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BACKGROUND AND PURPOSE: Antecedent surgery has been described to trigger Guillain-Barré syndrome (GBS), but its evidence is poor and based on case reports only. METHODS: We performed a retrospective analysis of 63 patients with GBS admitted to the University Hospital Basel and University Children's Hospital Basel from January 2005 to December 2010. We calculated and compared the incidences of post-surgical and non-exposed patients with GBS in the study population and those reported previously in literature. RESULTS: Six of 63 (9.5%) GBS cases had had a surgery within 6 weeks prior to GBS. The relative risk of developing GBS during the 6-week period after surgery is 13.1 times higher than the normal incidence in the study population (95% confidence interval: 5.68, 30.3; P ≤ 0.0001), suggesting an attributable risk of 4.1 cases per 100, 000 surgeries. In addition, the incidence of post-surgical GBS is significantly higher than influenza vaccine-associated GBS in the study population (P = 0.01) as well as in comparison with previous reported vaccine-associated GBS (P ≤ 0.0001) and background incidences (P ≤ 0.0001). CONCLUSION: Surgery must be considered to be a potential risk factor for developing GBS.
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Síndrome de Guillain-Barré/epidemiologia , Complicações Pós-Operatórias , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Síndrome de Guillain-Barré/etiologia , Humanos , Incidência , Lactente , Infecções/complicações , Masculino , Pessoa de Meia-Idade , Fatores Desencadeantes , Estudos Retrospectivos , Risco , Vacinação/efeitos adversosAssuntos
Oxirredutases do Álcool/deficiência , Deficiências do Desenvolvimento/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , 5-Hidroxitriptofano/uso terapêutico , Comportamento , Benserazida/uso terapêutico , Consanguinidade , Deficiências do Desenvolvimento/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Combinação de Medicamentos , Movimentos Oculares/fisiologia , Feminino , Humanos , Lactente , Levodopa/uso terapêutico , Transtornos dos Movimentos/etiologia , Hipotonia Muscular/etiologia , Doenças do Sistema Nervoso/tratamento farmacológico , Neurotransmissores/líquido cefalorraquidiano , Fenilcetonúrias/enzimologia , Fenilcetonúrias/genética , Resultado do TratamentoRESUMO
Fetal magnetic resonance imaging (MRI) is a well-established second line imaging modality in identifying complex pathologies of the central nervous system (CNS), especially when ultrasound (US) findings are equivocal. It may enable an early and precise diagnosis, which is essential in terms of management of pregnancy and pre-, peri- and postnatal care. We present three cases with rare complex midline malformations of the CNS, diagnosed prenatally by fetal MRI. Two cases revealed holoprosencephaly; one case demonstrated rhombencephalosynapsis. In addition, we reviewed the literature and provide a summary of recent findings regarding cerebral midline development and discuss the advantages of fetal MRI.
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Doenças Fetais/diagnóstico , Holoprosencefalia/diagnóstico , Imageamento por Ressonância Magnética , Mesencéfalo/anormalidades , Diagnóstico Pré-Natal , Adulto , Feminino , Humanos , GravidezRESUMO
AIM: This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity. METHOD: Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another. RESULT: Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie d>0.80; amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs vs placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as an obesity medication. Effects of methodological factors are also presented along with suggestions for future research.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Obesidade/prevenção & controle , Anfetaminas/uso terapêutico , Benzfetamina/uso terapêutico , Ciclobutanos/uso terapêutico , Fenfluramina/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The epithelial mucin MUC1 is overexpressed on the cell surface of many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. Recently, we identified two HLA-A2-restricted T-cell epitopes derived from the MUC1 protein. To further extend the potential application of these peptides, we analyzed the expression of MUC1 on blast cells from patients with acute myelogenous leukemia (AML; n = 43) and several other hematological malignancies including acute lymphoblastic leukemia (n = 24), chronic lymphocytic leukemia (n = 36), hairy cell leukemia (n = 9), follicular lymphoma (n = 7), and multiple myeloma (n = 12). Using reverse transcription-PCR and MUC1-specific monoclonal antibodies, MUC1 expression was found in 67% of AML samples and 92% of myeloma samples. To analyze the presentation of MUC1 peptides by primary AML blasts, we induced MUC1-specific CTLs in vitro using peptide-pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed in an antigen-specific and HLA-A2-restricted manner not only target cells pulsed with the antigenic peptide but also tumor cell lines including multiple myeloma cells and primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML and several other hematological malignancies that could potentially be used for immunotherapeutic approaches.
Assuntos
Neoplasias Hematológicas/imunologia , Mucina-1/imunologia , Linfócitos T Citotóxicos/imunologia , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Apresentação de Antígeno/imunologia , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Humanos , Leucemia Mieloide Aguda/imunologia , Ativação Linfocitária/imunologia , Mucina-1/biossíntese , Mieloma Múltiplo/imunologiaRESUMO
OBJECTIVE: This meta-analysis evaluated the types of lifestyle treatments used in published obesity drug studies and assessed their contribution to weight losses associated with pharmacological interventions. RESEARCH METHODS AND PROCEDURES: Randomized, placebo-controlled, double-blind clinical trials of anti-obesity agents that are/were Food and Drug Administration-approved for the treatment of obesity (both prescription and over-the-counter), and drugs that are Food and Drug Administration-approved and are used off-label for obesity were included. Studies were located by computer searches of databases (e.g., Medline, PsychInfo) and reviewing tables of content/reference sections of journals, abstracts, previous reviews, past empirical studies, relevant book chapters, and recent issues of journals that regularly publish obesity research. In addition, a number of individuals who regularly publish in the obesity literature were asked to provide personal lists of obesity-drug studies. Based on the above criteria, a total of 108 randomized clinical trials were located. RESULTS: Balanced-deficit diets, low-calorie diets, and self-monitoring were the most used lifestyle treatments in published obesity studies. They were incorporated into 40.7%, 25%, and 23.1% of pharmacotherapy studies, respectively. Physical activity and other behavioral or psychotherapeutic interventions rarely were used. A substantial portion of weight loss experienced by patients was attributable to both "placebo effects" and to the lifestyle treatments. DISCUSSION: Obesity-pharmacotherapy trials do not use lifestyle treatments with the frequency expected based on the official positions of most professional organizations concerned with the comprehensive management of obesity.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Estilo de Vida , Obesidade/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Dieta Redutora , Humanos , MEDLINE , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Redução de Peso/fisiologiaRESUMO
The epithelial mucin MUC1 is overexpressed on many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. In the present study, we described MUC1 expression also on primary AML blasts. To analyze the presentation of MUC1-derived HLA-A2 restricted peptides by primary AML blasts, we induced MUC1-specific cytotoxic T-lymphocytes (CTLs) in vitro using peptide pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML which could potentially be used for immunotherapeutic approaches.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Antígeno HLA-A2/imunologia , Neoplasias Hematológicas/terapia , Imunoterapia Ativa , Leucemia Mieloide/imunologia , Mucina-1/imunologia , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Doença Aguda , Apresentação de Antígeno , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/química , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Carcinoma/imunologia , Carcinoma/terapia , Citotoxicidade Imunológica , Epitopos/imunologia , Feminino , Antígeno HLA-A2/biossíntese , Neoplasias Hematológicas/imunologia , Humanos , Imunização , Leucemia Mieloide/patologia , Masculino , Repetições Minissatélites , Mucina-1/biossíntese , Mucina-1/química , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/química , Neoplasia Residual/terapia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Sinais Direcionadores de Proteínas , VacinaçãoRESUMO
The aim of this study was to evaluate the validity of the Dieter's Inventory of Eating Temptations (DIET). TJye DIET, Tennessee Self-Concept Scale (TSCS), and Binge Eating Scale (BES) were completed by 219 obese, binge-eating women. A 5-factor solution was generated that accounted for 46.9% and 95.0% of the total and common variance, respectively. The DIET demonstrated high internal consistency (alpha=0.93), as did the 5 factors (alphas ranging from 0.71-0.89). The DIET was correlated positively with the TSCS (r=0.212; p=0.002) and negatively with the BES (r=-0.199: p=0.003) suggesting that women who report higher ability to manage problematic diet situations have higher self-esteem and lower binge-related emotional distress. The results of this study suggest that the DIET is a reliable and valid instrument, but the six subscales could probably be reduced to five distinct domains.
RESUMO
This study examined the weight standards used by the U.S. Air Force and tested whether Air Force personnel who exceed the maximum allowable weight standard are more likely to engage in health risk behaviors compared with individuals who do not exceed current Air Force weight standards. Participants were 32,144 individuals who completed basic military training from August 1995 to August 1996. Compared with body mass levels known to predict increased health risks, the Air Force maximum allowable weight standards were found to be more stringent for women than for men. Furthermore, exceeding the maximum allowable weight standard of the weight management programs did not consistently indicate that an individual engaged in a less healthy lifestyle than other airmen. Perhaps other risk factors, such as cigarette smoking, may be more closely linked to negative health consequences than body weight.
Assuntos
Medicina Aeroespacial , Peso Corporal , Comportamentos Relacionados com a Saúde , Militares/psicologia , Assunção de Riscos , Adolescente , Adulto , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Valor Preditivo dos Testes , Inquéritos e Questionários , Estados UnidosRESUMO
Indicators of self-efficacy and motivation to change (stage of change) with regard to drinking and to drinking and driving were examined in a sample of Driving Under the Influence (DUI) offenders in a court-mandated intervention program. Self-administered questionnaires that contained pertinent measures were completed by 210 consenting offenders (34 of whom were female) during the intervention program. A factor analysis of efficacy and stages of change items showed distinct factors for the respective constructs; however, drinking and drinking-and-driving items of the same type (e.g., efficacy or stages of change) tended to codefine common factors, and the factor pattern suggested that motivations and efficacy for changing drinking behavior are critical for avoiding the drinking-and-driving sequence. Most participants were classified into the action stage in both drinking and drinking-and-driving domains. In regression analysis, contemplation of action and self-efficacy measures pertaining to drinking and driving predicted prior crashes and arrests; however, after accounting for recent alcohol problems, action items pertaining to drinking and driving were the best predictors of recent drinking-and-driving incidents.
Assuntos
Consumo de Bebidas Alcoólicas , Condução de Veículo/psicologia , Motivação , Psicometria/métodos , Autoavaliação (Psicologia) , Adulto , Consumo de Bebidas Alcoólicas/prevenção & controle , Consumo de Bebidas Alcoólicas/psicologia , Análise Fatorial , Feminino , Humanos , Masculino , Recidiva , Reprodutibilidade dos TestesRESUMO
Perceived stress and stressors of nontraditional (returning-adult) and traditional college students were compared. Forty-seven nontraditional students 24-54 years old and 47 traditional students, matched for demographics, completed the Adolescent Perceived Events Scale (Compas, Davis, Forsythe, & Wagner, 1987) for college students. They rated 210 life events according to the desirability, impact, and frequency of the events. Significant differences were found between the nontraditional and traditional students for events in the following categories: academics, peer and social relations, family and network, autonomy and responsibility, and intimacy. Nontraditional students enjoyed going to classes and doing homework more, whereas traditional students worried more about school performance. Peer events, including social activities, had much more impact on traditional students, whereas nontraditional students reported much more responsibility in the home. The results suggest that there are significant differences between the groups in their perceptions of stressors.
Assuntos
Estresse Psicológico/psicologia , Estudantes/psicologia , Adolescente , Adulto , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-IdadeRESUMO
We conducted a cross-sectional environmental and medical survey of 355 male sugarcane workers in Hawaii to determine whether exposure to biogenic silica fibers (BSF) affected their respiratory health. Exposures to BSF ranged from nondetectable to more than 0.700 BSF/mL and varied by job and department. Respiratory symptoms, chest radiograph findings, and pulmonary function were not associated with BSF exposures. Cigarette smoking was associated with respiratory symptoms and pulmonary obstruction. Fifteen workers had pleural thickening or pleural plaques and 3 of these workers were exposed to BSF for more than 10 years. BSF exposure does not appear to influence the respiratory health of sugarcane workers; however, further study is warranted.
Assuntos
Agricultura , Exposição Ocupacional , Respiração , Dióxido de Silício , Amianto , Estudos Transversais , Havaí , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This study examined the association between the amount of direct care time and total time (direct and administrative) spent by CNSs with families of 39 very low birth weight infants (< or = 1500 grams) and infant outcomes (rehospitalizations and acute care visits). Documentation of the CNSs' time spent with infants and families was recorded during infant hospitalization and for 18 months after infant discharge. The number of infant rehospitalizations and acute care visits was recorded from hospital and physician records. The mean total time the CNS spent per infant for the 18-month period was 27.3 hours. After discharge, there were significant relationships between the amount of CNS direct care time and the number of acute care visits (r = 0.45, p < 0.01) and infant rehospitalizations (r = 0.51, p < 0.01). Although the study findings did not demonstrate improved infant outcomes associated with the amount of time the CNS spent with this high risk population, they document the amount of CNS time spent in intervention and follow-up of these infants. This study provides data for costing home visiting by the CNS in this patient population.
Assuntos
Recém-Nascido de Baixo Peso , Enfermagem Neonatal/normas , Enfermeiros Clínicos/normas , Cuidados de Enfermagem/estatística & dados numéricos , Carga de Trabalho , Adolescente , Adulto , Feminino , Humanos , Recém-Nascido , Pesquisa em Avaliação de Enfermagem , Prognóstico , Estudos de Tempo e MovimentoRESUMO
A physician's alert prompted us to investigate workers' cancer risk at a paperboard printing manufacturer. We conducted a retrospective cohort mortality study of all 2,050 persons who had worked at the facility for more than 1 day, calculated standardized incidence ratios (SIRs) for bladder and renal cell cancer, and conducted a nested case-control study for renal cell cancer. Standardized mortality ratios (SMRs) from all causes [SMR = 1.0, 95% confidence interval (CI) = 0.9-1.2] and all cancers (SMR = 0.6, 95% CI = 0.3-1.0) were not greater than expected. One bladder cancer and one renal cell cancer were included in the mortality analysis. Six incident renal cell cancers were observed, however, compared with less than two renal cell cancers expected (SIR = 3.7, 95% CI = 1.4-8.1). Based on a nested case-control analysis, the risk of renal cell cancer was associated with overall length of employment but was not limited to any single department or work process. Although pigments containing congeners of dichlorobenzidine and o-toluidine had been used at the plant, environmental sampling could not confirm any current exposure. Several limitations and a potential selection bias limit the inferences that can be drawn.
Assuntos
Carcinoma de Células Renais/epidemiologia , Neoplasias Renais/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Papel , Impressão , Adolescente , Adulto , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/mortalidade , Estudos de Casos e Controles , Causas de Morte , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Renais/etiologia , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Doenças Profissionais/mortalidade , Razão de Chances , Fatores de RiscoRESUMO
Specimens from 45 patients with previously-untreated non-small cell lung cancer (NSCLC) were tested for in vitro chemosensitivity to ten drugs utilising the DiSC assay, which measures cell kill in the total (largely non-dividing) tumour cell population. Thirty-five assays were successful and 25 patients with advanced disease subsequently received chemotherapy with the 'best' three drugs selected by the assay. Six patients were Karnofsky performance status 60 or less and the median pretreatment weight loss was 8.5%. Nine patients had a partial response (response rate = 36%; 95% confidence interval = 17-55%) and the median survival of all patients was 202 days. Specimens from responding patients were significantly more sensitive in the assay to drugs in general (especially to etoposide and to 'natural product' drugs) and to the drugs used in treatment than were specimens from non-responding patients. In vitro drug resistance differences between responding and non-responding patients were of greater significance than were differences between other clinical and laboratory measurements. Assay results classified patients into two cohorts, having relatively high and low probabilities of responding to chemotherapy. Assay results also identified patient cohorts with above average and below average durations of survival. Five patients (20%) were found to have tumours with extreme drug resistance (EDR), defined as assay results for the average of all ten tested drugs falling greater than one standard deviation more resistant than the median for all tumours assayed, and none of these patients with EDR responded to chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Pessoa de Meia-Idade , PrognósticoRESUMO
This article offers nurses a conceptual framework for marketing their skills and discusses how that framework can be applied to obstetric nursing practice. A thorough understanding of the framework presented will provide maternity nurses with the foundation they need to participate effectively in a marketing plan. Examples of the application of the framework to specific clinical situations are examined.
Assuntos
Marketing de Serviços de Saúde/métodos , Enfermagem Obstétrica/normas , Prática Profissional/normas , Publicidade , Objetivos , Humanos , Auditoria de Enfermagem , Pesquisa em Enfermagem , Enfermagem Obstétrica/economia , Técnicas de Planejamento , Prática Profissional/economiaRESUMO
Tumor-specific cytotoxicity was measured in fresh human biopsy specimens by a modification of the differential staining cytotoxicity assay. ImuVert, a cytokine inducer derived from Serratia marcescens, which produces broad-spectrum activation of both macrophages and lymphocytes, was dramatically more effective when it was tested in tumors obtained from patients with previously treated, chemotherapy-responsive adenocarcinomas (breast and ovary) than when it was tested in tumors obtained from either previously untreated patients or previously treated patients with chemotherapy-refractory adenocarcinomas (colon, lung, pancreas, stomach, kidney, gallbladder, uterus, and prostate). Similar findings, relating to prior chemotherapy treatment status, were obtained for tumor necrosis factor and interferon gamma, but not for interleukin-2 or interferon alpha. On the basis of these findings and on other evidence in the literature, we speculate that response to chemotherapy produces massive release and processing of tumor antigens. We further speculate that this response leads to a state in which the human immune system is primed (via in situ vaccination) to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.
Assuntos
Fatores Imunológicos/farmacologia , Neoplasias/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Produtos Biológicos , Biópsia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Células Tumorais CultivadasRESUMO
BACKGROUND: In both animal and epidemiologic studies, exposure to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD) has been associated with an increased risk of cancer. METHODS: We conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Causes of death were taken from death certificates. RESULTS: Mortality from several cancers previously associated with TCDD (stomach, liver, and nasal cancers, Hodgkin's disease, and non-Hodgkin's lymphoma) was not significantly elevated in this cohort. Mortality from soft-tissue sarcoma was increased, but not significantly (4 deaths; standardized mortality ratio [SMR], 338; 95 percent confidence interval, 92 to 865). In the subcohort of 1520 workers with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency, however, mortality was significantly increased for soft-tissue sarcoma (3 deaths; SMR, 922; 95 percent confidence interval, 190 to 2695) and for cancers of the respiratory system (SMR, 142; 95 percent confidence interval, 103 to 192). Mortality from all cancers combined was slightly but significantly elevated in the overall cohort (SMR, 115; 95 percent confidence interval, 102 to 130) and was higher in the subcohort with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency (SMR, 146; 95 percent confidence interval, 121 to 176). CONCLUSIONS: This study of mortality among workers with occupational exposure to TCDD does not confirm the high relative risks reported for many cancers in previous studies. Conclusions about an increase in the risk of soft-tissue sarcoma are limited by small numbers and misclassification on death certificates. Excess mortality from all cancers combined, cancers of the respiratory tract, and soft-tissue sarcoma may result from exposure to TCDD, although we cannot exclude the possible contribution of factors such as smoking and occupational exposure to other chemicals.
Assuntos
Neoplasias/mortalidade , Exposição Ocupacional , Dibenzodioxinas Policloradas/efeitos adversos , Neoplasias Brônquicas/mortalidade , Indústria Química , Estudos de Coortes , Humanos , Tábuas de Vida , Masculino , Estudos Retrospectivos , Risco , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Neoplasias da Traqueia/mortalidade , Estados Unidos/epidemiologiaRESUMO
Fresh specimens of human lymphatic neoplasms were tested with the differential staining cytotoxicity assay. Cells from relapsed patients with acute lymphoblastic leukemia (ALL) were significantly more resistant to vincristine, dexamethasone, and doxorubicin in the assay than were cells from previously untreated patients. The putative C kinase inhibitors verapamil (V), imipramine (I), lidocaine (L), tamoxifen (T), chlorpromazine (C), and haloperidol (H) were then tested singly, in combination with each other (VILTCH, ITCH, and VL), and in combination with vincristine. At concentrations judged to be clinically achievable, VILTCH itself was occasionally toxic to ALL and chronic lymphocytic leukemia. The VILTCH combination clearly potentiated the cytotoxic activity of vincristine in five of eight ALL specimens from relapsed patients and potentiated vincristine in 18 of 30 chronic lymphocytic leukemia specimens. It also potentiated vincristine in two of six specimens of multiple myeloma and five of six specimens of non-Hodgkin's lymphoma. The VILTCH combination had no significant effects in fresh cultures of normal human lymphocytes. The most active drugs in the VILTCH combination appeared to be verapamil and lidocaine. We conclude that the differential staining cytotoxicity assay is a useful tool to study the circumvention of clinically acquired drug resistance. While the mechanism of the observed enhancement of the cytotoxic effects of vincristine is not known, it is possible that combinations of putative C kinase inhibitors may reduce drug resistance in human lymphatic neoplasms.
Assuntos
Leucemia/tratamento farmacológico , Proteína Quinase C/antagonistas & inibidores , Células Tumorais Cultivadas/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorpromazina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Haloperidol/farmacologia , Humanos , Imipramina/farmacologia , Técnicas In Vitro , Leucemia/patologia , Leucemia Linfoide/tratamento farmacológico , Lidocaína/farmacologia , Tamoxifeno/farmacologia , Verapamil/farmacologiaRESUMO
The effect of menadiol (vitamin K3) on fresh specimens of human lymphatic neoplasms (HLN) was tested by means of the differential staining cytotoxicity assay. Menadiol was tested alone and in combination with standard antineoplastic agents. Drug effects were then compared with the effects of the same drugs in normal human lymphocytes and in fresh specimens of human non-small cell lung cancer. By itself, menadiol was moderately toxic to HLN, but not to normal lymphocytes or non-small cell lung cancer. Menadiol, menadione, and two structurally related congeners were equitoxic to HLN cells, but sodium metabisulfite (present in menadiol solutions as a preservative) was nontoxic. Menadiol increased the cytotoxic effects of a number of standard agents in HLN but not in normal lymphocytes. Cell survival times with mechlorethamine, vincristine, and dexamethasone were converted from a range characteristic of drug resistance (ie, range observed in relapsed patients) to a range characteristic of drug sensitivity (ie, range observed in untreated patients) in the presence of menadiol. These effects occurred at a concentration (2.0 micrograms/ml; 4.7 microM) of menadiol which is probably clinically achievable and which did not deplete intracellular glutathione. Menadiol should receive clinical testing as a chemosensitizing agent in HLN.