boreal summer—a common shortcoming among AGCMs. The CGCM, on the other hand, did show a considerable enhancement in TISO variability in this region for this season. The second was that the wavenumber–frequency spectra of the AGCM exhibited an unrealistic peak in variability at low wavenumbers (1–3, depending on the variable) and about 3 cycles yr−1 (cpy). This unrealistic peak of variability was absent in the CGCM, which otherwise tended to show good agreement with the observations. The third difference was that the AGCM showed a less realistic phase lag between the TISO-related convection and SST anomalies. In particular, the CGCM exhibited a near-quadrature relation between precipitation and SST anomalies, which is consistent with observations, while the phase lag was reduced in the AGCM by about 1.5 pentads (∼1 week). The implications of the above results, including those for the notions of “perfect SST” and “two tier” experiments, are discussed, as are the caveats associated with the study's modeling framework and analysis.
Response of the Atlantic Thermohaline Circulation to Increased Atmospheric CO2 in a Coupled Model
Authors: Hu Aixue , Meehl Gerald A. , Washington Warren M. , Dai Aiguo
Published: November 2004

Changes in the thermohaline circulation (THC) due to increased CO2 are important in future climate regimes. Using a coupled climate model, the Parallel Climate Model (PCM), regional responses of the THC in the North Atlantic to increased CO2 and the underlying physical processes are studied here. The Atlantic THC shows a 20-yr cycle in the control run, qualitatively agreeing with other modeling results. Compared with the control run, the simulated maximum of the Atlantic THC weakens by about 5 Sv (1 Sv ≡ 106 m3 s−1) or 14% in an ensemble of transient experiments with a 1% CO2 increase per year at the time of CO2 doubling. The weakening of the THC is accompanied by reduced poleward heat transport in the midlatitude North Atlantic. Analyses show that oceanic deep convective activity strengthens significantly in the Greenland–Iceland–Norway (GIN) Seas owing to a saltier (denser) upper ocean, but weakens in the Labrador Sea due to a fresher (lighter) upper ocean and in the south of the Denmark Strait region (SDSR) because of surface warming. The saltiness of the GIN Seas are mainly caused by an increased salty North Atlantic inflow, and reduced sea ice volume fluxes from the Arctic into this region. The warmer SDSR is induced by a reduced heat loss to the atmosphere, and a reduced sea ice flux into this region, resulting in less heat being used to melt ice. Thus, sea ice–related salinity effects appear to be more important in the GIN Seas, but sea ice–melt-related thermal effects seem to be more important in the SDSR region. On the other hand, the fresher Labrador Sea is mainly attributed to increased precipitation. These regional changes produce the overall weakening of the THC in the Labrador Sea and SDSR, and more vigorous ocean overturning in the GIN Seas. The northward heat transport south of 60°N is reduced with increased CO2, but increased north of 60°N due to the increased flow of North Atlantic water across this latitude.
Predictability of Low-Level Winds by Mesoscale Meteorological Models
Authors: Rife Daran L. , Davis Christopher A. , Liu Yubao , Warner Thomas T.
Published: November 2004

This study describes the verification of model-based, low-level wind forecasts for the area of the Salt Lake valley and surrounding mountains during the 2002 Salt Lake City, Utah, Winter Olympics. Standard verification statistics (such as bias and mean absolute error) for wind direction and speed were compared for four models: the Eta, Rapid Update Cycle (RUC-2), and Global Forecast System of the National Centers for Environmental Prediction, and the fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5). Even though these models had horizontal grid increments that ranged over almost two orders of magnitude, the highest-resolution MM5 with a 1.33-km grid increment exhibited a forecast performance similar to that of the other models in terms of grid-average, conventional verification metrics. This is in spite of the fact that the MM5 is the only model capable of reasonably representing the complex terrain of the Salt Lake City region that exerts a strong influence on the local circulation patterns. The purpose of this study is to investigate why the standard verification measures did not better discriminate among the models and to describe alternative measures that might better represent the ability of high-horizontal-resolution models to forecast locally forced mesogamma-scale circulations. The spatial variability of the strength of the diurnal forcing was quantified by spectrally transforming the time series of wind-component data for each observation location. The amount of spectral power in the band with approximately a diurnal period varied greatly from place to place, as did the amount of power in the bands with periods longer (superdiurnal) and shorter (subdiurnal) than the diurnal. It is reasonable that the superdiurnal power is largely in the synoptic-scale motions, and thus can be reasonably predicted by all the models. In contrast, the subdiurnal power is mainly in nondiurnally forced small-scale fluctuations that are generally unpredictable with any horizontal resolution because they are unobserved in three dimensions by the observation network.

A strong positive relationship is demonstrated between the strength of the local forcing at each observation location, as measured by the spectral power in the diurnal band of the wind component time series, and forecast skill, as reflected by an alternative verification metric, a measure of anomaly correlation. However, the mean-absolute error showed no relationship to the power in the diurnal band. Two other measures of comparison among the low-level wind forecasts, the direction climatology and the spatial variance, showed a positive correlation between forecast quality and horizontal resolution.
A New Mixing-Length Formulation for the Parameterization of Dry Convection: Implementation and Evaluation in a Mesoscale Model
Authors: Teixeira J. , Ferreira J. P. , Miranda P. M. A. , Haack T. , Doyle J. , Siebsema A. P. , Salgado R.
Published: November 2004

A realistic representation of the evolution of the dry convective boundary layer in mesoscale and large-scale atmospheric models has been an elusive goal for many years. In this paper the performance of a new mixing-length formulation for the dry convective boundary layer is evaluated in the context of the Coupled Ocean– Atmosphere Mesoscale Prediction System (COAMPS). In this new formulation, the mixing length is proportional to a time scale and to the square root of the turbulent kinetic energy. The model results are tested against observations from the Climate Impact of Changes in Land Use (CICLUS) field experiment in the south of Portugal. It is shown that COAMPS with the new formulation produces a more realistic simulation of the boundary layer growth. A data assimilation experiment performed with COAMPS shows that the improvements provided by the new formulation are significant, particularly in terms of the humidity vertical distribution. Finally, one-dimensional simulations are used to confirm that the new formulation provides more accurate results because of a more realistic representation of the entrainment and of the vertical mixing in general.
Moving Toward Integrative Care: Rationales, Models, and Steps for Conventional-Care Providers
Authors: Mann Douglas , Gaylord Susan , Norton Sally
Published: November 2004

Integration of conventional and complementary care in the United States is driven by the growing use of complementary therapies by patients, limitations in the effectiveness of conventional care for a variety of chronic conditions, a growing emphasis on patient satisfaction as a legitimate outcome of care, and an awareness on the part of insurers and practitioners that complementary approaches can offer a broad array of options that may significantly enhance healing and promote more active patient participation in health maintenance. Many models of integrative care are possible, ranging from the informed practitioner, to fully integrated group practices, to hospital-based and academic center systems of integration. A variety of barriers and challenges can slow the process of integration, including limited personal financial and temporal resources, negative peer opinion, legislative hindrances, and reimbursement shortfalls. This review describes seven models of integrative health care and offers recommendations to conventional-care providers for moving toward the practice of integrative medicine.
The cellular prion protein modulates phagocytosis and inflammatory response
Authors: de Almeida Cecília J G , Chiarini Luciana B , da Silva Juliane Pereira , e Silva Patrícia M R , Martins Marco Aurélio , Linden Rafael
Published: November 2004

The cellular prion protein (PrPc) is a glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is abundantly expressed in the central nervous system. It is also expressed in a variety of cell types of the immune system. We investigated the role of PrPc in the phagocytosis of apoptotic cells and other particles. Macrophages from mice with deletion of the Prnp gene showed higher rates of phagocytosis than wild-type macrophages in in vitro assays. The elimination of GPI-anchored proteins from the cell surface of macrophages from wild-type mice rendered these cells as efficient as macrophages derived from knockout mice. In situ detection of phagocytosis of apoptotic bodies within the retina indicated augmented phagocytotic activity in knockout mice. In an in vivo assay of acute peritonitis, knockout mice showed more efficient phagocytosis of zymosan particles than wild-type mice. In addition, leukocyte recruitment was altered in knockout mice, as compared with wild type. The data show that PrPc modulates phagocytosis in vitro and in vivo. This activity is described for the first time and may be important for normal macrophage functions as well as for the pathogenesis of prion diseases.
The Application of Proteomics to the Human Alcoholic Brain
Authors: LEWOHL JOANNE M. , VAN DYK DEREK D. , CRAFT GEORGE E. , INNES DAVID J. , MAYFIELD R DAYNE , COBON GARY , HARRIS R ADRON , DODD PETER R.
Published: November 2004

Abstract: Alcoholism results in changes in the human brain that reinforce the cycle of craving and dependency, and these changes are manifest in the pattern of expression of proteins in key cells and brain areas. Described here is a proteomics‐based approach aimed at determining the identity of proteins in the superior frontal cortex (SFC) of the human brain that show different levels of expression in autopsy samples taken from healthy and long‐term alcohol abuse subjects. Soluble protein fractions constituting pooled samples combined from SFC biopsies of four well‐characterized chronic alcoholics (mean consumption > 80 g ethanol/day throughout adulthood) and four matched controls (<20 g/day) were generated. Two‐dimensional electrophoresis was performed in triplicate on alcoholic and control samples and the resultant protein profiles analyzed for differential expression. Overall, 182 proteins differed by the criterion of twofold or more between case and control samples. Of these, 139 showed significantly lower expression in alcoholics, 35 showed significantly higher expression, and 8 were new or had disappeared. To date, 63 proteins have been identified using MALDI‐MS and MS‐MS. The finding that the expression level of differentially expressed proteins is preponderantly lower in the alcoholic brain is supported by recent results from parallel studies using microarray mRNA transcript.
No Association Found between the Type 1 Sigma Receptor Gene Polymorphisms and Methamphetamine Abuse in the Japanese Population: A Collaborative Study by the Japanese Genetics Initiative for Drug Abuse
Authors: INADA T , IIJIMA Y , UCHIDA N , MAEDA T , IWASHITA S , OZAKI N , HARANO M , KOMIYAMA T , YAMADA M , SEKINE Y , IYO M , SORA I , UJIKEC H
Published: November 2004

Abstract: It has been suggested that individual genetic factors are involved in susceptibility to drug dependence and the manifestation of drug‐induced psychosis. The aim of this study was to examine the relation between methamphetamine abusers/psychosis and the type 1 sigma receptor gene polymorphisms. Subjects comprised 143 MAP abusers and 181 healthy controls. Two polymorphisms in the type 1 sigma receptor gene, GC‐241‐240TT and A61C (Gln2Pro), were examined in the present study. No significant differences were observed in either polymorphism between healthy controls and MAP abusers/psychosis. In the subgroup analyses, the rate of CC genotype of A61C tended to be higher in MAP patients who had experienced spontaneous relapse without MAP use than in those who had not (P= .06, OR = 3.02 95%CI = 0.92‐9.92). However, the level of this significant trend did not remain after the Bonferroni's multiple correction. This study suggests that type 1 sigma receptor gene is unlikely to play a major role in substance abuse liability and/or the development of MAP psychosis.
Serial Analysis of Gene Expression in Methamphetamine‐ and Phencyclidine‐Treated Rodent Cerebral Cortices: Are There Common Mechanisms?
Authors: OUCHI YUTA , KUBOTA YASUHIKO , ITO CHIHIRO
Published: November 2004

Abstract: Pharmacological actions of methamphetamine (METH) and phencyclidine (PCP) are different, but both of them can induce similar psychiatric disorders including abuse, intoxication, withdrawal, and psychotic symptoms like those of schizophrenia. These mental disorders are caused not only by their direct pharmacological effects, but also by secondary brain damage containing gene expression changes. In order to broadly grasp these alterations, we used serial analysis of gene expression (SAGE), a transcriptome analysis. We analyzed three cDNA libraries from cerebral cortices of saline (1 mL/kg)‐, METH (4 mg/kg)‐, or PCP (10 mg/kg)‐treated Wistar rats (one hour after i.p. administration). The numbers of total tags were about 50,000 in each library, and approximately 18,000 kinds of tags were identified respectively. From the comparisons of three groups, we found both METH‐ and PCP‐reactive genes. Upregulated genes contained calmodulin 2, stromal cell‐derived factor receptor 1, brain‐specific angiogenesis inhibitor 1‐associated protein 2, ras homologue enriched in brain, basigin and thyrotropin‐releasing hormone receptor. Downregulated genes contained lipocalin 2, aldolase A, importin 13, fatty acid binding protein 3, and glycine receptor α2 subunit. These data suggest important clues of common molecular basis in METH‐ and PCP‐related psychiatric disorders.
Involvement of Signal Transduction Cascade via Dopamine‐D1 Receptors in Phencyclidine Dependence
Authors: NODA YUKIHIRO , NABESHIMA TOSHITAKA
Published: November 2004

Abstract: We investigated the molecular mechanisms of development to phencyclidine (PCP)‐induced rewarding effect by using tyrosine hydroxylase (TH) heterozygous (TH+/−) mice. PCP (8 mg/kg) induced the place preference in wild‐type mice pretreated with PCP (10 mg/kg/day for 28 days). The place preference induced by PCP is attenuated by 6‐hydroxydopamine, a dopaminergic neurotoxin, and (+) SCH‐23390, a dopamine‐D1 receptor antagonist, but not by DSP‐4, a noradrenergic neurotoxin, and (−) sulpiride, a dopamine‐D2 receptor antagonist. In TH+/− mice pretreated with PCP (10 mg/kg/day for 28 days), no PCP (8 mg/kg)‐induced place preference was observed. In wild‐type mice pretreated with PCP, the levels of cAMP, cAMP response element binding protein (CREB), and c‐fos mRNA in the nucleus accumbens were increased. The levels of cAMP, CREB, and c‐fos mRNA in the nucleus accumbens were not increased by the same treatment schedule of PCP in TH+/− mice. These findings suggest that changes in dopaminergic and/or cAMP signal cascades induced by repeated PCP treatment play an important role in the development of PCP‐induced rewarding effect.
Differential Response of nNOS Knockout Mice to MDMA (“Ecstasy”)‐ and Methamphetamine‐Induced Psychomotor Sensitization and Neurotoxicity
Authors: ITZHAK YOSSEF , ANDERSON KAREN L. , ALI SYED F.
Published: November 2004

Abstract: It has been shown that mice deficient in neuronal nitric oxide synthase (nNOS) gene are resistant to cocaine‐induced psychomotor sensitization and methamphetamine (METH)‐induced dopaminergic neurotoxicity. The present study was undertaken to investigate the hypothesis that nNOS has a major role in dopamine (DA)‐ but not serotonin (5‐hydroxytryptamine; 5‐HT)‐mediated effects of psychostimulants. The response of nNOS knockout (KO) and wild‐type (WT) mice to the psychomotor‐stimulating and neurotoxic effects of 3,4‐methylenedioxymethamphetamine (MDMA; “Ecstasy”) and METH were investigated. Repeated administration of MDMA for 5 days resulted in psychomotor sensitization in both WT and nNOS KO mice, while repeated administration of METH caused psychomotor sensitization in WT but not in KO mice. Sensitization to both MDMA and METH was persistent for 40 days in WT mice, but not in nNOS KO mice. These findings suggest that the induction of psychomotor sensitization to MDMA and METH is NO independent and NO dependent, respectively, while the persistence of sensitization to both drugs is NO dependent. For the neurochemical studies, a high dose of MDMA caused marked depletion of 5‐HT in several brain regions of both WT and KO mice, suggesting that the absence of the nNOS gene did not afford protection against MDMA‐induced depletion of 5‐HT. Striatal dopaminergic neurotoxicity caused by high doses of MDMA and METH in WT mice was partially prevented in KO mice administered with MDMA, but it was fully precluded in KO mice administered with METH. The differential response of nNOS KO mice to the behavioral and neurotoxic effects of MDMA and METH suggests that the nNOS gene is required for the expression and persistence of DA‐mediated effects of METH and MDMA, while 5‐HT‐mediated effects of MDMA (induction of sensitization and 5‐HT depletion) are not dependent on nNOS.
Antagonists of the Neurokinin‐1 or Dopamine D1 Receptors Confer Protection from Methamphetamine on Dopamine Terminals of the Mouse Striatum
Authors: ANGULO JESUS A. , ANGULO NIEVES , YU JING
Published: November 2004

Abstract: Methamphetamine (METH) is a highly addictive compound that induces toxicity of the dopamine (DA) terminals of the neostriatum. Exposure to METH induces long‐term deficits in dopamine transporter (DAT) and tyrosine hydroxylase (TH) levels as well as induction of glial fibrillary acidic protein (GFAP) in the caudate putamen (CPu) and the nucleus accumbens (NAc). The primary effect of exposure to METH is elevation of the level of extracellular DA; therefore, we assessed the role of the DA D1 receptor (D1R) and neurokinin‐1 receptor (NK‐1R) on the expression of toxicity. METH was injected intraperitoneally (10 mg/kg) four times at 2‐h intervals (an acute toxic dose), and the mice were sacrificed three days after the treatment. Exposure to METH resulted in marked reduction of DAT sites (reduced to 30 and 21% relative to control in medial and lateral aspects of the CPu) assessed by binding of [125I]RTI‐121 by autoradiography or Western blot analysis. Pretreatment with the nonpeptide NK‐1R antagonist WIN‐51,708 (10 mg/kg) 30 min prior to the first and fourth injections of METH prevented the loss of DAT sites of the CPu. Moreover, pretreatment with WIN‐51,708 also prevented the reduction of TH levels induced by METH as well as the induction of GFAP in astrocytes. Pretreatment with the D1R antagonist SCH‐23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu. These results demonstrate that receptors postsynaptic to the DA terminals of the CPu are needed in order to express the neurotoxic effects of METH on integral components of the DA terminals of the nigrostriatal projection.
Augmentation of Serotonin‐Induced Inhibition of Neuronal Activity in the Hippocampus Following Repeated Treatment with Methamphetamine
Authors: KIMURA TAKESHI , ISHIHARA KUMATOSHI , OZAWA KOICHIRO , SASA MASASHI
Published: November 2004

Abstract: Electrophysiological studies were performed to determine whether or not hippocampal serotonergic modulation was affected following repeated administration of methamphetamine (MAP). Rats were i.p. administered with MAP (5 mg/kg) or saline once a day for 5 days. Hippocampal slices were prepared at 24 h, 5 and 10 days after the final MAP or saline injection. The population spikes (PS) induced by stimulation of Schaffer collateral/commissural fibers were recorded in the hippocampal CA1 region. Application of serotonin (5‐HT) via a bath perfusion system inhibited the PS in a concentration‐dependent manner. At 24 h after the final injection, 10‐μM 5‐HT‐induced inhibition of PS was not affected by MAP treatment. However, 5 days after the final injection, the inhibition by 5‐HT (10 μM) of PS was significantly augmented in the MAP‐treated group. Ten days after the final injection, this augmentation was not statistically significant compared with that of control group. 8‐OH‐DPAT, a 5‐HT1A receptor agonist, inhibited PS, but the inhibition was not enhanced or reduced 5 days after the final MAP treatment. However, the enhancement of PS by RS 67333, a 5‐HT4 receptor agonist, was attenuated 5 days after the MAP treatment. It was found that 5‐HT‐induced inhibition of PS in the hippocampal CA1 region was potentiated 5 days after cessation of MAP, and this effect was suggested to be due to reduction of excitatory 5‐HT4 receptor functions.
A Polymorphism of DRD2 Gene and Brain Atrophy in Methamphetamine Psychosis
Authors: HARANO M , UCHIMURA N , ABE H , ISHIBASHI M , IIDA N , YANAGIMOTO K , TANAKA T , MAEDA H , SORA I , IYO M , KOMIYAMA T , YAMADA M , SEKINE Y , INADA T , OZAKI N , UJIKE H
Published: November 2004

Abstract: Our group, Ujike et al., recently reported that the A1 allele of TaqI A polymorphism of the dopamine receptor D2 (DRD2) gene, associated with transient psychosis, significantly differs from that of patients with prolonged psychosis in methamphetamine psychosis. Therefore, we examined the association between the TaqI A polymorphism of the DRD2 gene and the brain MRI view for patients with methamphetamine psychosis. The subjects underwent brain MRI scans using the FLAIR method. Genotyping was performed by PCR‐RFLP methods using genomic DNA extracted from peripheral blood by the phenol method. Ten subjects had the A1/A2 genotype, eleven subjects had the A2/A2 genotype, and no subject had the A1/A1 genotype. The domain size, including the thalamus and basal ganglia that were inside each side of the putamens, did not differ between the three groups (the A1/A2‐group, the A2/A2‐group, and the young healthy person group). In the comparison based on this domain, the temporal lobe tended to narrow in the A2/A2‐group compared to the A1/A2‐group (P= .06). The other domain (cerebrum, corpus callosum, etc.) showed no difference between the A1/A2‐group and the A2/A2‐group. It is suggested that in methamphetamine psychosis the TaqI A polymorphism not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe.
Gene Polymorphisms of the Mu Opioid Receptor in Methamphetamine Abusers
Authors: IDE SOICHIRO , KOBAYASHI HIDEAKI , TANAKA KEIKO , UJIKE HIROSHI , SEKINE YOSHIMOTO , OZAKI NORIO , INADA TOSHIYA , HARANO MUTSUO , KOMIYAMA TOKUTARO , YAMADA MITSUHIKO , IYO MASAOMI , IKEDA KAZUTAKA , SORA ICHIRO
Published: November 2004

Abstract: In drug addiction, the opioid system is thought to mediate motivational effects through dopamine‐independent mechanisms. We have investigated associations of the μ‐opioid receptor gene (OPRM) variations with methamphetamine (MAP) dependence/psychosis. The allelic frequency of A118G (Asn40Asp) in exon 1 of ORPM was 45.3% in our control subjects, but only 7.5‐25.8% in the Caucasian or African‐American population of previous studies. We have identified several novel polymorphisms in intron 1 and the 5′ untranslated region (5′UTR) of OPRM. Polymorphisms in the functionally relevant 5′ regulatory region of OPRM were different in our Japanese population from Caucasian or African‐American populations. No significant differences between controls and MAP abusers were found in either genotype or allele frequency at any single nucleotide polymorphism (SNP) or (AC)n dinucleotide repeat in intron 1. A subdivision of our MAP group revealed that A118G of OPRM shows a significant association with MAP psychosis having latency less than three years. Further analysis should be capable of identifying associations between the OPRM variations and MAP dependence/psychosis.
Role of Cdk5 in Drug Abuse and Plasticity
Authors: BENAVIDES DAVID R. , BIBB JAMES A.
Published: November 2004

Abstract: Neuronal plasticity serves as the basis for learning and memory in the adult brain. Contextual, motor, and reward‐based learning are important in reinforcing survival behavior in animals. Most psychostimulant drugs of abuse target the dopaminergic reward system of the brain. Drugs of abuse cause long‐standing cellular and molecular neuroadaptations in the brain. The neuronal protein kinase Cdk5 is emerging as an important player in the cellular and physiological responses to drugs of abuse. Substantial evidence indicates that Cdk5 controls dopamine neurotransmission through regulation of the protein phosphatase‐1 inhibitor, DARPP‐32. Furthermore, the morphological changes associated with chronic cocaine exposure are dependent on Cdk5. Thus, Cdk5 mediates cellular responses to psychostimulant drug‐induced changes in dopamine signal transduction and cytoskeletal reorganization. In this regard, Cdk5, through its targeting of various substrates, integrates a number of intracellular pathways that are targeted by psychostimulant drugs. These studies and the emerging role of Cdk5 in various forms of neuronal plasticity are reviewed.
Negative Regulation of Opioid Receptor‐G Protein‐Ca2+ Channel Pathway by the Nootropic Nefiracetam
Authors: YOSHII MITSUNOBU , FURUKAWA TAIJI , OGIHARA YOSHIYASU , WATABE SHIGEO , SHIOTANI TADASHI , ISHIKAWA YASURO , NISHIMURA MASAO , NUKADA TOSHIHIDE
Published: November 2004

Abstract: It has recently been reported that nefiracetam, a nootropic agent, is capable of attenuating the development of morphine dependence and tolerance in mice. The mechanism of this antimorphine action is not clear. The present study was designed to address this issue using Xenopus oocytes expressing δ‐opioid receptors, G proteins (Gi3α or Go1α), and N‐type (α1B) Ca2+ channels. Membrane currents through Ca2+ channels were recorded from the oocytes under voltage‐clamp conditions. The Ca2+ channel currents were reduced reversibly by 40‐60% in the presence of 1 μM leucine‐enkephalin (Leu‐Enk). The Leu‐Enk‐induced current inhibition was recovered promptly by nefiracetam (1 μM), while control currents in the absence of Leu‐Enk were not influenced by nefiracetam. A binding assay revealed that 3H‐nefiracetam preferentially bound to the membrane fraction of oocytes expressing Gi3α. When δ‐opioid receptors were coexpressed, the binding was significantly increased. However, an additional expression of α1B Ca2+ channels decreased the binding. The results suggest that nefiracetam preferentially binds to Gi3α associated with δ‐opioid receptors, thereby inhibiting the association of G proteins with Ca2+ channels. In conclusion, nefiracetam negatively regulates the inhibitory pathway of opioid receptor‐G protein‐Ca2+ channel.
4‐Methylpyrazole Decreases 1,4‐Butanediol Toxicity by Blocking Its in Vivo Biotransformation to γ‐Hydroxybutyric Acid
Authors: QUANG LAWRENCE S. , DESAI MALHAR C. , SHANNON MICHAEL W. , WOOLF ALAN D. , MAHER TIMOTHY J.
Published: November 2004

Abstract: 1,4‐Butanediol (1,4‐BD), a prodrug converted in vivo to γ‐hydroxybutyric acid by alcohol dehydrogenase, has resulted in life‐threatening overdoses and deaths. We investigated whether 4‐methylpyrazole (4‐MP), an alcohol dehydrogenase antagonist, can be used as an antidote in a murine model of 1,4‐BD overdose. CD‐1 mice were overdosed with 1,4‐BD, 600 mg/kg i.p. Mice then received 4‐MP, 25 mg/kg i.p., or control injections after 1 min, 5 min, and symptom appearance. Mice were then evaluated for toxicity by the righting reflex and rotarod test every 10 min after intervention. When 4‐MP was administered 1 and 5 min after 1,4‐BD overdose, mice completely maintained their righting reflex. Conversely, control mice lost their righting reflex for 110 and 130 min, respectively (P= 0.05). When 4‐MP was administered after symptomatic 1,4‐BD overdose, mice lost their righting reflex but recovered it by 60 min. Conversely, control mice lost their righting reflex and recovered it by 140 min (P= 0.05). When 4‐MP was administered at 1 min after 1,4‐BD overdose, mice never failed the rotarod test. Conversely, control mice failed the rotarod test for 210 min (P= 0.05). When 4‐MP was administered 5 min after 1,4‐BD and after symptomatic 1,4‐BD overdose, mice failed the rotarod test for 100 and 110 min, respectively. Conversely, control mice failed the rotarod test for 210 and 180 min, respectively (P= 0.05). In addition, treatment of mice with 4‐MP significantly attenuated increases in blood γ‐hydroxybutyric acid concentrations and prevented loss of the righting reflex and failure of the rotarod test. In this murine model of 1,4‐BD overdose, 4‐MP conferred antidotal effects by inhibiting alcohol dehydrogenase‐mediated biotransformation of 1,4‐BD to γ‐hydroxybutyric acid.
Evaluation of γ‐Hydroxybutyric Acid for Genotoxicity in the Mouse Micronucleus Assay
Authors: DASS S BALACHANDRA , ALI SYED F.
Published: November 2004

Abstract: γ‐Hydroxybutyric acid (GHB) is an endogenous compound found in the brain and other tissues of mammals. Neurotransmitter/neuromodulator functions have been ascribed to GHB, which has lately become a drug of abuse. In this study, we tested GHB for genotoxicity by measuring its ability to induce micronuclei in polychromatic erythrocytes (reticulocytes) in the peripheral blood of mice. Intraperitoneal injection with a dose of 25 mg/kg/day for 3 days or 50 mg/kg/day × 3 days resulted in a significant (by Dunnett's test) increase of 1.9‐ to 2.1‐fold in micronuclei. However, because increases were small and because no consistent dose‐dependent increase in induced micronuclear frequency could be demonstrated, our results do not conclusively show that GHB is an in vivo genotoxicant in mammals.
Neonatal Toluene Exposure Alters Glutamate‐Induced Calcium Signaling in Developing Cerebellar Granule Neurons
Authors: CHEN HWEI‐HSIEN , WEI CHAO‐TING , CHAN MING‐HUAN
Published: November 2004

Abstract: Glutamatergic neurotransmission is critical both for neurogenesis and mature functioning of the central nervous system (CNS), and is thought to be one target for toluene‐induced damage. It has been reported that toluene antagonizes the function of N‐methyl‐d‐aspartate (NMDA) receptor. In this study, we examined the effect that neonatal toluene exposure has on NMDA receptor in cerebellar granule neurons. Sprague‐Dawley rats were treated with 0, 200, 500, and l000 mg/kg of toluene by intraperitoneal injection from postnatal day (PN) 4 to 7. After culture under toluene‐free condition, Ca2+ signaling in response to glutamate and NMDA was measured using fura‐2 Ca2+ imaging for up to 14 days. Toluene exposure dose‐dependently reduced glutamate/glycine and NMDA/glycine induced Ca2+ signaling in culture cerebellar granule neurons at DIV5 (day in vitro), and the effects were gradually recovered. The effects of toluene exposure on NMDA‐stimulated Ca2+ signals in response to NMDA receptor inhibitors were also compared. The results indicated that neonatal toluene exposure can induce long‐term but reversible changes in NMDA‐induced Ca2+ signaling pathway. Such changes could be involved in the impairment of CNS function and development observed in fetal solvent syndrome.
Comparison of G‐Protein Selectivity of Human 5‐HT2C and 5‐HT1A Receptors
Authors: OKADA MITSUKO , GOLDMAN DAVID , LINNOILA MARKKU , IWATA NAKAO , OZAKI NORIO , NORTHUP JOHN K.
Published: November 2004

Abstract: We compared the ability of human 5‐HT2C and 5‐HT1A receptors to couple to selected G proteins expressed in insect Sf9 cells through simultaneous infection with recombinant baculoviruses. We also examined the coupling of G proteins to these same receptors in membranes derived from the Sf9 cells using in situ reconstitution with purified G proteins. Our data show that unoccupied 5‐HT2C and 5‐HT1A receptors can attain an activated conformation that is stabilized by interaction with specific G proteins. While high‐affinity agonist binding to the 5‐HT2C receptor was increased to a greater extent by Gαq than by Gαi2, the high‐affinity agonist binding to the 5‐HT1A receptor was preferentially enhanced by Gαi2 coexpression. When the two 5‐HT receptors were expressed in cells also expressing G proteins, both 5‐HT2C and 5‐HT1A receptors appear to activate Gαi2 in preference to Gαq. In contrast, in situ reconstitution data show that 5‐HT2C receptors robustly activate Gαq and marginally activate Gαo or Gαi, whereas 5‐HT1A receptors only marginally activate Gαq and robustly activate Gαo and Gαi. These results suggest that the overexpression of receptor and potential G‐protein coupling partners in Sf9 cells may lead to erroneous conclusions as to the signaling selectivity of receptors.
Modulators of G Protein‐Activated Inwardly Rectifying K+ Channels: Potentially Therapeutic Agents for Addictive Drug Users
Authors: KOBAYASHI TORU , WASHIYAMA KAZUO , IKEDA KAZUTAKA
Published: November 2004

Abstract: G protein‐activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and heart rate through activation of various G protein‐coupled receptors, such as opioid, cannabinoid, and D2 dopamine receptors. Therefore, modulators of GIRK channels may affect many brain functions. We have shown using Xenopus oocyte expression assays that ethanol directly activates GIRK channels, whereas various antipsychotics (thioridazine, clozapine, pimozide, and haloperidol) inhibit the channels. Here we investigated not only the effects of various selective serotonin reuptake inhibitor (SSRI) antidepressants (fluoxetine, citalopram, fluvoxamine, and zimelidine) and risperidone, an atypical antipsychotic, on GIRK channels, but also those of the various drugs tested on other Kir channels using the Xenopus oocyte system. Fluoxetine inhibited GIRK channels, whereas the other SSRIs and risperidone had a small or no effect on the channels. In contrast, Kir1.1 and Kir2.1 channels were insensitive to ethanol and various SSRIs and antipsychotics, although thioridazine weakly inhibited Kir1.1 channels. It has been shown that the function of GIRK channels is involved in seizure susceptibility, antinociception by opioids, cannabinoids, or ethanol, and cocaine reinforcement in studies using GIRK knockout mice and weaver mutant mice that have mutant GIRK2 channels insensitive to G proteins and ethanol. Activation of GIRK channels by opioids, cannabinoids, or ethanol may be one of these key effects. Therefore, GIRK channel modulators might be potential agents for the treatment of users of addictive drugs, such as cocaine, opioids, cannabinoids, and ethanol, as well as for the treatment of epilepsy and pain.
Conditioned Place Preference and Locomotor Sensitization after Repeated Administration of Cocaine or Methamphetamine in Rats Treated with Epidermal Growth Factor during the Neonatal Period
Authors: MIZUNO MAKOTO , MALTA ROMULO S. , NAGANO TADASATO , NAWA HIROYUKI
Published: November 2004

Abstract: Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF‐receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF‐treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF‐treated rats. At the adult stage, EGF‐treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug‐naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF‐treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF‐receptor activation and drug addiction.
The Additional Value of Chemotherapy to Radiotherapy in Locally Advanced Nasopharyngeal Carcinoma: A Meta-Analysis of the Published Literature
Authors: Langendijk J.A. , Leemans Ch.R. , Buter J. , Berkhof J. , Slotman B.J.
Published: November 2004

Purpose

The purpose of this meta-analysis was to determine the additional value of neoadjuvant, concurrent, and/or adjuvant chemotherapy to radiation in the treatment of locally advanced nasopharyngeal carcinoma (NPC) with regard to the overall survival (OS) and the incidence of local-regional recurrences (LRR) and distant metastases (DM).

Patients and Methods

To be eligible, full published studies had to deal with biopsy-proven NPC and have patients randomly assigned to receive conventional radiotherapy (66 to 70 Gy in 7 weeks) or radiotherapy combined with chemotherapy.

Results

Ten randomized clinical studies were identified, including 2,450 patients. The pooled hazard ratio (HR) of death for all studies was 0.82 (95% CI, 0.71 to 0.95; P = .01) corresponding to an absolute survival benefit of 4% after 5 years. Three categories of trials were defined according to the sequence of chemotherapy, including neoadjuvant chemotherapy, at least concomitant chemoradiotherapy, and adjuvant chemotherapy. A significant interaction term (P = .02) was found among these three categories. The largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. Comparable results were found for the incidence of LRR and DM.

Conclusion

The results of this study indicate that concomitant chemotherapy in addition to radiation is probably the most effective way to improve OS in NPC.
Phase II Study of CT-2103 in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma
Authors: Sabbatini Paul , Aghajanian Carol , Dizon Don , Anderson Sybil , Dupont Jakob , Brown John V. , Peters William A. , Jacobs Andrew , Mehdi Aminder , Rivkin Saul , Eisenfeld Amy J. , Spriggs David
Published: November 2004

Purpose

To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-l-glutamic acid, in heavily pretreated patients with recurrent ovarian, fallopian tube, or peritoneal cancer.

Patients and Methods

Ninety-nine patients with measurable disease received intravenous CT-2103 at 175 mg/m2 of conjugated paclitaxel over 10 minutes every 3 weeks without routine premedications. Platinum-sensitive (n = 42) and platinum-refractory or platinum-resistant patients (n = 57) were enrolled. Thirty-nine patients (39%) had received one or two prior regimens, and 60 patients (61%) had received between three and 12 regimens.

Results

In 99 patients, the median number of cycles was three (range, one to 14 cycles). The response rate (RR) for all patients was 10% (10 of 99 patients), with median time to disease progression (TTP) of 2 months. The RR (partial response) in platinum-sensitive and platinum-resistant patients was 14% (six of 42 patients) and 7% (four of 57 patients), respectively. In patients with only one or two prior regimens, the RR in platinum-sensitive and platinum-resistant patients was 28% (five of 18 patients) and 10% (two of 21 patients), with a median TTP of 4 and 2 months, respectively. Grade 2 (15 patients) or 3 (15 patients) neuropathy was reported in 30 patients (30%). Grade 2 hypersensitivity occurred in eight patients (8%) who were subsequently treated with premedications; one patient had grade 3 hypersensitivity and was removed. Grade 2 alopecia was absent.

Conclusion

CT-2103 is active in patients with recurrent ovarian cancer. Neurotoxicity in these heavily pretreated patients was more frequent than predicted from phase I trials. Further study to define toxicity and efficacy in patients with less prior therapy is ongoing.