RESUMEN
Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.
Asunto(s)
Hipocampo/citología , Memoria a Corto Plazo/fisiología , Células-Madre Neurales/citología , Neurogénesis/genética , Neuronas/citología , Animales , Trastorno del Espectro Autista/genética , Catecol O-Metiltransferasa/genética , Cromosomas Humanos Par 22 , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Células HEK293 , Hipocampo/metabolismo , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Esquizofrenia/genética , Proteínas de Dominio T Box/genéticaRESUMEN
BACKGROUND: Train-of-four (TOF) fade during nerve-mediated muscle contraction is postulated to be attributable to inhibition of prejunctional nicotinic α3ß2 acetylcholine receptors (nAChRs), while decrease of twitch tension is attributable to block of postjunctional muscle nAChRs. The validity of these presumptions was tested using specific prejunctional and postjunctional nAChR antagonists, testing the hypothesis that fade is not always a prejunctional phenomenon. METHODS: Pentobarbital anaesthetized mice had TOF fade measured after administration of: either 0.9% saline; the prejunctional α3ß2 nAChR antagonist, dihydro-ß-erythroidine (DHßE); the postjunctional nAChR antagonists, α-bungarotoxin (α-BTX) or α-conotoxin GI; and a combination of α-BTX and DHßE; or a combination of α-conotoxin GI and DHßE. RESULTS: Saline caused no neuromuscular changes. Administration of muscle nAChR antagonists, α-BTX or α-conotoxin GI caused significant decrease of twitch tension and TOF fade compared with baseline (P<0.01). DHßE alone caused no change of twitch tension or fade even after 90 min, but its coadministration with α-BTX or α-conotoxin GI significantly accelerated the onset of paralysis and degree of fade compared with α-BTX or α-conotoxin GI alone (P<0.01). CONCLUSIONS: Occupation of postjunctional nAChRs alone by α-BTX or α-conotoxin GI causes fade. As the prejunctional effects of DHßE on fade became manifest only when co-administered with α-BTX or α-conotoxin GI, specific inhibition of prejunctional nAChR alone is not necessary and sufficient to cause fade. Fade observed during repetitive nerve stimulation can be because of block of either postjunctional nAChRs alone, or block of prejunctional and postjunctional nAChRs together.
Asunto(s)
Estimulación Eléctrica , Contracción Muscular/efectos de los fármacos , Unión Neuromuscular/efectos de los fármacos , Receptores Colinérgicos/efectos de los fármacos , Animales , Bungarotoxinas/administración & dosificación , Conotoxinas/administración & dosificación , Dihidro-beta-Eritroidina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Cloruro de Sodio/administración & dosificaciónRESUMEN
UNLABELLED: This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. INTRODUCTION: The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. METHODS: Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients' treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. RESULTS: In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being "less frequent dosing more convenient." Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. CONCLUSIONS: MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.
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Conservadores de la Densidad Ósea/administración & dosificación , Difosfonatos/uso terapéutico , Imidazoles/administración & dosificación , Osteoporosis/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Esquema de Medicación , Sustitución de Medicamentos , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Imidazoles/efectos adversos , Imidazoles/uso terapéutico , Dolor de la Región Lumbar/etiología , Dolor de la Región Lumbar/prevención & control , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Osteoporosis/complicaciones , Osteoporosis/fisiopatología , Prioridad del Paciente , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 2/genética , Metilasas de Modificación del ADN/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/etiología , Escalas de Valoración Psiquiátrica , Procedimientos de Cirugía Plástica/efectos adversos , Trastornos Relacionados con Sustancias/genética , Adulto JovenAsunto(s)
Gastroenteritis/tratamiento farmacológico , Fenitoína/uso terapéutico , Convulsiones/tratamiento farmacológico , Preescolar , Femenino , Gastroenteritis/complicaciones , Gastroenteritis/diagnóstico , Humanos , Lactante , Masculino , Estudios Retrospectivos , Convulsiones/complicaciones , Convulsiones/diagnóstico , Resultado del TratamientoRESUMEN
OBJECTIVES: To explore the possibility of a generally applicable tool for the immediate diagnosis of Parkinson's disease (PD) in its early stage, we compared the sensitivity and specificity of an acute levodopa challenge test with that of (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. MATERIALS AND METHODS: A consecutive series of 45 patients with extrapyramidal symptoms were recruited to the acute levodopa challenge and evaluated for improvement by use of the Unified Parkinson's Disease Rating Scale motor scores. Of these patients, 32 of them were also examined by MIBG scintigraphy. The patients were followed up for at least 24 months, and 22 patients were diagnosed as having clinically definite PD. RESULTS: The sensitivity and specificity of the acute levodopa challenge test to predict clinical diagnosis of PD were 81.8% and 81.8%, respectively, which were better than those obtained by MIBG scintigraphy (62.5% and 62.5%). In both early- and middle-stages of PD, the test gave better sensitivity than MIBG scintigraphy. CONCLUSIONS: Considering that the well-established and frequently referred clinical diagnostic criteria require longitudinal observation for at least 24 months, the acute levodopa challenge test can be used as an immediate diagnostic tool for PD with sensitivity and specificity comparable to those of MIBG.
Asunto(s)
3-Yodobencilguanidina , Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Radiofármacos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cintigrafía , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
A high-resolution measurement of inelastic proton scattering off (90)Zr near 0° was performed at 295 MeV with a focus on a pronounced strength previously reported in the low-energy tail of giant dipole resonance. A forest of fine structure was observed in the excitation energy region 7-12 MeV. A multipole decomposition analysis of the angular distribution for the forest was carried out using the ECIS95 distorted-wave Born approximation code with the Hartree-Fock plus random-phase approximation model of E1 and M1 transition densities and inclusion of E1 Coulomb excitation. The analysis separated pygmy dipole and M1 resonances in the forest at E(PDR)=9.15±0.18 MeV with Γ(PDR)=2.91±0.64 MeV and at E(M1)=9.53±0.06 MeV with Γ(M1)=2.70±0.17 MeV in the Lorentzian function, respectively. The B(E1)↑ value for pygmy dipole resonance over 7-11 MeV is 0.75±0.08 e(2)fm(2), which corresponds to 2.1±0.2% of the Thomas-Reiche-Kuhn sum rule.
RESUMEN
AIMS/HYPOTHESIS: Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined. RESULTS: Administration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation. CONCLUSIONS/INTERPRETATION: Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.
Asunto(s)
Apolipoproteínas E/metabolismo , Aterosclerosis/tratamiento farmacológico , Incretinas/farmacología , Acetil-CoA C-Acetiltransferasa/metabolismo , Animales , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Western Blotting , Antígenos CD36/metabolismo , Línea Celular , Células Cultivadas , Células Espumosas/citología , Células Espumosas/efectos de los fármacos , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Humanos , Masculino , Ratones , Ratones Noqueados , Microscopía Confocal , Fragmentos de Péptidos/farmacología , Péptidos/farmacología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVES: "IZUMI" is a new kind of vinegar resulting from an improvement in the manufacturing method of Kurosu, a traditional vinegar product made from unpolished rice. We evaluated the antioxidant activity of this new Kurosu by means of measuring the level of diacron-reactive oxygen metabolites (d-ROM), the biological antioxidant potential (BAP), as well as RBC deformability using the microchannel array flow method. PARTICIPANTS: Ten healthy, untrained female volunteers participated in this study. MEASUREMENTS: All subjects drank 50 ml of "IZUMI" on a daily basis, and blood samples were collected pre-"IZUMI" (I), after one month "IZUMI" consumption (II), and after two months "IZUMI" consumption (III). The subjects continuously wore a lifecorder during a 7-day period and the nutritional intake was measured before the initial blood sample collection. RESULTS: There were no significant changes in weight, BMI, fat mass, or fat-free mass. There were no significant differences in daily energy consumption, physical activity and nutritional intake. Peripheral blood variables did not change significantly. The drinking of " IZUMI " increased serum BAP level gradually, and after 30 days it was significantly higher as compared to the pre-drinking level. The serum level of d-ROM and blood filtration time (BFT) decreased by drinking "IZUMI"; with d-ROM significantly lower than the pre-drinking level after 30 days and BFT significantly decreased after 60 days (all P < 0.05). CONCLUSIONS: These results suggest that "IZUMI", a Kurosu containing a higher level of amino acids, increases antioxidant activity and reduces oxidative stress and blood filtration time in female subjects.
Asunto(s)
Ácido Acético/administración & dosificación , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Bebidas , Alimentos Funcionales , Estrés Oxidativo , Especies Reactivas de Oxígeno/sangre , Ácido Acético/efectos adversos , Aminoácidos/administración & dosificación , Aminoácidos/efectos adversos , Aminoácidos/análisis , Antioxidantes/efectos adversos , Bebidas/efectos adversos , Bebidas/análisis , Dieta , Registros de Dieta , Deformación Eritrocítica , Femenino , Fermentación , Alimentos Funcionales/efectos adversos , Alimentos Funcionales/análisis , Humanos , Persona de Mediana Edad , Oryza/química , Oryza/metabolismo , Semillas/química , Semillas/metabolismo , Factores de TiempoAsunto(s)
Divertículo/diagnóstico por imagen , Ectopía Cordis/diagnóstico por imagen , Cardiopatías/diagnóstico por imagen , Ectopía Cordis/cirugía , Femenino , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/cirugía , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Recién Nacido , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To determine the incidence of sudden cardiac death (SCD) according to left ventricular ejection fraction (LVEF) in survivors of myocardial infarction (MI) in the primary percutaneous coronary intervention (PCI) era. DESIGN: A multicentre observational prospective registered cohort study. SETTING: 18 medical centres in Japan. PATIENTS: 4122 consecutive patients (mean age 66 (SD 12) years, 73.7% male) with acute MI, who were discharged alive. MAIN OUTCOME MEASURES: The primary end-point was SCD, and a secondary end-point was death from any cause. RESULTS: Patients were categorised into three groups: LVEF >40% (n = 3416), LVEF < or =40% and >30% (n = 507) and LVEF < or =30% (n = 199). Among all patients, 77.8% received PCI and 3.7% received coronary artery bypass graft surgery. During an average follow-up of 4.1 years, SCD was 1.2% and mortality was 13.1%. Patients with LVEF < or =30% and LVEF < or =40% and >30% were at increased risk for SCD (HR 5.99, 95% CI 2.73 to 13.14, p<0.001, HR 3.37, 95% CI 1.74 to 6.50, p<0.001, respectively), and mortality (HR 3.85, 95% CI 2.96 to 5.00, p<0.001, HR 2.06, 95% CI 1.66 to 2.57, p<0.001, respectively), compared to patients with LVEF >40%. Kaplan-Meier estimates of SCD in patients with LVEF < or =30% were 2.9%, 5.1% and 5.1% at 1, 3 and 5 years, respectively. CONCLUSION: There is a low incidence of SCD in survivors of MI in the primary PCI era, although LVEF is a predictor of increased risk for SCD.
Asunto(s)
Angioplastia Coronaria con Balón/mortalidad , Muerte Súbita Cardíaca/prevención & control , Infarto del Miocardio/mortalidad , Volumen Sistólico/fisiología , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/métodos , Muerte Súbita Cardíaca/epidemiología , Desfibriladores Implantables , Femenino , Humanos , Japón/epidemiología , Masculino , Infarto del Miocardio/terapia , Estudios Prospectivos , Análisis de Supervivencia , Sobrevivientes , Resultado del TratamientoRESUMEN
BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) has been reported to affect wound healing and fibrotic processes, but its role in renal tubulointerstitial fibrosis remains unknown. OBJECTIVE: To study its potential role, we compared TAFI-deficient and wild-type mice for the degree of renal fibrosis caused by unilateral ureteral obstruction (UUO). METHODS: The grade of tubulointerstitial fibrosis, the activity of plasmin, MMP-2 and MMP-9 were evaluated on days 4 and 9 after UUO. RESULTS: The renal content of hydroxyproline and the activity of plasmin, MMP-2 and MMP-9 were significantly increased in kidneys with UUO from TAFI-deficient mice compared with those from wild-type mice. These differences disappeared when animals with UUO from both groups were treated with the plasmin inhibitor tranexamic acid. The renal concentrations of fibrogenic cytokines were also significantly elevated in kidneys with UUO from TAFI-deficient mice compared with those from wild-type mice. CONCLUSION: The results of this study suggest that increased renal activity of plasmin in TAFI-deficient mice causes increased renal interstitial fibrosis in obstructive nephropathy.
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Carboxipeptidasa B2/fisiología , Fibrinolisina/análisis , Fibrosis/etiología , Enfermedades Renales/etiología , Obstrucción Ureteral/complicaciones , Animales , Carboxipeptidasa B2/deficiencia , Citocinas/análisis , Hidroxiprolina/análisis , Enfermedades Renales/patología , Metaloproteinasa 2 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/análisis , Ratones , Ratones NoqueadosAsunto(s)
Anestésicos Intravenosos/sangre , Modelos Biológicos , Piperidinas/sangre , Estatura , Peso Corporal , Femenino , Humanos , Masculino , RemifentaniloAsunto(s)
Infarto Encefálico/complicaciones , Enfermedades Cerebelosas/complicaciones , Endoscopía/métodos , Hidrocefalia/cirugía , Tercer Ventrículo/cirugía , Ventriculostomía/métodos , Anciano , Anciano de 80 o más Años , Infarto Encefálico/diagnóstico por imagen , Infarto Encefálico/patología , Infartos del Tronco Encefálico/etiología , Infartos del Tronco Encefálico/patología , Infartos del Tronco Encefálico/fisiopatología , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/patología , Acueducto del Mesencéfalo/diagnóstico por imagen , Acueducto del Mesencéfalo/patología , Acueducto del Mesencéfalo/fisiopatología , Trastornos de la Conciencia/etiología , Trastornos de la Conciencia/fisiopatología , Progresión de la Enfermedad , Resultado Fatal , Femenino , Cuarto Ventrículo/diagnóstico por imagen , Cuarto Ventrículo/patología , Cuarto Ventrículo/fisiopatología , Humanos , Hidrocefalia/etiología , Hidrocefalia/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Medición de Riesgo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Ventriculostomía/instrumentación , Insuficiencia Vertebrobasilar/complicaciones , Insuficiencia Vertebrobasilar/diagnóstico por imagen , Insuficiencia Vertebrobasilar/patologíaRESUMEN
When the tumour suppressor p53 is activated by DNA damage, it stimulates the transcription of its target genes, which then induce cell cycle arrest or apoptosis. Here, we examined the role p53 plays in the antitumour effect of combination treatment with pegylated interferon (PEG-IFN)-alpha and 5-fluorouracil (5-FU), which has been shown to effectively treat advanced hepatocellular carcinoma (HCC). Nude mice were injected subcutaneously with cultured HepG2 cells, in which p53 is functional. They were treated a week later with PEG-IFN and/or 5-FU for 7 weeks, after which we measured and examined their tumours. Combination groups showed significantly lower tumour volumes and higher tumour cell apoptosis than the other groups. Combination treatment and PEG-IFN monotherapy also significantly elevated the p53 protein and mRNA levels in the tumour but only combination treatment increased the degree of p53 phosphorylation at serine46 and induced p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. The antitumour effects of combination treatment is due in part to the elevation by PEG-IFN of p53 protein and mRNA expression and in part to the DNA damage that is generated by 5-FU, which induces p53 serine46 phosphorylation, which in turn upregulates p53AIP1 expression.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Fluorouracilo/administración & dosificación , Humanos , Etiquetado Corte-Fin in Situ , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/efectos de los fármacos , Polietilenglicoles/administración & dosificación , Proteínas Recombinantes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Physiological changes in respiratory mechanics caused by aging may lead to a deterioration in pulmonary gas exchange, an increase in the alveolar-arterial oxygen gradient [(A-a)D(O2)] and a difference between the arterial carbon dioxide (CO(2)) tension (P(a)(CO(2))) and expired end-tidal CO(2) tension (P(ET)(CO(2))) [P((a-ET))(CO(2))] during laparoscopy in the Trendelenburg lithotomy position (TLP). METHODS: The subjects were 51 gynecologic patients. Pressure-controlled ventilation was used to maintain P(ET)(CO(2)), measured by the side stream method, within the range 4-4.67 kPa. During laparoscopy with CO(2) insufflation in TLP, the tidal volume was increased to keep P(ET)(CO(2)) within +/- 20% of the pre-insufflation value. The subjects were divided into three groups by age: young group (< 45 years); middle-aged group (45-64 years); and elderly group ( > or = 65 years). RESULTS: Before pneumoperitoneum (PPN), significant differences were found between the young and elderly groups in the arterial oxygen tension (P(a)(O(2))), (A-a)D(O(2)), P(a)(CO(2)) and P((a-ET))(CO(2)). In all groups, the peak inspiratory pressure and P(a)(CO(2)) increased progressively during PPN in TLP. P((a-ET))(CO(2)) increased gradually after starting CO(2) insufflation in TLP only in the elderly group. CONCLUSIONS: An increase in P((a-ET))(CO(2)) was seen during PPN in TLP in the elderly group. With CO(2) insufflation in TLP, the setting of mechanical ventilation based on the value of P(ET)(CO(2)) (measured by the side stream method) should be determined with caution in elderly patients.
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Insuflación , Laparoscopía , Monitoreo Intraoperatorio , Adulto , Anciano , Presión Sanguínea , Índice de Masa Corporal , Dióxido de Carbono/sangre , Femenino , Frecuencia Cardíaca , Humanos , Inhalación , Persona de Mediana Edad , Oxígeno/sangre , Postura , Posición SupinaRESUMEN
OBJECTIVE: To evaluate the vulnerability of the central nervous system (CNS) in patients with systemic lupus erythematosus (SLE). METHODS: Forty-eight patients with SLE, 58 with schizophrenia in remission and 39 healthy controls were enrolled in the study. Patients vocally generated 100 numbers in a random fashion, using numbers 0 to 9, and were evaluated with seriality scores. Patients with SLE were subgrouped according to differences in the presence of Raynaud's phenomenon, anti-phospholipid antibody, lupus activity, and a history of neuropsychiatric (NP) lupus, and these patients were also evaluated by comparison with their counterparts. RESULTS: In general, patients with SLE showed lower seriality scores than patients with schizophrenia, and higher seriality scores than normal controls. The scores of the patients with a history of NP lupus matched those with schizophrenia, and the scores of never having NP lupus matched those of the healthy controls. CONCLUSIONS: CNS vulnerability may be prolonged in patients who have a history of NP lupus even when they appear to be in normal NP status. The damage in random number generation (RNG) observed in patients with a history of NP lupus seemed equal to that found in those with schizophrenia, whereas those patients never having NP lupus appeared to be equal to the controls. The current study suggests a heterogeneous nature of SLE and prolonged damage, especially in CNS vulnerability, when evaluating with RNG.
Asunto(s)
Sistema Nervioso Central/fisiopatología , Lupus Eritematoso Sistémico/fisiopatología , Adulto , Síndrome Antifosfolípido/fisiopatología , Femenino , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad de Raynaud/fisiopatología , Esquizofrenia/fisiopatologíaRESUMEN
OBJECTIVE: To evaluate the effectiveness of disease-modifying antirheumatic drugs, namely, methotrexate (MTX), sulfasalazine (SSZ) and bucillamine (BUC) at low-doses (4, 6 or 8 mg MTX, 500 or 1,000 mg SSZ, and 100 or 200 mg BUC) in 1,358 patients with a follow-up of at least 12 months and more than 120 months. METHODS: Clinical assessments were based on the number of painful joints (NPJ) and that of swollen joints (NSJ), CRP level, erythrocyte sedimentation rate, rheumatoid factor level and morning stiffness before and after treatment. Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions (ADRs) as the other in single agent and combination therapy. The incidence and nature of ADRs in single and combination treatment are described. RESULTS: The effects of MTX, SSZ and BUC on clinical parameters were monitored over the first three months, and in particular, NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months. CRP levels remained significantly improved for more than 120 months with MTX. In the single and combination long-term treatments, continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1% for MTX, 76.0% for BUC, 68.5% for SSZ, and in the case of the combination treatments, these rates were 83.3% for MTX + BUC and 71.0% for MTX+SSZ. Continuation rates using ADRs as the end point were 88% for SSZ, 79.6% for BUC and 79.4% for MTX. The incidences of ADRs for the various treatments were: MTX 22.2%, SSZ 11.0%, BUC 20.6%, MTX + BUC 30.0% and MTX + SSZ 31.2%. CONCLUSION: MTX showed the highest efficacy even though it was administrated at a low dose (6-8 mg), as a single agent or in combination with other treatment. However, in combination treatments, the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX, SSZ and BUC.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cisteína/análogos & derivados , Metotrexato/uso terapéutico , Sulfasalazina/uso terapéutico , Artritis Reumatoide/fisiopatología , Cisteína/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Articulaciones/efectos de los fármacos , Articulaciones/patología , Articulaciones/fisiopatología , Masculino , Persona de Mediana Edad , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/fisiopatología , Prednisolona/uso terapéutico , Resultado del TratamientoRESUMEN
A 3-year-old boy suffered from the poor body weight gain under the diagnosis of partial anomalous pulmonary venous connection (PAPVC) to the high portion of the superior vena cava (SVC) associated with ventricular septal defect (VSD) and intact atrial septum (IAS). Preoperative cardiac catheterization revealed the pulmonary to systemic flow ratio 2.6 and mean pulmonary arterial pressure of 21 mmHg. He successfully underwent surgical repair with Williams method using right atrial (RA) flap out and VSD patch closure. Postoperative course was uneventful and echocardiography demonstrated no obstruction at the both routes of neo-SVC and neo-right upper pulmonary venous return.