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INTRODUCTION: Critical limb-threatening ischemia (CLTI) is a severe manifestation of peripheral artery disease (PAD) that can lead to limb amputation and significantly reduce quality of life. In addition to guideline-directed medical therapy (GDMT), endovascular therapy and surgical revascularization are the two revascularization options for CLTI. In recent years, there has been an ongoing debate about the best approach for CLTI patients. The purpose of this meta-analysis is to examine the current evidence and compare the clinical outcomes of endovascular therapy and surgical revascularization for CLTI. METHODS: We conducted a systematic search of electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) for studies comparing the outcomes of endovascular therapy versus surgery in patients with CLTI. The primary outcomes were major adverse limb events (MALE) and major adverse cardiovascular events (MACE), while secondary outcomes included risk of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure, and length of hospital stay. Pooled data was analyzed using the fixed-effect model or the random-effect model in Review Manager 5.3. The Newcastle-Ottawa Scale and Cochrane risk of bias assessment tool were used to assess the bias of included studies. RESULTS: A total of 16 studies (47,609 patients) were included in this meta-analysis. The overall effect favors surgery over endovascular intervention in terms of MALE [odds ratio (OR) 1.13, 95% CI (1.01-1.28), P = 0.04]. Endovascular therapy is associated with lower MACE rates compared to surgery [OR 0.62, 95% CI (0.51-0.76), P < 0.00001]. Furthermore, the risk of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure as well as the length of hospital stay was lower for endovascular intervention. Finally, there was no statistically significant difference in 30-day mortality between the two groups [OR 0.94, 95% CI 0.79-1.12, P = 0.52; Fig. 3i], and the pooled studies were homogeneous [P = 0.39; I2 = 5%]. CONCLUSION: Surgery may be the preferred treatment option for CLTI patients, as it is associated with a lower risk of MALE than endovascular therapy. However, endovascular therapy may be associated with a lower risk of MACE and lower rates of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure, and shorter hospital stays. There was no statistically significant difference in 30-day mortality between the two groups. Ultimately, the decision to use endovascular therapy or surgery as the primary treatment strategy should be based on a multi-disciplinary team approach with careful consideration of patient characteristics and anatomy.
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In our pursuit of a flexible energy storage solution, we have developed biocompatible (bc)-NG/PVA composite polymers by combining neem tree gum (NG) with polyvinyl alcohol (PVA). This innovative bio-inspired approach harnesses NG's unique properties for both the bio-electrolyte and bio-electrode components. The resulting bc-NG/PVA composites exhibit superior dielectric strength and versatility, surpassing traditional inorganic ceramic dielectrics in advanced electronics and pulsed power systems. Our study investigates the dielectric characteristics, conductivities, electric modulus, and impedance parameters of Pure PVA and NG-doped PVA composites. Adding 5 % NG to PVA significantly boosts its conductivity from 10-8 S cm-1 to 10-4 S cm-1, while the dielectric constant of PVA/5 % NG composite jumps to 104.5 compared to pure PVA. These improvements position the composite films of 5 % NG added PVA as promising materials for diverse applications. The heightened performance of these NG-blended PVA composite materials underscores their potential as a valuable resource for flexible energy storage solutions.
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BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention. METHODS: We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes. RESULTS: In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001]. CONCLUSION: In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.
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Fibrilación Atrial , Propanolaminas , Humanos , Metoprolol/uso terapéutico , Carvedilol/uso terapéutico , Fibrilación Atrial/epidemiología , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Bradicardia/complicaciones , Bradicardia/tratamiento farmacológico , Propanolaminas/uso terapéutico , Carbazoles/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéuticoRESUMEN
Electroencephalography (EEG) has recently gained popularity in user authentication systems since it is unique and less impacted by fraudulent interceptions. Although EEG is known to be sensitive to emotions, understanding the stability of brain responses to EEG-based authentication systems is challenging. In this study, we compared the effect of different emotion stimuli for the application in the EEG-based biometrics system (EBS). Initially, we pre-processed audio-visual evoked EEG potentials from the 'A Database for Emotion Analysis using Physiological Signals' (DEAP) dataset. A total of 21 time-domain and 33 frequency-domain features were extracted from the considered EEG signals in response to Low valence Low arousal (LVLA) and High valence low arousal (HVLA) stimuli. These features were fed as input to an XGBoost classifier to evaluate the performance and identify the significant features. The model performance was validated using leave-one-out cross-validation. The pipeline achieved high performance with multiclass accuracy of 80.97% and a binary-class accuracy of 99.41% with LVLA stimuli. In addition, it also achieved recall, precision and F-measure scores of 80.97%, 81.58% and 80.95%, respectively. For both the cases of LVLA and LVHA, skewness was the stand-out feature. We conclude that boring stimuli (negative experience) that fall under the LVLA category can elicit a more unique neuronal response than its counterpart the LVHA (positive experience). Thus, the proposed pipeline involving LVLA stimuli could be a potential authentication technique in security applications.
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Encéfalo , Electroencefalografía , Electroencefalografía/métodos , Encéfalo/fisiología , Emociones/fisiología , Biometría , Nivel de Alerta/fisiologíaRESUMEN
Marijuana is the most commonly abused illicit drug in the United States (US) and much of the Westernized World with a steadily increasing prevalence in usage and abuse over the past decade, especially among adolescents. Much of the available data on 9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, relates to its neurological effects and anti-emetic properties, with very little on the cardiovascular (CV) effects of THC. Available literature shows that THC has three major effects on the CV and the peripheral vasculature in the form of "cannabis arteritis," cannabis-induced vasospasms, and platelet aggregation, with an unknown verdict on the relationship between marijuana use and atherosclerosis progression. This manuscript reviews these effects and possible mechanisms of action. Moreover, limitations on current views of marijuana and indirect causes of CV toxicity will be investigated, such as concurrent drug use, lifestyle, and mental health. The effects of marijuana on the CV system are extremely worrisome and likely need more attention due to the growing legalization of cannabis for medicinal and recreational use across the US. As a result, awareness among health care professionals about potential side effects and toxicities associated with acute and chronic exposure of cannabis will increase in importance.
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Cannabis , Sistema Cardiovascular/fisiopatología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Abuso de Marihuana , Fumar Marihuana/efectos adversos , Adolescente , Cannabinoides/farmacología , Humanos , Estados UnidosRESUMEN
Mitoxantrone (MXT) is an androstenedione that is used to treat cancers and progressive forms of multiple sclerosis; however, its use is limited by its cardiotoxicity. Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the secretin/growth hormone-releasing hormone/vasoactive intestinal peptide family and has many functions, including cytoprotection and immunosuppression. We tested the hypothesis that PACAP can protect against MXT-induced cardiotoxicity in mice. Female BALB/c mice were treated once weekly for 4 weeks with saline (n=14) or MXT (3mg/kg, i.p.; n=14). Half of the mice in each group received PACAP (10µg, i.p.) 1h before and 24 and 48h after MXT, while the remaining mice received injections of saline on the same schedule. Echocardiography was used to assess cardiac structure and function. In mice treated with MXT and saline, body weight was significantly reduced after the third dose of MXT. PACAP significantly attenuated the reduction in body weight; however, the weights did not return to control level. Compared to controls, MXT-treated mice had significantly increased left ventricular (LV) diameter and LV volume and decreased LV posterior wall thickness. Fractional shortening (FS) and ejection fraction (EF) were also significantly decreased. Treatment with PACAP prevented MXT-induced LV dilation and significantly attenuated the reductions in FS and EF, although FS and EF did not return to control level. PACAP38 did not prevent MXT-induced decreases in LV posterior wall thickness. MXT dose-dependently decreased the viability of cultured U937 (human leukemia) cells; PACAP did not protect cultured U937 cells from MXT-mediated cell death. In conclusion, PACAP can attenuate MXT-mediated LV dilation and dysfunction in mice.
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Lesiones Cardíacas/tratamiento farmacológico , Mitoxantrona/efectos adversos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/administración & dosificación , Disfunción Ventricular Izquierda/tratamiento farmacológico , Animales , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/patología , Humanos , Ratones , Mitoxantrona/uso terapéutico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Sustancias Protectoras/administración & dosificación , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/patologíaRESUMEN
Although deficiency in Apolipoprotein E (ApoE) is linked to many diseases, its effect on colon homeostasis remains unknown. ApoE appears to control inflammation by regulating NF-kB. This study was designed to examine whether ApoE deficiency affects factors of colon integrity in vivo and given the likelihood that ApoE deficiency increases oxidized lipids and TNF-α, this study also examined whether such deficiency enhances the inflammatory potential of oxidized-LDL (oxLDL) and TNF-α, in colon epithelial cells in vitro Here we show that ApoE deficiency is associated with chronic inflammation systemically and in colonic tissues as assessed by TNF-α levels. Increased colon TNF-α mRNA coincided with a substantial increase in cyclooxygenase (COX)-2. ApoE deficiency enhanced the potential of oxLDL and TNF-a to induce COX-2 expression as well as several other inflammatory factors in primary colon epithelial cells. Interestingly, oxLDL enhanced TGF-ß expression only in ApoE-/-, but not in wild-type, epithelial cells. ApoE deficiency appears to promote COX-2 expression enhancement through a mechanism that involves persistent NF-κB nuclear localization, PI3 and p38 MAP kinases but independently of Src. In mice, ApoE deficiency promoted a moderate increase in crypt length, which was associated with opposing effects of an increase in cell proliferation and apoptosis at the bottom and top of the crypt, respectively. : Our results support the notion that ApoE plays a central role in colon homeostasis and that ApoE deficiency may constitute a risk factor for colon pathologies.
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STUDY DESIGN: In vitro human cadaveric study simultaneously quantifying sagittal plane flexibility and spinal canal stenosis. OBJECTIVE: To compare biomechanical stability and the change in cross-sectional area during flexion and extension after laminectomy and open-door laminoplasty. SUMMARY OF BACKGROUND DATA: Spinal canal stenosis has been quantified in vitro but has not been quantified in studies of laminectomy or laminoplasty. METHODS: Cadaveric specimens were loaded in physiologic-range flexion and extension using nonconstraining pure moments while recording segmental angles optoelectronically. Custom flexible tubing was placed within the spinal canal, and water was continuously pumped through the tubing while measuring upstream pressure. Spinal canal cross-sectional area correlated to water pressure, allowing continuous monitoring of the smallest cross-sectional area of the canal. Specimens were tested (1) normal, (2) after modeling stenosis by inserting hemispherical wooden beads in the spinal canal at 3 levels, (3) after open-door laminoplasty at 5 levels, and (4) after expanding laminoplasty to laminectomy. RESULTS: Range of motion (ROM) in the normal, stenotic, and laminoplasty conditions did not differ significantly. However, laminectomy increased ROM significantly more than other conditions. ROM after laminectomy was 13% greater than after laminoplasty. After modeling stenosis, the cross-sectional area decreased to 52% +/- 12% of normal. Laminoplasty restored the cross-sectional area to 70% +/- 12% of normal whereas laminectomy restored cross-sectional area to 101% +/- 4% of normal. Among all conditions, areas differed significantly except normal versus laminectomy. CONCLUSION: Laminoplasty leaves the spine in a significantly more stable condition than laminectomy. However, laminoplasty failed to relieve stenosis completely. In this study, stenosis was modeled as about 50% occlusion of the spinal canal. The degree of stenosis should be considered in clinical decisions of whether laminectomy or laminoplasty is more appropriate.
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Vértebras Cervicales/cirugía , Laminectomía/métodos , Canal Medular/cirugía , Estenosis Espinal/cirugía , Adulto , Anciano , Fenómenos Biomecánicos , Cadáver , Vértebras Cervicales/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Docilidad , Rango del Movimiento Articular , Canal Medular/patología , Canal Medular/fisiopatología , Estenosis Espinal/fisiopatologíaRESUMEN
BACKGROUND: Eotaxin is implicated in asthmatic eosinophilia. Oncostatin M (OSM) causes eotaxin release from fibroblasts. OBJECTIVE: We sought to examine the effects and mechanism of action of OSM and other IL-6 family cytokines on eotaxin release from human airway smooth muscle cells. METHODS: Eotaxin 1 release was measured by means of ELISA. Western blotting was used to examine mitogen-activated protein kinase and signal transducer and activator of transcription 3 (STAT-3) phosphorylation. Eotaxin promoter activity was analyzed in cells transfected with wild-type STAT-3, a mutant form of STAT-3 that cannot be phosphorylated, and a constitutively active form of STAT-3. The mRNA and protein expression of IL-4R alpha, the signaling receptor for IL-4 and IL-13, was evaluated by means of real-time PCR and flow cytometry, respectively. RESULTS: OSM increased eotaxin 1 release and augmented IL-4- or IL-13-induced eotaxin release, whereas other IL-6 family cytokines did not. OSM caused a greater increase in STAT-3 phosphorylation and STAT-3-mediated gene transcription than other IL-6 family cytokines. OSM increased eotaxin promoter activity and augmented IL-13- and IL-4-induced increases in promoter activity. The constitutively active form of STAT-3 increased eotaxin promoter activity, whereas the mutant form of STAT-3 that cannot be phosphorylated significantly reduced eotaxin promoter activity induced by OSM or IL-4 plus OSM. OSM increased IL-4R alpha mRNA and protein levels. CONCLUSIONS: OSM induces eotaxin 1 expression in human airway smooth muscle cells by a mechanism involving STAT-3. OSM synergizes with IL-13 and IL-4 to increase eotaxin 1 expression, possibly as a result of effects on IL-4R alpha expression.
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Quimiocinas CC/metabolismo , Inhibidores de Crecimiento/farmacología , Pulmón/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos/farmacología , Western Blotting , Quimiocina CCL11 , Quimiocinas CC/inmunología , Proteínas de Unión al ADN/efectos de los fármacos , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso/inmunología , Músculo Liso/metabolismo , Oncostatina M , Fosforilación , ARN Mensajero/análisis , Receptores de Interleucina-4/efectos de los fármacos , Receptores de Interleucina-4/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3 , Transactivadores/efectos de los fármacos , Transactivadores/inmunología , Transactivadores/metabolismoRESUMEN
BACKGROUND: Corticotropin-releasing hormone (CRH) is a major regulator of adrenocorticotropic hormone and the production of glucocorticoids by the adrenal gland. Abnormal regulation of CRH and endogenous glucocorticoids has been implicated in the pathogenesis of asthma. OBJECTIVE: We postulated that CRH deficiency could increase asthma severity by disrupting hypothalamus-pituitary-adrenal axis function and the induction of glucocorticoids through inflammatory and physiologic stress. However, CRH is expressed by several types of immune cells and might be induced at sites of inflammation, where it has local immunostimulatory actions. Thus CRH deficiency could decrease asthma severity. METHODS: To test these possibilities, we subjected CRH-knockout mice to an ovalbumin-induced airway inflammation protocol that mimics many features of asthma. RESULTS: CRH-knockout mice had an increase in airway inflammation of approximately 80% to 300% and an increase in goblet cell hyperplasia of approximately 70% compared with wild-type mice. In contrast, IgE induction was unaffected by CRH deficiency. The increased inflammation in knockout mice was associated with increased tissue resistance, elastance, and hysteresivity. Levels of IL-4, IL-5, IL-13, RANTES, IFN-gamma, and eotaxin were all increased in knockout mice. Serum corticosterone levels were decreased in knockout mice and might account for some of the differences between knockout and wild-type mice. CONCLUSION: We conclude that CRH deficiency disrupts endogenous glucocorticoid production and enhances allergen-induced airway inflammation and lung mechanical dysfunction in mice. Thus inherited or acquired CRH deficiency could increase asthma severity in human subjects.
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Alérgenos/efectos adversos , Asma/inmunología , Hormona Liberadora de Corticotropina/deficiencia , Hormona Liberadora de Corticotropina/inmunología , Neumonía/inmunología , Alérgenos/inmunología , Animales , Asma/fisiopatología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Femenino , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Neumonía/fisiopatologíaRESUMEN
Platelet-derived growth factors (PDGF) may contribute to the activation and growth of smooth muscle that is characteristic of airway remodeling in asthmatic patients. Early growth response 1 (EGR-1) is a transcription factor that is induced in several cell types by PDGF and may mediate some of the effects of PDGF. We show that human airway smooth muscle cells in cell culture express EGR-1 1 h after addition of PDGF. Analysis of the EGR-1 promoter indicates that a serum response element located between 663 and 654 bp 5' to the ATG start site is essential for this induction. Serum response factor, E26 transcription factor-like protein 1, and serum protein 1 bind to this region. PDGF causes phosphorylation of ERK1/2 and is temporally associated with E26 transcription factor-like protein 1 phosphorylation. Finally, the specific ERK1/2 inhibitor U-0126 abolishes PDGF-induced expression of EGR-1 in these cells. On the basis of these data, we speculated that EGR-1 would be increased in airway smooth muscle of asthmatic patients compared with nonasthmatic controls. Using immunohistochemistry, we found that EGR-1 protein was expressed in airway smooth muscle cells and epithelial cells of asthmatic patients and nonasthmatic controls; however, there was no significant difference in the intensity of staining between groups. EGR-1 was similarly expressed in the lungs of mice with and without ovalbumin-induced airway inflammation; however, there was no difference between groups by immunohistochemistry and quantitative PCR. Although EGR-1 is induced by PDGF in human airway smooth muscle cells in cell culture, the role of EGR-1 in airway remodeling and asthma remains to be established.
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Proteínas de Unión al ADN/genética , Proteínas Inmediatas-Precoces , Pulmón/citología , Músculo Liso/citología , Músculo Liso/fisiología , Factor de Crecimiento Derivado de Plaquetas/farmacología , Factores de Transcripción/genética , Células 3T3 , Animales , Asma/fisiopatología , Proteínas de Unión al ADN/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz , Genes Reporteros , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Músculo Liso/efectos de los fármacos , Ovalbúmina , Fosforilación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/análisis , Factor de Respuesta Sérica/metabolismo , Factor de Transcripción Sp1/metabolismo , Factores de Transcripción/metabolismo , Proteína Elk-1 con Dominio etsRESUMEN
Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.
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Resistencia de las Vías Respiratorias/genética , Resistencia de las Vías Respiratorias/fisiología , Pulmón/enzimología , Pulmón/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Asma/enzimología , Asma/metabolismo , Northern Blotting , Western Blotting , Líquido del Lavado Bronquioalveolar/citología , Broncodilatadores/farmacología , ADN Complementario/biosíntesis , ADN Complementario/genética , Doxiciclina/metabolismo , Inmunohistoquímica , Cloruro de Metacolina/farmacología , Ratones , Ratones Transgénicos , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Mecánica Respiratoria/genética , Mecánica Respiratoria/fisiología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tetraciclina/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Transgenes , Uteroglobina/genéticaRESUMEN
Transforming growth factor-beta1 (TGF-beta1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C-509T) in the TGF-beta1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case-control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C-509T polymorphism alters TGF-beta1 promoter-reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.
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Asma/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Asma/fisiopatología , Estudios de Casos y Controles , Proteínas de Unión al ADN/genética , Factores de Unión al ADN Específico de las Células Eritroides , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta1 , Factor de Transcripción YY1RESUMEN
Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site. The -887 variant alters a consensus binding motif for the transcription factor YY-1. Electrophoretic mobility shift assay demonstrated that YY-1 containing nuclear extracts from tumor necrosis factor-alpha-stimulated peripheral blood mononuclear cells had greater avidity for the wild-type (YY-1 motif intact) sequence than for the variant sequence. Increasing doses of a YY-1 expression vector induced significantly greater reporter activity from MCP-4 core promoter expression constructs of the wild-type compared with the variant sequence in transient transfection experiments. The external validity of these observations was demonstrated by measuring plasma levels of MCP-4 from individuals with the alternative forms of the gene. Individuals bearing haplotypic variants of the MCP-4 core promoter that avidly bind the transcription factor YY-1 had higher plasma levels of MCP-4 than did individuals with variants with lower binding avidity (490, 360, and 360 pg/ml; P < 0.01). Our findings suggest that the MCP-4 core promoter YY-1 binding motif is functional, modulates the transcriptional regulation of the MCP-4 gene, and that part of the variance in the systemic expression of MCP-4 is determined by core promoter genetic variants.
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Proteínas Quimioatrayentes de Monocitos/sangre , Proteínas Quimioatrayentes de Monocitos/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Factores de Unión al ADN Específico de las Células Eritroides , Genes Reporteros , Genotipo , Haplotipos , Humanos , Proteínas Nucleares/metabolismoRESUMEN
Family studies of asthma suggest that the genes ESE-2 and ESE-3 contain polymorphisms that contribute to disease susceptibility. Each gene codes for an ETS transcription factor that is characterized by epithelium-restricted constitutive expression and may function as a context-dependent activator or repressor of transcription; however, nothing is known about the role of these genes in lung homeostasis or the pathogenesis of airway disease. In this study, we show that ESE-3 mRNA and protein are constitutively expressed in bronchial and mucous gland epithelial cells. Consistent with these findings, ESE-3 mRNA is constitutively expressed in human bronchial epithelial cells grown in tissue culture. In contrast, ESE-2 mRNA could not be detected in the lung or cultured human bronchial epithelial cells. Human bronchial smooth muscle cells and fibroblasts do not constitutively express ESE-3; however, after stimulation with interleukin-1beta or tumor necrosis factor-alpha, levels of ESE-3 mRNA and protein increase dramatically by 24 h. This cytokine induction is dose-dependent and abrogated by specific inhibitors of the MEK1/2 (U0126) and p38 (SB03580) signal transduction pathways. Overexpression of ESE-3 protein in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity, suggesting that ESE-3 may function as a transcriptional repressor.