RESUMO
Although moderate-size earthquakes are poorly studied by lack of near-fault observations, they can provide key information about larger damaging earthquakes. Here we propose a new approach, inspired by double-difference relocation, that uses high-coherency waveforms recorded at neighboring sensors, to study the preparation phase and dynamics of moderate-size earthquakes. We validate this technique by analyzing the 2016, M w 5.2 Borrego Springs earthquake in Southern California and find consistent rupture velocities of 2 km/s highlighting two main rupture asperities. The analysis of the 2019, Ml5.2 Le Teil earthquake in France reveals slow nucleation at depth that migrates to the surface and propagates northward with a velocity of â¼2.8 km/s, highlighting two main rupture events also imaged by InSAR. By providing unprecedented resolution in our observation of the rupture dynamics, this approach will be useful in better understanding the preparation phase and rupture of both tectonic and induced earthquakes.
RESUMO
The problems of the diabetic foot in general are badly known by patients as well as caregivers. They represent yet a major health problem. Recall that if the ulcers are treated early and adequately, they will heal in 70 to 90% of cases. "The diabetic foot" encompasses the whole of the anomalies of the function and/or of the structure of the foot, linked directly or indirectly to hyperglycaemia. The involvement of nerves, arteries and infection can concentrate on the foot that is also called the "crossroads of complications". These various complications are reviewed in detail. The neuropathy mainly sensitive with the diminution or even the disappearance of the sensitivity to pain and its modes of detection as well as this awful and poorly known complication that is the Charcot foot. The arteriopathy sub-diagnosed and yet very frequent, its modes of detection and its treatment. The difficulties of diagnosis of infection, another serious danger for the foot, its classification and treatment. The care of the wounds whose size and depth are too often under-estimated, their classification of important prognostic value. The care of the diabetic foot wounds too often treated as "classic" wounds forgetting those topics mentioned above will be described focusing on their specific characteristics which are debridement and above all offloading. The importance of the primary and secondary prevention will be highlighted.
Assuntos
Pé Diabético , Angiopatias Diabéticas/complicações , Pé Diabético/etiologia , Pé Diabético/terapia , Neuropatias Diabéticas/complicações , HumanosRESUMO
AIM: To undertake a proof-of-concept study to determine whether a removable offloading device (the Ransart boot) for the management of diabetic foot ulcers (DFU) was as effective as reports of non-removable devices. RESEARCH DESIGN AND METHODS: This observational study used the Ransart boot for patients with DFU, in seven specialist centres. If a patient had two or more ulcers, one was selected as the index ulcer. Ulcers were classified by the University of Texas (UT) system. RESULTS: There were 135 patients (mean age 60.3 +/- 11.4 years); 96 (71.1%) male. Median ulcer duration at presentation was 90 [interquartile range (IQR) 30-1825] days. Seven were lost to follow-up, seven developed other major illnesses and four died; outcomes were documented in the remaining 117. Eighty-two (70.1% of 117) healed, after a median (IQR) 60 (43-99) days, while 22 (18.8%) ulcers were resolved by amputation (one major). The remaining 13 (11.1%) patients were judged non-compliant. There was a close correlation between ulcer classification at baseline and both time to healing (P < 0.001 chi(2)-test) and amputation (P < 0.001; Spearman's rank correlation coefficient). There was a positive correlation between ulcer duration at presentation and time to healing (P < 0.02), UT class (P < 0.01), glycated haemoglobin (P < 0.02) and amputation (P < 0.04). CONCLUSIONS: Time to healing and incidence of amputation were comparable with those previously reported for non-removable devices. Given that a removable device is much more acceptable to the patient, the effectiveness, cost and acceptability of the removable devices, such as the Ransart boot, need to be compared with a non-removable device in a randomized trial. Diabet. Med. 26, 778-782 (2009).
Assuntos
Pé Diabético/terapia , Sapatos , Cicatrização/fisiologia , Idoso , Desenho de Equipamento , Feminino , Úlcera do Pé/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Resultado do TratamentoRESUMO
Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO(2) (PaCO(2 approximately)65 mm Hg; pH approximately 7.2) caused a approximately 2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor Nomega-nitro-L-arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH approximately 7.15, PCO(2 approximately )40 mm Hg; 6 hours) produced similar increases in prostaglandin E(2) (PGE(2)) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca(2+) channel blocker SK&F96365, and by the K(ATP) channel blocker glybenclamide. Acidosis increased Ca(2+) transients in brain endothelial cells, which were blocked by glybenclamide and SK&F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE(2) was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE(2) generated by a K(ATP) and Ca(2+) channel-dependent process.
Assuntos
Dinoprostona/metabolismo , Hipercapnia/complicações , Hiperemia/etiologia , Óxido Nítrico Sintase/biossíntese , Canais de Potássio/metabolismo , Acidose/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Dióxido de Carbono/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Indução Enzimática , Técnicas In Vitro , NADPH Desidrogenase/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo III , Nitritos/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Suínos , Fatores de TempoRESUMO
The choroid is the main source of oxygen to the retina. In contrast to the adult, the absence of autoregulation of choroidal blood flow in the newborn leads to hyperoxygenation of the retina. In the immature retina which contains relatively low levels of antioxidants this hyperoxygenation favors peroxidation including the generation of biologically active isoprostanes, and results in vasoconstriction and vascular cytotoxicity leading to ischemia, which predisposes to the development of a vasoproliferative retinopathy, commonly termed retinopathy of prematurity. During frequently encountered oxidative stress to the perinate, the combined absence of vascular autoregulation and excessive oxygen delivery to the eyes of the developing subject is largely the result of a complex epigenetic and genetic interplay between prostanoids and nitric oxide (NO) systems on vasomotor regulation. The effects of certain prostaglandins are NO-dependent; conversely, those of NO have also been found to be largely prostaglandin I(2)-mediated in the eye; and NO synthase expression seems to be significantly regulated by other prostaglandins apparently through activation of functional perinuclear prostanoid receptors which affect gene transcription. The increased production of both prostaglandins and NO in the perinate augment ocular blood flow and as a result oxygen delivery to an immature retina partly devoid of antioxidant defenses. The ensuing peroxidation results in impaired circulation (partly thromboxane A(2)-dependent) and vascular integrity, leading to ischemia which predisposes to abnormal preretinal neovascularization, a major feature of ischemic retinopathy. Because tissue oxygenation is largely dependent upon circulation and critical in the generation of reactive oxygen species, and since the latter exert a major contribution in the pathogenesis of retinopathy of prematurity, it is important to understand the mechanisms that govern ocular blood flow. In this review we focus on the important and complex interaction between prostanoid, NO and peroxidation products on circulatory control of the immature retina.
Assuntos
Dinoprosta/metabolismo , Peroxidação de Lipídeos , Óxido Nítrico/metabolismo , Estresse Oxidativo , Retina/metabolismo , Retinopatia da Prematuridade/etiologia , Corioide/irrigação sanguínea , Fatores de Crescimento Endotelial/metabolismo , Radicais Livres/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro/metabolismo , Isquemia/metabolismo , Linfocinas/metabolismo , Neovascularização Patológica , Nitratos/metabolismo , Óxido Nítrico Sintase/metabolismo , Oxigênio/metabolismo , Receptores de Prostaglandina E/metabolismo , Vasos Retinianos , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/fisiopatologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Since urea and uric acid clearance are affected by the effective intravascular volume, we measured the fractional urea and uric acid excretion in cirrhosis. High urea and uric acid clearances were observed in 30 and 55 percent, respectively, of 20 consecutive cirrhotic patients with normal renal function. In seven patients with a high fractional uric acid excretion, 5 mg of isosorbide dinitrate every four hours for 24 hours induced a significant increase in the serum uric acid level (from 3.7 +/- 0.8 mg/dl to 4.4 +/- 0.8 mg/dl; less than 0.001) with a concomitant decrease in the fractional uric acid excretion (from 14.0 +/- 3.2 percent to 8.8 +/- 3.1 percent; less than 0.02). During the same test, the blood urea level increased from 3.3 +/- 1.1 mmol/liter to 4.1 +/- 1.2 mmol/liter (p less than 0.005) with a decrease in fractional excretion from 51 +/- 4.5 percent to 39 +/- 5 percent (p less than 0.001). The oral intake of sulfinpyrazone in six of these patients induced a normal uricosuric response. In two cirrhotic patients with ascites, 40 mg of furosemide associated with a 24-hour severe water restriction was also shown to normalize the high fractional excretion of both urea and uric acid. In nine patients with ascites, we observed a significant increase in blood urea and uric acid concentration despite the absence of change in creatinine clearance once ascites was removed by diuretics. On the basis of these findings, we believe that the high fractional excretion of both urea and uric acid frequently observed in cirrhosis is related to an increase in the effective vascular volume.
Assuntos
Volume Sanguíneo , Cirrose Hepática Alcoólica/urina , Ureia/urina , Ácido Úrico/urina , Creatinina/sangue , Creatinina/urina , Diurese , Furosemida/farmacologia , Humanos , Dinitrato de Isossorbida/farmacologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/fisiopatologia , Pessoa de Meia-Idade , Ureia/sangue , Ácido Úrico/sangueRESUMO
We examined whether nitric oxide (NO) generated from neuronal NO synthase (nNOS) contributes to the reduced ability of the newborn to autoregulate retinal blood flow (RBF) and choroidal blood flow (ChBF) during acute rises in perfusion pressure. In newborn pigs (1-2 days old), RBF (measured by microsphere) is autoregulated over a narrow range of perfusion pressure, whereas ChBF is not autoregulated. N(G)-nitro-L-arginine methyl ester (L-NAME) or specific nNOS inhibitors 7-nitroindazole, 3-bromo-7-nitroindazole, and 1-(2-trifluoromethyl-phenyl)imidazole as well as ganglionic blocker hexamethonium, unveiled a ChBF autoregulation as observed in juvenile (4- to 6-wk old) animals, whereas autoregulation of RBF in the newborn was only enhanced by L-NAME. All NOS inhibitors and hexamethonium prevented the hypertension-induced increase in NO mediator cGMP in the choroid. nNOS mRNA expression and activity were three- to fourfold higher in the choroid of newborn pigs than in tissues of juvenile pigs. It is concluded that increased production of NO from nNOS curtails ChBF autoregulation in the newborn and suggests a role for the autonomic nervous system in this important hemodynamic function, whereas, for RBF autoregulation, endothelial NOS seems to exert a more important contribution in limiting autoregulation.
Assuntos
Animais Recém-Nascidos/fisiologia , Plexo Corióideo/irrigação sanguínea , Homeostase/fisiologia , Óxido Nítrico Sintase/fisiologia , Animais , Gasometria , GMP Cíclico/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo III , Ensaios de Proteção de Nucleases , RNA Mensageiro/biossíntese , Fluxo Sanguíneo Regional/fisiologia , Vasos Retinianos/efeitos dos fármacos , SuínosRESUMO
The quantitative [14C]iodoantipyrine autoradiographic method was applied to study the effects of acute administration of caffeine and L-phenylisopropyladenosine (LPIA) separately or in combination on local cerebral blood flow in the rat. After the injection of caffeine, cerebral blood flow rates were decreased in 13 out of the 61 structures studied, mainly in motor and auditory areas. The administration of LPIA induced a general decrease in local cerebral blood flow, which was significant in only 4 regions. The combined administration of caffeine and LPIA induced decreases in blood flow rates in 17 brain areas, motor, limbic and hypothalamic structures and increases in 3 limbic regions. The results confirm previous data on the effect of caffeine on cerebral circulation. The consequences of LPIA administration on blood flow may originate partly from peripheral effects and may also be the reflection of the reduction in the energy demand of the brain. Finally, LPIA also seems to be able to modulate caffeine effects on local cerebral blood flow when injected simultaneously with caffeine.
Assuntos
Adenosina/análogos & derivados , Cafeína/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Fenilisopropiladenosina/farmacologia , Animais , Antipirina/análogos & derivados , Antipirina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Interações Medicamentosas , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
S 9977-2 is a new trimethylxanthine derivative with promnesic properties. Its effects on cerebral glucose utilization and blood flow were studied by means of quantitative autoradiography. S 9977-2 was injected intravenously into adult rats at doses of 0.1, 1.0 and 10 mg/kg. At 0.1 mg/kg, S 9977-2 induced a significant increase in cerebral glucose utilization over control values in two white matter areas and in the vestibular nucleus. At 1.0 mg/kg, glucose utilization was affected in 14 areas out of the 63 studied, mainly limbic regions such as the hippocampus, raphe nuclei and locus coeruleus, as well as some posterior areas. Conversely, after the injection of 10 mg/kg S 9977-2, cerebral glucose utilization was similar to that of control rats. At the three doses tested, S9977-2 did not induce any significant variation in local rates of cerebral blood flow compared to those of controls. Likewise, S 9977-2 did not change the level of coupling between cerebral blood flow and metabolism, except at 10 mg/kg, where a relative hypoperfusion at a constant metabolic level was recorded. These data show that, at 1.0 mg/kg, S 9977-2 increased glucose utilization in hippocampal areas, an effect which may be related to the promnesic properties of this compound at the same dose. Moreover, at low doses, the lack of change in the level of coupling between cerebral blood flow and metabolism is indicative of the rather selective action of this compound, compared to that of caffeine. Thus S9977-2 should have therapeutic effects, mainly via its promnesic properties, without having many side effects.
Assuntos
Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Glucose/metabolismo , Piperazinas/farmacologia , Xantinas/farmacologia , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Gasometria , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Piperazinas/administração & dosagem , Piperazinas/sangue , Ratos , Ratos Sprague-Dawley , Xantinas/administração & dosagem , Xantinas/sangueRESUMO
Visually responsive neurons were recorded in the superficial layers of rat superior colliculus from postnatal day 12 to 28. Receptive field properties such as size, type (ON, OFF, ON-OFF and motion sensitive) and direction selectivity were analyzed to disclose changes during maturation. Although some aspects of sensory properties are modified during development (latency, receptive field sizes, and proportions of receptive field types), a high level of sophistication is also present in young animals even before eyelid opening. For instance, direction selective and direction biased cells, which require complex synaptic relations, are already observed when the first light evoked responses emerge in the superior colliculus (P13), strongly suggesting that this property develops without visual experience. Furthermore, direction selectivity is present in the colliculus prior to the appearance of visually evoked activity in the cortex. This indicates that direction selectivity can not be attributable to incoming cortical afferents. This study provides the first direct evidence that, unlike the cat, the rat's cortico-tectal pathway is only weakly involved in the establishment of direction selectivity in collicular neurons.
Assuntos
Envelhecimento/fisiologia , Animais Recém-Nascidos/fisiologia , Colículos Superiores/crescimento & desenvolvimento , Vias Visuais/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Mapeamento Encefálico , Eletrofisiologia , Estimulação Luminosa , Ratos , Ratos Long-Evans , Tempo de Reação/fisiologia , Colículos Superiores/fisiologia , Vias Visuais/fisiologiaRESUMO
Bronchospasm induced by adenosine is blocked by representatives of all the major classes of drugs used in the treatment of asthma. Understanding the mechanism of this bronchospasm may help understand the way these drugs work. Clinical studies have suggested involvement of neural pathways, mast-like cells and mediators such as histamine, serotonin and lipoxygenase products. There is a strong link between responsiveness to adenosine and eosinophilia. In different animal models A1, A2b and A3 adenosine receptor subclasses have all been implicated in inducing bronchospasm. whilst occupation of the A2a receptor generally has no, or the opposite effect. At least two different mechanisms, both involving neural pathways, exist. One, involving the adenosine A1 receptor, functions in mast cell depleted animals; the other requires interaction with a population of mast-like cells activated over A2b or A3 receptors. Not only histamine but also serotonin and lipoxygenase products released from the mast-like cells are potential mediators. In animal models good reactivity to adenosine receptor agonists is generally only found when the animals are first sensitized and exposed to allergen in ways likely to induce an allergic inflammation. An exception is the BDE rat, which reacts to adenosine receptor agonists such as APNEA or NECA even without allergen exposure. This rat strain does however show evidence of spontaneous eosinophilic inflammation in the lung even without immunization. As mast cells both release adenosine and respond to adenosine, adenosine provides a non-specific method of amplifying specific signals resulting from IgE/antigen interaction. This mechanism may not only have a pathological significance in asthma; it may be part of a normal bodily defense response that in asthmatic subjects is inappropriately activated.
Assuntos
Adenosina-5'-(N-etilcarboxamida)/administração & dosagem , Asma/fisiopatologia , Espasmo Brônquico/fisiopatologia , Vasodilatadores/administração & dosagem , Administração por Inalação , Animais , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Modelos Animais de Doenças , Eosinofilia/fisiopatologia , Humanos , Técnicas In Vitro , Mastócitos/fisiologia , Ratos , Ratos Endogâmicos , Receptores Purinérgicos P1/classificação , Receptores Purinérgicos P1/fisiologiaRESUMO
The prevalence of painful diabetic peripheral neuropathy (PDN) is about 20% in patients with type 2 diabetes and 5% in those with type 1. Patients should be systematically questioned concerning suggestive symptoms, as they are not usually volunteers. As PDN is due to small-fibre injury, the 10 g monofilament pressure test as well as the standard electrophysiological procedures may be normal. Diagnosis is based on clinical findings: type of pain (burning discomfort, electric shock-like sensation, aching coldness in the lower limbs); time of occurrence (mostly at rest and at night); and abnormal sensations (such as tingling or numbness). The DN4 questionnaire is an easy-to-use validated diagnostic tool. Three classes of drugs are of equal value in treating PDN: tricyclic antidepressants; anticonvulsants; and selective serotonin-reuptake inhibitors. These compounds may be prescribed as first-line therapy following pain assessment using a visual analogue scale. If the initial drug at its maximum tolerated dose does not lead to a decrease in pain of at least 30%, another drug class should be prescribed; if the pain is decreased by 30% but remains greater than 3/10, a drug from a different class may be given in association.
Assuntos
Analgésicos/uso terapêutico , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Neuropatias Diabéticas/epidemiologia , Humanos , Incidência , PrevalênciaAssuntos
Neoplasias/terapia , Pais/educação , Pais/psicologia , Planejamento de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Grupos de Autoajuda/organização & administração , Adulto , Criança , Defesa da Criança e do Adolescente , Pré-Escolar , Humanos , Neoplasias/psicologia , Avaliação de Programas e Projetos de Saúde , Psicologia da Criança , Inquéritos e QuestionáriosRESUMO
We present 1 patient with hypouricemia and hyperuricosuria. Serum uric acid level ranged between 1.5 and 1.9 mg/dl and uric acid fractional excretion between 20 and 28%. Apart from that the renal function was normal. The pyrazinamide suppression test gave a normal response showing nearly complete suppression of urate excretion. The uricosuric response to sulfinpyrazone was normal too. The renal tubular response to extracellular fluid volume contraction induced by furosemide indicated a normal tubular sensitivity to extracellular fluid volume variations. From these results we conclude that our patient has a specific tubulopathy characterized by uric acid hypersecretion.
Assuntos
Túbulos Renais/metabolismo , Ácido Úrico/metabolismo , Adulto , Depressão Química , Espaço Extracelular/fisiologia , Feminino , Furosemida , Humanos , Testes de Função Renal , Meningite Viral/fisiopatologia , Pirazinamida , Sulfimpirazona , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
Kinetics of insulin fixation to chloroplasts, exponential dissociation of bound hormone, competition between radioactive and native insulins for binding and for release indicate that chloroplasts possess insulin receptors.
Assuntos
Acetabularia/metabolismo , Clorófitas/metabolismo , Insulina/metabolismo , Cloroplastos/metabolismo , Cinética , Receptores de Superfície CelularRESUMO
Hypouricemia seen with hyponatremia related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) results from an increase in uric acid renal clearance. We studied the mechanism of the increase of uric acid excretion in 6 SIADH patients through pyrazinamide (PZA), which decreases tubular secretion of uric acid, and sulfinpyrazone (SPZ) which decreases post-secretory reabsorption of uric acid. 3 g of PZA decreased the absolute uric acid excretion from 428 +/- 244 to 105 +/- 47 micrograms/min (mean +/- SD, p less than 0.01), and 300 mg of SPZ increased the uric acid to creatinine clearance ratio from 0.31 +/- 0.05 to 0.52 +/- 0.05 mg/dl glomerular filtration rate (mean +/- SEM, p less than 0.001), which represent an increment about half of that observed in the control group. The increase of uric acid clearance in SIADH seems to result from a decrease in the post-secretory reabsorption of uric acid. After SPZ, we saw a decrease of natriuresis from 5.6 +/- 1.4 to 1.8 +/- 0.3 mmol/h (p less than 0.001), without any change of urinary flow or urinary potassium excretion.
Assuntos
Síndrome de Secreção Inadequada de HAD/sangue , Ácido Úrico/sangue , Taxa de Filtração Glomerular , Humanos , Hiponatremia/etiologia , Síndrome de Secreção Inadequada de HAD/complicações , Síndrome de Secreção Inadequada de HAD/fisiopatologia , Rim/fisiopatologia , Pessoa de Meia-Idade , Natriurese , Pirazinamida , Sulfimpirazona , Ácido Úrico/metabolismoRESUMO
The effect of amphotericin B on the oxidation and degradation of low- and high-density lipoproteins was investigated by UV-vis spectroscopy, electron microscopy, electrophoresis, and size-exclusion chromatography. Two formulations of the drug were used: the commercial Fungizone and a new, less toxic, liposomal formulation, AmBisome. It was shown that Fungizone strongly enhanced the oxidative deformation of low-density lipoprotein structure while AmBisome did not bind to this lipoprotein fraction and did not affect its oxidation. It was shown that amphotericin B contained in Fungizone extracted cholesterol from low-density lipoproteins which sensitized them to oxidation. Both formulations of amphotericin B studied here did not bind to high-density lipoprotein and did not affect the process of its oxidation.
Assuntos
Anfotericina B/toxicidade , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas LDL/efeitos dos fármacos , Cromatografia em Gel , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/ultraestrutura , Lipossomos , Microscopia Eletrônica , Oxirredução , Espectrofotometria Atômica , Espectrofotometria UltravioletaRESUMO
Serum of rabbits with a turpentine-induced acute inflammatory reaction (RS(INFLA)) and serum of humans with a viral infection (HS(INF)) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (H(INFLA)) were incubated with RS(INFLA) and HS(INF) for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RS(INFLA) or HS(INF) decreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 H(INFLA). Exposure of H(CONT) or H(INFLA) to hydrogen peroxide (0.01-1.0 mM) and sodium nitroprusside (0.01-1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of L-NAME (0.05-1.0 mM), dimethylthiourea (6.25-50 mM), or N-acetylcysteine (0.01-1.0 mM) with H(INFLA) partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RS(INFLA) and HS(INF). On the other hand, 3-amino-1,2,4-triazole (10-100 mM) or diethyldithiocarbamate (1.0-10 mM) potentiated RS(INFLA)- and HS(INF)-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2; DL-buthionine-(S,R)-sulfoximine (2.5-25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of H(INFLA) P450 content and activity induced by 4 h of exposure to RS(INFLA) or HS(INF).
Assuntos
Reação de Fase Aguda/enzimologia , Sistema Enzimático do Citocromo P-450/metabolismo , Espécies Reativas de Oxigênio/fisiologia , Reação de Fase Aguda/sangue , Amitrol (Herbicida)/farmacologia , Animais , Biotransformação , Butionina Sulfoximina/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Ditiocarb/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Coelhos , Teofilina/farmacocinética , Tioureia/análogos & derivados , Tioureia/farmacologiaRESUMO
Both ageing and vitamin C (VC) deficiency result in immune defect. Since low serum and tissue levels of VC are found in the elderly, we have in a placebo-controlled study, tested the effect of VC supplements (500 mg/day i.m. for 1 month) on various immune parameters. Indeed, VC enhances the proliferative response of T lymphocytes in vitro, and the tuberculin skin hypersensitivity in vivo. Neither the serum concentrations of IgA, IgG and IgM, nor the proportion of E-rosette-forming cells were modified. No significant change was observed in the placebo-treated group.
Assuntos
Ácido Ascórbico/farmacologia , Imunidade Celular/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Idoso , Ácido Ascórbico/administração & dosagem , Feminino , Humanos , Imunoglobulinas/análise , Injeções Intramusculares , Masculino , Mitógenos/farmacologia , Formação de Roseta , Linfócitos T/efeitos dos fármacos , Teste TuberculínicoRESUMO
Ontogenic changes in choroidal vascular prostaglandin E2 (PGE2) receptors (EP1, EP2, EP3, and EP4), changes in receptor-coupled functions, and the possible role of high perinatal prostaglandin levels in regulating expression and function of these receptors were studied. PGE2 receptors and their functions on choroidal tissues were characterized by radioligand binding; by measurements of second messengers to receptor stimulation; and by vasomotor response to EP1, EP2, EP3, and EP4 ligands on perfused choroidal vascular beds from saline- and ibuprofen-treated (40 mg/kg every 4 every 4 hours for 48 hours) newborn pigs and from adult animals. PGE2 as well as EP2- and EP4-attributed choroidal stimulation elicited greater vasorelaxation in the saline-treated newborn and was associated with higher nitrite (oxidation product of NO, N omega-nitro-L-arginine inhibitable) production than in adult tissues. In contrast, EP1 and EP3 stimulation caused significantly more constriction in the adult than in the newborn, and this was associated with increased production of inositol 1,4,5-trisphosphate (IP3) and greater reduction of cAMP synthesis in the adult. Maximum [3H]PGE2 binding was also higher (3-fold) in adult than in newborn tissues. Competition binding studies revealed that of the PGE2 receptors in the adult choroid, approximately 55% were of the EP1 subtype, 8% were EP2, 22% were EP3, and 15% were EP4. Newborn choroid contained approximately 33% each of EP1 and EP2 receptors, 20% of EP3, and 15% of EP4. Inhibition of endogenous prostaglandin synthesis for 48 hours with ibuprofen in newborns to attain levels found in the adult resulted in an upregulation of [3H]PGE2 binding, EP1- and EP3-mediated vasoconstriction, and increases and decreases in IP3 and cAMP production, respectively, in newborn tissues compared with adult tissues. On the other hand, ibuprofen treatment of newborns led to a decrease in PGE2- and EP4-mediated vasorelaxation and nitrite synthesis (associated with decreased expression of endothelial NO synthase) to levels observed in adults: EP2-elicited responses in newborns were not affected by ibuprofen. In conclusion, fewer EP1 receptors (associated with vasoconstriction), more EP2 receptors, and greater EP4-coupled NO production (coupled to vasorelaxation) seem to be responsible for the increased vasodilation to PGE2 in the newborn. The decrease in prostaglandin levels with age appears to cause, on one hand, upregulation of EP1 and EP3 receptors and receptor-coupled vasoconstriction and, on the other hand, decreased EP4-coupled NO synthesis and choroidal vasodilation. Altogether, these factors result in increased vasorelaxation to PGE2 in the newborn compared with the adult. These findings may help to explain the inability of the newborn to autoregulate choroidal blood flow.