RESUMEN
As of March 7, 2023, a total of 30,235 confirmed and probable monkeypox (mpox) cases were reported in the United States, predominantly among cisgender men§ who reported recent sexual contact with another man (1). Although most mpox cases during the current outbreak have been self-limited, cases of severe illness and death have been reported (2-4). During May 10, 2022-March 7, 2023, 38 deaths among persons with probable or confirmed mpox¶ (1.3 per 1,000 mpox cases) were reported to CDC and classified as mpox-associated (i.e., mpox was listed as a contributing or causal factor). Among the 38 mpox-associated deaths, 94.7% occurred in cisgender men (median age = 34 years); 86.8% occurred in non-Hispanic Black or African American (Black) persons. The median interval from symptom onset to death was 68 days (IQR = 50-86 days). Among 33 decedents with available information, 93.9% were immunocompromised because of HIV. Public health actions to prevent mpox deaths include integrated testing, diagnosis, and early treatment for mpox and HIV, and ensuring equitable access to both mpox and HIV prevention and treatment, such as antiretroviral therapy (ART) (5).
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Mpox , Adulto , Humanos , Masculino , Negro o Afroamericano , Brotes de Enfermedades , Mpox/mortalidad , Salud Pública , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Autism prevalence has increased rapidly in recent years, however, nationally representative estimates on the ages of first identification and intervention are out of date. Objectives: (1) To estimate the ages at which children with autism receive their first diagnosis, intervention plan, and developmental services; and (2) To evaluate differences in ages at events by birth cohort and sociodemographic characteristics. METHODS: Using cross-sectional data from the 2016-2018 National Survey of Children's Health (NSCH), we examined associations via linear regression among a sample of 2303 children aged 2-17 years old, who had ever been diagnosed with autism and either (1) ever had a plan for special education or early intervention, or (2) ever received special services to meet developmental needs. Exposures included age cohort, child, household and healthcare provider characteristics. RESULTS: Most children in the study sample (n = 2303) were over age 6 years, male, of non-Hispanic white race/ethnicity and had mild/moderate autism. Mean ages (years) at first diagnosis was 4.56 (SE = 0.13); first plan was 4.43 (SE = 0.11); and first services was 4.10 (SE = 0.11). After adjustment for exposures and survey year, the middle childhood cohort was 18 months older at first intervention (ß = 1.49, 95% CI, 1.18-1.81), and adolescents were 38 months older at first diagnosis (ß = 3.16, 95% CI, 2.72-3.60) compared to those in early childhood. Younger ages at events were observed among: Hispanic/Latinx as compared to white children, those with moderate or severe symptoms as compared to mild symptoms, and children who received their diagnosis from a specialist as compared to psychologists or psychiatrists. CONCLUSIONS: Children with autism receive their first diagnosis, intervention plans and developmental services at younger ages than they had in the past. Future research is needed to identify the mechanisms for these improvements in early identification and intervention to accelerate additional progress.
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TNF-alpha modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-alpha is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-alpha modulates EC cell cycle and angiogenesis. Using primary ECs, we show that ezrin, previously considered to act primarily as a cytoskeletal protein and in cytoplasmic signaling, is a TNF-alpha-induced transcriptional repressor. TNF-alpha exposure leads to Rho kinase-mediated phosphorylation of ezrin, which translocates to the nucleus and binds to cell cycle homology region repressor elements within the cyclin A promoter. Overexpression of dominant-negative ezrin blocks TNF-alpha-induced modulation of ezrin function and rescues cyclin A expression and EC proliferation. In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model. These observations suggest that TNF-alpha regulates angiogenesis via Rho kinase induction of a transcriptional repressor function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.
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Ciclina A/genética , Proteínas del Citoesqueleto/fisiología , Células Endoteliales/citología , Fosfoproteínas/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Bovinos , Proliferación Celular , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/genética , Células Endoteliales/fisiología , Células Endoteliales/trasplante , Extremidades , Expresión Génica , Humanos , Isquemia/terapia , Ratones , Ratones Desnudos , Neovascularización Fisiológica , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , Transcripción Genética , TransfecciónRESUMEN
We have identified a subpopulation of stem cells within adult human BM, isolated at the single-cell level, that self-renew without loss of multipotency for more than 140 population doublings and exhibit the capacity for differentiation into cells of all 3 germ layers. Based on surface marker expression, these clonally expanded human BM-derived multipotent stem cells (hBMSCs) do not appear to belong to any previously described BM-derived stem cell population. Intramyocardial transplantation of hBMSCs after myocardial infarction resulted in robust engraftment of transplanted cells, which exhibited colocalization with markers of cardiomyocyte (CMC), EC, and smooth muscle cell (SMC) identity, consistent with differentiation of hBMSCs into multiple lineages in vivo. Furthermore, upregulation of paracrine factors including angiogenic cytokines and antiapoptotic factors, and proliferation of host ECs and CMCs, were observed in the hBMSC-transplanted hearts. Coculture of hBMSCs with CMCs, ECs, or SMCs revealed that phenotypic changes of hBMSCs result from both differentiation and fusion. Collectively, the favorable effect of hBMSC transplantation after myocardial infarction appears to be due to augmentation of proliferation and preservation of host myocardial tissues as well as differentiation of hBMSCs for tissue regeneration and repair. To our knowledge, this is the first demonstration that a specific population of multipotent human BM-derived stem cells can induce both therapeutic neovascularization and endogenous and exogenous cardiomyogenesis.
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Células de la Médula Ósea/fisiología , Diferenciación Celular/fisiología , Corazón/fisiología , Células Madre Multipotentes/trasplante , Infarto del Miocardio/terapia , Regeneración/fisiología , Adulto , Animales , Células de la Médula Ósea/citología , Linaje de la Célula/fisiología , Proliferación Celular , Células Cultivadas , Femenino , Humanos , Masculino , Células Madre Multipotentes/fisiología , Infarto del Miocardio/patología , Miocardio/patología , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/fisiología , Neovascularización Fisiológica/fisiología , Ratas , Ratas DesnudasRESUMEN
BACKGROUND: We compared the therapeutic potential of purified mobilized human CD34+ cells with that of mobilized total mononuclear cells (tMNCs) for the preservation/recovery of myocardial tissue integrity and function after myocardial infarction (MI). METHODS AND RESULTS: CD34+ cells were purified from peripheral blood tMNCs of healthy volunteers by magnetic cell sorting after a 5-day administration of granulocyte colony-stimulating factor. Phosphate-buffered saline (PBS), 5x10(5) CD34+ cells/kg, 5x10(5) tMNCs/kg (low-dose MNCs [loMNCs]), or a higher dose of tMNCs (hiMNCs) containing 5x10(5) CD34+ cells/kg was transplanted intramyocardially 10 minutes after the induction of MI in athymic nude rats. Hematoxylin and eosin staining revealed that moderate to severe hemorrhagic MI on day 3 was more frequent in the hiMNC group than in the PBS and CD34+ cell groups. Immunostaining for human-specific CD45 revealed abundant distribution of hematopoietic/inflammatory cells derived from transplanted cells in the ischemic myocardium of the hiMNC group. Capillary density on day 28 was significantly greater in the CD34+ cell group (721.1+/-19.9 per 1 mm2) than in the PBS, loMNC, and hiMNC groups (384.7+/-11.0, 372.5+/-14.1, and 497.5+/-24.0 per 1 mm2) (P<0.01). Percent fibrosis area on day 28 was less in the CD34(+) cell group (15.6+/-0.9%) than in the PBS, loMNC, and hiMNC groups (26.3+/-1.2%, 27.5+/-1.8%, and 22.2+/-1.8%) (P<0.05). Echocardiographic fractional shortening on day 28 was significantly higher in the CD34+ cell group (30.3+/-0.9%) than in the PBS, loMNC, and hiMNC groups (22.7+/-1.5%, 23.4+/-1.1%, and 24.9+/-1.7%; P<0.05). Echocardiographic regional wall motion score was better preserved in the CD34+ cell group (21.8+/-0.5) than in the PBS, loMNC, and hiMNC groups (25.4+/-0.4, 24.9+/-0.4, and 24.1+/-0.6; P<0.05). CONCLUSIONS: CD34+ cells exhibit superior efficacy for preserving myocardial integrity and function after MI than unselected circulating MNCs.
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Antígenos CD34/metabolismo , Monocitos/metabolismo , Monocitos/trasplante , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/cirugía , Neovascularización Fisiológica , Animales , Diferenciación Celular , Ecocardiografía , Femenino , Hemorragia/etiología , Humanos , Monocitos/patología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Miocardio/patología , Periodo Posoperatorio , Ratas , Ratas Desnudas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Factores de Tiempo , Trasplante Heterólogo , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis, which leads to progressive heart failure; however, the pathogenesis of DCM remains uncertain. METHODS AND RESULTS: Using the streptozotocin-induced diabetic rat model, we evaluated the natural course of DCM over a period of 1 year by serial echocardiography, Western blot analysis for vascular endothelial growth factor (VEGF), endothelial progenitor cell assays, myocardial blood flow measurements, and histopathologic analysis that included terminal dUTP nick end-labeling (TUNEL), capillary and cardiomyocyte density, and fibrosis area. Downregulation of myocardial VEGF expression preceded all other features of DCM and was followed by increased apoptosis of endothelial cells, decreased numbers of circulating endothelial progenitor cells, decreased capillary density, and impaired myocardial perfusion. Apoptosis and necrosis of cardiomyocytes ensued, along with fibrosis and progressive diastolic and then systolic dysfunction. To provide further evidence of the central role of VEGF in the pathophysiology of DCM, we replenished myocardial VEGF expression using naked DNA gene therapy via direct intramyocardial injection of plasmid DNA encoding VEGF (phVEGF165). VEGF-replenished rats showed increased capillary density, decreased endothelial cell and cardiomyocyte apoptosis, and in situ differentiation of bone marrow-derived endothelial progenitor cells into endothelial cells. These anatomic findings were accompanied by significant improvements in cardiac function. CONCLUSIONS: These findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.
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Cardiomiopatías/etiología , Complicaciones de la Diabetes/etiología , Miocardio/química , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/análisis , Animales , Cardiomiopatías/terapia , Complicaciones de la Diabetes/terapia , Diabetes Mellitus Experimental , Regulación hacia Abajo , Femenino , Terapia Genética , Homeostasis/efectos de los fármacos , Masculino , Microcirculación/efectos de los fármacos , Microcirculación/fisiopatología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Tumor necrosis factor-alpha (TNF-alpha) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells (ECs), thereby delaying reendothelialization. Prior studies have shown that direct antagonism of TNF-alpha, using a systemically administered soluble receptor, can enhance endothelial recovery and reduce neointimal thickening. These studies have also shown that downregulation of the transcription factor E2F1 was a key mechanism of TNF's effect on ECs. We now show that Ad-E2F1 overexpression at sites of balloon injury accelerates functional endothelial recovery, consistent with the prior in vitro findings. Moreover these studies also reveal divergent effects of TNF-alpha and overexpression of E2F1 on ECs versus VSMCs. TNF-alpha exposure of VSMCs had no affect on proliferation or apoptosis, in contrast to the effect seen in ECs. In Ad-E2F1-transduced VSMCs, however, TNF-alpha-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-kappaB may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-kappaB was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-alpha. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-alpha-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-kappaB activation. The divergent responses of VSMCs and ECs to E2F1 overexpression provide unique therapeutic possibilities: simultaneously targeting the cell cycle of two different cell types, within same tissue microenvironment resulting in opposite and biologically complimentary effects.
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Traumatismos de las Arterias Carótidas/metabolismo , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Endotelio Vascular/metabolismo , Músculo Liso Vascular/metabolismo , Factores de Transcripción/metabolismo , Túnica Íntima/crecimiento & desarrollo , Transporte Activo de Núcleo Celular , Animales , Apoptosis , Traumatismos de las Arterias Carótidas/patología , Caspasas/metabolismo , Bovinos , División Celular/efectos de los fármacos , División Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Endotelio Vascular/citología , Regulación de la Expresión Génica , Genes Reporteros , Humanos , Hiperplasia/patología , Proteínas I-kappa B/metabolismo , Ratones , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factores de Transcripción/genética , Transfección , Factor de Necrosis Tumoral alfa/farmacología , Túnica Íntima/lesiones , Túnica Íntima/patologíaRESUMEN
BACKGROUND: We hypothesized that estrogen-induced acceleration of reendothelialization might be mediated in part by effects involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells (EPCs). METHODS AND RESULTS: Carotid injury was induced in ovariectomized wild-type mice receiving either 17beta-estradiol or placebo. Estradiol treatment significantly accelerated reendothelialization of injured arterial segments within 7 days and resulted in a significant reduction of medial thickness 14 and 21 days after the injury. Significant increases in circulating EPCs 3 days after the injury were observed in the estradiol group compared with placebo-treated mice. These data were further supported by fluorescence-activated cell sorting analysis, which disclosed a significant increase in Sca-1/Flk-1-positive cells in estradiol versus control mice. To evaluate the effects of estradiol on bone marrow-derived EPC incorporation at sites of reendothelialization, carotid injury was established in ovariectomized wild-type mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the Tie-2 promoter. Significantly greater numbers of X-gal-positive cells were observed at reendothelialized areas in the estradiol group 3 days after injury as compared with placebo. Fluorescent immunohistochemistry 14 days after the injury documented a marked increase in cells expressing both beta-gal, indicating bone marrow origin and Tie-2 expression, and isolectin B4, also indicating endothelial lineage, in the estradiol group compared with control. In contrast, estradiol did not accelerate reendothelialization or augment EPC mobilization into the peripheral circulation after injury in endothelial nitric oxide synthase-deficient mice (eNOS-/-). Furthermore, estradiol exhibited direct stimulatory effects on EPC mitogenic and migration activity and inhibited EPC apoptosis. CONCLUSIONS: Estradiol accelerates reendothelialization and attenuates medial thickening after carotid injury in part by augmenting mobilization and proliferation of bone marrow-derived EPCs and their incorporation into the recovering endothelium at the site of injury.
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Arteriopatías Oclusivas/tratamiento farmacológico , Células de la Médula Ósea/fisiología , Endotelio Vascular/citología , Estradiol/uso terapéutico , Óxido Nítrico Sintasa/fisiología , Células Madre/fisiología , Animales , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Arterias Carótidas/citología , Arterias Carótidas/patología , Estenosis Carotídea/tratamiento farmacológico , Estenosis Carotídea/etiología , Estenosis Carotídea/patología , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Endotelio Vascular/patología , Endotelio Vascular/fisiología , Estradiol/farmacología , Femenino , Cinética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Regeneración , Células Madre/efectos de los fármacosRESUMEN
BACKGROUND: We performed a series of investigations to test the hypothesis that combining angiogenic gene therapy and cytokine (CK)-induced endothelial progenitor cell mobilization would be superior to either strategy alone for treatment of chronic myocardial ischemia. METHODS AND RESULTS: A swine model of chronic myocardial ischemia and a murine model of acute myocardial infarction were used in this study. In both models, animals were randomly assigned to 1 of 4 treatment groups: Combo group, intramyocardial vascular endothelial growth factor (VEGF)-2 gene transfer plus subcutaneous injection of CKs; VEGF-2, VEGF-2 gene transfer plus saline subcutaneously injected; CK, empty vector transfer plus CKs; and control, empty vector plus subcutaneous saline. Acute myocardial infarction was also induced in wild-type mice 4 weeks after bone marrow transplantation from enhanced green fluorescent protein transgenic mice to permit observation of bone marrow-derived cells in the myocardium after acute myocardial infarction. In chronic myocardial ischemia, combination therapy resulted in superior improvement in all indexes of perfusion and function compared with all other treatment groups. In the bone marrow transplant mice, double immunofluorescent staining revealed that the combination of CK-induced mobilization and local VEGF-2 gene transfer resulted in a significant increase in the number of bone marrow-derived cells incorporating into the neovasculature, indicating that recruitment and/or retention of bone marrow-derived progenitors was enhanced by mobilization and that local VEGF-2 gene transfer can provide signals for recruitment or incorporation of circulating progenitor cells. CONCLUSIONS: Mobilization of endothelial progenitor cells with cytokines potentiates VEGF-2 gene therapy for myocardial ischemia and enhances bone marrow cell incorporation into ischemic myocardium.
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Terapia Genética , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Infarto del Miocardio/terapia , Isquemia Miocárdica/terapia , Proteínas Recombinantes/uso terapéutico , Factor de Células Madre/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Terapia Combinada , Angiografía Coronaria , Técnicas Electrofisiológicas Cardíacas , Genes Reporteros , Vectores Genéticos/administración & dosificación , Vectores Genéticos/uso terapéutico , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , Humanos , Inyecciones Intralesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/patología , Quimera por Radiación , Distribución Aleatoria , Proteínas Recombinantes de Fusión/fisiología , Sus scrofa , Ultrasonografía , Factor A de Crecimiento Endotelial Vascular/genética , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiologíaRESUMEN
BACKGROUND: Secretoneurin is an abundant neuropeptide of the central, peripheral, and autonomic nervous systems, located in nerve fibers characterized by a close interaction with blood vessels and known to stimulate endothelial cell migration. METHODS AND RESULTS: We hypothesized that secretoneurin might act as an angiogenic cytokine and tested for these effects in vivo using a mouse cornea neovascularization model and in vitro by assessing capillary tube formation in a matrigel assay. In vivo, secretoneurin-induced neovasculature is characterized by a distinct pattern of arterial and venous vessels of large diameter and length. Immunohistochemical staining for CD-31 revealed endothelial lining of the inner surface of these vessels, and recruitment of alpha-smooth muscle actin-positive perivascular cells suggests vessel maturation. In vitro, secretoneurin-induced capillary tube formation was dose dependent and specific, confirming that effects of secretoneurin occur directly on endothelial cells. Secretoneurin also stimulated proliferation and exerted antiapoptotic effects on endothelial cells and activated intracellular phosphatidylinositol 3' kinase/Akt and mitogen-activated protein kinase pathways, as demonstrated by increased phosphorylation of Akt and extracellular signal-regulated kinase. CONCLUSIONS: These data show that secretoneurin represents a novel direct angiogenic cytokine and reiterate the coordinated relationship between nervous and vascular systems.
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Inductores de la Angiogénesis/farmacología , Neuropéptidos/farmacología , Proteínas Serina-Treonina Quinasas , Animales , Apoptosis/efectos de los fármacos , División Celular , Células Cultivadas , Córnea/anatomía & histología , Córnea/irrigación sanguínea , Citocinas/farmacología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Humanos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Secretogranina II , Transducción de SeñalRESUMEN
BACKGROUND: Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. METHODS AND RESULTS: phVEGF 2-plasmid (100 or 200 microg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7+/-1% versus 79.0+/-6%, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2+/-0.4 versus 2.27+/-0.3 mm(2), P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4+/-6 versus 51.2+/-10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. CONCLUSIONS: Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.
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Arteriopatías Oclusivas/prevención & control , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Stents , Factores de Crecimiento Endotelial Vascular/genética , Animales , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/patología , Terapia Combinada , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Expresión Génica , Masculino , Óxido Nítrico/biosíntesis , Plásmidos/administración & dosificación , Conejos , Células Madre/citología , Ultrasonografía , Factores de Crecimiento Endotelial Vascular/análisisRESUMEN
BACKGROUND: We investigated whether catheter-based, intramyocardial transplantation of autologous endothelial progenitor cells can enhance neovascularization in myocardial ischemia. METHODS AND RESULTS: Myocardial ischemia was induced by placement of an ameroid constrictor around swine left circumflex artery. Four weeks after constrictor placement, CD31+ mononuclear cells (MNCs) were freshly isolated from the peripheral blood of each animal. After overnight incubation of CD31+ MNCs in noncoated plates, nonadhesive cells (NA/CD31+ MNCs) were harvested as the endothelial progenitor cell-enriched fraction. Nonadhesive CD31- cells (NA/CD31- MNCs) were also prepared. Autologous transplantation of 10(7) NA/CD31+ MNCs, 10(7) NA/CD31- MNCs, or PBS was performed with a NOGA mapping injection catheter to target ischemic myocardium. In a parallel study, 10(5) human CD34+ MNCs, 10(5) human CD34- MNCs, or PBS was transplanted into ischemic myocardium of nude rats 10 minutes after ligation of the left anterior descending coronary artery. In the swine study, ischemic area by NOGA mapping, Rentrop grade angiographic collateral development, and echocardiographic left ventricular ejection fraction improved significantly 4 weeks after transplantation of NA/CD31+ MNCs but not after injection of NA/CD31- MNCs or PBS. Capillary density in ischemic myocardium 4 weeks after transplantation was significantly greater in the NA/CD31+ MNC group than the control groups. In the rat study, echocardiographic left ventricular systolic function and capillary density were significantly better preserved in the CD34+ MNC group than in the control groups 4 weeks after myocardial ischemia. CONCLUSIONS: These favorable outcomes encourage future clinical trials of catheter-based, intramyocardial transplantation of autologous CD34+ MNCs in the setting of chronic myocardial ischemia.
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Endotelio Vascular/citología , Isquemia Miocárdica/terapia , Miocardio/citología , Neovascularización Fisiológica , Trasplante de Células Madre/métodos , Animales , Antígenos CD34/análisis , Cateterismo Cardíaco , Diferenciación Celular , Linaje de la Célula , Enfermedad Crónica , Angiografía Coronaria , Fibrosis , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/diagnóstico por imagen , Ratas , Ratas Desnudas , Células Madre/química , Células Madre/citología , Células Madre/fisiología , Porcinos , Ultrasonografía , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Induction of postnatal vasculogenesis, the mobilization of bone marrow-derived endothelial progenitor cells and incorporation of these cells into sites of blood vessel formation, is a well-known feature of angiogenic cytokines such as vascular endothelial growth factor. We hypothesized that the angiogenic neuropeptide secretoneurin induces this kind of neovascularization. METHODS AND RESULTS: Secretoneurin induced mobilization of endothelial progenitor cells to sites of vasculogenesis in vivo in the cornea neovascularization assay. Progenitor cells were incorporated into vascular structures or were located adjacent to them. Systemic injection of secretoneurin led to increase of circulating stem cells and endothelial progenitor cells. In vitro secretoneurin induced migration, exerted antiapoptotic effects, and increased the number of these cells. Furthermore, secretoneurin stimulated the mitogen-activated protein kinase system, as shown by phosphorylation of extracellular signal-regulated kinase, and activated the protein kinase B/Akt pathway. Activation of mitogen-activated protein kinase was necessary for increase of cell number and migration, whereas Akt seemed to play a role in migration of endothelial progenitor cells. CONCLUSIONS: These data show that the angiogenic neuropeptide secretoneurin stimulates postnatal vasculogenesis by mobilization, migration, and incorporation of endothelial progenitor cells.
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Neovascularización de la Córnea , Neuropéptidos/fisiología , Androstadienos/farmacología , Animales , Apoptosis/efectos de los fármacos , Trasplante de Médula Ósea , Células Cultivadas/citología , Células Cultivadas/efectos de los fármacos , Quimiotaxis/efectos de los fármacos , Neovascularización de la Córnea/tratamiento farmacológico , Flavonoides/farmacología , Citometría de Flujo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Operón Lac , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos , Ratones Transgénicos , Neuropéptidos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-akt , Quimera por Radiación , Ratas , Receptor TIE-2/genética , Secretogranina II , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacología , WortmaninaRESUMEN
The challenges of gathering in-vivo measures of brain anatomy from young children have limited the number of independent studies examining neuroanatomical differences between children with autism and typically developing controls (TDCs) during early life, and almost all studies in this critical developmental window focus on global or lobar measures of brain volume. Using a novel cohort of young males with Autistic Disorder and TDCs aged 2 to 5 years, we (i) tested for group differences in traditional measures of global anatomy (total brain, total white, total gray and total cortical volume), and (ii) employed surface-based methods for cortical morphometry to directly measure the two biologically distinct sub-components of cortical volume (CV) at high spatial resolution-cortical thickness (CT) and surface area (SA). While measures of global brain anatomy did not show statistically significant group differences, children with autism showed focal, and CT-specific anatomical disruptions compared to TDCs, consisting of relative cortical thickening in regions with central roles in behavioral regulation, and the processing of language, biological movement and social information. Our findings demonstrate the focal nature of brain involvement in early autism, and provide more spatially and morphometrically specific anatomical phenotypes for subsequent translational study.
RESUMEN
The transcription factor E2F1 is known to regulate cell proliferation and has been thought to modulate tumorigenesis via this mechanism alone. Here we show that mice deficient in E2F1 exhibit enhanced angiogenesis. The proangiogenic phenotype in E2F1 deficiency is the result of overproduction of vascular endothelial growth factor (VEGF) and is prevented by VEGF blockade. Under hypoxic conditions, E2F1 down-regulates the expression of VEGF promoter activity by associating with p53 and specifically down-regulating expression of VEGF but not other hypoxia-inducible genes, suggesting a promoter structure context-dependent regulation mechanism. We found that the minimum VEGF promoter mediating transcriptional repression by E2F1 features an E2F1- binding site with four Sp-1 sites in close proximity. These data disclose an unexpected function of endogenous E2F1: regulation of angiogenic activity via p53-dependent transcriptional control of VEGF expression.