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1.
Am Heart J ; 271: 182-187, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38658076

RESUMO

In the Emergency Department, patients with suspected myocardial infarction can be risk stratified using the HEART pathway, which has recently been amended for prehospital use and modified for the incorporation of a high-sensitivity cardiac troponin test. In a prospective analysis, the performance of both HEART pathways in the prehospital setting, with a high-sensitivity cardiac troponin test using 3 different thresholds, was evaluated for major adverse cardiac events at 30 days. We found that both low-risk HEART pathways, when using the most conservative cardiac troponin thresholds, approached but did not reach accepted rule-out performance in the Emergency Department.


Assuntos
Serviços Médicos de Emergência , Infarto do Miocárdio , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/sangue , Serviços Médicos de Emergência/métodos , Estudos Prospectivos , Medição de Risco/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Serviço Hospitalar de Emergência , Pessoal Técnico de Saúde , Troponina/sangue , Auxiliares de Emergência , Paramédico
2.
Emerg Med J ; 40(7): 474-481, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37268413

RESUMO

INTRODUCTION: The History, Electrocardiogram (ECG), Age, Risk Factors and Troponin (HEART) score is commonly used to risk stratify patients with possible myocardial infarction as low risk or high risk in the Emergency Department (ED). Whether the HEART score can be used by paramedics to guide care were high-sensitivity cardiac troponin testing available in a prehospital setting is uncertain. METHODS: In a prespecified secondary analysis of a prospective cohort study where paramedics enrolled patients with suspected myocardial infarction, a paramedic Heart, ECG, Age, Risk Factors (HEAR) score was recorded contemporaneously, and a prehospital blood sample was obtained for subsequent cardiac troponin testing. HEART and modified HEART scores were derived using laboratory contemporary and high-sensitivity cardiac troponin I assays. HEART and modified HEART scores of ≤3 and ≥7 were applied to define low-risk and high-risk patients, and performance was evaluated for an outcome of major adverse cardiac events (MACEs) at 30 days. RESULTS: Between November 2014 and April 2018, 1054 patients were recruited, of whom 960 (mean 64 (SD 15) years, 42% women) were eligible for analysis and 255 (26%) experienced a MACE at 30 days. A HEART score of ≤3 identified 279 (29%) as low risk with a negative predictive value of 93.5% (95% CI 90.0% to 95.9%) for the contemporary assay and 91.4% (95% CI 87.5% to 94.2%) for the high-sensitivity assay. A modified HEART score of ≤3 using the limit of detection of the high-sensitivity assay identified 194 (20%) patients as low risk with a negative predictive value of 95.9% (95% CI 92.1% to 97.9%). A HEART score of ≥7 using either assay gave a lower positive predictive value than using the upper reference limit of either cardiac troponin assay alone. CONCLUSIONS: A HEART score derived by paramedics in the prehospital setting, even when modified to harness the precision of a high-sensitivity assay, does not allow safe rule-out of myocardial infarction or enhanced rule-in compared with cardiac troponin testing alone.


Assuntos
Síndrome Coronariana Aguda , Infarto do Miocárdio , Humanos , Feminino , Masculino , Estudos Prospectivos , Síndrome Coronariana Aguda/diagnóstico , Dor no Peito/etiologia , Medição de Risco , Troponina I , Serviço Hospitalar de Emergência , Eletrocardiografia , Biomarcadores
3.
Ann Emerg Med ; 77(6): 575-588, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33926756

RESUMO

STUDY OBJECTIVE: To determine whether risk stratification in the out-of-hospital setting could identify patients with chest pain who are at low and high risk to avoid admission or aid direct transfer to cardiac centers. METHODS: Paramedics prospectively enrolled patients with suspected acute coronary syndrome without diagnostic ST-segment elevation on the ECG. The History, ECG, Age and Risk Factors (HEAR) score was recorded contemporaneously, and out-of-hospital samples were obtained to measure cardiac Troponin I (cTnI) level on a point-of-care device, to allow calculation of the History, ECG, Age, Risk Factors, and Troponin (HEART) score. HEAR and HEART scores less than or equal to 3 and greater than or equal to 7 were defined as low and high risk for major adverse cardiac events at 30 days. RESULTS: Of 1,054 patients (64 years [SD 15 years]; 42% women), 284 (27%) experienced a major adverse cardiac event at 30 days. The HEAR score was calculated in all patients, with point-of-care cTnI testing available in 357 (34%). A HEAR score less than or equal to 3 identified 32% of patients (334/1,054) as low risk, with a sensitivity of 84.9% (95% confidence interval [CI] 80.7% to 89%), whereas a score greater than or equal to 7 identified just 3% of patients (30/1,054) as high risk, with a specificity of 98.7% (95% CI 97.9% to 99.5%). A point-of-care HEART score less than or equal to 3 identified a similar proportion as low risk (30%), with a sensitivity of 87.0% (95% CI 80.7% to 93.4%), whereas a score greater than or equal to 7 identified 14% as high risk, with a specificity of 94.8% (95% CI 92.0% to 97.5%). CONCLUSION: Paramedics can use the HEAR score to discriminate risk, but even when used in combination with out-of-hospital point-of-care cTnI testing, the HEART score does not safely rule out major adverse cardiac events, and only a small proportion of patients are identified as high risk.


Assuntos
Ambulâncias , Dor no Peito/diagnóstico , Admissão do Paciente/estatística & dados numéricos , Transferência de Pacientes/estatística & dados numéricos , Medição de Risco/métodos , Idoso , Biomarcadores/sangue , Institutos de Cardiologia/estatística & dados numéricos , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Escócia , Troponina T/sangue
4.
Diabet Med ; 36(9): 1149-1157, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30552780

RESUMO

AIMS: To examine (1) the prevalence of depressive symptoms in women with Type 2 diabetes, (2) the associations between depressive symptoms and the following dependent variables: sleep disturbance; physical activity; physical health-related; and global quality of life, and (3) the potential moderating effects of antidepressants and optimism on the relationship between depressive symptoms and dependent variables. METHODS: Participants in the Women's Health Initiative who had Type 2 diabetes and data on depressive symptoms (N=8895) were included in the analyses. In multivariable linear regression models controlling for sociodemographic, medical and psychosocial covariates, we examined the main effect of depressive symptoms, as well as the interactions between depressive symptoms and antidepressant use, and between depressive symptoms and optimism, on sleep disturbance, physical activity, physical health-related quality of life; and global quality of life. RESULTS: In all, 16% of women with Type 2 diabetes reported elevated depressive symptoms. In multivariable analyses, women with depressive symptoms had greater sleep disturbance (P<0.0001) and lower global quality of life (P<.0001). We found evidence of significant statistical interaction in the models for quality-of-life outcomes: the increased risk of poor physical health-related quality of life associated with antidepressant use was stronger in women without vs with depressive symptoms, and the association between greater optimism and higher global quality of life was stronger in women with vs without depressive symptoms. CONCLUSIONS: To improve health behaviours and quality of life in women with Type 2 diabetes, sociodemographic and medical characteristics may identify at-risk populations, while psychosocial factors including depression and optimism may be important targets for non-pharmacological intervention.


Assuntos
Depressão/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Exercício Físico/fisiologia , Qualidade de Vida , Transtornos do Sono-Vigília/epidemiologia , Idoso , Antidepressivos/uso terapêutico , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Transtornos do Sono-Vigília/complicações , Fatores Socioeconômicos , Inquéritos e Questionários , Estados Unidos/epidemiologia
5.
Eur J Surg Oncol ; 50(4): 108032, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38489938

RESUMO

INTRODUCTION: Follow-up care after treatment for colorectal cancer (CRC) is increasingly focused on health-related quality of life (HRQoL) and functional outcomes. The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is developed to measure these outcomes and support patient-oriented care. The tool comprises items assessing burden of disease and lifestyle parameters. It consists of a generic module combined with one of the three CRC specific modules. The objective of this study is to assess the construct validity and reliability of the items of the ABCRC-tool. METHODS: Patients who were receiving follow-up care after surgical CRC treatment were invited to complete the ABCRC-tool together with other validated patient-reported outcome measures (PROMs). Construct validity was assessed by testing expected correlations between items of the ABCRC-tool and domains of other PROMs and by examining predefined hypotheses regarding differences in subgroups of patients. Patients completed the ABCRC-tool twice, with 8 days apart, to evaluate its reliability. RESULTS: In total, 177 patients participated (64% male) with a mean age of 67 years (range 33-88). The colon, rectum and stoma module were completed by subsequently 89, 53 and 35 patients. Most items correlated as expected with anticipated domains of the EORTC QLQ-C30 or EORTC QLQ-CR29 (all p-values <0.05). Furthermore, the ABCRC-tool could discriminate between subgroups of patients. The intraclass correlation coefficient (ICC) was good (>0.70) for most items, indicating good reliability. CONCLUSION: The ABCRC-tool is a valid and reliable instrument that is ready for use in a clinical setting to support personalized follow-up care after CRC treatment.


Assuntos
Neoplasias Colorretais , Estomas Cirúrgicos , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e Questionários , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia
6.
Ann Oncol ; 24(8): 1999-2004, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23562929

RESUMO

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Paclitaxel/uso terapêutico , Sobrevida , Taxoides/uso terapêutico , Trastuzumab , Resultado do Tratamento , Adulto Jovem
8.
Oncogene ; 26(29): 4209-15, 2007 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-17297477

RESUMO

Inactivation of the p53 tumor suppressor pathway is a critical step in human tumorigenesis. In addition to mutations, p53 can be functionally silenced through its increased degradation, inhibition of its transcriptional activity and/or its inappropriate subcellular localization. Using a proteomic approach, we have found that members of the Ras network of proteins, Ras-GTPase activating protein-SH3-domain-binding proteins 1 and 2 (G3BP1 and 2), bind to p53 in vitro and in vivo. Our data show that expression of G3BPs leads to the redistribution of p53 from the nucleus to the cytoplasm. The G3BP2 isoform additionally associated with murine double minute 2 (MDM2), a negative regulator of p53. G3BP2 expression resulted in significant reduction in MDM2-mediated p53 ubiquitylation and degradation. Interestingly, MDM2 was also stabilized in G3BP2-expressing cells and its ability to ubiquitylate itself was compromised. Accordingly, short hairpin RNA (shRNA)-mediated knockdown of G3BP2 caused a reduction in MDM2 protein levels. Furthermore, expression of shRNA targeting either G3BP1 or G3BP2 in human cancer cell lines resulted in marked upregulation of p53 levels and activity. Our results suggest that both G3BP isoforms may act as negative regulators of p53.


Assuntos
Proteínas de Transporte/metabolismo , Endorribonucleases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas de Transporte/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , DNA Helicases , Endorribonucleases/fisiologia , Células HCT116 , Humanos , Isoenzimas/metabolismo , Isoenzimas/fisiologia , Proteínas de Ligação a Poli-ADP-Ribose , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , RNA Helicases , Proteínas com Motivo de Reconhecimento de RNA , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteínas Ativadoras de ras GTPase/fisiologia
10.
Pediatrics ; 97(5): 676-81, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8628606

RESUMO

OBJECTIVES: To examine the degree of agreement between parental reporting of the development of high-risk infants and professional assessment by a multidisciplinary team. METHODS: The developmental status of 196 infants discharged from neonatal intensive care units (NICUs) was assessed by their parents using the Infant Monitoring Questionnaire (IMQ) at 4, 8, or 12 months' corrected age. On the same day, a clinical assessment was done by a multidisciplinary team consisting of a developmental pediatrician, physical therapist, and psychologist. The kappa statistic was used to measure agreement between the assessments. Logistic regression was used to investigate factors that might influence agreement. RESULTS: Both the IMQ and the multidisciplinary team classified infants as developing normally ("normal"), being at risk for abnormal development ("suspect"), or developing abnormally ("abnormal"). Although the same proportion of children fell into the three categories by both assessments, parents and the multidisciplinary team showed poor agreement with respect to the classification of individual infants (kappa = 0.276). No infant or family characteristic was found to have an influence on agreement. CONCLUSIONS: For a group of high-risk infants discharged from NICUs, the agreement between parental assessment of developmental status using the IMQ and the professional assessment by a multidisciplinary team is poor in the first year of life. We do not recommend the use of this questionnaire as a substitute for clinical assessment of biologically at-risk infants discharged from NICUs. However, it may be useful for those groups of infants for whom no other information is available or as an adjunct to clinical assessment when infants are not behaving typically because of an unfamiliar setting or concurrent illness.


Assuntos
Desenvolvimento Infantil , Doenças do Recém-Nascido/fisiopatologia , Pais , Médicos , Adulto , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Leucomalácia Periventricular/fisiopatologia , Modelos Logísticos , Masculino , Equipe de Assistência ao Paciente , Alta do Paciente , Pediatria , Modalidades de Fisioterapia , Psicologia , Fatores de Risco , Sensibilidade e Especificidade
11.
Eye (Lond) ; 28(7): 819-24, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24788017

RESUMO

PURPOSE: The aim of this study is to investigate the difference of the clinical course in recurrent intermittent exotropia after second surgery compared with both recurrent intermittent exotropia after its first of two surgeries and intermittent exotropia after only a single surgery. METHODS: We retrospectively reviewed the medical records of patients diagnosed with intermittent exotropia who underwent lateral rectus recession and medial rectus resection (R&R) between January 1992 and January 2011 at Yeungnam University Hospital. Repeated measure ANOVA (rmANOVA) was used to compare the clinical course of recurrent intermittent exotropia before and after a second surgery with that of intermittent exotropia with a single surgery. RESULTS: A total of 352 intermittent exotropia patients who underwent one R&R procedure and 77 recurrent intermittent exotropia patients who underwent a second R&R in the contralateral eye were included in this study. Although exodrift of recurrent intermittent exotropia was observed at 24 months of follow-up even after a second surgery, it was significantly lower than both intermittent exotropia with a single surgery and after its first of two surgeries (P<0.001, rmANOVA). CONCLUSION: The clinical course of recurrent intermittent exotropia after a second surgery was improved compared with both recurrent intermittent exotropia after its first of two surgeries and intermittent exotropia after a single surgery.


Assuntos
Exotropia/diagnóstico , Exotropia/cirurgia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Criança , Pré-Escolar , Exotropia/fisiopatologia , Movimentos Oculares/fisiologia , Feminino , Humanos , Masculino , Músculos Oculomotores/fisiopatologia , Período Pós-Operatório , Recidiva , Reoperação , Estudos Retrospectivos , Resultado do Tratamento , Visão Binocular/fisiologia , Acuidade Visual/fisiologia
12.
Eye (Lond) ; 26(6): 846-52, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22441025

RESUMO

PURPOSE: The purpose of this study is to evaluate prognostic factors, specifically age, at the time of surgery, for recurrence after bilateral lateral rectus recession (BLR) in patients with intermittent exotropia. METHODS: Medical records of 511 subjects who underwent BLR procedures between the ages of 3 and 10 years with more than 12 months of follow-up were retrospectively reviewed. Patients' surgical outcomes with a deviation of less than 10 prism diopters (PD) exotropia and less than 5 PD esotropia were defined as a success. Outcomes with more than 11 PD exotropia were designated as recurrences, and those with esotropia of more than 5 PD after 3 months of surgery were noted as overcorrection. Prognostic factors for recurrence were analyzed by multivariate logistic regression test. RESULTS: Of the 511 subjects, 371 had successful surgical outcomes and 129 had recurrences, whereas 11 were found to be overcorrected. Age at surgery and immediate postoperative alignment proved to be significant factors influencing a favorable outcome by multivariate logistic regression analysis (P<0.05). However, gender, photophobia, age at onset, spherical equivalent (SE) refractive error, astigmatism, SE anisometropia, and preoperative deviation size were not significantly predictive of success (P>0.05). CONCLUSION: In BLR procedures, increasing patient age at surgery was associated with lower recurrence rates.


Assuntos
Exotropia/diagnóstico , Músculos Oculomotores/patologia , Complicações Pós-Operatórias , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Exotropia/fisiopatologia , Exotropia/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos , Prognóstico , Recidiva , Erros de Refração/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Acuidade Visual/fisiologia
13.
Eye (Lond) ; 25(4): 449-54, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21311571

RESUMO

PURPOSE: To evaluate the prognostic factors, particularly age at the time of surgery, for recurrence after unilateral medial rectus resection and lateral rectus recession (R&R) procedures in patients with intermittent exotropia, or X(T). METHODS: Medical records of 489 subjects who received unilateral R&R procedures with more than 12 months of follow-up were reviewed. The patients' surgical outcomes with a deviation of less than 10 prism diopters (PD) of exotropia and less than 5 PD of esotropia were defined as a success. Outcomes with more than 11 PD of exotropia were designated as recurrences, and those with esotropia of more than 5 PD after 3 months of operation were noted as overcorrection. The prognostic factors for recurrence were analyzed by the multivariate logistic regression test. RESULTS: Of the 489 subjects, 209 had successful surgical outcomes and 280 had recurrences, whereas overcorrection was not found. Mean age at operation was 8.9 ± 6.5 years, mean preoperative distant X(T) size was 32.9 ± 6.0 PD, and mean follow-up period was 27.5 ± 17.9 months. On the basis of the survival analysis in which survival represented time of recurrence, the mean duration was 31.2 ± 1.7 months. Age at onset, age at surgery, and immediate postoperative alignment proved to be significant factors influencing a favorable outcome by multivariate logistic regression analysis (P<0.05). However, gender, family history, and preoperative deviation size were not significantly predictive of success (P>0.05). CONCLUSION: In unilateral R&R procedures, increasing patient age at the time of surgery was associated with lower recurrence rates. Recurrence rates also increased with the immediate postoperative angle and with the postoperative angle of deviation at 1, 3, 6, and 12 months.


Assuntos
Exotropia/cirurgia , Músculos Oculomotores/cirurgia , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Análise Multivariada , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
14.
J Biol Chem ; 276(23): 20085-92, 2001 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-11274215

RESUMO

Selenium, an essential biological trace element, has been shown to reduce and prevent the incidence of cancer. Our previous studies have shown that selenite is involved in the chemoprevention of cancer and induction of apoptosis of cancer cells. In this study, we demonstrate that selenite also inhibits the invasion of tumor cells. Cancer cell invasion requires coordinated processes, such as changes in cell-cell and cell-matrix adhesion, degradation of the extracellular matrix, and cell migration. We found that selenite inhibited invasion of HT1080 human fibrosarcoma cells. Adhesion of HT1080 cells to the collagen matrix was also inhibited by treatment with selenite, but cell-cell interaction and cell motility were not affected by selenite. Moreover, selenite reduced expression of matrix metalloproteinase-2 and -9 and urokinase-type plasminogen activator, which are involved in matrix degradation, but increased a tissue inhibitor of metalloproteinase-1. This inhibitory effect of selenite on the protease expressions was mediated by the suppression of transcription factors, NF-kappaB and AP-1. However, selenate showed no remarkable effect on all the steps of cancer cell invasion.


Assuntos
Invasividade Neoplásica/prevenção & controle , Selenito de Sódio/farmacologia , Adesão Celular , Divisão Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Humanos , Metástase Neoplásica/prevenção & controle , Ácido Selênico , Compostos de Selênio/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas , Regulação para Cima
15.
Biopharm Drug Dispos ; 16(4): 279-93, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7548777

RESUMO

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (IV) and intramuscular (IM) injection of free MTX (treatment I), freshly prepared MTX-bearing positively charged liposomes (large unilamellar vesicles), PLUVs (treatment II), and empty PLUVs mixed manually with free MTX (treatment III), 4 mg kg-1 as free MTX to rats, using HPLC assay. After 1 min IV infusion, the plasma concentrations of MTX (Cp), the area under the plasma concentration-time curve (AUC, 173 against 314 micrograms mL min-1), the terminal half-life (t1/2, 24.0 against 412 min), the mean residence time (MRT, 13.0 against 324 min), and the apparent volume of distribution at steady state (VSS, 289 against 3370 mL kg-1) were significantly larger, but the total body clearance (CL, 23.1 against 12.8 mL min-1 kg-1), the renal clearance (CLR, 8.38 against 3.09 mL min-1 kg-1), the non-renal clearance (CLNR, 14.6 against 9.56 mL min-1 kg-1), and the amount of MTX excreted in urine (Xu, 415 against 275 micrograms) were significantly lower in treatment II than in treatment I. This could be due to the fact that some of the MTX-bearing PLUVs were entrapped in tissues and the rest were present in plasma (larger MRT and Vss in treatment II), and MTX is slowly released from MTX-bearing PLUVs (longer t1/2 in treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX in MTX-bearing PLUVs (larger Cp and AUC and slower CL in treatment II). Saturable formation of 7-hydroxymethotrexate from MTX was reported in rabbit blood and nonlinear disposition of MTX was also reported in rats and rabbits (lower Xu and CLR in treatment II). After 1 min IV infusion, some pharmacokinetic parameters of MTX, such as AUC, CL, CLR, CLNR, and Xu, were significantly different between treatments I and III, but nonetheless the differences were smaller than those between treatments I and II. After both IV and IM administration, the amount of MTX remaining per gram of tissue or organ in the kidney, stomach, small intestine, and large intestine was significantly smaller in treatment II than in treatment I.(ABSTRACT TRUNCATED AT 400 WORDS)


Assuntos
Lipossomos/metabolismo , Metotrexato/farmacocinética , Animais , Injeções Intramusculares , Injeções Intravenosas , Masculino , Metotrexato/administração & dosagem , Farmacocinética , Coelhos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual
16.
Proc Natl Acad Sci U S A ; 95(24): 14453-8, 1998 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-9826721

RESUMO

Radiation is the primary modality of therapy for all commonly occurring malignant brain tumors, including medulloblastoma and glioblastoma. These two brain tumors, however, have a distinctly different response to radiation therapy. Medulloblastoma is very sensitive to radiation therapy, whereas glioblastoma is highly resistant, and the long-term survival of medulloblastoma patients exceeds 50%, while there are few long-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma. We found that the medulloblastoma-derived cell lines underwent extensive radiation-induced apoptotic cell death, while those from glioblastomas did not exhibit significant radiation-induced apoptosis. p53-mediated induction of p21(BAX) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expression of mRNA encoding p21(BAX) was correlated with these cell lines undergoing radiation-induced apoptosis. The failure of p53 to induce p21(BAX) expression in glioblastoma-derived cell lines is likely to be of biologic significance, since inhibition of p21(BAX) induction in medulloblastoma resulted in a loss of radiation-induced apoptosis, while forced expression of p21(BAX) in glioblastoma was sufficient to induce apoptosis. The failure of p53 to induce p21(BAX) in glioblastoma-derived cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.


Assuntos
Apoptose/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/genética , Tolerância a Radiação , Proteína Supressora de Tumor p53/fisiologia , Neoplasias Encefálicas , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/genética , Inibidores Enzimáticos , Genes p53 , Glioblastoma , Humanos , Proteínas Proto-Oncogênicas/biossíntese , Radiação Ionizante , Proteínas Recombinantes de Fusão/biossíntese , Transfecção , Células Tumorais Cultivadas , Proteína X Associada a bcl-2
17.
Proc Natl Acad Sci U S A ; 98(14): 7982-7, 2001 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-11438744

RESUMO

The ribonucleoprotein telomerase synthesizes telomeric DNA by copying an intrinsic RNA template. In most cancer cells, telomerase is highly activated. Here we report a telomerase-based antitumor strategy: expression of mutant-template telomerase RNAs in human cancer cells. We expressed mutant-template human telomerase RNAs in prostate (LNCaP) and breast (MCF-7) cancer cell lines. Even a low threshold level of expression of telomerase RNA gene constructs containing various mutant templates, but not the control wild-type template, decreased cellular viability and increased apoptosis. This occurred despite the retention of normal levels of the endogenous wild-type telomerase RNA and endogenous wild-type telomerase activity and unaltered stable telomere lengths. In vivo tumor xenografts of a breast cancer cell line expressing a mutant-template telomerase RNA also had decreased growth rates. Therefore, mutant-template telomerase RNAs exert a strongly dominant-negative effect on cell proliferation and tumor growth. These results support the potential use of mutant-template telomerase RNA expression as an antineoplastic strategy.


Assuntos
Neoplasias/genética , Neoplasias/patologia , RNA/genética , Telomerase/genética , Divisão Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Moldes Genéticos , Células Tumorais Cultivadas
18.
Br J Dermatol ; 142(4): 733-9, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10792224

RESUMO

Since the advent of psoralen-ultraviolet A (PUVA) therapy, the value of plasma 8-methoxypsoralen (8-MOP) concentrations to predict PUVA-induced erythema has been widely investigated. Plasma 8-MOP concentrations have not been proportional to, and cannot alone predict, the degree of PUVA-induced erythema. We assumed that PUVA-induced erythema was related more closely to psoralen concentrations in the skin tissue rather than those within blood vessels. This study was designed to investigate the correlations between the 8-MOP concentrations in suction blister fluid (SBF) and in plasma, with the degree of PUVA-induced erythema. 8-MOP concentrations in plasma and SBF were measured in 15 vitiligo patients and 11 volunteers. Blood and SBF samples were collected 2 h after taking 8-MOP, and 8-MOP concentrations in plasma and SBF were quantified using reverse-phase high-performance liquid chromatography. Eleven volunteers were phototested using a series of doses of ultraviolet A at the time of sampling. The erythema responses were estimated visually to determine the minimal phototoxic dose (MPD). SBF 8-MOP concentrations showed a weak positive correlation with plasma 8-MOP concentrations, which means that we could not predict the exact SBF 8-MOP concentrations using the plasma 8-MOP concentrations. The MPD showed a better correlation with the log of the SBF 8-MOP concentration than with that of the plasma 8-MOP concentration. These results show that plasma 8-MOP concentration cannot represent the exact SBF 8-MOP concentration, and that SBF 8-MOP concentrations, which are representative of the skin tissue 8-MOP level, are more closely related to the erythemal sensitivity during PUVA therapy.


Assuntos
Eritema/etiologia , Terapia PUVA/efeitos adversos , Adolescente , Adulto , Vesícula/metabolismo , Vesícula/cirurgia , Eritema/sangue , Eritema/metabolismo , Feminino , Humanos , Masculino , Metoxaleno/sangue , Metoxaleno/farmacocinética , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade
19.
Pathol Int ; 48(3): 215-20, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9589490

RESUMO

One hundred and fifteen patients with chronic hepatitis C were administered interferon (IFN) and classed into two groups: (i) complete responders (CR), HCV-RNA continuously negative 1 year after treatment; and (ii) non-responders (NR), positive 1 year after treatment. Multivariate analysis comprised eight variables: age, sex, transfusion history, alanine aminotransferase level, viral genotype, level of viremia, type of IFN, and total amount of IFN. The HCV-RNA level was correlated with complete response (P = 0.0175). Liver biopsy specimens were classified into four grades and stages according to the measure of severity and the extent of fibrosis, respectively. There was no correlation between the efficacy rate and grading. However, in staging there was a difference in the efficacy of IFN between stages 1 or 2, and stage 3 (0.05 < P < 0.1 and 0.01 < P < 0.025, respectively). Of the CR patients, 0% (0/5) were at stage 0 (no fibrosis); 27.5% (22/80) at stage 1 (mild); 42.9% (6/14) at stage 2 (moderate); and 6.3% (1/16) at stage 3 (severe fibrosis). Thus the new classification would be useful in predicting roughly the efficacy of IFN.


Assuntos
Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Feminino , Hepatite C Crônica/classificação , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , RNA Viral/análise , Resultado do Tratamento
20.
Invest New Drugs ; 19(1): 81-3, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11291836

RESUMO

Lovastatin, an inhibitor of mevalonate synthesis, demonstrated in vitro antitumor activity against a variety of human cancer cells, especially in gastric adenocarcinoma cells at pharmacologically achievable concentrations. To determine the antitumor activity of this drug in advanced measurable gastric adenocarcinoma as well as to assess the toxicities and the pharmacokinetic features, we carried out a phase II study of high-dose lovastatin. Patients received lovastatin 35 mg/kg/day for 7 consecutive days, with ubiquinone (60 mg qid p.o.) to prevent rhabdomyolysis. The treatment was repeated every 28 days. From March 1996 to January 1997, 16 patients (median age, 57 years; range, 34-68) were entered into the study, 14 of whom were evaluated for response and toxicity. No patient achieved a response. A total of 28 cycles were administered. The median number of cycles was 2 (range, 1 to 4). Anorexia was the most common toxicity (64%), but decreased oral intake was observed only in 3 cycles. Two patients developed myalgia with elevated muscle enzyme. When used in this dosage and schedule, lovastatin does not appear to be effective for patients with advanced gastric adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Lovastatina/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Avaliação de Medicamentos , Feminino , Humanos , Lovastatina/efeitos adversos , Lovastatina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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