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1.
Science ; 350(6256): 64-7, 2015 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-26272904

RESUMO

Directly detecting thermal emission from young extrasolar planets allows measurement of their atmospheric compositions and luminosities, which are influenced by their formation mechanisms. Using the Gemini Planet Imager, we discovered a planet orbiting the ~20-million-year-old star 51 Eridani at a projected separation of 13 astronomical units. Near-infrared observations show a spectrum with strong methane and water-vapor absorption. Modeling of the spectra and photometry yields a luminosity (normalized by the luminosity of the Sun) of 1.6 to 4.0 × 10(-6) and an effective temperature of 600 to 750 kelvin. For this age and luminosity, "hot-start" formation models indicate a mass twice that of Jupiter. This planet also has a sufficiently low luminosity to be consistent with the "cold-start" core-accretion process that may have formed Jupiter.

2.
J Pharmacol Exp Ther ; 296(2): 623-31, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11160651

RESUMO

Delivery of chemotherapeutic agents to solid peripheral tumors is compromised because the impaired microvasculature within and surrounding tumors limits diffusion and convection of agents from the vasculature to the tumor. Using a variety of rat tumor models, we show that intravenous administration of a vasoactive bradykinin B2 receptor agonist (Cereport, or labradimil; formerly RMP-7) enhances by nearly 3 times the delivery of the chemotherapeutic agent carboplatin, as well as the larger 70-kDa marker dextran, into ectopic and orthotopic solid tumors. This effect was selective for tumor tissue, with little or no increase seen in nontumor tissues and organs. Additionally, the increased carboplatin levels observed in tumors persisted for at least 90 min (the longest time point measured). In contrast to the consistent effects with hydrophilic compounds, delivery of the lipophilic, high protein-binding chemotherapeutics paclitaxel and 1,3-bis[2-chloroethyl]-1-nitrourea (BNCU) was not enhanced. Administration of Cereport with either carboplatin or another hydrophilic chemotherapeutic agent, doxorubicin, significantly increased efficacy of both agents, manifested by suppression of tumor growth and prolonged survival in tumor-bearing rats. These data demonstrate that delivery of chemotherapeutics to tumors can be pharmacologically increased (by stimulating bradykinin B2 receptors) without increasing the systemic exposure, or therefore, the toxic liability associated with higher chemotherapeutic doses.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Bradicinina/fisiologia , Bradicinina/uso terapêutico , Neoplasias Experimentais/irrigação sanguínea , Receptores da Bradicinina/agonistas , Animais , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Sobrevivência Celular/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Infusões Intravenosas , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Receptor B2 da Bradicinina , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Análise de Sobrevida , Células Tumorais Cultivadas
3.
J Pharmacol Exp Ther ; 296(2): 632-41, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11160652

RESUMO

Intravenous infusions of the bradykinin agonist Cereport (labradimil, formerly RMP-7) enhance delivery of concomitantly administered hydrophilic chemotherapeutic agents to solid tumors. The enhanced delivery produces greater in vivo efficacy of chemotherapeutic agents, manifested as suppressed tumor growth and increased survival in tumor-bearing rats. Here we elucidate the mechanisms of action involved with this unique phenomenon, at both the physical and biochemical levels. At the physical level we demonstrate that Cereport modifies the tumor vasculature in several important ways, including transient 1) reductions in interstitial fluid pressure within the tumor, 2) increases in pore size of the vasculature, and 3) increases in total vascular surface area. All three of these changes modify tumor-specific characteristics of the vasculature known to impede drug delivery to the tumor interstitium. Biochemically, we demonstrate that the activation of both of bradykinin's major signaling pathways, the nitric oxide and phospholipase A2/prostaglandin E2 are necessary events. Although pharmacologically blocking either pathway greatly reduced the effects of Cereport, stimulation of either pathway alone did not enhance delivery. However, simultaneous stimulation of both pathways (without exogenous bradykinin B2 receptor stimulation) produced a nearly 2-fold increase in delivery of carboplatin to the tumor. Thus, stimulation of endogenous bradykinin B2 receptors induces at least two parallel biochemical cascades that act synergistically to uniquely modify the tumor vasculature in ways that increase delivery and efficacy of chemotherapeutic agents.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Bradicinina/fisiologia , Bradicinina/uso terapêutico , Neoplasias Experimentais/irrigação sanguínea , Óxido Nítrico/metabolismo , Fosfolipases A/metabolismo , Prostaglandinas/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Transdução de Sinais/efeitos dos fármacos , Algoritmos , Animais , Autorradiografia , Biotransformação/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Bradicinina/análogos & derivados , Espaço Extracelular/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Fosfolipases A2 , Porosidade/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Células Tumorais Cultivadas
4.
J Voice ; 14(3): 387-97, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11021506

RESUMO

This project is designed to provide initial data regarding the use of polylactic acid/polyglycolic acid (PLA/PGA) copolymer ("LactoSorb" [Walter Lorenz Corp]), an alloplastic, resorbable material, as a prosthesis in an animal model of vocal fold medialization. Fifteen New Zealand white rabbits were utilized for left medialization laryngoplasty with LactoSorb implants after undergoing left recurrent laryngeal nerve section. At 1, 3, 6, and 9 months, the rabbits were sacrificed and their larynges were evaluated both grossly and histologically for tissue response to, and resorption characteristics of the implant, tissue cellularity, maintenance of vocal fold medialization, and airway patency. Additionally, 4 rabbits were used as controls, implanted with silicone rubber medialization implants, and sacrificed at 9 months for comparison. One rabbit underwent no surgery and was likewise used as a control. Grossly, no airway obstruction was noted, and no extrusions of the implants occurred. The LactoSorb implant maintained medialization in each group of sacrificed rabbits. Histologic findings revealed a very discrete, fibrous capsule around the implant in the 1- and 3-month rabbits, and the LactoSorb was still grossly visible. At 6 months, the thin fibrous capsule partially remained; at 9 months, the capsule was no longer evident, and the implant was no longer grossly visible. Endoscopic findings at the time of sacrifice in those rabbits implanted with silicone rubber included grossly patent airways with maintenance of medialization. In the rabbits implanted with silicone rubber, the histologic findings are similar to those described elsewhere. LactoSorb, because of its intermittent resorption rate, could offer an ideal alternative to currently utilized temporary, or resorbable, materials, and as such will hopefully prove an invaluable tool in the laryngologist's treatment planning and surgical repair of the patient with a paralyzed vocal fold.


Assuntos
Materiais Biocompatíveis , Ácido Láctico , Laringe/citologia , Laringe/cirurgia , Ácido Poliglicólico , Polímeros , Próteses e Implantes , Implantação de Prótese , Animais , Reação a Corpo Estranho , Procedimentos Cirúrgicos Otorrinolaringológicos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Elastômeros de Silicone
5.
Pharm Res ; 17(7): 767-75, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10990193

RESUMO

PURPOSE: Implantation of biodegradable polymers provides a powerful method to deliver high, sustained concentrations of chemotherapeutics to brain tumors. The present studies examined the ability of injectable polymeric microspheres, formulated to release carboplatin or BCNU for 2-3 weeks, to enhance survival in a rodent model of surgically-resected glioma. METHODS: Rat glioma (RG2) cells were implanted into the cortex of rats and allowed to grow for 10 days prior to surgical resection. Rats were given either surgical resection only, bolus injection (100 microg) or microspheres containing 10, 50, or 100 microg of carboplatin or BCNU. The microspheres were implanted, via hypodermic injection, either directly into the surgical cavity or into the tissue along the perimeter of the cavity. RESULTS: The order of survival among treatment groups was: no resection < resection only < bolus chemotherapy < sustained release chemotherapy. Carboplatin and BCNU did not differ in this respect and in each case, the enhanced survival achieved with sustained release was dose-related. However, the enhanced survival achieved with carboplatin was substantially greater when the microspheres were implanted into the perimeter wall of the resection cavity, compared to implantation into the cavity itself. The enhanced survival produced by carboplatin implants along the resection perimeter was associated with a significant attenuation of regrowth of the tumor. Finally, in a separate study in non-tumor brain, atomic absorption spectrophotometry revealed that while the microspheres produced significantly prolonged tissue levels of carboplatin relative to a bolus injection, carboplatin diffusion was limited to brain tissue extending primarily 0.5 mm from the injection site. CONCLUSIONS: These data demonstrate: (1) that sustained delivery of chemotherapy is superior to equipotent bolus doses following tumor resection, and (2) that direct injection of sustained release microspheres into the tissue surrounding a growing tumor mass may provide superior effects over injections into the surgical cavity. They also suggest that successful implementation of this approach in humans may require measures or circumstances that improve upon the limited spatial drug diffusion from the implantation site.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/administração & dosagem , Glioma/tratamento farmacológico , Polímeros/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Preparações de Ação Retardada , Glioma/metabolismo , Glioma/mortalidade , Masculino , Microesferas , Polímeros/farmacocinética , Ratos , Ratos Endogâmicos F344
6.
Pharm Res ; 17(7): 776-81, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10990194

RESUMO

PURPOSE: Delivery of chemotherapeutics using implantable, biodegradable polymers provides a potentially powerful method of treating brain tumors. The present studies examined the ability of injectable microspheres, formulated to release carboplatin or BCNU for 2-3 weeks, to enhance survival in a rodent model of deep, inoperable glioma. METHODS: Rat glioma (RG2) cells were implanted into the striatum of rats. In a first experiment, the tumors were allowed to grow for 3 days, followed by either no treatment, bolus chemotherapy (100 microg), or implantation of microspheres containing 10, 50, or 100 microg of carboplatin. The microspheres were implanted, via hypodermic injection, directly into the center of the small, 3-day-old tumors. In a second experiment, tumors grew for 8 days prior to treatment with either carboplatin- or BCNU-loaded microspheres. The microspheres were then injected either directly into the center of these larger tumors or into three sites along the perimeter of the tumor. Separate sets of animals received bolus chemotherapy (100 microg) into either the tumor center or around the tumor perimeter. RESULTS: Injection of carboplatin-loaded microspheres into the center of the small 3 day old, tumors produced dose-related increases in survival. When injections of carboplatin- or BCNU-loaded microspheres were made into the center of the larger, 8-day-old tumors, survival was not enhanced. However, when the microspheres were injected along the perimeter of the larger tumors, sustained-release chemotherapy did significantly prolong survival. Bolus chemotherapy was less effective than sustained release chemotherapy. CONCLUSIONS: Together, these data: (1) demonstrate that sustained delivery of chemotherapy in or near the tumor site is superior to equipotent bolus doses in inoperable tumors, (2) demonstrate that injection of sustained release microspheres into the tissue surrounding a growing tumor may provide superior effects over injections directly into the tumor mass, and (3) suggest that this approach may provide a useful means of selectively delivering chemotherapeutics to tumors or portions of tumors that cannot otherwise be treated with conventional surgical approaches.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carboplatina/administração & dosagem , Carmustina/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Glioma/tratamento farmacológico , Polímeros/administração & dosagem , Animais , Neoplasias Encefálicas/mortalidade , Preparações de Ação Retardada , Glioma/mortalidade , Masculino , Microesferas , Ratos , Ratos Endogâmicos F344
7.
Otolaryngol Head Neck Surg ; 123(1 Pt 1): 85-90, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10889487

RESUMO

The cytokine growth-related oncogene-alpha (GRO-alpha) is a potent mediator of leukocyte recruitment and proliferation in inflammatory diseases. We hypothesized that GRO-alpha is produced in the inflammatory nasal polyp microenvironment. Evaluation of nasal polyps from 27 patients for distribution and content of GRO-alpha antigen, by use of immunohistochemical techniques and ELISA, revealed its presence in all 27 tissue samples. It was found predominantly within the eosinophils and neutrophils, with tissue levels ranging from 34 pg/mg total protein (TP) to 1746 pg/mg TP, with a mean value of 631 +/-98 pg/mg TP. Control tissues contained between 82 pg/mg TP and 316 pg/mg TP (mean 176+/-38 pg/mg TP). These results were statistically significant (P<0.03). Clinical correlations and statistical comparisons were calculated. These data suggest that GRO-alpha may be an important factor in the recruitment and activation of leukocytes in nasal polyposis, making it a potential target for therapeutic intervention.


Assuntos
Quimiocinas CXC , Fatores Quimiotáticos/análise , Inibidores do Crescimento/análise , Substâncias de Crescimento/análise , Peptídeos e Proteínas de Sinalização Intercelular , Pólipos Nasais/patologia , Neoplasias Nasais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL1 , Endoscopia , Ensaio de Imunoadsorção Enzimática , Eosinófilos/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/cirurgia , Neutrófilos/patologia , Neoplasias Nasais/cirurgia
8.
Pharm Res ; 17(10): 1212-9, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11145226

RESUMO

PURPOSE: The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. METHODS: Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydrophilic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. RESULTS: Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport's uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vinorelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. CONCLUSIONS: These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeability of the blood-brain tumor barrier, can increase the delivery hydrophilic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats.


Assuntos
Antineoplásicos/farmacocinética , Bradicinina/farmacologia , Neoplasias Encefálicas/metabolismo , Vimblastina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Autorradiografia , Barreira Hematoencefálica/efeitos dos fármacos , Bradicinina/análogos & derivados , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carboplatina/farmacocinética , Carboplatina/farmacologia , Carmustina/farmacocinética , Carmustina/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Masculino , Ratos , Ratos Endogâmicos F344 , Vimblastina/farmacocinética , Vimblastina/farmacologia , Vinorelbina , Gencitabina
9.
Laryngoscope ; 108(7): 1066-70, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9665258

RESUMO

OBJECTIVE: To characterize the existence and role of transforming growth factor-beta (TGF-beta) in otitis media with effusion (OME). STUDY DESIGN: Retrospective. METHODS: The levels of two major TGF-beta isoforms, TGF-beta1 and TGF-beta2, in the middle ear effusions (MEEs) of 44 children were evaluated using enzyme-linked immunospecific assays (ELISAs). Forty-eight MEEs were separated into three clinically relevant groups (i.e., serous, mucoid, and purulent), and TGF-beta levels were correlated with clinical parameters of disease for these MEEs. RESULTS: Both TGF-beta1 and TGF-beta2 were present in the samples. Mean levels of TGF-beta1 (920.36 +/- 437.75 pg/mg total protein) were generally 100-fold greater than those of TGF-beta2 (9.65 +/- 11.19 pg/mg total protein). TGF-beta1 levels were elevated in association with a history of previous tympanostomy tube placements (TTPs) (P = .029) and mucoid effusions (P = .042). TGF-beta2 levels were elevated in association with a history of previous TTPs (P = .100) and chronic (i.e., serous or mucoid) effusions (P = .003). CONCLUSIONS: TGF-beta1 is present in the MEEs of children with OME. Furthermore, TGF-beta1 and TGF-beta2 levels were elevated differentially in the presence of chronic disease indicators in OME, suggesting that these isoforms may have differing roles in the inflammatory processes that characterize OME.


Assuntos
Exsudatos e Transudatos/química , Otite Média com Derrame/imunologia , Otite Média Supurativa/imunologia , Fator de Crescimento Transformador beta/análise , Criança , Pré-Escolar , Doença Crônica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Isomerismo , Masculino , Ventilação da Orelha Média , Otite Média com Derrame/classificação , Otite Média com Derrame/cirurgia , Otite Média Supurativa/classificação , Otite Média Supurativa/cirurgia , Recidiva , Fatores de Risco , Fator de Crescimento Transformador alfa/análise , Fator de Crescimento Transformador beta/imunologia
11.
Ann Otol Rhinol Laryngol ; 107(5 Pt 1): 416-20, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9596221

RESUMO

Previous studies have demonstrated that the cytokine RANTES (Regulated And Normal T cell Expressed and Secreted) has been shown to be a potent mediator of eosinophil chemotaxis in vitro and of leukocyte recruitment. Because eosinophils are the hallmark cells in nasal polyposis, we hypothesize that RANTES is locally produced within the nasal polyp microenvironment and is responsible for the eosinophil recruitment seen in nasal polyposis. To begin to test this hypothesis, we evaluated nasal polyps from 17 patients and 3 control specimens for distribution and content of RANTES using immunohistochemical techniques and enzyme-linked immunosorbent assay technology. Our immunohistochemical studies demonstrated that in nasal polyposis, RANTES antigen staining occurred predominantly within eosinophils and epithelial cells. To quantify the relative levels of RANTES in normal and nasal polyp specimens, tissue homogenates were prepared, quantified, and normalized to protein levels. We detected RANTES in all 17 nasal polyp tissue homogenates (566 +/- 16 pg/mg total protein). The RANTES levels in nasal polyp homogenates were nearly 40-fold higher than the RANTES levels in normal tissue (15.7 +/- 28.2 pg/mg total protein). Thus, it appears that increased expression of RANTES by eosinophils and epithelial cells within the nasal polyp microenvironment promotes eosinophil recruitment and activation within nasal polyps. We hypothesize that RANTES induces increased recruitment and activation of eosinophils, presumably contributing to the increased tissue changes associated with nasal polyposis.


Assuntos
Quimiocina CCL5/análise , Eosinófilos/imunologia , Pólipos Nasais/imunologia , Neoplasias Nasais/imunologia , Adulto , Idoso , Quimiotaxia de Leucócito/imunologia , Eosinófilos/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/patologia , Neoplasias Nasais/patologia
12.
Am J Otolaryngol ; 18(6): 405-11, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9395018

RESUMO

PURPOSE: Nasal polyposis (NP) is characterized by an increase in inflammatory processes including fibrosis. Because transforming growth factor beta (TGF-beta) has been proven to induce fibrosis, we hypothesize that TGF-beta and its receptors are present in NP and influence polyp development. MATERIALS AND METHODS: To test this hypothesis, we evaluated distribution (immunohistochemistry) of TGF-beta isoforms (TGF-beta 1, TGF-beta 2, and TGF-beta 3) and its receptors [(TGF-beta(RI) & TGF-beta(RII)] in NP from 36 NP patients and in five normal sinus tissue specimens obtained from septoplasty/inferior turbinectomy. Tissue levels of TGF-beta 1 and TGF-beta 2 levels were determined by enzyme-linked immunosorbent assay (ELISA) and protein content was determined by Bio Rad assay (Bio Rad, Richmond, CA). All tissue levels of TGF-beta were normalized and expressed as pg of TGF-beta per mg of total protein (pg/mg TP). RESULTS: Immunohistochemical studies showed eosinophils as the major cells positively staining for TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta(RI), and TGF-beta. In fibrotic sections, increased staining of eosinophils, fibroblast, and mononuclear cells was found for all three isoforms and both receptors. Evaluation of tissue levels indicated mean levels of TGF-beta 1 in the NP were 11.64 +/- 22.12 pg/mg TP versus normal control mean 44.36 +/- 22.12 pg/mg TP.TGF-beta 2 mean levels were 11.46 +/- 23.73 pg/mg TP versus normal control mean of 2.03 +/- 1.13 pg/mg TP. NP showed decreased expression of TGF-beta 1 and enhanced expression of TGF-beta 2 isoforms with presence of their receptors. Higher levels of TGF-beta 2 correlated with an increase in previous polypectomies perhaps indicative of severity of disease (P < or = .0001). CONCLUSION: Our studies show the presence of the TGF-beta isoforms and receptors in NP tissue. The results support our hypothesis that the eosinophil continues to be a pivotal inflammatory cell in NP, a differential regulation may govern the activity of TGF-beta in NP, and hence, the TGF-beta family of cytokines and receptors likely play a key role in controlling NP formation.


Assuntos
Eosinófilos/metabolismo , Pólipos Nasais/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Técnicas de Cultura , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Pólipos Nasais/química , Fator de Crescimento Transformador beta/análise
13.
Otolaryngol Head Neck Surg ; 117(5): 535-41, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9374180

RESUMO

The cytokine interleukin 8 (IL-8) has been shown to be a potent mediator of leukocyte recruitment and neovascularization in inflammatory and neoplastic diseases. In this study we hypothesize that IL-8 produced in the nasal polyp microenvironment is responsible for the leukocyte recruitment seen in nasal polyposis. To test this hypothesis we evaluated nasal polyps for distribution and content of IL-8 antigen with immunohistochemical techniques and radioimmunoassay to determine tissue levels of IL-8. The immunohistochemical results demonstrated that IL-8 antigen staining occurred predominantly within inflammatory cells and epithelium. IL-8 was detected in all nasal polyp tissue homogenates (a mean value of 1767 +/- 1633 pg/mg total protein (TP) with a range of 134 to 3668 pg/mg TP vs control specimens with a mean value of 77 pg/mg TP with a range of 0.09 to 255 pg/mg TP). These data demonstrate the presence and distribution and levels of IL-8 antigen in nasal polyps in vivo, supporting our hypothesis that local production of IL-8 could be an important factor in the sustained recruitment of leukocytes in nasal polyposis. Thus IL-8 likely plays a significant role in the pathogenesis of this disease process and therefore is a potential target for therapeutic intervention.


Assuntos
Interleucina-8/análise , Pólipos Nasais/imunologia , Adulto , Idoso , Antígenos , Corantes , Eosinófilos/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Imuno-Histoquímica , Interleucina-8/genética , Leucócitos/imunologia , Leucócitos/patologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pólipos Nasais/genética , Pólipos Nasais/patologia , Proteínas de Neoplasias/análise , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Plasmócitos/patologia , Radioimunoensaio
14.
Laryngoscope ; 107(5): 626-30, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9149164

RESUMO

One feature among nasal polyps (NPs) is the predominance of lymphocytes and eosinophils. We hypothesize that elevated levels of interferon gamma (IFN-gamma) activate lymphocytes and eosinophils within the NP microenvironment. Nasal polyps were evaluated for distribution and levels of IFN-gamma in specimens from 27 patients with nasal polyposis and 4 controls. Immunohistochemical study revealed IFN-gamma staining of eosinophils, glandular cells, and epithelium (27 of 27 patients). ELISA analysis indicated elevated IFN-gamma levels in total NP tissues (25.6 +/- 7.23 pg/mg total protein [TP]) compared with controls (16.27 +/- 6.54 pg/mg TP). Three subpopulations were identified based on IFN-gamma levels: low IFN-gamma group (10.7 +/- 5.51 pg/mg TP); medium IFN-gamma group (25.70 +/- 5.90 pg/mg TP); and high IFN-gamma group (52.58 +/- 10.29 pg/mg TP). The latter levels were approximately 3.5 times the control levels (P<0.0025). Patients with previous polypectomy surgery showed higher levels of IFN-gamma compared with controls (P<0.0423). A trend was found with increased IFN-gamma levels and allergy, asthma, and topical steroid use.


Assuntos
Interferon gama/análise , Pólipos Nasais/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Epitélio/química , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/patologia , Pólipos Nasais/cirurgia
15.
Arch Otolaryngol Head Neck Surg ; 123(4): 367-72, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9109781

RESUMO

OBJECTIVE: To establish the efficacy of topical corticosteroid nasal spray treatment of severe olfactory loss associated with severe nasal and sinus disease. DESIGN: Efficacy before and after open-label trial of topical corticosteroid nasal spray used exclusively in the head-down-forward position. SETTING: Taste and smell clinic of a university teaching hospital and research facility. PATIENTS: Taste and smell clinic patients with anosmia or severe hyposmia associated with paranasal sinus disease and nasal polyposis including 39 of 45 patients recruited from 1988 to 1994 who completed the topical corticosteroid treatment course and returned for subsequent testing. INTERVENTION: At least 8 weeks of treatment with flunisolide (Nasalide), 2 sprays in each nostril twice a day, with concurrent antibiotic treatment of any bacterial infection. MAIN OUTCOME MEASURES: Subjective olfactory symptoms, objective olfactory function tests, and otolaryngological evaluation (including endoscopic examination). RESULTS: Olfactory scores significantly improved following treatment (P < .001); signs of nasal and sinus disease significantly decreased (P < .001); and 26 (66%) of the patients reported a subjective improvement in their sense of smell. CONCLUSION: Topical corticosteroid nasal spray administered in a head-down-forward position is an effective treatment of severe olfactory loss associated with severe nasal and sinus disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fluocinolona Acetonida/análogos & derivados , Pólipos Nasais/complicações , Transtornos do Olfato/tratamento farmacológico , Doenças dos Seios Paranasais/complicações , Administração Tópica , Adulto , Idoso , Feminino , Fluocinolona Acetonida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/complicações , Resultado do Tratamento
16.
Laryngoscope ; 103(12): 1334-41, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8246651

RESUMO

Distortion product otoacoustic emissions (DPOEs) and click-evoked otoacoustic emissions (CEOEs) characteristics of the normal newborn population have been previously reported in the literature. There is little information about DPOE evaluations in the newborn population at risk for hearing loss. The authors now report the DPOE and/or CEOE data from six full-term subjects at risk for hearing loss or with highly suspected hearing loss. These subjects were less than 1 year of age and at risk for hearing loss secondary to a history of hereditary hearing loss, meningitis, hyperbilirubinemia, and ototoxic drug exposure. Audiometric evaluation included auditory brainstem responses (ABR), behavioral observation audiometry, and tympanometry. The CEOEs and DPOEs were found to be decreased or absent in the subjects with suspected hearing loss secondary to cochlear pathology; they were found to be normal in a subject with a suspected central hearing loss. This study's data suggest that otoacoustic emissions when combined with ABR can provide a frequency-specific evaluation of cochlear function and help determine the anatomic site of a pathologic lesion.


Assuntos
Perda Auditiva/fisiopatologia , Recém-Nascido/fisiologia , Emissões Otoacústicas Espontâneas , Testes de Impedância Acústica , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Central/fisiopatologia , Humanos , Masculino , Risco
17.
Ear Hear ; 14(4): 258-74, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8405730

RESUMO

Full-term and preterm infants were evaluated with click-evoked and distortion-product otoacoustic emissions (CEOEs and DPOEs). The CEOEs and DPOEs recorded from each individual ear were analyzed by calculating the root-mean-square levels within half-octave bands. The fail criterion of the OE tests was that the half-octave RMS DPOE or CEOE levels of an ear under test were below the 10th percentile of full-term newborns in two or more bands. The DPOE data were collected from 118 ears of 61 premature babies; 80 (68%) ears passed the DPOE test, 30 (25%) ears without middle ear effusions failed the test, and 8 (7%) ears with effusions also failed. The CEOE data were collected from 128 ears of 65 premature babies; 102 (80%) ears passed the CEOE test, 18 (14%) ears without middle ear effusions failed the test, and 8 (6%) ears with effusions also failed. In 23 of 80 ears (29%) that passed the DPOE test and in 23 of 102 ears (23%) that passed the CEOE test, RMS OE levels of preterm infants were above the 90th percentile of full-term newborns. The analyses of the combined DPOE and CEOE data obtained from a group of 25 ears of full-term newborns and from a group of 72 ears of preterm babies showed statistically significant correlations between the DPOE and CEOE root-mean-square levels in each of the half-octave bands in the 1.4 to 4 kHz region. For 42 preterm infants tested with auditory brain stem response (ABR), specificity was 86% for CEOE and 74% for DPOE. All infants who failed the ABR also failed OE tests. To the best of our knowledge, this study is the first using combined DPOEs, CEOEs, and ABRs for preterm babies. It showed the feasibility of DPOEs and CEOEs for this population.


Assuntos
Cóclea/fisiologia , Recém-Nascido/fisiologia , Recém-Nascido Prematuro/fisiologia , Emissões Otoacústicas Espontâneas/fisiologia , Testes de Impedância Acústica , Estimulação Acústica , Fatores Etários , Feminino , Audição/fisiologia , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Ruído , Tempo de Reação , Reprodutibilidade dos Testes
18.
Arch Otolaryngol Head Neck Surg ; 117(12): 1382-9, 1991 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-1845266

RESUMO

Distortion-product otoacoustic emissions (DPOEs) are believed to provide frequency-specific information about cochlear function. The DPOEs have been reported in the adult population but have not been reported previously in the neonatal population. We recorded DPOEs from a group of healthy full-term newborn human subjects (35 ears) to establish the characteristics of these emissions in the newborn population. To our knowledge, this is the first study of DPOEs in newborns. The "DPOE audiograms" from the newborns tested revealed characteristics qualitatively similar to those seen in adults with normal hearing. This study demonstrates the feasibility of DPOE measurements among newborns and provides a normal baseline for this age group, thus fulfilling a necessary step toward the development of an objective, noninvasive frequency-specific test of cochlear function. Click-evoked otoacoustic emissions were also recorded from the newborn population and compared with click-evoked otoacoustic emissions from adults. The spectrum of the click-evoked emissions was variable and individualistic, similar to findings previously reported in adult subjects. The click-evoked otoacoustic emissions of the newborns had a higher overall level and contained stronger high-frequency (4.5 to 6 kHz) spectral components than those of the adults. We also found that the low-frequency components of the click stimulus spectrum were attenuated in the neonatal ears exhibiting a high-pass slope below about 2.5 kHz, whereas the stimulus spectrum was nearly flat in this frequency region in adult ears.


Assuntos
Recém-Nascido/fisiologia , Emissões Otoacústicas Espontâneas , Estimulação Acústica , Adulto , Humanos , Processamento de Sinais Assistido por Computador
19.
Arch Otolaryngol Head Neck Surg ; 116(11): 1309-16, 1990 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2242262

RESUMO

Distortion product otoacoustic emissions (DPOEs) were recorded in a group of normally hearing subjects (29 ears) and a group of subjects whose conditions were diagnosed as sensorineural hearing loss (23 ears) to study any correlation that might exist between DPOE characteristics and hearing impairment of different configurations. Three different DPOE paradigms have been used to investigate the influence of different test parameters on the DPOE data for normal and hearing-impaired ears. All normally hearing ears demonstrated detectable DPOEs, provided that the primary tone level was above a certain value. Hearing-impaired ears produced substantially reduced DPOEs compared with normally hearing subjects when the primary frequencies f1 and f2 corresponded to the region of hearing loss. Our data also suggested that, in general, more than one f2/f1 ratio is needed to examine any particular frequency region. The DPOEs provide frequency-specific information about cochlear function, which after further development, may form a basis for a noninvasive, objective method of evaluating cochlear function.


Assuntos
Cóclea/fisiologia , Perda Auditiva Neurossensorial/fisiopatologia , Testes Auditivos/métodos , Acústica , Cóclea/fisiopatologia , Humanos , Som
20.
Prostaglandins Leukot Med ; 30(1): 29-36, 1987 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3481085

RESUMO

Human decidua was obtained from nonlaboring women after elective cesarean section. Decidua was incubated with media alone for 20 hours and this media (decidual conditioned media) was then incubated with amnion cells in monolayer culture and amnion rings. A 90% decrease in PGE2 production by amnion cells in monolayer culture was demonstrated in the presence of decidual conditioned media when compared to controls. In short term incubations with fresh amnion, decidual conditioned media decreased the production of PGE2 in amnion by greater than 25% of the control rate of production in 17 of 21 experiments. These observations suggest that human decidua produces a factor capable of inhibiting prostaglandin production by amnion.


Assuntos
Âmnio/metabolismo , Decídua/fisiologia , Prostaglandinas E/antagonistas & inibidores , Células Cultivadas , Dinoprostona , Feminino , Humanos , Gravidez , Prostaglandinas E/biossíntese
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