RESUMEN
BACKGROUND AND AIMS: It remains unclear whether glycemic fluctuation can affect plaque rupture in acute myocardial infarction (AMI). Here we investigate the impact of glucose fluctuation on plaque rupture, as observed by optical coherence tomography (OCT), and monocyte subsets in patients with AMI. METHODS AND RESULTS: We studied 37 consecutive patients with AMI. All patients underwent OCT examination, which revealed 24 patients with plaque rupture and 13 patients without plaque rupture at the culprit site. Peripheral blood sampling was performed on admission. Three monocyte subsets (CD14(+)CD16(-), CD14(bright)CD16(+), and CD14(dim)CD16(+)) were assessed by flow cytometry. Glycemic variability, expressed as the mean amplitude of glycemic excursion (MAGE), was determined by a continuous glucose monitoring system 7 days after the onset of AMI. MAGE was significantly higher in the rupture patients than in the non-rupture patients (P=0.036). Levels of CD14(bright)CD16(+) monocytes from the rupture patients were significantly higher than those from the non-rupture patients (P=0.042). Of interest, levels of CD14(bright)CD16(+) monocytes correlated positively and significantly with MAGE (r=0.39, P=0.02). CONCLUSION: Dynamic glucose fluctuation may be associated with coronary plaque rupture, possibly through the preferential increase in CD14(bright)CD16(+) monocyte levels.
Asunto(s)
Glucemia/metabolismo , Monocitos/citología , Placa Aterosclerótica/sangre , Anciano , Angiografía Coronaria , Electrocardiografía , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Placa Aterosclerótica/patología , Estudios Prospectivos , Tomografía de Coherencia ÓpticaRESUMEN
OBJECTIVES: There is accumulating evidence that ceruloplasmin, a copper protein with ferroxidase activity, plays an important role in iron metabolism. The genetic disorder, aceruloplasminemia, can lead to tissue storage of iron as in hemochromatosis. Because most patients with Wilson's disease, a genetic copper toxicosis, have hypoceruloplasminemia, some could be affected by iron overload. METHODS: Four male patients with Wilson's disease were enrolled in this study of pre- and post-treatment iron metabolism. RESULTS: Pretreatment copper contents of the liver were high in all four male patients studied as diagnostic of Wilson's disease. Genetic analysis supported their clinical diagnosis of Wilson's disease without a background of hemochromatosis. Pretreatment serum ceruloplasmin levels were <20 mg/dl in all four patients. A standard penicillamine treatment for 3-8.5 yr further decreased their serum ceruloplasmin levels. Post-treatment serum ferroxidase activity was low as was the serum ceruloplasmin protein. Copper contents in the liver decreased after treatment in all subjects. In contrast, nonheme iron in the liver increased during treatment. Pretreatment liver specimens were positive for histochemical iron in two patients, and post-treatment specimens were positive in all four patients. In two patients, serum aminotransferase levels rebounded with elevation of serum ferritin concentration during the treatment period. Subsequent iron reduction by phlebotomy ameliorated their biochemical liver damage. CONCLUSION: Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilson's disease.
Asunto(s)
Quelantes/uso terapéutico , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Penicilamina/uso terapéutico , Adolescente , Adulto , Humanos , MasculinoRESUMEN
Actinomycin D (AD)-induced apoptosis in CMK-7 cells is greatly accelerated by cytoskeletal poisons such as colcemid (CL) and cytochalasin D (CD). This phenomenon is important in the combination chemotherapy of cancer so that its generality was investigated. Four human leukemia and two human solid tumor cell lines were treated with combinations of one DNA-damaging agent [AD, mitomycin C (MMC), or etoposide (VP- 16)] and one cytoskeletal poison [CL, CD, or vinblastine (VBL)]. The apoptosis was monitored by assaying caspase-3 activity and the DNA cleavage ratio. The caspase-3 activation in all leukemia and HeLa S3 cell lines was, except for a few cases, 1.3-to 6.0-fold enhanced by combinations of the DNA-damaging agent with a cytoskeletal poison. The DNA cleavage ratio as well as the dead cell ratio was also 1.4-to 23.7-fold enhanced in CMK-7, U-937, HeLa S3, and Colo320 DM cell lines by the combinations of AD with CL, CD, or VBL. The combination index for caspase-3 activation by AD and CL in U-937 cells was smaller than 1 at Fa of more than 0.03. Thus, apoptosis in many tumor cell lines is synergistically enhanced by various combinations of DNA- and cytoskeleton-damaging agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Daño del ADN , Citocalasina D/administración & dosificación , Dactinomicina/administración & dosificación , Demecolcina/administración & dosificación , Sinergismo Farmacológico , Etopósido/administración & dosificación , Humanos , Leucemia/tratamiento farmacológico , Mitomicina/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de la Síntesis del Ácido Nucleico/administración & dosificación , Células Tumorales Cultivadas , Vinblastina/administración & dosificaciónRESUMEN
OBJECTIVE: The gene responsible for hereditary hemochromatosis close to the human leukocyte antigen A locus was previously identified and designated as HFE. This study was performed to evaluate the clinical significance of two mutations, C282Y and H63D of HFE, in Japanese patients with hepatic iron overload. PATIENTS AND METHODS: We examined C282Y and H63D in 11 patients with primary hemochromatosis, 94 patients with chronic hepatitis C, 54 patients with miscellaneous liver diseases, and 151 healthy volunteers. The HFE gene region of DNA samples extracted from peripheral leukocytes was amplified by polymerase chain reaction. Restriction enzyme analysis was performed using SnaBI for C282Y and BclI for H63D. Direct sequence analysis was then performed when products suggested the presence of a mutation. RESULTS: All the subjects studied were free from C282Y. None of the patients with hemochromatosis had H63D. One patient with chronic hepatitis C was homozygous, and 4 patients were heterozygous for H63D. Two patients with alcoholic liver disease were heterozygous for H63D. The prevalence of chromosomes with H63D was 6/188 (3.2%) in patients with chronic hepatitis C, 2/108 (1.9%) in patients with miscellaneous liver diseases, and 8/302 (2.6%) in healthy volunteers. These differences were not significant. CONCLUSION: Our results suggested that neither C282Y nor H63D in HFE affect Japanese patients with hemochromatosis or chronic hepatitis C.
Asunto(s)
Pueblo Asiatico/genética , Ácido Aspártico/genética , Cisteína/genética , Antígenos HLA/genética , Hemocromatosis/genética , Histidina/genética , Antígenos de Histocompatibilidad Clase I/genética , Hepatopatías/genética , Proteínas de la Membrana , Mutación Puntual , Tirosina/genética , Adulto , Femenino , Hemocromatosis/epidemiología , Proteína de la Hemocromatosis , Hepatitis C Crónica/genética , Humanos , Sobrecarga de Hierro/genética , Japón/epidemiología , Hepatopatías/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
There is accumulating evidence that ceruloplasmin, a copper-containing protein with ferroxidase activity, plays an important role in iron metabolism. Reduction of ferroxidase activity secondary to ceruloplasmin deficiency may induce iron accumulation in various organs as the result of impaired iron transport. A 37-year-old man presented with intention tremor of the right hand. Liver function tests were almost normal, but parameters of trace elements were abnormal: hypocupremia, hypoceruloplaminemia, and hyperferritinemia. Imaging of the abdomen showed a cirrhotic liver with increased density. A diagnosis of the neurological form of Wilson disease was confirmed by copper deposits in the liver obtained by a blind biopsy, and the patient was diagnosed as compound heterozygous for ATP7B mutations. He was treated with 2500 mg/day trientine hydrochloride per os. The second examination was performed after 20 months of treatment. The treatment further reduced serum ceruloplasmin level from 8.9 to less than 4.0 mg/dl. Serum ferroxidase activity was as low as 70 U/l during treatment. Posttreatment liver histology became negative for copper but remained positive for iron. Copper X-rays from hepatocyte lysosomes were no longer detected, but the iron X-ray was still very high post treatment. Thus, microanalysis confirmed compound overload of copper and iron in this male patient with Wilson disease.
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Cobre/metabolismo , Degeneración Hepatolenticular/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Adulto , Biopsia , Ceruloplasmina/análisis , Quelantes/uso terapéutico , Cobre/análisis , Microanálisis por Sonda Electrónica , Ferritinas/análisis , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/tratamiento farmacológico , Histocitoquímica , Humanos , Hierro/análisis , Hígado/ultraestructura , Masculino , Microscopía Electrónica , Trientina/uso terapéuticoRESUMEN
Information on the level of iron stores in chronic hepatitis C is clinically important because its reduction is technically simple and therapeutically effective. This study was performed to measure the levels of iron stores from the total amounts of hemoglobin removed during iron reduction therapy. The C282Y and H63D mutations of HFE gene were analyzed in 94 patients. All of the patients were negative for C282Y mutation. One patient was homozygous, and 4 patients were heterozygous for H63D mutation. The body iron stores and iron restoration rate were measured in 59 patients in serial courses of iron reduction therapy. Mean values of body iron stores in the two groups with and without H63D mutation were 890 and 606 mg, while those of iron restoration rate were 1.85 and 1.52 mg/day, respectively. None of the indices of iron metabolism were different from the reference values measured similarly in healthy subjects, suggesting that the iron deposition in chronic hepatitis C is limited to the liver, probably due to changes in the iron distribution in tissues.
Asunto(s)
Antígenos HLA/genética , Hepatitis C Crónica/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Proteínas de la Membrana , Femenino , Ferritinas/sangre , Hemocromatosis/genética , Proteína de la Hemocromatosis , Humanos , Japón , Masculino , Mutación , Flebotomía , Estadística como AsuntoRESUMEN
MDR3 is a phospholipid translocator homologous to MDR1 P-glycoprotein. MDR3 localizes to the canalicular membrane and contributes to the secretion of bile. To elucidate the role of protein kinase C in the regulation of MDR3 gene expression, we investigated the effect of phorbol 12-myristate 13-acetate (PMA) on the level of MDR3 mRNA in human Chang liver cells by a reverse transcription-polymerase chain reaction method. The steady-state expression of MDR3 mRNA was decreased by PMA after treatment for 8-20 hr and at concentrations of 1-100 nM. PMA also decreased the doxorubicin-induced expression of MDR3 mRNA. 4alpha-Phorbol 12,13-didecanoate, a negative control compound, did not decrease the expression at these concentrations. The down-regulatory effect of PMA was partially suppressed by the protein kinase C inhibitors 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (GF109203X) and calphostin C. Furthermore, cycloheximide, a protein synthesis inhibitor, antagonized the effect of PMA. From these results, it was suggested that the level of MDR3 mRNA was negatively regulated by a protein kinase C- and protein synthesis-dependent system and that the system regulated both the stable and inducible expression of MDR3 mRNA.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Expresión Génica/efectos de los fármacos , Hígado/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/biosíntesis , Antibióticos Antineoplásicos/farmacología , Carcinógenos/farmacología , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Doxorrubicina/farmacología , Interacciones Farmacológicas , Humanos , Hígado/enzimología , Hígado/metabolismo , Proteína Quinasa C/fisiología , Inhibidores de la Síntesis de la Proteína/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/efectos de los fármacosRESUMEN
A 70-year-old male with right renal mass incidentally found by annual check-up using ultrasound, was referred to Department of Urology, Jikei University Affiliated Kashiwa Hospital. He was diagnosed as having right renal cell carcinoma with vena caval tumor thrombus extending above the diaphragm (T3c) preoperatively. The day before the scheduled day of operation, right pulmonary infarction caused by spontaneous migration of vena caval tumor thrombus of right renal cell carcinoma developed. Although arterial blood gas findings were poor, he only had low grade chest pain without shock. Therefore, we successfully performed right radical nephrectomy and thrombectomy of right pulmonary artery the next day. He was discharged 42 days postoperatively, but, he died from acute heart failure 9 months after the operation.
Asunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Células Neoplásicas Circulantes/patología , Embolia Pulmonar/etiología , Neoplasias Vasculares/patología , Vena Cava Inferior/patología , Anciano , Humanos , Masculino , Neoplasias Vasculares/complicacionesRESUMEN
Four degraded okaramine B (2) products, 4',5'-dihydrookaramine B (3), two azetidine ring-opened compounds (4 and 5) and 1',2',4',5'-tetrahydrookaramine B (6), were prepared and their insecticidal activity was examined. Neither compounds 4 nor 5 showed such activity against silkworms, indicating that the azetidine ring moiety played an important role in the insecticidal activity. Moreover, both compounds 3 and 6 exhibited lower activity than 2, which means that the azocine ring moiety was indispensable to form the active conformation.
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Alcaloides/farmacología , Azetidinas/farmacología , Azocinas/farmacología , Insecticidas/farmacología , Alcaloides/química , Animales , Azetidinas/química , Azocinas/química , Bombyx/efectos de los fármacos , Alcaloides Indólicos , Insecticidas/química , Espectroscopía de Resonancia Magnética/métodos , Estructura Molecular , Penicillium/químicaRESUMEN
The gene ATP7B responsible for Wilson's disease (WD) produces a protein which is predicted to be a copper-binding P-type ATPase, homologous to the Menkes disease gene (ATP7A). Various mutations of ATP7B have been identified. This study aimed to detect disease-causing mutations, to clarify their frequency and distribution, to determine whether genotype correlates with phenotype, and to determine the rate of abnormal findings in heterozygotes for the WD gene. We analyzed 41 unrelated Japanese WD families, including 47 patients. Twenty-one mutations, including nine novel ones, were identified. 2871delC (15.9%), 1708-5T-->G (11. 0%), and Arg778Leu (13.4%) were the most common mutations. 2871delC was detected mainly in eastern Japan and 1708-5T-->G in western Japan. The homozygotes for the 1708-5T-->G, 2871delC, or Arg778Leu mutations did not show a correlation with their phenotypes. Ceruloplasmin and copper levels were abnormally low in 28.6% and 35. 0% of heterozygotes, respectively. When patients and their families are screened for WD, a high rate of abnormal laboratory data in heterozygotes must be taken into account.
Asunto(s)
Adenosina Trifosfatasas/genética , Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Degeneración Hepatolenticular/genética , Mutación , Sustitución de Aminoácidos , Pueblo Asiatico , Ceruloplasmina/análisis , Cobre/sangre , ATPasas Transportadoras de Cobre , Análisis Mutacional de ADN , Elementos Transponibles de ADN , Femenino , Mutación del Sistema de Lectura , Genotipo , Geografía , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/enzimología , Humanos , Japón , Masculino , Mutación Missense , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Eliminación de SecuenciaRESUMEN
Five new okaramine congeners, okaramines N, O, P, Q, and R, were isolated from Penicillium simplicissimum ATCC 90288. Their structures were determined by an analysis of spectroscopic data. The insecticidal activity of these new okaramines was evaluated against silkworms.
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Alcaloides/aislamiento & purificación , Insecticidas/aislamiento & purificación , Penicillium/química , Alcaloides/farmacología , Animales , Bombyx/efectos de los fármacos , Insecticidas/farmacología , Dosificación Letal Mediana , Espectroscopía de Resonancia Magnética , Modelos Químicos , Espectrofotometría Infrarroja , Espectrofotometría UltravioletaRESUMEN
We described a 28-year-old woman with systemic lupus erythematosus (SLE) presented with digestive tract, skin and renal symptoms and afterwards developed acute cerebellar ataxia, a paresis of the right inferior rectus muscle, left abducens paralysis and left facial palsy which seemed to be consistent with a brainstem lesion visible on magnetic resonance imaging (MRI). This lesion disappeared within 9 days of corticosteroid treatment. It is suggested that this lesion is focal edema induced by acute changes in the blood brain barrier secondary to a vasculopathy. Other causes, including local infarction, are unlikely.
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Ataxia Cerebelosa/etiología , Lupus Eritematoso Sistémico/complicaciones , Enfermedad Aguda , Adulto , Antiinflamatorios/uso terapéutico , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/patología , Tronco Encefálico/patología , Ataxia Cerebelosa/diagnóstico , Parálisis Facial/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Prednisolona/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
Two new congeners of okaramine, okaramines H (3) and I (4), were isolated from okara fermented with Aspergillus aculeatus KF-428. Their structures were elucidated by spectroscopic methods. Neither okaramine H nor I showed insecticidal activity against silkworms.
RESUMEN
1. The metabolism and pharmacokinetics of dihydrocodeine have been studied in dog. Urinary metabolites after oral administration of dihydrocodeine were identified using hplc with diode-array and ms. 2. In urine, dihydronorcodeine, dihydromorphine and dihydrocodeine glucuronide were identified in comparison with their authentic standards, and dihydronorcodeine 6-glucuronide also appeared to be excreted as a metabolite. 3. The major urinary metabolite was dihydrocodeine glucuronide, recovered as 49% of the dose, and other metabolites were found to be 0.1-3%, 24 h after 3 mg/kg oral administration of dihydrocodeine. Plasma concentrations of unchanged dihydrocodeine were significantly lower after oral rather than intramuscular administration; the maximum concentrations were 40 and 549 ng/ml after oral and intramuscular administration, respectively. This suggests that dihydrocodeine was metabolized via a hepatic first-pass effect after oral administration. 4. Overall, our results indicate that the metabolic pathways of dihydrocodeine in dog were similar to that of codeine metabolism in animals and man.
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Codeína/análogos & derivados , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Codeína/metabolismo , Codeína/farmacocinética , Codeína/orina , Perros , Electroquímica/métodos , Inyecciones Intramusculares , MasculinoRESUMEN
An HPLC method with electrochemical and UV detection was established for the simultaneous determination of dihydrocodeine and its metabolites, dihydronorcodeine, dihydromorphine, and dihydrocodeine glucuronide, in dog plasma using N-ethylnormorphine as the internal standard. The method involved sample pretreatment with a C18-bonded disposable column, and the injected fraction was separated and detected on the C18-bonded column with serially coupled UV and coulometric detectors. Dihydromorphine was detected with the coulometric detector at 0.4 V, and dihydrocodeine and dihydronorcodeine at 0.8 V. Dihydrocodeine glucuronide was detected with UV at 210 nm. Recoveries of the studied compounds were quantitative at the individual assay ranges, and validation of the assay gave results that were satisfactory in terms of within-run or between-run precision and accuracy. Lower limits of quantitation were 2 ng/ml for dihydrocodeine and dihydronorcodeine, 0.5 ng/ml for dihydromorphine, and 200 ng/ml for dihydrocodeine glucuronide.