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1.
Cancer Res ; 61(1): 110-7, 2001 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11196147

RESUMO

The up-regulation of rates of choline uptake and phosphorylation in certain malignancies has motivated the development of positron-labeled choline analogues for noninvasive detection of cancer using positron emission tomography (PET). The choline analogue, no-carrier-added [18F]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium (FCH), was synthesized through the intermediate [18F]fluorobromomethane. FCH was evaluated in relationship to 2-[18F]fluoro-2-deoxyglucose (FDG) as an oncological probe in cultured PC-3 human prostate cancer cells, a murine PC-3 human prostate cancer xenograft model, and in PET imaging studies of patients with prostate cancer. FCH was synthesized in 20-40% radiochemical yield and >98% radiochemical purity. Accumulation of FCH and FDG were comparable in cultured prostate cancer cells, whereas only FCH was inhibited (90%) by hemicholinium-3, a specific inhibitor of choline transport and phosphorylation. FCH showed similar biodistribution to [14C]choline in the tumor-bearing mouse, with prominent renal and hepatic uptake. Tumor uptake of FCH was similar to choline and FDG in the mouse model, although tumor:blood ratios were moderately higher for FCH. Initial PET imaging studies in prostate cancer patients showed high uptake of FCH in advanced prostate carcinoma and detection of osseous and soft tissue metastases. FCH uptake by tumors was markedly reduced in patients rescanned during androgen deprivation therapy. It is concluded that FCH closely mimics choline uptake by normal tissues and prostate cancer neoplasms. FCH is potentially useful as a PET tracer for detection and localization of prostate cancer and monitoring effects of therapy.


Assuntos
Colina/análogos & derivados , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Compostos de Amônio Quaternário/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Animais , Radioisótopos de Flúor/química , Fluordesoxiglucose F18/farmacocinética , Humanos , Marcação por Isótopo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Compostos de Amônio Quaternário/síntese química , Compostos Radiofarmacêuticos/síntese química , Distribuição Tecidual , Tomografia Computadorizada de Emissão , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Pharmacol Ther ; 88(3): 281-309, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11337028

RESUMO

Adrenergic receptors (ARs) are members of the G-protein-coupled receptor family, which includes alpha 1ARs, alpha 2ARs, beta 1ARs, beta 2ARs, beta 3ARs, adenosine, muscarinic, angiotensin, endothelin receptors, and many others that are responsible for a large variety of physiologic effects through G-protein coupling. This review focuses on alpha 1ARs and their regulation at both the mRNA and protein levels. Currently, three alpha 1AR subtypes have been characterized both pharmacologically and at the gene level: alpha 1aAR, alpha 1bAR, and alpha 1dAR. These are expressed in a species- and tissue-dependent manner. Mutagenesis approaches have been extremely valuable in the identification of key residues that govern alpha 1AR ligand binding and signaling. These studies reveal that alpha 1ARs have evolved an exquisitely sensitive regulation of their activity in which any disruption of the native structure has profound effects on subsequent function and effector coupling. Significant advances have also been made in the elucidation of signaling pathway components, resulting in the identification of novel pathways that can lead to pathologic conditions. Specific topics include mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and G-protein-coupled receptor cross-talk pathways. Within this context, recent studies identifying underlying transcriptional mechanisms involved in the regulation of the alpha 1AR subtypes are also discussed. Finally, given the potentially important role of alpha 1ARs in the vasculature, as well as in the pathology of many diseases, such as myocardial hypertrophy and benign prostatic hyperplasia, the clinical relevance of alpha 1AR distribution, pharmacology, and therapeutic intervention is reviewed.


Assuntos
Receptores Adrenérgicos alfa 1/fisiologia , Transcrição Gênica , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Ligação ao GTP/farmacologia , Humanos , Ligantes , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Hiperplasia Prostática/fisiopatologia , RNA Mensageiro/biossíntese , Receptores Adrenérgicos alfa 1/biossíntese , Transdução de Sinais , Regulação para Cima
3.
Clin Cancer Res ; 7(4): 846-53, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11309332

RESUMO

Zinc alpha-2-glycoprotein (ZAG) is a M(r) 41,000 glycoprotein secreted by a variety of normal epithelia. ZAG was recently shown to stimulate lipolysis in adipocytes, leading to the development of cachexia in animals with ZAG-producing tumors. To understand the possible contribution of ZAG to the development of cachexia in men with prostate cancer, ZAG production by normal and malignant prostate tissue was investigated using immunohistochemical assays. Anti-ZAG monoclonal antibodies reacted strongly with normal prostate epithelium but not with other components of prostate or seminal vesicles. The majority of prostate cancers tested (35 of 48; 73%) also reacted with anti-ZAG antibodies. High-grade tumors expressed significantly less ZAG than moderate-grade tumors (mean ZAG score 1.1 versus 1.9; P < 0.01). Men with ZAG-producing prostate carcinomas had elevated levels of serum ZAG relative to their normal age- and race-matched controls (P < 0.02). Furthermore, s.c. growth of human ZAG-producing murine tumors in syngeneic mice and orthotopic growth of ZAG-producing human prostate carcinomas in nude rats resulted in readily detectable levels of human ZAG in the serum. Taken together, these studies show that ZAG production by prostate cancer can lead to systemically elevated serum ZAG levels that may be useful diagnostically. The effects of elevated systemic ZAG on cachexia-associated complications in patients with advanced prostate cancer deserves additional investigation.


Assuntos
Biomarcadores Tumorais/biossíntese , Glicoproteínas/biossíntese , Neoplasias da Próstata/metabolismo , Proteínas de Plasma Seminal , Idoso , Animais , Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/sangue , Caquexia/metabolismo , Modelos Animais de Doenças , Epitélio/metabolismo , Feminino , Glicoproteínas/sangue , Glicoproteínas/imunologia , Glicoproteínas/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Glândulas Seminais/metabolismo , Glicoproteína Zn-alfa-2
4.
Am J Psychiatry ; 142(5): 643-4, 1985 May.
Artigo em Inglês | MEDLINE | ID: mdl-3985204

RESUMO

Fifty-nine subjects 5-16 years old with major depressive disorder were assessed for the presence of separation anxiety and antisocial behavior, mentioned in DSM-III as associated features of the disorder in children and adolescents. The findings of the study support the existence of these associated features.


Assuntos
Transtorno da Personalidade Antissocial/complicações , Ansiedade de Separação/complicações , Transtorno Depressivo/complicações , Fatores Etários , Transtorno da Personalidade Antissocial/diagnóstico , Transtorno da Personalidade Antissocial/psicologia , Ansiedade de Separação/diagnóstico , Ansiedade de Separação/psicologia , Criança , Pré-Escolar , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Manuais como Assunto
5.
Antioxid Redox Signal ; 2(4): 919-35, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11213492

RESUMO

NO is an important component of vascular homeostasis and abnormal NO bioactivity has been implicated in number of disease states with important public health implications. One clear mechanism of impaired NO bioactivity and vascular disease is excess vascular oxidative stress. There is now a wealth of developing data that manipulation of vascular antioxidant stress is the considerable influence of the biologic activity of endothelium-derived NO. It remains to be seen if this influence can be exploited in a manner that truly alters the course of human disease.


Assuntos
Vasos Sanguíneos/metabolismo , Óxido Nítrico/metabolismo , Animais , Antioxidantes/metabolismo , Disponibilidade Biológica , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Peroxidação de Lipídeos , Nitratos/metabolismo , Oxirredução , Estresse Oxidativo , Solubilidade , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
6.
J Nucl Med ; 42(12): 1805-14, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11752077

RESUMO

UNLABELLED: Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [(18)F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncologic probe in comparison with several other closely related molecules. METHODS: FCH, [(18)F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [(18)F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [(18)F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [(18)F]fluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and [methyl-(14)C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. RESULTS: FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. CONCLUSION: The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.


Assuntos
Radioisótopos de Flúor , Compostos de Amônio Quaternário , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Adulto , Idoso , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Colina/análogos & derivados , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico por imagem , Radiometria , Distribuição Tecidual
7.
Am J Cardiol ; 85(8): 996-1001, 2000 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-10760342

RESUMO

The effect of long-term arm exercise on cardiac morphology and function is unknown. To study these effects, highly trained wheelchair athletes were compared with long-distance runners and controls. In addition, the wheelchair athletes were compared with the long-distance runners to determine if long-term leg exercise confers a training effect during the performance of dynamic arm exercise. The study included 31 male subjects (mean age of 33+/-5 years), who comprised 3 groups matched for age and weight: wheelchair athletes (n = 9), long-distance runners (n = 12), and healthy controls (n = 10). All underwent echocardiography at rest and arm ergometry exercise testing with expiratory gas analysis. The peak work rate during arm exercise was highest among the wheelchair athletes, and was significantly higher in both groups of trained athletes compared with the control group (p<0.001). Runners demonstrated a significantly lower submaximal heart rate response to arm exercise compared with wheelchair and control subjects. Wheelchair athletes had increased left ventricular (LV) volume and mass by echocardiography compared with controls, but not to the same degree as that of runners. Although chamber dimensions and wall thickness did not differ among the groups, the LV volume index tended to be largest in the runners. Doppler indexes of diastolic LV filling were similar between the trained and untrained subjects. These data demonstrate that both long-term arm and leg exercise yield increases in LV volume and mass compared with untrained control subjects, although to a lesser degree in arm-trained athletes. Runners demonstrated a transfer of training effect in the performance of dynamic arm exercise, as demonstrated by their ability to achieve a higher peak work rate than controls, and showed a lower heart rate response to submaximal exercise than the wheelchair athletes and control subjects.


Assuntos
Pessoas com Deficiência , Tolerância ao Exercício/fisiologia , Exercício Físico/fisiologia , Corrida/fisiologia , Esportes , Cadeiras de Rodas , Adaptação Fisiológica , Adulto , Composição Corporal , Peso Corporal , Estudos de Casos e Controles , Ecocardiografia Doppler , Teste de Esforço , Extremidades/fisiologia , Humanos , Masculino , Paraplegia/fisiopatologia
8.
Urology ; 48(4): 639-43, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8966846

RESUMO

Endometriosis is a common gynecologic disease in which endometrial tissue is deposited outside the normal confines of the uterine cavity. In rare instances, endometriosis involves the urinary tract, with the bladder the most frequent organ affected. Classic presenting symptoms include cyclic irritative voiding symptoms and suprapubic discomfort with or without hematuria. Both medical and surgical management have been advocated, but surgical extirpation is probably more efficacious. Two cases of endometriosis involving the the bladder are presented and contrasted in terms of pathophysiology. Contemporary management of this condition is reviewed, and guidelines for diagnosis and treatment are proposed.


Assuntos
Endometriose , Doenças da Bexiga Urinária , Adulto , Endometriose/diagnóstico , Endometriose/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Doenças da Bexiga Urinária/diagnóstico , Doenças da Bexiga Urinária/terapia
9.
Urology ; 48(2): 335-41, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8753753

RESUMO

OBJECTIVES: Benign prostatic hyperplasia (BPH), the most common benign tumor in men, consists of two components-static (enlargement regulated by androgens) and dynamic (smooth muscle contraction through alpha 1-adrenergic receptors [alpha 1-ARs]). Because medical therapy of BPH involves tissue androgen deprivation, we studied the influence of androgen deprivation and replacement on regulation of rat ventral prostate alpha 1-ARs. METHODS: Prostate weight, alpha 1-AR density, autoradiographic images, histologic features, and cell-specific protein were examined before and after castration and androgen replacement. RESULTS: Castration decreases ventral prostate wet weight, a process reversed by testosterone administration. In contrast, there is an apparent increase in alpha 1-AR density (29 +/- 4 versus 65 +/- 6 fmol/mg total protein, mean +/- SEM) after castration, returning to baseline with testosterone replacement; alpha 1-AR density remains constant in control liver membranes. Alpha 1-ARs predominate in stroma throughout androgen deprivation therapy. Epithelially derived cells decrease (83% to 67%) after castration, resulting in a relative doubling in stroma (17% to 33%); the protein content of epithelial and stromal cells remains identical. Therefore, prostate-specific increases in alpha 1-ARs appear to result from relative increases in the ratio of smooth muscle to epithelium after castration rather than from direct upregulation of alpha 1-AR protein. CONCLUSIONS: Because alpha 1-AR density does not decrease with androgen deprivation, these studies suggest that alpha 1-AR antagonists remain an important component in BPH therapy, even when 5-alpha-reductase inhibitors are utilized.


Assuntos
Orquiectomia , Hiperplasia Prostática/fisiopatologia , Receptores Adrenérgicos alfa 1/fisiologia , Animais , Autorradiografia , Masculino , Tamanho do Órgão , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Proteínas/análise , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/análise
10.
Urology ; 56(1): 31-5; discussion 35-6, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10869615

RESUMO

OBJECTIVES: To characterize patients with primary necrotizing fasciitis of the male genitalia (Fournier's gangrene) and to identify risk factors and prognostic variables of survival. METHODS: Fifty consecutive patients with primary necrotizing fasciitis of the male genitalia treated at our institution during a 15-year period between 1984 and 1998 were retrospectively analyzed. Of these patients, 44 (88.0%) were found to be eligible for analysis of the outcome parameters. Univariate survival analysis was performed using the Kaplan-Meier algorithm followed by multivariate analysis of statistically significant variables. Six patients (12.0%) who were severely immunocompromised were studied separately. RESULTS: Medical comorbidities were prevalent, with diabetes being the most common condition (50%). The overall mortality rate was 20% (10 of 50). Three statistically significant predictors of outcome were identified among the variables analyzed. These were the extent of the infection (P = 0.0262), the depth of the necrotizing infection (P = 0.0107), and treatment with hyperbaric oxygen (P = 0.0115). Multivariate regression analysis of these variables identified the extent of the infection (P = 0.0234) as the only statistically significant, independent predictor of outcome in the presence of other covariables. CONCLUSIONS: The involved body surface area appears to be the most important prognostic variable, with a significant impact on outcome. Given the high mortality of the disease entity and a trend toward the improved survival of patients receiving hyperbaric oxygen, this treatment form appears indicated in more severe cases. Immunocompromised patients, who frequently have an atypical and fulminant clinical course, appear to constitute a separate group with a dismal prognosis.


Assuntos
Fasciite Necrosante/cirurgia , Doenças dos Genitais Masculinos/cirurgia , Adulto , Idoso , Fasciite Necrosante/complicações , Doenças dos Genitais Masculinos/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
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