RESUMEN
Despite the outstanding results generally obtained with imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), some patients show a poor molecular response. To evaluate the relationship between steady-state trough plasma IM concentration (IM-C(min)) and clinical response in CML patients, we integrated data from six independent Japanese studies. Among 254 CML patients, the mean IM-C(min) was 1,010.5 ng/ml. Importantly, IM-C(min) was significantly higher in patients who achieved a major molecular response (MMR) than in those who did not (P = 0.002). Multivariate analysis showed that an MMR was associated with both age (odds ratio (OR) = 0.97 (0.958-0.995); P = 0.0153) and with IM-C(min) (OR = 1.0008 (1.0003-1.0015); P = 0.0044). Given that patients with IM-C(min) values >1,002 ng/ml had a higher probability of achieving an MMR in our large cohort (P = 0.0120), the data suggest that monitoring of IM levels in plasma may improve the efficacy of IM therapy for CML patients.
Asunto(s)
Pueblo Asiatico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/metabolismo , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Estudios de Cohortes , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52-64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF-alpha and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.
Asunto(s)
Isquemia Encefálica/patología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/patología , Fragmentación del ADN/fisiología , Oligodendroglía/patología , Proteínas Proto-Oncogénicas c-bcl-2 , Animales , Northern Blotting , Caspasa 3 , Caspasas/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Flujometría por Láser-Doppler , Masculino , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Wistar , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Proteína X Asociada a bcl-2RESUMEN
BACKGROUND: Primary malignant lymphoma of the heart is extremely rare. Because its clinical signs and symptoms are typically nonspecific, it is often very difficult to detect cardiac involvement while the patient is alive. We describe a case of malignant lymphoma involving predominantly the heart and pericardium and diagnosed by pericardiac effusion cytology antemortem. CASE: An 83-year-old woman presented with dyspnea on exertion. Echocardiography revealed a low-echoic tumor mass close to the right ventricular wall and massive pericardiac effusion. Diagnosis of diffuse large B-cell lymphoma was made by cytomorphologic examination and flow cytometry of the tumor cells obtained from the effusion. Although chemotherapy was instituted immediately, the patient died of progressive heart failure. Diffuse large B-cell lymphoma predominantly involving the intracardiovascular region was confirmed at autopsy. CONCLUSION: From the experience in this case, we conclude that cytopathologic examination of sonographically guided aspiration of the cardiovascular region is very useful for antemortem diagnosis of primary malignant lymphoma of the heart.
Asunto(s)
Neoplasias Cardíacas/diagnóstico , Linfoma de Células B/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Quimioterapia Combinada , Ecocardiografía , Resultado Fatal , Femenino , Citometría de Flujo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/patología , Neoplasias Cardíacas/química , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/tratamiento farmacológico , Humanos , Inmunofenotipificación , Linfoma de Células B/química , Linfoma de Células B/complicaciones , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/química , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Derrame Pericárdico/diagnóstico , Prednisona/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND AND PURPOSE: Postoperative brain dysfunction, such as delirium, is a common complication of anesthesia and is sometimes prolonged, especially in patients with cerebrovascular disease. In the present study we investigated the effect of hypocapnia during anesthesia on neuronal damage using a rat model of chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced by clipping the bilateral common carotid arteries in male Wistar rats. Fourteen days after the operation, these animals were mechanically ventilated for 2 hours and then kept in suitable conditions for an additional 14 days. Twenty-four rats were assigned to 4 groups: those with chronic cerebral hypoperfusion with either hypocapnia or normocapnia during anesthesia, and those given sham operation with either hypocapnia or normocapnia. White matter lesions in the brain sections were evaluated with Klüver-Barrera staining. Proliferation of glial cells was estimated with the use of immunohistochemistry of glial fibrillary acidic protein, a marker for astroglia, and CD11b, a marker for microglia. Computer-assisted morphometry was applied to the immunohistochemical results of microtubule-associated protein 2 to evaluate the loss of neurons. RESULTS: The histological damage was localized almost exclusively in the white matter in the rats subjected to chronic cerebral hypoperfusion but without hypocapnia. Neuronal damage and astroglial proliferation occurred with aggravated white matter lesions in the caudoputamen in the rats with chronic cerebral hypoperfusion and hypocapnia. No lesions were observed in sham-operated rats with either hypocapnia or normocapnia. CONCLUSIONS: These results indicate that hypocapnia during anesthesia causes tissue damage in the caudoputamen, which may be responsible for long-lasting postoperative delirium in patients with stroke and/or dementia.
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Enfermedades de los Ganglios Basales/patología , Isquemia Encefálica/patología , Hipocapnia/patología , Respiración Artificial , Anestesia , Animales , Antígenos de Diferenciación/biosíntesis , Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/metabolismo , Velocidad del Flujo Sanguíneo , Isquemia Encefálica/complicaciones , Isquemia Encefálica/metabolismo , Núcleo Caudado/metabolismo , Núcleo Caudado/patología , Circulación Cerebrovascular , Enfermedad Crónica , Demencia Vascular/etiología , Modelos Animales de Enfermedad , Hipocapnia/complicaciones , Hipocapnia/metabolismo , Inmunohistoquímica , Masculino , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Putamen/metabolismo , Putamen/patología , Ratas , Ratas Wistar , Tasa de Supervivencia , TiempoRESUMEN
Photocatalytic effects of TiO2 powder on marine plankton were examined by the use of either brine shrimp Artemia salina or noxious red tide flagellate Chattonella antiqua as a probe. After UV (365 nm) irradiation for ca. 1 hour, A. salina stopped moving and the body surface was completely covered by TiO2 powder. Similar photoirradiation of C. antiqua, on the other hand, induced deformation of the body from spindle to round shape within 20 minutes. The deformed C. antiqua recovered to normal shapes, when the cells were kept in the same conditions but without UV irradiation for more than 40 minutes. On the prolonged UV irradiation (more than 100 minutes), however, the cells burst and came to annihilation. The photocatalytic reactions of TiO2 on the body surface are thus concluded to induce fatal damages to these microorganisms.
Asunto(s)
Anomalías Congénitas/fisiopatología , Eucariontes , Fármacos Fotosensibilizantes/efectos adversos , Plancton , Titanio/efectos adversos , Animales , Artemia , Catálisis , Exposición a Riesgos Ambientales , Movimiento , Fotólisis , Polvos/efectos adversos , Pruebas de Toxicidad , Rayos UltravioletaRESUMEN
A novel two dimensional imaging technique of the chemical bonding state was developed by combining the extended X-ray emission fine structure method with an electron probe X-ray microanalyzer mapping technology. With this method, chemical state images of some aluminum standard samples were obtained. It was confirmed that the obtained images provide correct information of chemical states.
RESUMEN
White matter lesions are closely associated with cognitive impairment and motor dysfunction in the aged. To explore the pathophysiology of these lesions, the authors examined the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the white matter in a rat model of chronic cerebral hypoperfusion. After bilateral clipping of the common carotid arteries, myelin staining revealed demyelinating changes in the optic tract and the corpus callosum on day 7. Zymographic analyses indicated an increase in the level of MMP-2, but not MMP-9, after the hypoperfusion. Immunohistochemical analyses revealed the presence (most abundantly on day 3) of MMP-2-expressing activated microglia in the optic tract and corpus callosum. In contrast, the capillary endothelial cells expressed MMP-2 later. IgM-immunoreactive glial cells were absent in the sham-operated animals, but were present in the hypoperfused animals by day 3, reflecting the disrupted blood-brain barrier. These findings suggest that the main sources of the elevated MMP-2 were the microglia and the endothelium, and that these cells may contribute to the remodeling of the white matter myelin and microvascular beds in chronic cerebral hypoperfusion.
Asunto(s)
Encéfalo/irrigación sanguínea , Endotelio Vascular/enzimología , Expresión Génica , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Microglía/enzimología , Animales , Northern Blotting , Encéfalo/enzimología , Capilares/enzimología , Arteria Carótida Común , Constricción , Cuerpo Calloso/enzimología , Inmunoglobulina M/análisis , Inmunohistoquímica , Masculino , Vaina de Mielina/enzimología , ARN Mensajero/análisis , Ratas , Ratas Wistar , Vías Visuales/enzimologíaRESUMEN
There have been few studies on the white matter lesions of spontaneously hypertensive rats (SHR). From the point of view of hypertension and arteriosclerosis, white matter lesions were examined in SHR and stroke-prone SHR (SHRSP), and were then compared with Wistar-Kyoto (WKY) rats. The vasculopathy was analyzed by morphometric immunohistochemistry for collagen and smooth muscle actin. Both SHR and SHRSP had hypertension at > or = 12 weeks of age, and the latter developed severe white matter lesions at 20 weeks. Immuno- histochemistry revealed proliferation of microglia in the white matter and an increase in smooth muscle actin in the vessels of SHRSP compared with the WKY rats and SHR, but there were no changes in the collagen. These results indicate a role of hypertension in the pathogenesis of white matter lesions. However, genetic difference may also be responsible since SHR and SHRSP showed similar hypertension.
Asunto(s)
Arterias Cerebrales/patología , Trastornos Cerebrovasculares/patología , Hipertensión/complicaciones , Hipertensión/patología , Músculo Liso Vascular/patología , Fibras Nerviosas Mielínicas/patología , Ratas Endogámicas SHR/anomalías , Actinas/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Arterias Cerebrales/metabolismo , Trastornos Cerebrovasculares/etiología , Trastornos Cerebrovasculares/fisiopatología , Hipertensión/fisiopatología , Inmunohistoquímica , Complejo Mayor de Histocompatibilidad/inmunología , Microglía/metabolismo , Microglía/patología , Músculo Liso Vascular/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Ratas , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas WKY/anomalías , Ratas Endogámicas WKY/metabolismo , Telencéfalo/metabolismo , Telencéfalo/patología , Telencéfalo/fisiopatologíaRESUMEN
Ni L- and Ti L-edge as well as Ti K-edge X-ray absorption experiments for TiO2 thin films and Ni-doped TiO2 thin films coated on glass plates were performed using synchrotron radiation to investigate the structures around Ni and Ti ions in the films. The obtained spectra were compared with the results of theoretical calculations. It has consequently been found that the spectral features were affected by a change in the oxidizing form of Ni ions due to hydrogen reduction, by the charge variation and/or slight orbital splitting of Ti ions, and by the magnitude of the interaction between the center Ti ion and neighboring Ti ions.
RESUMEN
BACKGROUND: CHOP is accepted as the gold standard for first line chemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalation study of CHOP was conducted to determine the maximal tolerated dose (MTD) and toxicity profile of CHOP at three-week intervals with or without prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patients with aggressive NHL. PATIENTS AND METHODS: The doses of drugs were escalated from 50 mg/m2 to 70 mg/m2 for doxorubicin and from 750 mg/m2 to 2250 mg/m2 for cyclophosphamide, with conventional doses of vincristine and oral prednisolone. After the MTD was determined without rHuG-CSF, dose escalation was conducted with prophylactic rHuG-CSF. RESULTS: Thirty-three patients with NHL were enrolled into the study. The MTD without prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 1250 mg/m2 of cyclophosphamide, with neutropenia as a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 2250 mg/m2 of cyclophosphamide. The overall response rate was 100% (76% complete response and 24% partial response). Progression-free survival and overall survival at five years were 45% and 66%, respectively. CONCLUSIONS: Significant dose escalation of doxorubicin and cyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy of dose-escalated CHOP should be compared with that of standard CHOP.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Proteínas Recombinantes , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
The blood coagulation system has been shown to be activated in subacute exacerbations of Binswanger disease (BD). In our previous study, the antithrombin drug argatroban t ameliorated the neurological exacerbations in a BD patient with antiphospholipid antibody syndrome. We have further examined the therapeutic efficacy of argatroban in 3 BD patients with subacute exacerbations, but without any immune-mediated prothrombotic complications. In 1 out of these 4 patients, treatment with sodium ozagrel, an antiplatelet drug was applied, but was ineffective. In all patients, argatroban treatment reduced the levels of the hemostatic markers, with a corresponding improvement in cognitive dysfunction and gait disorders. These results suggest that the antithrombin effect is true also for BD patients not compromised by the immune-mediated prothrombotic condition.
Asunto(s)
Antitrombinas/uso terapéutico , Demencia Vascular/tratamiento farmacológico , Ácidos Pipecólicos/uso terapéutico , Enfermedad Aguda , Anciano , Arginina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , SulfonamidasRESUMEN
The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40-50 mg/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Paclitaxel/análogos & derivados , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Taxoides , Adulto , Anciano , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Área Bajo la Curva , Neoplasias de la Mama/sangre , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Docetaxel , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacocinética , Doxorrubicina/toxicidad , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia , Paclitaxel/farmacocinética , Paclitaxel/toxicidad , Factores de TiempoRESUMEN
BACKGROUND AND PURPOSE: It has been hypothesized that fibrohyalinosis of the medullary arteries may cause white matter lesions in Binswanger's disease (BD). However, previous reports have been inconsistent on the pathological alterations of the cellular components, which may vary in terms of vessel sizes. We therefore quantitatively examined vasculopathy in the medullary arteries of a defined caliber in BD brains with a quantitative technique. METHODS: A total of 20 brains were examined: 10 from patients with BD and 10 from age-matched nonneurological control patients. The alterations in the vascular cell components were examined with quantitative immunohistochemistry and immunoelectron microscopy for collagen and smooth muscle actin. RESULTS: The nonneurological control patients showed no white matter lesions. In contrast, the patients with BD invariably had marked white matter lesions, as well as fibrohyalinosis of the medullary arteries. The ratio of the area immunolabeled for collagen type I and type IV to the cross-sectional area was 2-fold higher in the BD patients than in the control patients, regardless of the vessel caliber (P<0.005). Although the ratio for smooth muscle actin in the BD brains was increased in arteries of <100 microm (P<0.0001), there was no corresponding increase in the arteries of >100 microm. However, in the ultrastructure of these vessels, the cell bodies immunolabeled for smooth muscle actin were hypertrophic and segregated from each other by proliferated fibrils. The basal lamina appeared multilayered, and the endothelial cells were swollen. Collagen type I and type IV immunoreactive fibrils also proliferated in the pericapillary space of the BD brains. CONCLUSIONS: The proliferation of collagen fibrils in the media and adventitia of the blood vessels in BD brains was not specific to small arteries and arterioles but also occurred in the pericapillary spaces. Pericapillary sclerosis, smooth muscle cell proliferation in the terminal arterioles, and their morphological transformation in the proximal arteries may alter the shear rates and thus cause profound microcirculatory disturbances in BD brains.
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Encéfalo/irrigación sanguínea , Arterias Cerebrales/ultraestructura , Demencia Vascular/patología , Endotelio Vascular/ultraestructura , Microscopía Inmunoelectrónica , Músculo Liso Vascular/ultraestructura , Actinas/metabolismo , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales , Cadáver , Arterias Cerebrales/metabolismo , Colágeno/metabolismo , Demencia Vascular/metabolismo , Endotelio Vascular/metabolismo , Humanos , Músculo Liso Vascular/metabolismoRESUMEN
Cyclooxygenase-2 (COX-2) is known to be up-regulated in ischemic rodent brains, but only little information is available for the human brain. Using immunohistochemistry for COX-2, we investigated brains from control subjects and from patients with cerebrovascular diseases. COX-2 was markedly up-regulated in the neurons and endothelial cells in acute cerebral infarction, but was detected sparsely at chronic stages in these cellular compartments. In contrast, COX-2 immunoreactivity in glial cells was localized to the perinuclear region even in control brains. This immunolabeling was more intense and occurred also in the glial cytoplasm in the brains with chronic cerebral ischemia such as Binswanger's disease. Double-labeling immunohistochemistry confirmed that COX-2-immunoreactive glia were mostly microglia. These results indicate that prostanoid synthesis is up-regulated in microglia during chronic cerebral ischemia, and that these cells may be involved in tissue repair or inflammation-mediated cell responses.
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Isquemia Encefálica/enzimología , Isoenzimas/metabolismo , Microglía/enzimología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/enzimología , Encéfalo/patología , Enfermedad Crónica , Ciclooxigenasa 2 , Endotelio Vascular/embriología , Endotelio Vascular/patología , Inducción Enzimática , Femenino , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Neuroglía/enzimología , Neuronas/enzimología , Valores de Referencia , Distribución TisularRESUMEN
A new synthetic retinoid, Am80, is effective in treating acute promyelocytic leukemia relapsed from all-trans-retinoic acid-induced complete remission (CR). We report here the long-term clinical outcomes of patients who achieved second CR with Am80. Of 24 evaluable patients, 14 achieved a second CR by Am80 therapy. Of those patients, 4 relapsed within 6 months, despite subsequent consolidation chemotherapy. Six patients underwent sibling or unrelated HLA-matched allogeneic bone marrow transplantation (BMT), and 4 are alive without relase for more than 49 months after achieving second CR. Four of 8 patients who did not receive BMT are alive without relapse for more than 49 months. Promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) fusion transcript was undetectable by reverse transcriptase-polymerase chain reaction in all living patients. Therefore, if patients achieve second CR with Am80 and HLA-matched donors are available, BMT is the treatment of choice. However, it is noteworthy that CR was maintained for more than 49 months in half of the patients who did not receive BMT.
Asunto(s)
Leucemia Promielocítica Aguda/tratamiento farmacológico , Retinoides/administración & dosificación , Adulto , Anciano , Antineoplásicos/administración & dosificación , Benzoatos/administración & dosificación , Benzoatos/normas , Femenino , Estudios de Seguimiento , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Inducción de Remisión/métodos , Retinoides/normas , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/normas , Tretinoina/administración & dosificaciónRESUMEN
The biological effects of epidermal growth factor receptor (EGFR) activation may differ between epidermal suprabasal and basal keratinocytes, since growth factors are mitogenic in adherent cells only in the presence of cell-extracellular matrix (ECM) interaction. To investigate biological effects of EGFR activation on keratinocytes without cell-ECM interaction, we cultured normal human keratinocytes on polyhydroxyethylmethacrylate-coated plates, which disrupt cell-ECM but not cell-cell interaction. The cells initially expressed keratin 10 (K10) and then profilaggrin, mimicking sequential differentiation of epidermal suprabasal keratinocytes. The addition of EGF or transforming growth factor-alpha promoted late terminal differentiation (profilaggrin expression, type 1 transglutaminase expression and activity, and cornified envelope formation) of the suspended keratinocytes, while suppressing K10 expression, an early differentiation marker. These effects were attenuated by EGFR tyrosine kinase inhibitor PD153035 or an anti-EGFR monoclonal antibody, whereas protein kinase C inhibitors H7 and bisindolylmaleimide I or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059 abolished profilaggrin up-regulation but not K10 suppression. Since the antidifferentiative role of EGFR on cell-ECM interaction-conserved keratinocytes has been well documented, our results indicate that the biological effects of EGFR on keratinocytes are influenced by cell-ECM interaction and suggest that EGFR activation promotes rather than inhibits the terminal differentiation of suprabasal epidermal keratinocytes.
Asunto(s)
Receptores ErbB/fisiología , Matriz Extracelular/fisiología , Queratinocitos/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Activación Enzimática , Factor de Crecimiento Epidérmico/farmacología , Proteínas Filagrina , Flavonoides/farmacología , Humanos , Proteínas de Filamentos Intermediarios/biosíntesis , Queratinas/biosíntesis , Ratones , Proteína Quinasa C/fisiología , Precursores de Proteínas/biosíntesis , Transglutaminasas/biosíntesisRESUMEN
Sphingolipids such as ceramide and sphingosine are abundantly present in the stratum corneum of epidermis. In atopic stratum corneum, sphingosylphosphorylcholine (SPC) is present in association with a reduction in the amount of ceramides. We have previously shown that the cellular kinetics of T cells are affected by exogenous addition of sphingosine and synthetic ceramides, raising the possibility that sphingolipids diffusing from the stratum corneum modulate skin-infiltrating T cells. By using two natural ceramides and murine T cells, this study further clarified the conditions under which exogenous ceramides enhance the proliferation of T cells. KLH-specific T cell clones 28-4 and 24-2 proliferated in response to natural ceramides when cultured for 44-48 h in the presence of concanavalin A at 1 microg per ml. Elongation of culture periods adversely inhibited the T cell proliferation, suggesting the existence of an optimal exposure time. Augmentation of DNA synthesis by natural ceramides was more pronounced in tumor necrosis factor alpha (TNFalpha)-sensitive 28-4 cells than in less sensitive 24-2 cells, and TNFalpha-induced proliferation of 28-4 cells was suppressed by the concomitant addition of natural ceramides. Similar to ceramides, SPC augmented the proliferation of resting spleen cells. Our study suggests that ceramide modulation of T cell proliferation depends on the TNFalpha sensitivity and activation level of T cells and that SPC also has a mitogenic potential for T cells.
Asunto(s)
Ceramidas/farmacología , Fosforilcolina/análogos & derivados , Esfingosina/análogos & derivados , Linfocitos T/efectos de los fármacos , Animales , División Celular/efectos de los fármacos , Células Cultivadas , Concanavalina A/farmacología , Replicación del ADN/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos BALB C , Fosforilcolina/farmacología , Esfingosina/farmacología , Bazo/citología , Bazo/efectos de los fármacos , Linfocitos T/citología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Keratinocyte cytotoxicity is an important component of the immunopathology of photosensitive lupus erythematosus, and antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be an important mechanism by which autoantibodies, especially those specific for SS-A/Ro, can induce keratinocyte damage in models of photosensitive lupus. We provide further evidence that keratinocytes from patients with photosensitive lupus show significantly greater ultraviolet radiation (UVR)-induced cytotoxicity, and that ADCC of these targets is especially enhanced by autologous patient's serum or by anti-SS-A/Ro+ sera. Keratinocytes from normal uninvolved skin of 29 patients with cutaneous lupus erythematosus (LE) were grown in cell culture and tested as targets in cytotoxicity experiments in vitro. Cultured keratinocytes from patients with systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE) showed significantly greater cytotoxicity following UVR treatment than did keratinocytes from normal adult controls or from neonatal foreskins (P < 0.01). The same cultures also showed greater UVR-induced binding of IgG from fractionated anti-SS-A/Ro+ preparations. ADCC experiments were also performed using keratinocytes cultured from patients with SLE, SCLE, discoid lupus erythematosus (DLE), and normal controls. When keratinocytes were incubated in autologous serum plus a standard mononuclear cell effector population, the percentage of ADCC observed was significantly greater in cultures containing keratinocytes and sera from the SLE and SCLE patients (P < 0.001). When cultured keratinocytes were added to different IgG antibody probes, plus standard mononuclear effector populations, greater ADCC was seen using the anti-SS-A/Ro probe and keratinocytes from patients with SLE or SCLE. With normal human neonatal keratinocyte targets, the anti-SS-A/Ro probe induced greater ADCC than that seen with anti-ssDNA or normal human serum. We have shown that keratinocytes from patients with some forms of lupus erythematosus (SLE and SCLE) show greater cytotoxicity in vitro when irradiated with UVR, and greater susceptibility to ADCC whether the antibody source is their own serum or an anti-SS-A/Ro probe.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de la radiación , Queratinocitos/inmunología , Queratinocitos/efectos de la radiación , Lupus Eritematoso Sistémico/patología , Rayos Ultravioleta , Adulto , Anticuerpos Antinucleares/aislamiento & purificación , Anticuerpos Antinucleares/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Membrana Celular/metabolismo , Células Cultivadas , Pruebas Inmunológicas de Citotoxicidad , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: A hypercoagulable state is often associated with an acute stroke in cerebrovascular disease (CVD). However, in Binswanger disease (BD), no information is available on the coagulation-fibrinolysis pathway except for the presence of high plasma fibrinogen levels. OBJECTIVE: To determine the association of BD and coagulation-fibrinolysis pathway activation. PATIENTS AND METHODS: We examined the levels of fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), and cross-linked D-dimer in 17 patients with BD, 24 neurologic patients without CVD, and 26 patients with lacunar infarction in either the acute or chronic stage. RESULTS: As compared with the non-CVD and lacunar infarction groups, the patients with BD had significantly elevated levels of thrombin-antithrombin complex (P<.001), prothrombin fragment(1+2) (P<.05), and cross-linked D-dimer (P<.01). There was also a significant increase in fibrinogen levels compared with the non-CVD group (P<.05). In the BD group, 8 patients in stable condition (ie, those without obvious neurologic deficits in the past 3 months) showed normal levels or a mild increase in their fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), or cross-linked D-dimer levels. In contrast, 9 patients with BD with a subacute aggravation of their focal or subcortical cerebral functions (deteriorating group) showed a significant increase in their thrombin-antithrombin complex levels compared with the stable patients (P<.01). Similarly, the fibrinogen, prothrombin fragment(1+2), and cross-linked D-dimer levels were elevated in the deteriorating patients, but this trend did not reach statistical significance. CONCLUSIONS: These results indicate that the coagulation-fibrinolysis pathway is activated in patients with BD with a subacute aggravation. Coagulation activation may result in the formation of microthrombi and microcirculatory disturbances in the brains of these patients, and thus promote further biological and neurologic insults.
Asunto(s)
Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/complicaciones , Coagulación Sanguínea , Demencia Vascular/sangre , Demencia Vascular/etiología , Anciano , Anciano de 80 o más Años , Antitrombina III , Encefalopatías/sangre , Estudios de Casos y Controles , Femenino , Fibrinógeno/metabolismo , Fibrinólisis , Humanos , Masculino , Persona de Mediana Edad , Péptido Hidrolasas , Protrombina/metabolismoRESUMEN
Throat infection with Streptococcus pyogenes is the most important trigger for acute guttate psoriasis. We examined the in vitro responses of peripheral blood mononuclear cells (PBMC) to streptococcal superantigens, SPEA and SPEC, and staphylococcal superantigens, SEB and TSST-1, in patients with guttate psoriasis, in patients with chronic plaque psoriasis, and in healthy subjects. PBMC from patients with guttate psoriasis responded poorly to SPEA and SPEC at concentrations of 0.1 and 1 ng/ml as compared with those from patients with plaque psoriasis, but showed high responses to SEB and TSST-1. The hyporesponsiveness recovered after improvement of the skin eruption. There was no significant difference between guttate and chronic types of psoriasis in the percentage of circulating T-cell receptor BV2 or BV8-bearing T cells, responsive to streptococcal superantigens, indicating that T-cell clonal anergy was a mechanism underlying the hyporesponsiveness. Our results suggest that superantigens released from focally infecting S. pyogenes induce a transient activation of relevant T cells, leading to the development of skin eruption and, subsequently, temporary T-cell anergy to these toxins.