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Peribiliary glands are complex lobular structures containing mucus and serous glands, distributed along the extrahepatic and intrahepatic bile ducts. In this report, we describe a case of intraductal papillary neoplasm of the bile duct suspected to be of peribiliary glands origin. The patient was an 80-year-old man who was referred to our hospital for a hepatic mass. On further examination, a 38 × 34 mm cystic lesion with papillary growth was found in S1/4. Because the lesion was extensively bordered by both hepatic ducts and the connection was unclear, it was difficult to determine the extent of hepatic resection. To confirm the location, a peroral cholangioscopy was performed. The connection with the cyst was detected in the right hepatic duct and a villous tumor mucosa protruded through the conduit lumen. Since we found that the lesion communicated with the right hepatic duct, a right hepatectomy was subsequently performed. The postoperative pathological diagnosis was an intraductal papillary neoplasm of the blie duct with associated invasive carcinoma. The postoperative course was good, and the patient experienced no recurrence.
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BACKGROUND: Endoscopic ultrasonography (EUS) is useful for the differential diagnosis of subepithelial lesions (SELs); however, not all of them are easy to distinguish. Gastrointestinal stromal tumors (GISTs) are the commonest SELs, are considered potentially malignant, and differentiating them from benign SELs is important. Artificial intelligence (AI) using deep learning has developed remarkably in the medical field. This study aimed to investigate the efficacy of an AI system for classifying SELs on EUS images. METHODS: EUS images of pathologically confirmed upper gastrointestinal SELs (GIST, leiomyoma, schwannoma, neuroendocrine tumor [NET], and ectopic pancreas) were collected from 12 hospitals. These images were divided into development and test datasets in the ratio of 4:1 using random sampling; the development dataset was divided into training and validation datasets. The same test dataset was diagnosed by two experts and two non-experts. RESULTS: A total of 16,110 images were collected from 631 cases for the development and test datasets. The accuracy of the AI system for the five-category classification (GIST, leiomyoma, schwannoma, NET, and ectopic pancreas) was 86.1%, which was significantly higher than that of all endoscopists. The sensitivity, specificity, and accuracy of the AI system for differentiating GISTs from non-GISTs were 98.8%, 67.6%, and 89.3%, respectively. Its sensitivity and accuracy were significantly higher than those of all the endoscopists. CONCLUSION: The AI system, classifying SELs, showed higher diagnostic performance than that of the experts and may assist in improving the diagnosis of SELs in clinical practice.
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Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Inteligencia Artificial , Endosonografía/métodos , Tumores del Estroma Gastrointestinal/patología , Humanos , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues. PURPOSE: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II. METHODS: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion. RESULTS: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE. CONCLUSION: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.
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Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/prevención & control , Proteína Inhibidora del Complemento C1/administración & dosificación , Administración Intravenosa , Niño , Proteína Inhibidora del Complemento C1/farmacocinética , Humanos , Japón , Calidad de VidaRESUMEN
Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.
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Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Conducta Exploratoria , Metanfetamina/farmacología , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/genética , Animales , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Locomoción/efectos de los fármacos , Locomoción/genética , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismoRESUMEN
A woman in her 70s presented to our hospital with epigastric pain, back pain, and weight loss. Esophagogastroduodenoscopy was performed, and numerous protuberances, which were suspected to be submucosal tumors, were found at the gastric corpus. The patient was diagnosed with gastric tuberculosis based on the biopsy results of these protuberances. Histopathological analysis demonstrated non-caseating epithelioid granuloma. A positive culture for Mycobacterium tuberculosis was also obtained on gastric juice analysis and confirmed using polymerase chain reaction assay. In the rapidly aging population in Japan, our findings emphasize on the importance of differentiating gastrointestinal tuberculosis, including gastric tuberculosis, from other diseases. This case may provide information about the development of gastric tuberculosis.
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Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis Gastrointestinal/diagnóstico , Anciano , Antituberculosos , Femenino , Humanos , Japón , Estómago , Tuberculosis Gastrointestinal/microbiologíaRESUMEN
A 67-year-old male patient presented with an irregular mass involving the pancreatic body and tail with multiple liver/lymph node metastases. A biopsy indicated the presence of a poorly differentiated adenocarcinoma. Fever and increased white blood cell count, C-reactive protein levels, and granulocyte-colony stimulating factor (G-CSF) levels led to the diagnose of G-CSF-producing pancreatic cancer. The patient did not respond to FOLFIRINOX therapy (leucovorin, fluorouracil, irinotecan, and oxaliplatin), but nab-paclitaxel plus gemcitabine treatment was effective, resulting in tumor shrinkage and reduced G-CSF levels. After the fifth course of this therapy, exacerbation was noted, and the patient died of primary cancer 6 months after initiating the therapy. Here we report the case of this patient with G-CSF-producing pancreatic cancer who responded to chemotherapy.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/biosíntesis , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Albúminas/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resultado Fatal , Humanos , Masculino , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , GemcitabinaRESUMEN
The N-methyl-d-aspartate (NMDA) receptor channel is involved in various physiological functions, including learning and memory. The GluN2D subunit of the NMDA receptor has low expression in the mature brain, and its role is not fully understood. In the present study, the effects of GluN2D subunit deficiency on emotional and cognitive function were investigated in GluN2D knockout (KO) mice. We found a reduction of motility (i.e., a depressive-like state) in the tail suspension test and a reduction of sucrose preference (i.e., an anhedonic state) in GluN2D KO mice that were group-housed with littermates. Despite apparently normal olfactory function and social interaction, GluN2D KO mice exhibited a decrease in preference for social novelty, suggesting a deficit in social recognition or memory. Golgi-Cox staining revealed a reduction of the complexity of dendritic trees in the accessory olfactory bulb in GluN2D KO mice, suggesting a deficit in pheromone processing pathway activation, which modulates social recognition. The deficit in social recognition may result in social stress in GluN2D KO mice. Isolation housing is a procedure that has been shown to reduce stress in mice. Interestingly, 3-week isolation and treatment with agomelatine or the 5-hydroxytryptamine-2C (5-HT2C) receptor antagonist SB242084 reversed the anhedonic-like state in GluN2D KO mice. In contrast, treatment with the 5-HT2C receptor agonist CP809101 induced depressive- and anhedonic-like states in isolated GluN2D KO mice. These results suggest that social stress that is caused by a deficit in social recognition desensitizes 5-HT2c receptors, followed by an anhedonic- and depressive-like state, in GluN2D KO mice. The GluN2D subunit of the NMDA receptor appears to be important for the recognition of individuals and development of normal emotionality in mice. 5-HT2C receptor antagonism may be a therapeutic target for treating social stress-induced anhedonia. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
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Anhedonia/fisiología , Receptor de Serotonina 5-HT2C/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Reconocimiento en Psicología/fisiología , Conducta Social , Estrés Psicológico/fisiopatología , Acetamidas/farmacología , Aminopiridinas/farmacología , Animales , Dendritas/patología , Indoles/farmacología , Ratones , Ratones Noqueados , Bulbo Olfatorio/patología , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Receptores de N-Metil-D-Aspartato/genética , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Aislamiento SocialRESUMEN
The differential diagnosis of primary gastrointestinal EBV T-cell lymphoma (GITCL) includes enteropathy-associated T-cell lymphoma (EATL), peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma, and anaplastic large cell lymphoma. Type II EATL is considered to be a tumor of intraepithelial lymphocytes. However, the evaluation of intraepithelial lymphocytosis by biopsy specimens is challenging, which poses a diagnostic problem between the EATL and peripheral T-cell lymphoma, not otherwise specified. This situation requested us to establish a pragmatic diagnostic approach for the classification of GITCL. We identified 42 cases of GITCL and analyzed clinicopathologic features, especially addressing their T-cell receptor (TCR) phenotype. Nine (21%) of 42 GITCL cases were positive for TCRγ protein expression. Among these TCRγ cases, TCRß expression or not was detected in 5 and 4, respectively, but resulted in no further clinicopathologic differences. TCRß positivity without TCRγ expression (ßγ) was seen in 9 GITCL patients (21%). Twenty-four patients (57%) were negative for TCRß and γ expression (ßγ). Compared with TCRßγ or ßγ type, TCRγ cases were characterized by exclusive involvement of intestinal sites (100% vs. 11%, P<0.001; 100% vs. 58%, P=0.032, respectively), but not of stomach (0% vs. 78%, P=0.002; 0% vs. 38%, P=0.039, respectively). Notably, TCRγ positivity was an independent unfavorable prognostic factor among our GITCL patients (P<0.001). Considering our results, TCRγ GITCL, that is, intestinal γδ T-cell lymphoma, appears to constitute a distinct disease entity.
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Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/patología , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Receptores de Antígenos de Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Citometría de Flujo , Neoplasias Gastrointestinales/mortalidad , Humanos , Inmunohistoquímica , Inmunofenotipificación , Estimación de Kaplan-Meier , Linfoma de Células T/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
The present study aimed to investigate the involvement of the NMDA receptor (NMDAR) and/or nitric oxide (NO) pathway in ketamine-induced behavioral sensitization. Mice received repeated subcutaneous administration of ketamine (25mg/kg), once daily or once weekly for a total of five doses. Even three administrations of ketamine, daily or weekly, induced a rapid increase in locomotor activity in wild-type (WT), but not in GluN2D knockout (GluN2D-KO) mice. Furthermore, for WT mice receiving daily ketamine, elevated locomotor activity was maintained after a 1-month withdrawal period; however, this was not the case when ketamine was administered weekly. The effect of acute ketamine on nNOS activities was estimated with nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. Ketamine rapidly increased the number of NADPH-d activated cells and strongly stained dendrites in the dorsal striatum and prefrontal cortex of WT mice, but not GluN2D-KO mice. These results suggest that ketamine-induced locomotor sensitization and nNOS activation in the frontal cortex-striatum neuronal circuit are positively correlated and that the NMDAR GluN2D subunit plays an important role in the acquisition and maintenance of ketamine-induced behavioral sensitization.
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Cuerpo Estriado/efectos de los fármacos , Ketamina/farmacología , Actividad Motora/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo I/metabolismo , Corteza Prefrontal/efectos de los fármacos , Psicotrópicos/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Cuerpo Estriado/metabolismo , Activación Enzimática , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , NADP/metabolismo , Neuronas/metabolismo , Óxido Nítrico/biosíntesis , Especificidad de Órganos , Corteza Prefrontal/metabolismo , Subunidades de Proteína/metabolismo , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
BACKGROUND: Noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists evoke a behavioral and neurobiological syndrome in experimental animals. We previously reported that phencyclidine (PCP), an NMDA receptor antagonist, increased locomotor activity in wildtype (WT) mice but not GluN2D subunit knockout mice. Thus, the aim of the present study was to determine whether the GluN2D subunit is involved in PCP-induced motor impairment. RESULTS: PCP or UBP141 (a GluN2D antagonist) induced potent motor impairment in WT mice but not GluN2D KO mice. By contrast, CIQ, a GluN2C/2D potentiator, induced severe motor impairment in GluN2D KO mice but not WT mice, suggesting that the GluN2D subunit plays an essential role in the effects of PCP and UBP141, and an appropriate balance between GluN2C and GluN2D subunits might be needed for appropriate motor performance. The level of the GluN2D subunit in the mature mouse brain is very low and restricted. GluN2D subunits exist in brainstem structures, the globus pallidus, thalamus, and subthalamic nucleus. We found that the expression of the c-fos gene increased the most among PCP-dependent differentially expressed genes between WT and GluN2D KO mice, and the number of Fos-positive cells increased after PCP administration in the basal ganglia motor circuit in WT mice but not GluN2D KO mice. CONCLUSION: These results suggest that the GluN2D subunit within the motor circuitry is a key subunit for PCP-induced motor impairment, which requires an intricate balance between GluN2C- and GluN2D-mediated excitatory outputs.
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Regulación de la Expresión Génica/efectos de los fármacos , Fenciclidina/toxicidad , Subunidades de Proteína/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Biología Computacional , Dantroleno/administración & dosificación , Dantroleno/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Reproducibilidad de los Resultados , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genéticaRESUMEN
The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion. The expression of human VMAT2 in noradrenergic neurons extended the life of VMAT2-/- mice for up to three weeks, and these mice showed severe growth deficiency compared with VMAT2+/+ mice. These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival. Although VMAT2 rescue in noradrenergic neurons did not eliminate the increased morbidity and lethality associated with VMAT2 deletion, the extension of the lifespan in VMAT2 transgenic mice will enable behavioral, pharmacological and pathophysiological studies of VMAT2 function.
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Neuronas Adrenérgicas/metabolismo , Longevidad/genética , Proteínas de Transporte Vesicular de Monoaminas/fisiología , Animales , Ataxia/genética , Marcha/genética , Ratones , Ratones Noqueados , Actividad Motora/genética , Transgenes , Proteínas de Transporte Vesicular de Monoaminas/genéticaRESUMEN
Increasing evidence suggests that µ opioid receptor (MOP) expression is altered during the development of and withdrawal from substance dependence. Although anti-MOP antibodies have been hypothesized to be useful for estimating MOP expression levels, inconsistent MOP molecular weights (MWs) have been reported in studies using anti-MOP antibodies. In the present study, we generated a new anti-MOP antibody (N38) against the 1-38 amino acid sequence of the mouse MOP N-terminus and conducted Western blot analysis with wildtype and MOP knockout brain lysates to determine the MWs of intrinsic MOP. The N38 antibody detected migrating bands with relative MWs of 60-67 kDa in the plasma membrane fraction isolated from wildtype brain, but not from the MOP knockout brain. These migrating bands exhibited semi-linear density in the range of 3-30 µg membrane proteins/lane. The N38 antibody may be useful for quantitatively detecting MOP.
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Chloroquine, a widely used anti-malarial and anti-rheumatoid agent, has been reported to induce apoptotic and non-apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis by inhibiting autophagy. However, chloroquine is reported to induce GM1 ganglioside accumulation in cultured cells at low µM concentrations and prevent damage to the blood brain barrier in mice. It remains unknown whether chloroquine has neuroprotective properties at concentrations below its reported ability to inhibit lysosomal enzymes and autophagy. In the present study, we demonstrated that chloroquine protected mouse hippocampal HT22 cells from glutamate-induced oxidative stress by attenuating production of excess reactive oxygen species. The concentration of chloroquine required to rescue HT22 cells from oxidative stress was much lower than that sufficient enough to induce cell death and inhibit autophagy. Chloroquine increased GM1 level in HT22 cells at low µM concentrations but glutamate-induced cell death occurred before GM1 accumulation, suggesting that GM1 induction is not related to the protective effect of chloroquine against glutamate-induced cell death. Interestingly, BD1047 and NE-100, sigma-1 receptor antagonists, abrogated the protective effect of chloroquine against glutamate-induced cell death and reactive oxygen species production. In addition, cutamesine (SA4503), a sigma-1 receptor agonist, prevented both glutamate-induced cell death and reactive oxygen species production. These findings indicate that chloroquine at concentrations below its ability to inhibit autophagy and induce cell death is able to rescue HT22 cells from glutamate-induced cell death by reducing excessive production of reactive oxygen species through sigma-1 receptors. These results suggest potential use of chloroquine, an established anti-malarial agent, as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases.
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Cloroquina/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores sigma/metabolismo , Animales , Anisoles/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Etilenodiaminas/farmacología , Gangliósidos/metabolismo , Ácido Glutámico/toxicidad , Glutatión/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Piperazinas/farmacología , Propilaminas/farmacología , Receptores sigma/agonistas , Receptores sigma/antagonistas & inhibidores , Factores de Tiempo , Receptor Sigma-1RESUMEN
BACKGROUND: The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is highly expressed in the central nervous system and functions as a repressor of cAMP response element-binding protein (CREB) transcription. The present study sought to clarify the role of ICER in the effects of methamphetamine (METH). METHODS AND FINDINGS: We tested METH-induced locomotor sensitization in wildtype mice, ICER knockout mice, and ICER I-overexpressing mice. Both ICER wildtype mice and knockout mice displayed increased locomotor activity after continuous injections of METH. However, ICER knockout mice displayed a tendency toward higher locomotor activity compared with wildtype mice, although no significant difference was observed between the two genotypes. Moreover, compared with wildtype mice, ICER I-overexpressing mice displayed a significant decrease in METH-induced locomotor sensitization. Furthermore, Western blot analysis and quantitative real-time reverse transcription polymerase chain reaction demonstrated that ICER overexpression abolished the METH-induced increase in CREB expression and repressed cocaine- and amphetamine-regulated transcript (CART) and prodynorphin (Pdyn) expression in mice. The decreased CART and Pdyn mRNA expression levels in vivo may underlie the inhibitory role of ICER in METH-induced locomotor sensitization. CONCLUSIONS: Our data suggest that ICER plays an inhibitory role in METH-induced locomotor sensitization.
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Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Locomoción/efectos de los fármacos , Metanfetamina/farmacología , Animales , Western Blotting , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Encefalinas/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Precursores de Proteínas/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.
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Metanfetamina/farmacología , Fenciclidina/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Locomoción , Metanfetamina/farmacocinética , Ratones , Ratones Noqueados , Fenciclidina/farmacocinética , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
Serotonergic axons from the raphe nuclei in the brainstem project to every region of the brain, where they make connections through their extensive terminal arborizations. This serotonergic innervation contributes to various normal behaviors and psychiatric disorders. The protocadherin-alpha (Pcdha) family of clustered protocadherins consists of 14 cadherin-related molecules generated from a single gene cluster. We found that the Pcdhas were strongly expressed in the serotonergic neurons. To elucidate their roles, we examined serotonergic fibers in a mouse mutant (Pcdha(Delta CR/Delta CR)) lacking the Pcdha cytoplasmic region-encoding exons, which are common to the gene cluster. In the first week after birth, the distribution pattern of serotonergic fibers in Pcdha(Delta CR/Delta CR) mice was similar to wild-type, but by 3 weeks of age, when the serotonergic axonal termini complete their arborizations, the distribution of the projections was abnormal. In some target regions, notably the globus pallidus and substantia nigra, the normally even distribution of serotonin axonal terminals was, in the mutants, dense at the periphery of each region, but sparse in the center. In the stratum lacunosum-molecular of the hippocampus, the mutants showed denser serotonergic innervation than in wild-type, and in the dentate gyrus of the hippocampus and the caudate-putamen, the innervation was sparser. Together, the abnormalities suggested that Pcdha proteins are important in the late-stage maturation of serotonergic projections. Further examination of alternatively spliced exons encoding the cytoplasmic tail showed that the A-type (but not the B-type) cytoplasmic tail was essential for the normal development of serotonergic projections.
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Encéfalo/crecimiento & desarrollo , Cadherinas/metabolismo , Neuronas/fisiología , Núcleos del Rafe/crecimiento & desarrollo , Serotonina/metabolismo , Empalme Alternativo , Animales , Animales Recién Nacidos , Axones/fisiología , Encéfalo/fisiología , Cadherinas/genética , Masculino , Ratones , Ratones Mutantes , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/fisiología , Núcleos del Rafe/fisiologíaRESUMEN
The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [(3)H]dopamine uptake in vitro. The rank order of potency was reserpine>>fluoxetine, paroxetine>fluvoxamine, methamphetamine>MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.
Asunto(s)
Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte Vesicular de Monoaminas/efectos de los fármacos , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Dopamina/metabolismo , Fluoxetina/farmacología , Fluvoxamina/farmacología , Haloperidol/farmacología , Masculino , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Paroxetina/farmacología , Ratas , Ratas Wistar , Reserpina/farmacología , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismoRESUMEN
Diverse protocadherins (Pcdhs), which are encoded as a large cluster (composed of alpha, beta and gamma clusters) in the genome, are localized to axons and synapses. The Pcdhs have been proposed to contribute to the generation of sophisticated neural networks and to regulate brain function. To address the molecular roles of Pcdhs in regulating individual behavior, here we generated knockdown mice of Pcdh-alpha proteins and examined their behavioral abnormalities. There are two alternative splicing variants of the Pcdh-alpha constant region, Pcdh-alpha A and B isoforms, with different cytoplasmic tails. Pcdh-alpha(DeltaBneo/DeltaBneo) mice, in which the Pcdh-alpha B splicing variant was absent and the Pcdh-alpha A isoforms were down-regulated to approximately 20% of the wild-type level, exhibited enhanced contextual fear conditioning and disparities in an eight-arm radial maze. Similar abnormalities were found in Pcdh-alpha(DeltaAneo/DeltaAneo) mice, which lacked 57 amino acids of the Pcdh-alpha A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-alpha(DeltaB/DeltaB) mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-alpha(DeltaBneo/DeltaBneo) alleles], in which the expression level of the Pcdh-alpha A isoforms was recovered, although the Pcdh-alpha B isoforms were still completely missing in the brain. In addition, the amount of 5-hydroxytryptamine increased in the hippocampus of the hypomorphic Pcdh-alpha A mutant mice but not in recovery Pcdh-alpha(DeltaB/DeltaB). These results suggested that the level of Pcdh-alpha A isoforms in the brain has an important role in regulating learning and memory functions and the amount of 5-hydroxytryptamine in the hippocampus.
Asunto(s)
Encéfalo/metabolismo , Cadherinas/genética , Condicionamiento Psicológico/fisiología , Miedo/fisiología , Memoria a Corto Plazo/fisiología , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/genética , Percepción Espacial/fisiología , Empalme Alternativo/genética , Animales , Cadherinas/metabolismo , Línea Celular , Regulación hacia Abajo/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Proteínas del Tejido Nervioso/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Superficie Celular/metabolismoRESUMEN
OBJECTIVE: Genetic factors are hypothesized to be involved in interindividual differences in opioid sensitivity. Inbred mouse strains that are genetically different and isogenic within each strain are useful for elucidating the genetic mechanisms underlying the interindividual differences in opioid-induced analgesia. METHODS: We examined the effects of morphine in 10 inbred mouse strains, including wild-derived strains that have a wide range of genetic diversity, including BLG2, CHD, KJR, MSM, NJL, PGN2, and SWN. We also performed full sequencing of the 5' flanking region and exons of the mouse mu opioid receptor gene Oprm1 and analyzed the association between genotypes and phenotypes in these mice. RESULTS: The effects of morphine on locomotor activation and antinociception varied among the inbred strains. The nucleotide differences that cause amino acid substitutions were not found in the Oprm1 gene in the inbred strains analyzed in this study. In the 5' flanking region and 3' untranslated region of the Oprm1 gene, four highly variable regions containing novel short tandem repeat polymorphisms (GA, T, TA, and CA/CT) were identified. The GA, T, and TA repeat numbers were significantly associated with morphine-induced antinociception. CONCLUSION: These results suggest that the short tandem repeats in the 5' flanking and 3' untranslated regions of the mu opioid receptor gene are involved in interstrain differences in opioid sensitivity in mice. Wild-derived inbred mouse strains with different numbers of these repeats may be useful models for examining interindividual differences in opioid sensitivity.
Asunto(s)
Regiones no Traducidas 3'/genética , Regiones no Traducidas 5'/genética , Variación Genética , Morfina/farmacología , Dolor/genética , Receptores Opioides mu/genética , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Variación Genética/efectos de los fármacos , Haplotipos , Ratones , Ratones Endogámicos , Repeticiones de Microsatélite/genética , Morfina/administración & dosificación , Sistemas de Lectura Abierta/genéticaRESUMEN
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct low-grade lymphoma that often regresses upon Helicobacter pylori eradication. It was reported that the chemokine receptor CXCR3 is expressed not only on activated T cells, but also on MALT lymphoma cells, and that CXCR3-positive B lymphocytes migrate or home to the MALT of MALT lymphoma. In the present study, we aimed to elucidate the correlation between CXCR3 expression and the clinicopathological features of gastric MALT lymphoma, and to determine whether CXCR3 expression was predictive of responsiveness to H. pylori eradication. Sixty-seven patients with gastric MALT lymphoma in a single-center study were treated with H. pylori eradication therapy. We evaluated the correlation of CXCR3 expression with response to H. pylori eradication therapy by logistic regression stratified according to potential confounders. Immunohistochemical analysis revealed that 28 of 67 cases (42%) were positive for CXCR3 expression. CXCR3 expression was significantly more prevalent in those without H. pylori infection, advanced-stage disease, and in those with API2-MALT1 fusion. In overall analysis, those with CXCR3 expression showed a significantly increased risk of non-responsiveness to H. pylori eradication therapy (odds ratio = 28.6; 95% confidence interval 5.70-143.4) compared to those without CXCR3 expression. This higher risk was observed consistently regardless of sex, API2-MALT1 fusion, H. pylori infection, or clinical stage. We showed that CXCR3 expression was an independent predictive factor for non-responsiveness to H. pylori eradication therapy in patients with gastric MALT lymphoma.