RESUMEN
BACKGROUND AND OBJECTIVE: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitors (ACEI-AAE) are types of bradykinin-mediated angioedema without wheals characterized by recurrent swelling episodes. Recent evidence suggests that a state of "vascular preconditioning" predisposes individuals to attacks, although no data are available on possible structural alterations of the vessels. Objective: This study aims to compare the features of nailfold capillaries to highlight possible structural anomalies between patients affected by C1-INH-HAE and controls and between patients with ACEI-AAE and hypertensive controls. METHODS: We used nailfold videocapillaroscopy (NVC) to assess the following: apical, internal, and external diameter; loop length; intercapillary distance; and capillary density, distribution, and morphology. Plasma levels of vascular endothelial growth factor (VEGF) A, VEGF-C, angiopoietin (Ang) 1, and Ang2 were also measured. RESULTS: Compared with healthy controls (n=28), C1-INH-HAE patients (n = 34) were characterized by significant structural alterations of the capillaries, such as greater intercapillary distance (216 vs 190 µm), increased apical, internal, and external diameter (28 vs 22 µm; 22 vs 20 µm; and 81 vs 65 µm, respectively), decreased density (4 vs 5 capillaries/mm2), more irregular capillary distribution, and more tortuous morphology. Apical diameter was enlarged in patients with ≥12 attacks per year. In ACEI-AAE patients, NVC showed no alterations with respect to hypertensive controls. NVC performed in 2 C1-INH-HAE patients during attacks showed no changes compared with the remission phase. CONCLUSIONS: We detected major structural capillary alterations in C1-INH-HAE patients, thus confirming the involvement of microcirculation in the pathogenesis of angioedema.
Asunto(s)
Angioedema , Angioedemas Hereditarios , Bradiquinina , Proteína Inhibidora del Complemento C1 , Humanos , Angioscopía Microscópica , Factor A de Crecimiento Endotelial VascularRESUMEN
BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. METHODS: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. RESULTS: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. CONCLUSIONS: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.
Asunto(s)
Angioedema/inmunología , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antígenos de Plaqueta Humana/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Factor C de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Cambio de Tratamiento , Regulación hacia ArribaAsunto(s)
Angioedemas Hereditarios , Bradiquinina , Proteína Inhibidora del Complemento C1 , Humanos , PlasmaRESUMEN
The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine adrenergic system that controls cytokine release through locally synthetized noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the mRNA and at the protein level. To evaluate whether α2 adrenoreceptors controlled cytokine release from HMLs, we measured IL-6, IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists clonidine, medetomidine or dexdemetomidine or with the α2-adrenergic antagonist yohimbine caused significant changes in the response of any of these cytokines to LPS. These results show that, different from what reported in rodents, clonidine and dexdemetomidine do not directly suppress cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients.
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Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/inmunología , Autoanticuerpos/sangre , Anciano de 80 o más Años , Angioedemas Hereditarios/sangre , Angioedemas Hereditarios/patología , Proteínas Inactivadoras del Complemento 1/genética , Proteínas Inactivadoras del Complemento 1/inmunología , Proteína Inhibidora del Complemento C1 , Femenino , Expresión Génica , HumanosRESUMEN
The search for a degradable metal simultaneously showing mechanical properties equal or higher to that of stainless steel and uniform degradation is still an open challenge. Several magnesium-based alloys have been studied, but their degradation rate has proved to be too fast and rarely homogeneous. Fe-based alloys show appropriate mechanical properties but very low degradation rate. In the present work, four novel Zn-Mg and two Zn-Al binary alloys were investigated as potential biodegradable materials for stent applications. The alloys were developed by casting process and homogenized at 350°C for 48h followed by hot extrusion at 250°C. Tube extrusion was performed at 300°C to produce tubes with outer/inner diameter of 4/1.5mm as precursors for biodegradable stents. Corrosion tests were performed using Hanks׳ modified solution. Extruded alloys exhibited slightly superior corrosion resistance and slower degradation rate than those of their cast counterparts, but all had corrosion rates roughly half that of a standard purity Mg control. Hot extrusion of Zn-Mg alloys shifted the corrosion regime from localized pitting to more uniform erosion, mainly due to the refinement of second phase particles. Zn-0.5Mg is the most promising material for stent applications with a good combination of strength, ductility, strain hardening exponent and an appropriate rate of loss of mechanical integrity during degradation. An EBSD analysis in the vicinity of the laser cut Zn-0.5Mg tube found no grain coarsening or texture modification confirming that, after laser cutting, the grain size and texture orientation of the final stent remains unchanged. This work shows the potential for Zn alloys to be considered for stent applications.
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Implantes Absorbibles , Materiales Biocompatibles/química , Diseño de Prótesis , Stents , Zinc , Aleaciones , Corrosión , Magnesio , Ensayo de MaterialesRESUMEN
BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited genetic disease characterized by recurrent swelling episodes of the skin, gastrointestinal tract, and upper airways. Angioedema attacks result from increased vascular permeability due to the release of bradykinin from high molecular weight kininogen. Currently, there are no biomarkers predicting the frequency of angioedema attacks. Vascular permeability is modulated by several factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (Angs). As increased circulating levels of VEGFs and Angs have been observed in diseases associated with higher vascular permeability (e.g., systemic capillary leak syndrome and sepsis), we sought to analyze plasma concentrations of VEGFs and Angs in patients with C1-INH-HAE. METHODS: Sixty-eight healthy controls and 128 patients with C1-INH-HAE were studied. Concentrations of angiogenic (VEGF-A, Ang1, Ang2), anti-angiogenic (VEGF-A165b ) and lymphangiogenic (VEGF-C) factors were evaluated by ELISA. C1-INH functional activity was assessed by EIA. RESULTS: Plasma concentrations of VEGF-A, VEGF-C, Ang1, and Ang2 were higher in patients with C1-INH-HAE in remission than in healthy controls. Concentration of VEGF-A was further increased in patients with lower C1-INH functional activity. Patients with C1-INH-HAE experiencing more than 12 angioedema attacks per year were characterized by higher plasma levels of VEGF-A, VEGF-C, and Ang2 compared with the other patients. CONCLUSIONS: We hypothesize that VEGFs and Angs induce a state of 'vascular preconditioning' that may predispose to angioedema attacks. In addition, the identification of increased plasma levels of VEGFs and Angs in patients with C1-INH-HAE may prompt the investigation of VEGFs and Angs as biomarkers of C1-INH-HAE severity.
Asunto(s)
Angioedema Hereditario Tipos I y II/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Angioedema Hereditario Tipos I y II/diagnóstico , Angioedema Hereditario Tipos I y II/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factor C de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
BACKGROUND: Mastocytosis is characterized by clonal proliferation of mast cells limited to the skin (cutaneous mastocytosis: CM and mastocytosis in the skin: MIS) and/or involving internal organs (systemic mastocytosis: SM). Oxidative stress occurring in various inflammatory and neoplastic disorders causes molecular damage with the production of advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs). We evaluated these markers of oxidative stress in patients with CM/MIS and SM and correlated their levels with the presence of symptoms related to mast cell activation. METHODS: Serum levels of AOPPs and AGEs in 34 patients with mastocytosis (23 CM/MIS and 11 SM) and 27 healthy controls were measured by spectrofluorimetric and spectrophotometric methods. Serum tryptase levels were measured by immunofluorescence. RESULTS: Serum AOPPs, but not AGEs, were significantly higher in patients with mastocytosis as compared to healthy controls. While serum tryptase levels were higher in patients with SM as compared to those with CM/MIS, there was no difference in AOPP and AGE concentrations between these two groups of patients. Patients with recurrent mediator-related symptoms had lower AOPPs and AGEs as compared to patients without symptoms. AOPPs and AGEs were inversely correlated with the severity of symptoms, and in patients with symptoms, AOPPs correlated with tryptase levels. DISCUSSION: Our data show that mastocytosis is associated with a state of increased oxidative stress that, in patients with mediator-related symptoms, correlates with mast cell burden as assessed by tryptase. Patients with symptoms presumably have an adaptive response resulting in lower blood levels of AOPPs and AGEs.
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Mastocitosis/sangre , Mastocitosis/diagnóstico , Estrés Oxidativo , Adolescente , Adulto , Productos Avanzados de Oxidación de Proteínas/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Productos Finales de Glicación Avanzada/sangre , Humanos , Lactante , Masculino , Mastocitos/metabolismo , Persona de Mediana Edad , Triptasas/sangre , Adulto JovenRESUMEN
Benzene and its metabolites have been involved in the pathogenesis of chronic lung inflammation and allergic disorders such as bronchial asthma. However, the effects of these xenobiotics on human basophils, key cells in the development of respiratory allergy, have not been investigated. We examined the effects of hydroquinone (HQ) and benzoquinone (BQ), two important chemicals implicated in benzene toxicity, on the release of preformed (histamine) and de novo synthesized mediators (cysteinyl leukotriene C4, LTC4, and IL-4) from human basophils. Preincubation of basophils purified from normal donors with HQ (3-100 microM) inhibited up to 30% histamine release induced by anti-IgE and up to 55% of that induced by the Ca2+ ionophore A23187. HQ had no effect on histamine release induced by formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Preincubation of basophils with BQ (3-100 microM) resulted in the concentration-dependent inhibition of histamine release (up to 70%) induced by anti-IgE, A23187 and f-Met-Leu-Phe. HQ completely suppressed the de novo synthesis of LTC4 from basophils challenged with anti-IgE or f-Met-Leu-Phe and the production of IL-4 in cells stimulated with anti-IgE. These results indicate that two major benzene metabolites, HQ and BQ, inhibit the release of proinflammatory mediators and Th2-promoting cytokines from basophils activated by different stimuli. These results suggest that benzene metabolites interfere with multiple intracellular signals involved in the activation of human basophils.
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Basófilos/metabolismo , Derivados del Benceno/farmacología , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Basófilos/efectos de los fármacos , Basófilos/inmunología , Benzoquinonas/farmacología , Calcimicina/farmacología , Liberación de Histamina/efectos de los fármacos , Humanos , Hidroquinonas/farmacología , Inmunoglobulina E/inmunología , Indicadores y Reactivos , Interleucina-4/biosíntesis , Cinética , Leucotrieno C4/biosíntesis , N-Formilmetionina Leucil-Fenilalanina/farmacologíaRESUMEN
Psoriasis and psoriatic arthritis are chronic inflammatory disorders resulting from a combination of genetic and environmental factors, though the precise causal agents have not yet been identified. The immune system has a major role in their development and the possibility exists that self antigens or antigens from microbial agents, or microbial superantigens initiate a vigorous immune response. Different subsets of T-lymphocytes and dendritic cells, mast cells and granulocytes participate in the pathogenesis and several cytokines and chemokines have been identified in tissue lesions. TNF-alpha is a key proinflammatory cytokine with important pathogenetic role in psoriasis and psoriatic arthritis. Evidence from clinical trials targeting the TNF-alpha-TNF-alpha-receptor supports a central role for this cytokine in the pathogenesis of psoriasis and psoriatic arthritis. Angiogenesis is a prominent early event in lesional psoriatic skin and in synovial membrane psoriatic arthritis. Future potential targets in the treatment of these disorders include biologic agents aimed at blockade of other cytokines, chemokines and angiogenic factors.
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Biomarcadores/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Artritis Psoriásica/inmunología , Quimiocinas/inmunología , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Células Dendríticas/inmunología , Humanos , Mastocitos/inmunología , Neutrófilos/inmunología , Psoriasis/patología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Left caloric vestibular stimulation (CVS) transiently reduces impairments of right-brain-damaged patients with left unilateral neglect, including left hemianesthesia, contralateral to the side of the lesion (contralesional). Conversely, no effect on right contralesional hemianesthesia in left-brain-damaged patients is seen with right CVS. This discrepancy is unexplained. METHODS: The authors explored the effect of CVS on right- and left-brain-damaged patients with hemianesthesia. One left-brain-damaged patient had an fMRI study during tactile stimulation before and after left CVS. The same fMRI touch study, without CVS, was performed in neurologically unimpaired subjects. RESULTS: A transient remission of right hemianesthesia associated with left brain damage was observed, provided that cold CVS was administered to the left ear. In the left-brain-damaged patient studied with fMRI, left CVS modulated the neural response to right hand tactile stimuli of a portion of the secondary somatosensory area (SII) of the right hemisphere. In neurologically unimpaired subjects, fMRI scans showed that the same part of area SII in the right hemisphere was activated by ipsilateral right-sided touches and to a larger extent than area SII in the left hemisphere by left-sided touches. CONCLUSIONS: Left caloric vestibular stimulation is effective on both left and right hemianesthesia because it modulates the hemisphere that has a more complete representation of, or is capable to attend to, the whole somatosensory surface of the body. These results suggest a hardwired hemispheric asymmetry in hand representation, starting from a somatotopically organized brain region such as area SII.
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Trastornos de la Percepción/fisiopatología , Trastornos de la Percepción/terapia , Corteza Somatosensorial/fisiopatología , Vestíbulo del Laberinto/fisiología , Adulto , Vías Aferentes/fisiología , Anciano , Anciano de 80 o más Años , Daño Encefálico Crónico/diagnóstico , Daño Encefálico Crónico/fisiopatología , Pruebas Calóricas , Femenino , Lateralidad Funcional/fisiología , Mano/inervación , Mano/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estimulación Física , Tacto/fisiología , Núcleos Vestibulares/fisiologíaRESUMEN
The ovarian hormone estrogen is presumed to modulate processes of learning and memory in adulthood. In this study, we examined the effects of short-term estrogen replacement on associative memory formation. Adult ovariectomized female rats received two injections of estradiol (10, 20 or 40 microg) 24 h apart and were trained 4 h following each injection on the hippocampal-dependent task of trace eyeblink conditioning. Only the highest dose of estrogen, which produced plasma estradiol levels >250 pg/ml, enhanced conditioned responding. One day after the last injection, estrogen treated rats continued to exhibit elevated levels of conditioning and extinguished responding when the conditioned stimulus was no longer presented. Exposure to estrogen did not alter pain sensitivity or activity levels, but did greatly increase uterine weight. These results provide additional support to the view that that ovarian steroids are beneficial to the performance of certain forms of learning and memory tasks, albeit at supraphysiological doses. They are discussed with reference to hormone replacement and its effects on cognitive processes.
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Aprendizaje por Asociación/fisiología , Condicionamiento Palpebral/fisiología , Estradiol/fisiología , Memoria/fisiología , Animales , Relación Dosis-Respuesta a Droga , Estradiol/administración & dosificación , Estradiol/sangre , Femenino , Ovariectomía , Ratas , Ratas Sprague-DawleyRESUMEN
Heat shock proteins are intracellular proteins associated with a generalized response of cells to stress. The purpose of this study was to assess RNA levels of heat shock protein 70 and 90 in fed or fasted rat livers during ischemia-reperfusion. Northern blot analysis of heat shock proteins was performed. Adenosine triphosphate and glutathione were assessed. In baseline conditions, livers of fasted rats showed a twofold increase in mRNA for both heat shock proteins and 38% and 43% reductions in adenosine triphosphate and glutathione, respectively, when compared with organs from fed rats. After ischemia, livers of fasted rats presented a twofold decrease in heat shock protein mRNA, while no changes were observed in livers of fed rats; reduced glutathione and adenosine triphosphate decreased 55% and 50% in fasted livers and 25% and 20% in fed organs, respectively. After 120 min of reperfusion, heat shock protein mRNA rose threefold in fasted livers, while a slight decrease was observed in the fed group; reduced glutathione and adenosine triphosphate returned to 65% and 70% of baseline values in fasted livers and 85% and 90% in fed organs, respectively. In conclusion, the nutritional status affects heat shock protein expression determined by reperfusion. The reduced antioxidant status leading to increased oxidative stress could be the mechanism underlying the phenomenon.