RESUMEN
BACKGROUND AND PURPOSE: We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion. EXPERIMENTAL APPROACH: Caco-2 cells were grown on cell culture inserts to confluence. Trans-epithelial electrical resistance (TEER) was used to measure permeability. To generate hypoxia (0% O2), a GasPak™ EZ anaerobe pouch system was used. Endocannabinoids were applied to the apical or basolateral membrane in the presence or absence of receptor antagonists. KEY RESULTS: Complete hypoxia decreased TEER (increased permeability) by ~35% after 4â¯h (recoverable) and ~50% after 6â¯h (non-recoverable). When applied either pre- or post-hypoxia, apical application of N-arachidonoyl-dopamine (NADA, via TRPV1), oleamide (OA, via TRPV1) and oleoylethanolamine (OEA, via TRPV1) inhibited the increase in permeability. Apical administration of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) worsened the permeability effect of hypoxia (both via CB1). Basolateral application of NADA (via TRPV1), OA (via CB1 and TRPV1), noladin ether (NE, via PPARα), and palmitoylethanolamine (PEA, via PPARα) restored permeability after 4â¯h hypoxia, whereas OEA increased permeability (via PPARα). After 6â¯h hypoxia, where permeability does not recover, only basolateral application PEA sustainably decreased permeability, and NE decreased permeability. CONCLUSIONS AND IMPLICATIONS: A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB1 antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.
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Permeabilidad de la Membrana Celular/efectos de los fármacos , Endocannabinoides/metabolismo , PPAR alfa/metabolismo , Receptor Cannabinoide CB1/metabolismo , Canales Catiónicos TRPV/metabolismo , Células CACO-2 , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Permeabilidad de la Membrana Celular/fisiología , Endocannabinoides/farmacología , Humanos , Receptor Cannabinoide CB1/agonistas , Migración Transendotelial y Transepitelial/efectos de los fármacos , Migración Transendotelial y Transepitelial/fisiologíaRESUMEN
AIMS: Cannabidiol (CBD) is a cannabis-derived medicinal product with potential application in a wide-variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts. METHODS: Publications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov. RESULTS: A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty-three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on reducing seizure frequency or severity (average 15 mg/kg/d within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n = 6-62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/kg/d) were used in these studies. CONCLUSION: This review highlights that CBD has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.
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Cannabidiol/administración & dosificación , Ansiedad/sangre , Ansiedad/diagnóstico , Ansiedad/tratamiento farmacológico , Cannabidiol/farmacocinética , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Humanos , Trastornos Psicóticos/sangre , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Convulsiones/sangre , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Injury to the bronchial epithelium in respiratory diseases such as asthma and COPD results in the loss of barrier function and an elevated sensitivity to environmental insults. An increased release of the endogenous cannabinoid, anandamide in response to inhalation of allergen in asthmatic patients has been reported. The aim of this study was, therefore, to determine the effects of endocannabinoids on bronchial epithelial cell permeability and to investigate the mechanisms involved. Calu-3 human bronchial epithelial cells were cultured at air-liquid interface to allow development of tight junctions. Changes in Transepithelial Electrical Resistance (TEER), a reflection of epithelial permeability, were measured at various time points post-treatment, and expression of the tight junction proteins, occludin and ZO-1, were determined using Western immunoblotting. Anandamide produced a significant reduction in TEER, which was unaffected by cannabinoid receptor antagonists, but attenuated by URB597, an inhibitor of fatty acid amide hydrolase, and by a combination of cyclooxygenase (COX) and lipoxygenase (LOX) blockade. The anandamide metabolite, arachidonic acid, showed similar TEER decrease that was also prevented in the presence of COX and LOX inhibitor. Expression of occludin and ZO-1 were also reduced by anandamide. These findings indicate a pro-inflammatory-like effect of anandamide on bronchial epithelial permeability, mediated by cyclooxygenase and lipoxygenase metabolites, and suggest that inhibition of anandamide degradation might provide a novel approach to treat airway inflammation.
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Ácidos Araquidónicos/metabolismo , Bronquios/metabolismo , Endocannabinoides/metabolismo , Células Epiteliales/metabolismo , Permeabilidad , Alcamidas Poliinsaturadas/metabolismo , Mucosa Respiratoria/metabolismo , Bronquios/citología , Línea Celular , Humanos , Inflamación/metabolismo , Ocludina/metabolismo , Transducción de Señal , Uniones Estrechas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Juvenile angiofibromas are hypervascular tumors that may benefit from preoperative devascularization to reduce intraoperative blood loss. Our purpose was to evaluate the extent of angiographic devascularization and intraoperative blood loss by using only Onyx for percutaneous juvenile angiofibroma tumor embolization. MATERIALS AND METHODS: We reviewed the clinical records and preoperative and postoperative imaging studies of a consecutive series of 9 patients with juvenile angiofibromas who were treated with preoperative embolization with direct percutaneous injection of Onyx followed by resection from a standard open surgical or endoscopic approach. RESULTS: Two Fisch type I, 1 Fisch type II, 5 Fisch type IIIa, and 1 Fisch type IVa tumor were treated. Complete devascularization was achieved in all cases percutaneously with only Onyx. There were no complications. The average intraoperative blood loss was 567.7 mL (range, 10-1700 mL). An average of 2.2 needles (range, 1-5 needles) was placed into the tumor. An average of 14.6 mL of Onyx (range, 2-25 mL) was injected into each tumor. Four Fisch type IIIa tumors were removed completely from only an ENE approach. CONCLUSIONS: Presurgical direct percutaneous embolization of a juvenile angiofibroma with only EVOH before surgical resection is safe and feasible. Our preliminary experience suggests that Onyx may offer a higher degree of devascularization compared with other embolic agents. This may facilitate an easier surgical resection with lower blood loss.
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Angiofibroma/diagnóstico por imagen , Angiofibroma/terapia , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Dimetilsulfóxido/uso terapéutico , Embolización Terapéutica/métodos , Polivinilos/uso terapéutico , Procedimientos Quirúrgicos Vasculares/métodos , Adolescente , Niño , Preescolar , Femenino , Hemostáticos/uso terapéutico , Humanos , Lactante , Masculino , Proyectos Piloto , Cuidados Preoperatorios/métodos , Radiografía , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro. EXPERIMENTAL APPROACH: Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids. KEY RESULTS: Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation. CONCLUSIONS AND IMPLICATIONS: These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
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Cannabinoides/farmacología , Mucosa Intestinal/metabolismo , Permeabilidad/efectos de los fármacos , Amidohidrolasas/antagonistas & inhibidores , Benzamidas/farmacología , Benzodioxoles/farmacología , Células CACO-2 , Carbamatos/farmacología , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Indoles/farmacología , Inflamación/metabolismo , Interferón gamma/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion, and intestinal motility. However, the effects of cannabinoids on intestinal permeability have not yet been established. The aim of the present study is to examine the effects of cannabinoids on intestinal permeability in an in vitro model. Caco-2 cells were grown until fully confluent on inserts in 12-well plates. Transepithelial electrical resistance (TEER) measurements were made as a measure of permeability. EDTA (50 µM) was applied to reversibly increase permeability (reduce TEER). The effects of cannabinoids on permeability in combination with EDTA, or alone, were assessed. Potential target sites of action were investigated using antagonists of the cannabinoid (CB)(1) receptor, CB(2) receptor, transient receptor potential vanilloid subtype 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)γ, PPARα, and a proposed cannabinoid receptor. When applied to the apical or basolateral membrane of Caco-2 cells, Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) enhanced the speed of recovery of EDTA-induced increased permeability. This effect was sensitive to cannabinoid CB(1) receptor antagonism only. Apical application of endocannabinoids caused increased permeability, sensitive to cannabinoid CB(1) receptor antagonism. By contrast, when endocannabinoids were applied basolaterally, they enhanced the recovery of EDTA-induced increased permeability, and this involved additional activation of TRPV1. All cannabinoids tested increased the mRNA of the tight junction protein zona occludens-1, but only endocannabinoids also decreased the mRNA of claudin-1. These findings suggest that endocannabinoids may play a role in modulating intestinal permeability and that plant-derived cannabinoids, such as THC and CBD, may have therapeutic potential in conditions associated with abnormally permeable intestinal epithelium.
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Cannabinoides/farmacología , Absorción Intestinal/efectos de los fármacos , Algoritmos , Transporte Biológico Activo , Células CACO-2 , Cannabidiol/farmacología , Dronabinol/farmacología , Impedancia Eléctrica , Electrofisiología , Enterocitos/efectos de los fármacos , Enterocitos/ultraestructura , Humanos , Microvellosidades/efectos de los fármacos , PPAR alfa/efectos de los fármacos , PPAR gamma/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Cannabinoides/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacos , Uniones Estrechas/efectos de los fármacosRESUMEN
Cannabinoids act via cell surface G protein-coupled receptors (CB(1) and CB(2)) and the ion channel receptor TRPV1. Evidence has now emerged suggesting that an additional target is the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. There are three PPAR subtypes alpha, delta (also known as beta) and gamma, which regulate cell differentiation, metabolism and immune function. The major endocannabinoids, anandamide and 2-arachidonoylglycerol, and ajulemic acid, a structural analogue of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), have anti-inflammatory properties mediated by PPARgamma. Other cannabinoids which activate PPARgamma include N-arachidonoyl-dopamine, THC, cannabidiol, HU210, WIN55212-2 and CP55940. The endogenous acylethanolamines, oleoylethanolamide and palmitoylethanolamide regulate feeding and body weight, stimulate fat utilization and have neuroprotective effects mediated through PPARalpha. Other endocannabinoids that activate PPARalpha include anandamide, virodhamine and noladin ether. There is, as yet, little direct evidence for interactions of cannabinoids with PPARdelta. There is a convergence of effects of cannabinoids, acting via cell surface and nuclear receptors, on immune cell function which provides promise for the targeted therapy of a variety of immune, particularly neuroinflammatory, diseases.
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Moduladores de Receptores de Cannabinoides/metabolismo , Cannabinoides/metabolismo , Inflamación/metabolismo , Neuroinmunomodulación/inmunología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Animales , Moduladores de Receptores de Cannabinoides/inmunología , Cannabinoides/inmunología , Humanos , Inflamación/inmunología , Receptores Activados del Proliferador del Peroxisoma/inmunologíaRESUMEN
BACKGROUND AND PURPOSE: Few reports have described the embolization of head and neck lesions by using direct percutaneous techniques. We report our preliminary experience in the direct percutaneous embolization of hypervascular head and neck tumors by using Onyx in conjunction with standard endovascular embolization techniques. We describe the technical aspects of the procedure and its efficacy in reducing intraoperative blood loss. MATERIALS AND METHODS: We retrospectively studied 14 patients (3 females and 11 males; mean age, 33.4 years; range, 11-56 years) with 15 hypervascular tumors of the head and neck that underwent direct percutaneous embolization with Onyx in conjunction with particulate embolization. Nine paragangliomas and 6 JNAs underwent treatment. Documented blood loss was obtained from operative reports in these 15 patients with surgical resection performed 24-48 hours after the embolization. RESULTS: Intratumoral penetration with progressive blood flow stasis was achieved during each injection. A mean of 3.1 needles (20-gauge, 3.5-inch spinal needle) were placed percutaneously into the lesion (range, 1-6). The mean intraoperative blood loss was 780 mL (range, <50-2200 mL). Near total angiographic devascularization was achieved in 13 of 15 tumors. There were no local complications or neurologic deficits from the percutaneous access or embolization of these hypervascular tumors. CONCLUSIONS: In this study, the use of percutaneous injected Onyx in conjunction with standard endovascular embolization techniques in patients with hypervascular head and neck tumors seemed to enhance the ability to devascularize these tumors before operative removal.
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Embolización Terapéutica/métodos , Neoplasias de Cabeza y Cuello/terapia , Polivinilos/administración & dosificación , Adolescente , Adulto , Anciano , Niño , Terapia Combinada , Femenino , Hemostáticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Cuidados Preoperatorios , Estudios Retrospectivos , Estadística como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter-gated channel transient receptor potential vanilloid type-1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator-activated receptors (PPARs, with three subtypes alpha, beta (delta) and gamma), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPAR alpha. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPAR alpha. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti-inflammatory properties mediated by PPAR alpha. Other endocannabinoids that activate PPAR alpha include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPAR gamma; anandamide and 2-arachidonoylglycerol have anti-inflammatory properties mediated by PPAR gamma. Similarly, ajulemic acid, a structural analogue of a metabolite of Delta(9)-tetrahydrocannabinol (THC), causes anti-inflammatory effects in vivo through PPAR gamma. THC also activates PPAR gamma, leading to a time-dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPAR gamma include N-arachidonoyl-dopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPAR delta. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro- and cardioprotective benefits as other PPAR alpha and PPAR gamma agonists? This review will summarize the published literature implicating cannabinoid-mediated PPAR effects and discuss the implications thereof.
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Cannabinoides/farmacología , Receptores Activados del Proliferador del Peroxisoma/agonistas , Animales , Cannabinoides/química , Cannabinoides/metabolismo , Humanos , Ligandos , Modelos Biológicos , Estructura Molecular , Receptores Activados del Proliferador del Peroxisoma/metabolismoRESUMEN
The important role of nitric oxide (NO) in the regulation of vascular tone has been well studied. By contrast, the vascular significance of another gaseous mediator, hydrogen sulphide (H2S), is still poorly understood. A study published in this issue of the British Journal of Pharmacology now provides evidence that in addition to the vasorelaxant effects of H2S reported in vitro, low concentrations of H2S also cause arterial vasoconstriction, reverse NO-mediated vasorelaxation and cause an NO-dependent pressor effect in vivo. This commentary discusses the implications and questions raised by these results.
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Vasos Sanguíneos/metabolismo , Sulfuro de Hidrógeno/metabolismo , Animales , Vasos Sanguíneos/fisiología , Humanos , VasoconstricciónRESUMEN
This study investigated the effects of fitness and of acute exercise on a range of markers of endothelial function in young, healthy adult male subjects who were classified on the basis of maximum oxygen consumptions as being fit VO(2 peak) 71 +/- 2 [ml x min (-1)] x kg (-1) or sedentary VO(2 peak) 53 +/- 2 [ml x min (-1)] x kg (-1). Fit and sedentary subjects had similar resting plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM). Acute maximal aerobic exercise doubled plasma vWF in fit subjects but had no effect in the sedentary population; plasma TM rose with acute exercise in each group but to a greater extent in the fit population. Fit subjects also had higher numbers of circulating endothelial cells (CECs) at rest and exhibited substantially greater forearm reactive hyperaemia responses following a standardized period of arterial occlusion. A cohort of sedentary subjects was given a 5-week training programme of moderate aerobic exercise on a cycle ergometer. Following this, absolute fitness was increased by only 8 % but reactive hyperaemia responses rose to values similar to those in the chronically fit group. The results suggest that both acute and chronic exercise increase endothelial turnover. Chronic exercise is also associated with enhanced endothelium-dependent dilator function and this effect becomes maximal after only a short period of moderate training.
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Endotelio Vascular/fisiología , Ejercicio Físico/fisiología , Trombomodulina/sangre , Factor de von Willebrand/análisis , Adulto , Biomarcadores/sangre , Estudios Transversales , Células Endoteliales/fisiología , Humanos , Hiperemia , Estudios Longitudinales , Masculino , Aptitud Física/fisiología , Flujo Sanguíneo RegionalRESUMEN
BACKGROUND: Therapeutic cerebral angiogenesis, utilizing angiogenic factors to enhance collateral vessel formation within the central nervous system, is a potential method for cerebral revascularization. A prior dose-response study determined that intracerebroventricular infusion of vascular endothelial growth factor (VEGF) increases vascular density with minimal associated brain edema at a concentration of 5 microg/ml. The purpose of this study was to assess effects of intracerebroventricular infusion of VEGF (5 microg/ml) on cerebral blood flow, infarct volume, and brain edema after ischemia. METHODS: Recombinant human VEGF(165) was infused into the right lateral ventricle of rats with an osmotic minipump at a rate of 1 microl/hr for 7 days. Control animals received vehicle only. Ischemia was produced by transient (2 hours) middle cerebral artery occlusion (MCAO). After MCAO, cerebral blood flow was determined with the indicator fractionation technique: infarct volume was assessed with 2,3,5-triphenlytetrazolium chloride staining, and brain edema was determined by measuring brain water content. FINDINGS: Cerebral blood flow was not significantly different in animals treated with VEGF compared to controls. There was a significant reduction in total infarct volume after temporary MCAO in VEGF-treated animals compared to controls (163+/-37 mm(3) vs. 309+/-54 mm(3), P<0.05). Brain water content after transient MCAO was also significantly reduced in VEGF-treated animals compared to controls (80.9+/-0.7% vs. 83.3+/-0.6%, P<0.05). INTERPRETATION: Intracerebroventricular infusion of VEGF(165) (5 microg/ml) decreases infarct volume and brain edema after temporary MCAO without a significant increase in cerebral blood flow. These results indicate that VEGF may have a direct neuroprotective effect in cerebral ischemia.
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Edema Encefálico/etiología , Edema Encefálico/prevención & control , Infarto Encefálico/etiología , Infarto Encefálico/prevención & control , Circulación Cerebrovascular/efectos de los fármacos , Factores de Crecimiento Endotelial/farmacología , Factores de Crecimiento Endotelial/uso terapéutico , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Linfocinas/farmacología , Linfocinas/uso terapéutico , Animales , Edema Encefálico/fisiopatología , Infarto Encefálico/fisiopatología , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Factores de Crecimiento Endotelial/administración & dosificación , Humanos , Infarto de la Arteria Cerebral Media/fisiopatología , Infusiones Parenterales , Inyecciones Intraventriculares , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Linfocinas/administración & dosificación , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Training attenuates the sympathetic pressor response to dynamic exercise. However, it is uncertain how training alters other patterns of cardiovascular autonomic activation. Therefore, we have quantified circulatory responses to a series of standard autonomic tests in highly fit and unfit subjects and examined the effects of a short-term training programme on these responses. Subjects were defined as either unfit (n = 8) or fit (n = 8) on the basis of training history and a maximal fitness test (VO2peak 54 +/- 2.3 cf. 68 +/- 2.8 (ml min(-1)) kg(-1), means + S.E.M., P < 0.05). On a separate day, the blood pressure, heart rate and forearm vascular conductance responses to a sustained handgrip to fatigue, 2 min mental arithmetic and 2 min of cold exposure were measured. All stimuli were associated with elevated blood pressures and heart rates, but these responses were significantly attenuated in the trained group. In the untrained subjects, forearm vascular conductance increased during exercise (from 0.032 +/- 0.004 to 0.05 +/- 0.007 (ml min(-1)) 100 ml(-1) mm Hg(-1), P < 0.05) and during mental arithmetic (from 0.028 +/- 0.003 to 0.04 +/- 0.006 (ml min(-1)) 100 ml(-1) mm Hg(-1) , p < 0.05), but trained subjects showed no rise in conductance during either test. All untrained subjects undertook a moderate intensity 5-week training programme, which significantly increased VO2peak (54 +/- 2.3 to 57 +/- 2 (ml min(-1)) kg(-1), p < 0.05). Qualitatively similar blunting of pressor, tachycardic and vasodilator responses were seen in this group post-training. These results demonstrate that the blunting of sympathetic vasomotor activation that follows training is not restricted to reflexes associated with exercise, and does not depend on training being prolonged or intense.
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Presión Sanguínea/fisiología , Ejercicio Físico/fisiología , Frecuencia Cardíaca/fisiología , Sistema Nervioso Simpático/fisiología , Adulto , Nivel de Alerta/fisiología , Cognición/fisiología , Frío , Fuerza de la Mano/fisiología , Humanos , Masculino , Músculo Esquelético/irrigación sanguínea , Flujo Sanguíneo Regional/fisiología , Estrés Psicológico/fisiopatología , Vasodilatación/fisiologíaRESUMEN
Although common in the neonatal intensive care unit, eosinophilia is often overlooked or ignored. The latter might be, at least in part, because evaluating the neonate with eosinophilia can be a complex process. This article reviews the physiologic features of eosinophilia, reference ranges, and clinical conditions associated with eosinophilia in the neonate. Recommendations for the evaluation of the neonate with eosinophilia are presented.
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Eosinofilia/diagnóstico , Eosinofilia/fisiopatología , Unidades de Cuidados Intensivos , Eosinofilia/etiología , Eosinofilia/patología , Eosinofilia/terapia , Eosinófilos/patología , Humanos , Recién Nacido , Valores de ReferenciaAsunto(s)
Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/terapia , Hematología/métodos , Neonatología/métodos , Transfusión de Eritrocitos , Eritropoyetina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Granulocitos/trasplante , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Transfusión de Plaquetas , Medicina Preventiva/métodos , Proteínas Recombinantes/uso terapéuticoRESUMEN
During physical activity, there is a graded withdrawal of vagal cardiac tone and a graded increase in sympathetic cardiac and vasomotor tone, initiated through both central command from the somatic motor cortex and muscle chemoreceptive and mechanoreceptive inputs. In parallel, there is an upward resetting of the operating point of the arterial baroreflex, with preserved reflex sensitivity. In contrast to the traditional interpretation that blood flow through exercising muscle is independent of vasomotor neural influences because of the dominance of local dilator metabolites, recent evidence suggests that both constrictor and dilator sympathetic neural influences may be involved in determining absolute levels of perfusion. Post-exercise, there is a period of relative hypotension that is associated with decreased peripheral resistance. Some, but not all, evidence indicates a causal role for reduced sympathetic drive. Chronic exercise training appears to reduce resting sympathetic activity, with parallel changes in the gain of a variety of cardiovascular autonomic reflexes initiated from cardiovascular sites. These changes may be attributable at least partly to masking of arterial baroreflexes by the impact of elevated blood volume on low-pressure baroreceptors. The reductions in sympathetic drive that follow training are more pronounced in patients with essential hypertension than in normotensive individuals and are likely to underlie the anti-hypertensive effect of exercise.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Ejercicio Físico/fisiología , Aptitud Física/fisiología , Reflejo/fisiología , Presión Sanguínea/fisiología , Humanos , Hipertensión/fisiopatología , Sistema Nervioso Simpático/fisiología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
OBJECTIVE: Eosinophilia is common among premature neonates, but little is known about the cytokines responsible for influencing its onset in neonates. In adults and transgenic mice, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) influence the development of eosinophilia. We sought to prospectively determine whether these cytokines correlated with the development of eosinophilia in premature infants. STUDY DESIGN: We measured the absolute eosinophil count (AEC) and serial serum concentrations of GM-CSF and IL-5 in premature neonates with eosinophilia. RESULTS: Among 201 premature neonates, 21 had an eosinophil count of > 700/microliter (occurrence, 10.5%). Of these 21 neonates, 4 had mild (700/microliter to 999/microliter), 13 had moderate (1000/microliter to 2999/microliter), and 4 had severe (> 3000/microliter) eosinophilia. No differences in gestational age or age at onset of eosinophilia were observed between the groups, but the duration of eosinophilia was less with mild than with moderate or severe eosinophilia. A total of 20 of the 21 patients had an infection or necrotizing enterocolitis diagnosed within 48 hours of the onset of eosinophilia. In patients with mild and moderate eosinophilia, serial GM-CSF and IL-5 concentrations were below the lowest enzyme-linked immunosorbent assay standard. There was no correlation between AEC and GM-CSF or IL-5 concentration in these infants. However, in one patient with severe eosinophilia, two distinct elevations in IL-5 were noted (34.6 and 46.0 pg/ml); each peak occurred 7 to 8 days before a peak in eosinophil count. CONCLUSION: Eosinophilia is relatively common, and in those neonates with the highest AECs, the duration of eosinophilia can last for > 6 weeks. The majority of cases of eosinophilia occurred in temporal proximity to an infectious illness or necrotizing enterocolitis. Serum concentrations of IL-5 were elevated in only one of our patients with severe eosinophilia.
Asunto(s)
Eosinofilia/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Enfermedades del Prematuro/sangre , Recien Nacido Prematuro/sangre , Interleucina-5/sangre , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/patología , Humanos , Recién Nacido , Recuento de Leucocitos , Pronóstico , Estudios ProspectivosRESUMEN
In previous studies, we demonstrated that the neuropeptide, N-acetylaspartylglutamate (NAAG), meets the traditional criteria for a neurotransmitter and selectively activates metabotropic glutamate receptor mGluR2 or mGluR3 in cultured cerebellar granule cells and glia. Sequence homology and pharmacological data suggest that these two receptors are highly related structurally and functionally. To define more rigorously the receptor specificity of NAAG, cloned rat cDNAs for mGluR1-6 were transiently or stably transfected into Chinese hamster ovary cells and human embryonic kidney cells and assayed for their second messenger responses to the two endogenous neurotransmitters, glutamate and NAAG, as well as to metabotropic receptor agonists, trans-1-aminocyclopentane-1,3-dicarboxylate (trans-ACPD) and L-2-amino-4-phosphonobutyrate (L-AP4). Despite the high degree of relatedness of mGluR2 and mGluR3, NAAG selectively activated the mGluR3 receptor. NAAG activated neither mGluR2 nor mGluR1, mGluR4, mGluR5, or mGluR6. The mGluR agonist, trans-ACPD, activated each of the transfected receptors, whereas L-AP4 activated mGluR4 and mGluR6, consistent with the published selectivity of these agonists. Hybrid cDNA constructs of the extracellular domains of mGluR2 and mGluR3 were independently fused with the transmembrane and cytoplasmic domain of mGluR1a. This latter receptor domain is coupled to phosphoinositol turnover, and its activation increases intracellular calcium. The cells transfected with these chimeric receptors responded to activation by glutamate and trans-ACPD with increases in intracellular calcium. NAAG activated the chimeric receptor that contained the extracellular domain of mGluR3 and did not activate the mGluR2 chimera.