RESUMO
Extensive remodeling of the follicular extracellular matrix occurs during the process of ovulation. This remodeling involves the breakdown of collagen, which is regulated, in part, by the action of the metalloproteinase collagenase and its associated inhibitors. In the present study, follicular metalloproteinase inhibitors were characterized to determine whether they were serum-borne or of ovarian origin, possibly a tissue-derived inhibitor known as tissue inhibitor of metalloproteinase (TIMP). Human follicular fluid and granulosa cells were obtained from preovulatory follicles of patients in an in vitro fertilization program. Chromatographic separation of follicular fluid on Sepharose 6B resulted in two peaks of inhibitory activity. The large molecular radius (Mr) inhibitor was similar in size to the serum-borne metalloproteinase inhibitor alpha 2-macroglobulin (i.e. Mr 700,000) whereas the small Mr inhibitor approximated the size of TIMP (i.e. Mr 29,000). Incubation of aliquots from either of the two peaks of inhibitor activity or an alpha 2-macroglobulin standard with an antibody to alpha 2-macroglobulin decreased the inhibitory activity in both the large Mr peak and the alpha 2-macroglobulin standard by 86.6 +/- 1.7% and 71.5 +/- 7.7% (n = 4, P less than 0.005), respectively, implying cross-reactivity with the alpha 2-macroglobulin antibody. The inhibitory activity in the small Mr peak, however, was unchanged. Northern analysis of total granulosa cell RNA demonstrated TIMP messenger RNA (mRNA) in all eight granulosa cell samples examined whereas alpha 2-macroglobulin mRNA was virtually undetectable. A positive correlation (r = 0.85, P less than 0.01) was observed between the levels of TIMP mRNA and the ratio of the follicular estradiol-progesterone concentration. However, inhibitor activity in the follicular fluid was not correlated with the levels of TIMP mRNA (r = 0.05). These findings confirm the presence of alpha 2-macroglobulin in follicular fluid and demonstrate that human preovulatory granulosa cells contain mRNA for TIMP, an inhibitor that regulates metalloproteinases such as collagenase, gelatinase, and proteoglycanase. Additionally, the expression of TIMP mRNA is steroid related and may be hormonally regulated. It is proposed that TIMP produced in the granulosa cell compartment in conjunction with alpha 2-macroglobulin from the serum may act to control the site and extent of ovarian connective tissue remodeling.
Assuntos
Glicoproteínas/isolamento & purificação , Metaloendopeptidases/antagonistas & inibidores , Ovário/análise , Ovulação/fisiologia , alfa-Macroglobulinas/análise , Anticorpos/farmacologia , Estradiol/análise , Feminino , Líquido Folicular/análise , Glicoproteínas/genética , Glicoproteínas/farmacologia , Células da Granulosa/análise , Humanos , Peso Molecular , Progesterona/análise , RNA Mensageiro/análise , Inibidores Teciduais de Metaloproteinases , alfa-Macroglobulinas/imunologiaRESUMO
Metalloproteinases, such as collagenase or gelatinase, and their associated inhibitors appear to control connective tissue remodeling during follicular rupture. We examined the regulation of metalloproteinase inhibitor activity by various treatments in cultured rat granulosa cells. Granulosa cells were harvested from immature PMSG-primed rats and cultured with LH, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), cAMP, or forskolin. Inhibitor activity was measured in the medium. Increasing concentrations of either LH (0.1-1000 ng/ml) or TPA (2.5-100 nM) resulted in a dose-dependent increase in metalloproteinase inhibitor activity (2.9- and 2.4-fold increases above control, respectively). There was also a time-dependent induction of inhibitor activity in cells incubated in the presence of LH (100 ng/ml) for 6, 12, 18, or 24 h. Forskolin (0.1 mM) or cAMP (1 mM) treatment increased inhibitor activity 2.8- and 1.6-fold above that in control cultures. LH and TPA treatment in combination resulted in an additive increase in inhibitor activity compared to LH or TPA treatment alone. This finding suggested that the granulosa cell inhibitor activity might be induced through separate intracellular pathways. The inhibitor present in conditioned medium was isolated by chromatographic separation on a Sepharose 6B mol wt exclusion column. The inhibitor present was approximately 28,000 mol wt, which is consistent with the size of tissue inhibitor of metalloproteinase (TIMP). In addition to the granulosa cell experiments, changes in ovarian mRNA levels for TIMP were determined. There was a preovulatory increase in TIMP mRNA from whole rat ovaries, with the highest levels detected 12 h after hCG administration. The present study establishes that metalloproteinase inhibitor activity from rat granulosa cells is induced through separate pathways: a LH-cAMP-dependent protein kinase-A pathway and a cAMP-independent protein kinase-C pathway. Furthermore, a TIMP-like protein is observed in granulosa cell-conditioned medium, while TIMP mRNA is present in rat ovaries and increases before ovulation, suggesting that the granulosa cell metalloproteinase inhibitor is TIMP. We propose that TIMP acts in part to control the site and extent of follicular connective tissue remodeling associated with ovulation.
Assuntos
Matriz Extracelular/enzimologia , Células da Granulosa/enzimologia , Metaloendopeptidases/metabolismo , Ovário/enzimologia , Animais , Células Cultivadas , Gonadotropina Coriônica/farmacologia , Colforsina/farmacologia , AMP Cíclico/farmacologia , Feminino , Glicoproteínas/genética , Glicoproteínas/farmacologia , Gonadotropinas Equinas/farmacologia , Células da Granulosa/efeitos dos fármacos , Hormônio Luteinizante/farmacologia , Ovário/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Acetato de Tetradecanoilforbol/farmacologia , Inibidores Teciduais de MetaloproteinasesRESUMO
Aortic infusion of prostaglandin E1 in a moribund infant resulted in marked clinical improvement. Appropriate studies were conducted and the diagnosis of hypoplastic left heart syndrome was made. Although the outcome was unaltered, the improved clinical condition allowed us to exclude potentially curable defects such as aortic coarctation and interruption.
Assuntos
Permeabilidade do Canal Arterial/complicações , Cardiopatias Congênitas/tratamento farmacológico , Prostaglandinas E/uso terapêutico , Aorta/anormalidades , Aortografia , Ecocardiografia , Valvas Cardíacas/anormalidades , Ventrículos do Coração/anormalidades , Humanos , Recém-Nascido , MasculinoRESUMO
RATIONALE AND OBJECTIVES: Dynamic magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium, albumin-(Gd-DTPA)35, was used to detect changes in microvascular characteristics in R3230 mammary adenocarcinomas induced by x-irradiation. METHODS: Tumors were implanted in either flank in nine rats. One of the tumors was exposed to single-dose x-irradiation (30 Gy) 3 days before MRI. The contralateral control tumor was shielded from irradiation. RESULTS: Capillary permeability to macromolecular contrast medium in irradiated tumors was elevated significantly (P < .05) compared to the control nonirradiated tumors. The mean estimated permeability surface area product for the irradiated tumors increased more than three-fold; 0.511 +/- .046 mL hr-1 cm-3 compared with 0.121 +/- .011 mL hr-1 cm-3 for the nonirradiated tumors. This radiation-induced increase in permeability was corroborated using a macromolecular Evans blue-protein complex measured in the same tumors using an invasive spectrophotometric technique. CONCLUSIONS: Dynamic MRI-enhanced with macromolecular contrast medium permits noninvasive quantitative estimates of capillary permeability in tumors, with and without x-irradiation. Because the transendothelial permeability for macromolecular solutes likely influences tumoral accumulation of macromolecular chemotherapeutic agents, this noninvasive technique may prove to be clinically useful in tailoring tumor treatment programs which combine radiation and chemotherapy.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Albuminas , Permeabilidade Capilar/efeitos da radiação , Meios de Contraste , Gadolínio DTPA , Gadolínio , Imageamento por Ressonância Magnética , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Compostos Organometálicos , Ácido Pentético/análogos & derivados , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Animais , Capilares/metabolismo , Capilares/patologia , Capilares/efeitos da radiação , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/efeitos da radiação , Azul Evans , Imageamento por Ressonância Magnética/métodos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/radioterapia , Transplante de Neoplasias , Radiografia , Ratos , Ratos Endogâmicos F344 , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/radioterapia , EspectrofotometriaRESUMO
Adenosine, AMP, and ADP all caused similar concentration-related bronchoconstriction when inhaled by patients with asthma, whereas the adenosine hydrolysis product inosine had no effect. Geometric mean provocation concentrations of adenosine AMP and ADP causing a 20% fall in forced expiratory volume in 1 s (PCf20) were 2.34, 4.27, and 2.19 mumol/ml and 40% fall in specific airway conductance (PCs40) 3.16, 5.01, and 2.0 mumol/ml. Bronchoconstriction was rapid in onset, reaching a maximum 2-5 min after a single inhalation of AMP. In 31 asthmatic subjects a positive correlation was established between airway responsiveness to histamine, as an index of non-specific responsiveness, and airway reactivity to adenosine (PCf20, r = 0.60; PCs40, r = 0.64; P less than 0.01). Following bronchial provocation with allergen in nine subjects, plasma levels of adenosine increased from a mean base line of 5.4 +/- 0.9 to 9.6 +/- 2.0 ng/ml at 15 min (P less than 0.01) in parallel with a fall in forced expiratory volume in 1 s. With methacholine provocation bronchoconstriction reached maximum 2-5 min postchallenge being followed by, but not accompanied by, significant increases in plasma levels of adenosine. These data suggest that adenosine is a specific bronchoconstrictor that may contribute to airflow obstruction in asthma.
Assuntos
Difosfato de Adenosina , Monofosfato de Adenosina , Adenosina , Asma/fisiopatologia , Brônquios/fisiopatologia , Adenosina/sangue , Testes de Provocação Brônquica , Volume Expiratório Forçado , Histamina , Humanos , Inosina/sangue , Cinética , Cloreto de Metacolina , Compostos de MetacolinaRESUMO
Growing parent stock (breeders) of meat-type chickens (broilers), subjected routinely to chronic food restriction, show increased pacing before a single daily meal and increased drinking and pecking at non-food objects (oral stereotypies) afterwards. Expression of these activities is correlated positively with the level of restriction imposed, and is thought to be controlled mainly by central dopaminergic mechanisms. There is published evidence that glucocorticoids can amplify dopamine mediated behaviours, and this paper describes four experiments examining the relationship between corticosterone and behaviour in individually caged broiler breeders. In Experiment 1 (with 3 levels of food restriction), plasma corticosterone concentration was correlated positively with the level of restriction imposed when blood samples were taken in the morning, but not when they were taken in the afternoon. This may be because corticosterone level declines from morning to afternoon with mild but not severe restriction. In Experiment 2 (severe restriction only), plasma corticosterone level did not change significantly with time of day, and mean values of individual birds were not correlated with their observed times spent in oral stereotypies. In Experiment 3 (severe restriction), object pecking increased in a dose-related way after systemic injection of 1-4 mg/kg corticosterone (significant) and 7.5-30 IU/kg ACTH (not significant), and 10-40 mg/kg metyrapone (corticosterone synthesis inhibitor) had no effect. In Experiment 4 (severe restriction), 180 mg/day metyrapone administered in food for 5 days reduced the plasma corticosterone response to injection of 15 IU/kg ACTH on the fourth day, but otherwise had no effect. Significant increases in drinker directed activity after injection of ACTH on the fourth day and 4 mg/kg corticosterone on the fifth day coincided with greatly elevated plasma levels of corticosterone. It is concluded that the oral stereotypies of restricted-fed broiler breeders do respond to induced increases in plasma corticosterone concentration that are supra-physiological, but there may be only a weak association between behaviour and corticosterone within the physiological range.
Assuntos
Nível de Alerta/fisiologia , Corticosterona/sangue , Comportamento de Ingestão de Líquido/fisiologia , Comportamento Alimentar/fisiologia , Privação de Alimentos/fisiologia , Comportamento Estereotipado/fisiologia , Hormônio Adrenocorticotrópico/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Galinhas , Dopamina/fisiologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Metirapona/farmacologia , Comportamento Estereotipado/efeitos dos fármacosRESUMO
A single dose, single point method of predicting patients' oral maintenance theophylline dosage has been compared with a noninvasive method. Twenty patients with obstructive lung disease received an oral dose (6 mg kg-1) of micro-crystalline theophylline. The plasma theophylline concentration after 8-10 h was then used to calculate the optimum maintenance dose of sustained release aminophylline required to achieve steady state concentrations between 55 and 110 mumols l-1. The mean steady state plasma theophylline concentration for this dosage schedule was also predicted by a method using population average pharmacokinetic parameters (assumed clearance method). These predictions were then compared with observed concentration-time profiles at steady state. The mean difference between the observed values and those predicted from a morning test dose was -0.11 mumol l-1 (95% CI -7.0 to +7.2). A larger difference (-7.4 mumol l-1 95% CI -18.2 to +3.4) was found for the assumed clearance method. Since the confidence intervals contain zero, these differences are not significantly different from zero at the 5% level, although the morning test dose method allowed prediction of the whole concentration-time profile and was more precise. An evening test dose was also used in the study, but the mean difference between the observed values and those predicted from this method was larger at -24.8 mumol l-1 (95% CI -32.89 to -17.21) and was significantly different from zero. This study indicates that a morning test dose followed by a single blood sample can be used to establish maintenance theophylline therapy quickly and safely in selected patients.
Assuntos
Pneumopatias Obstrutivas/sangue , Teofilina/farmacocinética , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Pneumopatias Obstrutivas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Teofilina/sangue , Teofilina/uso terapêutico , Fatores de TempoRESUMO
The purpose of this study was to demonstrate a technique, in a pilot study, for measuring abnormal capillary permeability in synovial tissue of rabbit arthritic knees using dynamic MRI with a gadolinium-based blood pool agent. Arthritis, simulating rheumatoid arthritis, was induced in knees of 8 rabbits by intra-articular injection of carrageenan (n = 4) or ovalbumin (n = 4). Sequential fat presaturated T1-weighted Spoiled Grass images were obtained before and up to 30 min after intravenous administration of albumin-(Gd-DTPA)30. Estimates of synovial tissue plasma-volume (PV), fractional-leak-rate (FLR), and permeability-surface-area-product (PS) were computed. Histologic correlation was obtained in the corresponding regions. Dynamic MRI showed extravasation of albumin-(Gd-DTPA)30 into hypertrophic synovium in six of the eight arthritic knees. Histologic examination of these six knees showed markedly inflamed synovium. The two knees that did not show abnormal vascular permeability contained non-hypertrophic synovium. None of the rabbits showed abnormal permeability in muscle. MRI derived microvascular characteristics (PV, FLR and PS) correlated positively (r2 = 0.51, 0.97 and 0.86) with the histology. Factors involving the structural and functional microvascular characteristics of synovial tissue can be estimated non-invasively using albumin-(Gd-DTPA)30. This technique may be useful for monitoring disease progression and treatment response in rheumatoid arthritis.
Assuntos
Albuminas , Artrite Reumatoide/patologia , Gadolínio DTPA , Articulação do Joelho/patologia , Imageamento por Ressonância Magnética/métodos , Animais , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Permeabilidade Capilar , Carragenina , Meios de Contraste , Processamento de Imagem Assistida por Computador , Masculino , Ovalbumina , Projetos Piloto , Coelhos , Membrana Sinovial/irrigação sanguínea , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
RATIONALE AND OBJECTIVES: We compared the peritumoral vascular definition in rats using either a paramagnetic extracellular or a macromolecular contrast medium in combination with high-resolution magnetic resonance (MR) imaging. METHODS: High-resolution, three-dimensional spoiled gradient-refocused acquisition in a steady state (SPGR) images were acquired from tumor-bearing Fischer-344 rats before, immediately after, and again 40 min after administration of gadopentetate dimeglumine (0.1 mmol Gd/kg; n = 10) and albumin-(Gd-DTPA)30 (0.05 mmol Gd/kg; n = 5). Small peritumoral vessels were analyzed semiquantitatively on maximum intensity projection angiograms using a 4-point scoring system; quantitative analyses included signal-to-background ratios (SBRs) and signal-to-noise ratios. RESULTS: Gadopentetate dimeglumine caused a transient and low-scoring (0.2 +/- 0.1, SBR = 1.9 +/- 0.2) vessel definition but strong rim enhancement (score = 1.4 +/- 0.2). Albumin-(Gd-DTPA)30 produced persistent, high-quality angiograms (score = 2.6 +/- 0.2, SBR = 7.4 +/- 0.2) but minimal rim enhancement (score = 0.3 +/- 0.2). CONCLUSION: Albumin-(Gd-DTPA)30 combined with high-resolution MR imaging produces time-persistent, detailed angiographic definition of peritumoral vessels. Vascular maps obtained with gadopentetate dimeglumine enhancement are not time persistent or of equal quality.
Assuntos
Albuminas , Meios de Contraste , Gadolínio DTPA , Angiografia por Ressonância Magnética/métodos , Neoplasias Mamárias Experimentais/diagnóstico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/diagnóstico , Animais , Feminino , Neoplasias Mamárias Experimentais/irrigação sanguínea , Ratos , Ratos Endogâmicos F344RESUMO
OBJECTIVES: To evaluated quality of outpatient sputum cytology and whether written instructions to patients improve sample quality and to identify variables that predict satisfactory samples. DESIGN: Prospective randomised study. SETTING: Outpatient department of a district general hospital. PATIENTS: 224 patients recruited over 18 months whenever their clinicians requested sputum cytology, randomized to receive oral or oral and written advice. INTERVENTIONS: Oral advice from nurse on producing a sputum sample (114 patients); oral advice plus written instructions (110). MAIN MEASURES: Percentages of satisfactory sputum samples and of patients who produced more than one satisfactory sample; clinical or radiological features identified from subsequent review of patients' notes and radiographs associated with satisfactory samples; final diagnosis of bronchial cancer. RESULTS: 588 sputum samples were requested and 477 received. Patients in the group receiving additional written instructions produced 75(34%) satisfactory samples and 43(39%) of them one or more sets of satisfactory samples. Corresponding figures for the group receiving only oral advice (80(31%) and 46(40%) respectively)were not significantly different. Logistic regression showed that radiological evidence of collapse or consolidation (p<0.01) and hilar mass (p<0.05) were significant predictors of the production of satisfactory samples. Sputum cytology confirmed the diagnosis in only 9(17%) patients with bronchial carcinoma. CONCLUSIONS: The quality of outpatients' sputum samples was poor and was not improved by written instructions. Sputum cytology should be limited to patients with probable bronchial cancer unsuitable for surgery. IMPLICATIONS: Collection of samples and requests for sputum cytology should be reviewed in other hospitals.
Assuntos
Ambulatório Hospitalar/normas , Educação de Pacientes como Assunto/normas , Garantia da Qualidade dos Cuidados de Saúde/normas , Manejo de Espécimes/normas , Escarro/citologia , Neoplasias Brônquicas/diagnóstico , Inglaterra , Feminino , Hospitais de Distrito/normas , Hospitais Gerais/normas , Humanos , Modelos Logísticos , Masculino , Educação de Pacientes como Assunto/métodos , Estudos Prospectivos , Fala , RedaçãoAssuntos
Adenocarcinoma/irrigação sanguínea , Albuminas/farmacocinética , Permeabilidade Capilar , Meios de Contraste/farmacocinética , Gadolínio DTPA , Imageamento por Ressonância Magnética , Neoplasias Mamárias Experimentais/irrigação sanguínea , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Adenocarcinoma/diagnóstico , Adenocarcinoma/radioterapia , Animais , Permeabilidade Capilar/efeitos da radiação , Feminino , Substâncias Macromoleculares , Neoplasias Mamárias Experimentais/diagnóstico , Neoplasias Mamárias Experimentais/radioterapia , Transplante de Neoplasias , Ácido Pentético/farmacocinética , Ratos , Ratos Endogâmicos F344Assuntos
Meios de Contraste/farmacocinética , Imagem Cinética por Ressonância Magnética , Imageamento por Ressonância Magnética , Infarto do Miocárdio/diagnóstico , Traumatismo por Reperfusão Miocárdica/diagnóstico , Albuminas/farmacocinética , Animais , Velocidade do Fluxo Sanguíneo , Permeabilidade Capilar , Cloretos/farmacocinética , Combinação de Medicamentos , Espaço Extracelular/metabolismo , Gadolínio DTPA , Líquido Intracelular/metabolismo , Compostos de Manganês/farmacocinética , Meglumina/farmacocinética , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição TecidualAssuntos
Meios de Contraste/farmacocinética , Imagem Ecoplanar , Gadolínio/farmacocinética , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Animais , Meios de Contraste/administração & dosagem , Espectroscopia de Ressonância de Spin Eletrônica , Gadolínio DTPA , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Imagens de Fantasmas , Radiografia , Ratos , Ratos Endogâmicos F344 , Distribuição TecidualAssuntos
Albuminas/farmacocinética , Permeabilidade Capilar/fisiologia , Meios de Contraste/farmacocinética , Gadolínio DTPA , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Adenocarcinoma/irrigação sanguínea , Animais , Circulação Coronária/fisiologia , Doença das Coronárias/fisiopatologia , Feminino , Inflamação/fisiopatologia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Microcirculação/fisiopatologia , Transplante de Neoplasias , Ácido Pentético/farmacocinética , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-DawleyAssuntos
Adenocarcinoma/irrigação sanguínea , Albuminas/farmacocinética , Antineoplásicos/farmacologia , Permeabilidade Capilar/fisiologia , Cisplatino/farmacologia , Meios de Contraste/farmacocinética , Gadolínio DTPA , Imageamento por Ressonância Magnética , Neoplasias Mamárias Experimentais/irrigação sanguínea , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Adenocarcinoma/radioterapia , Animais , Antineoplásicos/farmacocinética , Permeabilidade Capilar/efeitos da radiação , Cisplatino/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Neoplasias Mamárias Experimentais/radioterapia , Microcirculação/fisiopatologia , Microcirculação/efeitos da radiação , Ácido Pentético/farmacocinética , Ratos , Ratos Endogâmicos F344Assuntos
Albuminas , Meios de Contraste , Imageamento por Ressonância Magnética , Neoplasias Mamárias Experimentais/irrigação sanguínea , Meglumina , Compostos Organometálicos , Ácido Pentético/análogos & derivados , Animais , Combinação de Medicamentos , Gadolínio DTPA , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Células Tumorais CultivadasRESUMO
Gd(III) toxicity is such that, for in vivo use, the ion must be incorporated into stable, ionically bound complexes with organic chelating agents. Although metal-chelate-based contrast agents have been demonstrated safe in phase I-III studies, their potential toxicities must be considered, particularly in the development of new contrast media. The potential for adverse effects is thought to arise from in vivo dissociation into constituent metal ion and ligand. Release of Gd(III) from ligand may also be facilitated by endogenous metals [e.g., Zn(II)] that compete with Gd(III) for ligand-binding sites. In vivo complex stability toward dissociation depends on several closely balanced characteristics of the metal and ligand that maintain metal-chelate integrity during residence in the body. Among design strategies explored to minimize the potential for in vivo Gd(III) release are the use of ligands that: form Gd(III) complexes with high thermodynamic stabilities; have binding selectivity for Gd(III) over endogenous metal ions; incorporate rigid cyclic structures and form Gd(III) complexes with greater kinetic stabilities than their open-chain homologs; or incorporate slight excess ligand to "scavenge" loosely bound or free endogenous metal ions that might otherwise compete with Gd(III) for ligand binding.
Assuntos
Gadolínio/química , Animais , Química Farmacêutica , Estabilidade de Medicamentos , Gadolínio/efeitos adversos , HumanosRESUMO
The airway response to increasing concentrations of inhaled-adenosine and histamine after oral theophylline or matched placebo was studied in nine asthmatic subjects. Changes in airway calibre were followed as sGaw and FEV1 and concentration-response curves constructed. Inhaled adenosine caused concentration-related bronchoconstriction and was four-five times less potent than inhaled histamine. Theophylline, which achieved a mean plasma level of 15.9 and 16.6 micrograms/ml on the histamine and adenosine study days respectively, caused significant increases in FEV1 (17%) and sGaw (41-53%) whereas placebo had no effect. Theophylline also protected the airways against histamine-and adenosine-induced bronchoconstriction. However theophylline had a greater protective effect against adenosine (concentration-ratio 17.4 for FEV1 and 12.8 for sGaw) than against histamine (concentration ratio 5.6 for FEV1 and 5.4 for sGaw (P less than 0.05]. At therapeutic concentrations theophylline is a specific antagonist of the airway effects of adenosine in addition to being a bronchodilator and a functional antagonist.
Assuntos
Adenosina/antagonistas & inibidores , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Teofilina/farmacologia , Adulto , Resistência das Vias Respiratórias/efeitos dos fármacos , Broncodilatadores/farmacologia , Feminino , Volume Expiratório Forçado , Histamina/farmacologia , Humanos , Masculino , Distribuição Aleatória , Teofilina/sangueRESUMO
1. Behavioural development in groups of 8 pullets kept in pens with litter floors, and fed on either mash or pellets, was studied from 0 to 10 weeks in a White Leghorn x broiler (F2) hybrid line (experiment 1) and from 0 to 24 weeks in Hisex, White Leghorn and Brown Leghorn strains (experiment 2). The aim was to identify precursors of feather pecking and cannibalism. 2. Rates of body weight gain were consistently greater with pellets than with mash in both experiments. In experiment 2, the onset of lay was at 17 weeks of age in Hisex, 21 weeks in White Leghorns and 23 weeks in Brown Leghorns. 3. Persistent feather pecking, which was not seen in experiment 1, developed in 2 of 12 groups (one Hisex and one White Leghorn, both fed on pellets) in experiment 2, and was studied in detail at 23 and 24 weeks. The more damaging pecking in the Hisex group was followed by cannibalism in the same group. 4. Based on the (often inconsistent) effects of genetic strain, age and food form on behaviour that were observed, a working hypothesis was constructed to account for the aetiology of feather pecking and cannibalism in situations where there is floor litter. 5. An age-related decline in one or more foraging activities may coincide with increases in preening and non-damaging pecking at other birds. Consumption of litter particles and moulted feathers may be reinforcing. Dustbathing may enhance the stimulus value of litter particles when they are contrasted against background plumage colour. This may direct pecking towards the backs of birds, where feathers as well as litter particles may be removed and eaten. Regular pecking and feather removal may lead eventually, after the onset of lay, to vent pecking and cannibalism. This sequence of events may be more likely in groups where activity levels are high.
Assuntos
Comportamento Animal , Galinhas , Agressão , Envelhecimento , Ração Animal , Animais , Canibalismo , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Asseio Animal , Especificidade da Espécie , Aumento de PesoRESUMO
1. As part of a programme investigating the causation of pecking damage in fowls, this experiment tested a proposal that birds may receive more feather pecks when their plumage colour contrasts with floor litter colour, because litter particles on plumage (as a consequence of dustbathing) may then have greater stimulus value. 2. Groups consisting of 7 light- and 7 dark-coloured bantams were reared from 1 to 11 weeks of age in pens with either wood shavings (light coloured, n=6) or peat (dark coloured, n=6) floor litter. 3. Feather loss from pecking commenced in the 3rd week of life and increased thereafter, but observed pecking damage scores were not consistent with the hypothesis being tested. 4. Despite many more pecks at birds being seen (over 10 weeks) in the wood shavings groups' (661 at particles on plumage, 1795 not at particles) than in peat groups (205, 787), there was no effect of litter substrate on pecking damage. The only evidence supporting the proposal was the finding that, in groups on wood shavings, significantly more pecks at particles on plumage were directed from light coloured birds towards dark ones, than from light to light, dark to light, or dark to dark. 5. Feather eating was confirmed from the presence of feather material in 2% to 15% of faecal droppings collected from each group at 11 weeks, but these proportions were not correlated with pecking damage scores. 6. The results imply that only some feather pecks/pulls were damaging and only some eaten feathers were pulled from other birds.