Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
MMWR Morb Mortal Wkly Rep ; 72(15): 404-410, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37053126

RESUMO

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).


Assuntos
Mpox , Adulto , Humanos , Masculino , Negro ou Afro-Americano , Surtos de Doenças , Mpox/mortalidade , Saúde Pública , Estados Unidos/epidemiologia
2.
Child Adolesc Psychiatry Ment Health ; 15(1): 58, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34629109

RESUMO

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in recent years, however, nationally representative estimates on the ages of first identification and intervention are out of date.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.

3.
J Clin Invest ; 115(7): 1785-96, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15965500

RESUMO

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.


Assuntos
Ciclina A/genética , Proteínas do Citoesqueleto/fisiologia , Células Endoteliais/citologia , Fosfoproteínas/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Bovinos , Proliferação de Células , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Células Endoteliais/fisiologia , Células Endoteliais/transplante , Extremidades , Expressão Gênica , Humanos , Isquemia/terapia , Camundongos , Camundongos Nus , Neovascularização Fisiológica , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Transcrição Gênica , Transfecção
4.
J Clin Invest ; 115(2): 326-38, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15690083

RESUMO

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.


Assuntos
Células da Medula Óssea/fisiologia , Diferenciação Celular/fisiologia , Coração/fisiologia , Células-Tronco Multipotentes/transplante , Infarto do Miocárdio/terapia , Regeneração/fisiologia , Adulto , Animais , Células da Medula Óssea/citologia , Linhagem da Célula/fisiologia , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Masculino , Células-Tronco Multipotentes/fisiologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Neovascularização Fisiológica/fisiologia , Ratos , Ratos Nus
5.
Circulation ; 114(20): 2163-9, 2006 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17075009

RESUMO

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.


Assuntos
Antígenos CD34/metabolismo , Monócitos/metabolismo , Monócitos/transplante , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/cirurgia , Neovascularização Fisiológica , Animais , Diferenciação Celular , Ecocardiografia , Feminino , Hemorragia/etiologia , Humanos , Monócitos/patologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miocárdio/patologia , Período Pós-Operatório , Ratos , Ratos Nus , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Fatores de Tempo , Transplante Heterólogo , Função Ventricular Esquerda , Remodelação Ventricular
6.
Circulation ; 111(16): 2073-85, 2005 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15851615

RESUMO

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.


Assuntos
Cardiomiopatias/etiologia , Complicações do Diabetes/etiologia , Miocárdio/química , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/análise , Animais , Cardiomiopatias/terapia , Complicações do Diabetes/terapia , Diabetes Mellitus Experimental , Regulação para Baixo , Feminino , Terapia Genética , Homeostase/efeitos dos fármacos , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética
7.
Circ Res ; 93(2): 162-9, 2003 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12829616

RESUMO

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.


Assuntos
Lesões das Artérias Carótidas/metabolismo , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Endotélio Vascular/metabolismo , Músculo Liso Vascular/metabolismo , Fatores de Transcrição/metabolismo , Túnica Íntima/crescimento & desenvolvimento , Transporte Ativo do Núcleo Celular , Animais , Apoptose , Lesões das Artérias Carótidas/patologia , Caspases/metabolismo , Bovinos , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Endotélio Vascular/citologia , Regulação da Expressão Gênica , Genes Reporter , Humanos , Hiperplasia/patologia , Proteínas I-kappa B/metabolismo , Camundongos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Inibidor de NF-kappaB alfa , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Transcrição/genética , Transfecção , Fator de Necrose Tumoral alfa/farmacologia , Túnica Íntima/lesões , Túnica Íntima/patologia
8.
Circulation ; 108(25): 3115-21, 2003 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-14676142

RESUMO

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.


Assuntos
Arteriopatias Oclusivas/tratamento farmacológico , Células da Medula Óssea/fisiologia , Endotélio Vascular/citologia , Estradiol/uso terapêutico , Óxido Nítrico Sintase/fisiologia , Células-Tronco/fisiologia , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Artérias Carótidas/citologia , Artérias Carótidas/patologia , Estenose das Carótidas/tratamento farmacológico , Estenose das Carótidas/etiologia , Estenose das Carótidas/patologia , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Estradiol/farmacologia , Feminino , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Regeneração , Células-Tronco/efeitos dos fármacos
9.
Circulation ; 110(11): 1398-405, 2004 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-15337699

RESUMO

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.


Assuntos
Terapia Genética , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Infarto do Miocárdio/terapia , Isquemia Miocárdica/terapia , Proteínas Recombinantes/uso terapêutico , Fator de Células-Tronco/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Terapia Combinada , Angiografia Coronária , Técnicas Eletrofisiológicas Cardíacas , Genes Reporter , Vetores Genéticos/administração & dosagem , Vetores Genéticos/uso terapêutico , Proteínas de Fluorescência Verde/análise , Proteínas de Fluorescência Verde/genética , Humanos , Injeções Intralesionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/patologia , Quimera por Radiação , Distribuição Aleatória , Proteínas Recombinantes de Fusão/fisiologia , Sus scrofa , Ultrassonografia , Fator A de Crescimento do Endotélio Vascular/genética , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia
10.
Circulation ; 107(3): 461-8, 2003 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-12551872

RESUMO

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.


Assuntos
Endotélio Vascular/citologia , Isquemia Miocárdica/terapia , Miocárdio/citologia , Neovascularização Fisiológica , Transplante de Células-Tronco/métodos , Animais , Antígenos CD34/análise , Cateterismo Cardíaco , Diferenciação Celular , Linhagem da Célula , Doença Crônica , Angiografia Coronária , Fibrose , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/diagnóstico por imagem , Ratos , Ratos Nus , Células-Tronco/química , Células-Tronco/citologia , Células-Tronco/fisiologia , Suínos , Ultrassonografia , Função Ventricular Esquerda
11.
Circulation ; 109(6): 777-83, 2004 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-14970115

RESUMO

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.


Assuntos
Indutores da Angiogênese/farmacologia , Neuropeptídeos/farmacologia , Proteínas Serina-Treonina Quinases , Animais , Apoptose/efeitos dos fármacos , Divisão Celular , Células Cultivadas , Córnea/anatomia & histologia , Córnea/irrigação sanguínea , Citocinas/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Humanos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Secretogranina II , Transdução de Sinais
12.
Circulation ; 110(9): 1121-7, 2004 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-15326074

RESUMO

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.


Assuntos
Neovascularização da Córnea , Neuropeptídeos/fisiologia , Androstadienos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Transplante de Medula Óssea , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Neovascularização da Córnea/tratamento farmacológico , Flavonoides/farmacologia , Citometria de Fluxo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Óperon Lac , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Neuropeptídeos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt , Quimera por Radiação , Ratos , Receptor TIE-2/genética , Secretogranina II , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Wortmanina
13.
Circulation ; 110(1): 36-45, 2004 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-15210598

RESUMO

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.


Assuntos
Arteriopatias Oclusivas/prevenção & controle , Técnicas de Transferência de Genes , Terapia Genética/métodos , Stents , Fatores de Crescimento do Endotélio Vascular/genética , Animais , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/patologia , Terapia Combinada , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Expressão Gênica , Masculino , Óxido Nítrico/biossíntese , Plasmídeos/administração & dosagem , Coelhos , Células-Tronco/citologia , Ultrassonografia , Fatores de Crescimento do Endotélio Vascular/análise
15.
Neuroimage Clin ; 2: 111-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-24179764

RESUMO

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.

16.
Proc Natl Acad Sci U S A ; 103(29): 11015-20, 2006 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-16835303

RESUMO

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.


Assuntos
Ciclo Celular , Fator de Transcrição E2F1/metabolismo , Transcrição Gênica/genética , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Células Cultivadas , Regulação para Baixo , Fator de Transcrição E2F1/deficiência , Fator de Transcrição E2F1/genética , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Supressora de Tumor p53/genética
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa