Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
MMWR Morb Mortal Wkly Rep ; 69(1): 1-5, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31917782

RESUMO

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.


Assuntos
Infecções por HIV/diagnóstico , Defeitos do Tubo Neural/epidemiologia , Complicações Infecciosas na Gravidez/diagnóstico , Adolescente , Adulto , Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estados Unidos/epidemiologia , Adulto Jovem
2.
Obstet Gynecol ; 135(1): 133-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31809437

RESUMO

OBJECTIVE: To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects. METHODS: We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified. RESULTS: Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0-57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368-623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7-15), transverse limb deficiencies (26; 95% CI 16-39), longitudinal limb deficiencies (11; 95% CI 3-28), and limb defects due to amniotic bands (110; 95% CI 68-171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2-47), isolated spina bifida (24/1,000; 95% CI 17-34), and holoprosencephaly (30/1,000; 95% CI 10-68). CONCLUSION: Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis.

3.
Birth Defects Res ; 111(18): 1436-1447, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642616

RESUMO

BACKGROUND/OBJECTIVES: In this report, the National Birth Defects Prevention Network (NBDPN) examines and compares gastroschisis and omphalocele for a recent 5-year birth cohort using data from 30 population-based birth defect surveillance programs in the United States. METHODS: As a special call for data for the 2019 NBDPN Annual Report, state programs reported expanded data on gastroschisis and omphalocele for birth years 2012-2016. We estimated the overall prevalence (per 10,000 live births) and 95% confidence intervals (CI) for each defect as well as by maternal race/ethnicity, maternal age, infant sex, and case ascertainment methodology utilized by the program (active vs. passive). We also compared distribution of cases by maternal and infant factors and presence/absence of other birth defects. RESULTS: The overall prevalence estimates (per 10,000 live births) were 4.3 (95% CI: 4.1-4.4) for gastroschisis and 2.1 (95% CI: 2.0-2.2) for omphalocele. Gastroschisis was more frequent among young mothers (<25 years) and omphalocele more common among older mothers (>40 years). Mothers of infants with gastroschisis were more likely to be underweight/normal weight prior to pregnancy and mothers of infants with omphalocele more likely to be overweight/obese. Omphalocele was twice as likely as gastroschisis to co-occur with other birth defects. CONCLUSIONS: This report highlights important differences between gastroschisis and omphalocele. These differences indicate the importance of distinguishing between these defects in epidemiologic assessments. The report also provides additional data on co-occurrence of gastroschisis and omphalocele with other birth defects. This information can provide a basis for future research to better understand these defects.

4.
Dig Dis Sci ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385097

RESUMO

BACKGROUND: While Roux-en-Y gastric bypass (RYGB) is one of the most effective and durable treatment options for obesity and its comorbidities, it is complicated by long-term weight regain in over 20% of patients. AIMS: We sought to determine the metabolite signatures of serum samples of patients with weight regain (RYGB-WR) after RYGB and features distinguishing these patients from patients with sustained weight loss (RYGB-SWL). METHODS: We prospectively analyzed serum samples from 21 RYGB-WR patients, 14 RYGB-SWL patients, and 11 unoperated controls. The main outcome measure was their serum metabolite profile. RESULTS: Weight regain after RYGB was associated with a unique serum metabolomic fingerprint. Most of the statistically different metabolites were involved in amino acid metabolism, one-carbon metabolism, and related nucleotide metabolism. A principal component analysis identified groups of metabolites that correlate with weight regain. Specifically, weight regain was associated with lower serum levels of metabolites related to the serine, glycine and threonine pathway, phenylalanine metabolism, tricyclic acid cycle, alanine and glutamate metabolism, and higher levels of other amino acids. CONCLUSIONS: Weight regain after RYGB is associated with unique serum metabolite signatures. Metabolite profiling may eventually help us to identify markers that could differentiate the patients who will regain weight versus those who will likely sustain weight loss.

5.
Cell Metab ; 28(2): 310-323.e6, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30043755

RESUMO

The effectiveness of Roux-en-Y gastric bypass (RYGB) against obesity and its comorbidities has generated excitement about developing new, less invasive treatments that use the same molecular mechanisms. Although controversial, RYGB-induced improvement of metabolic function may not depend entirely upon weight loss. To elucidate the differences between RYGB and dieting, we studied several individual organ molecular responses and generated an integrative, interorgan view of organismal physiology. We also compared murine and human molecular signatures. We show that, although dieting and RYGB can bring about the same degree of weight loss, post-RYGB physiology is very different. RYGB induces distinct, organ-specific adaptations in a temporal pattern that is characterized by energetically demanding processes, which may be coordinated by HIF1a activation and the systemic repression of growth hormone receptor signaling. Many of these responses are conserved in rodents and humans and may contribute to the remarkable ability of surgery to induce and sustain metabolic improvement.


Assuntos
Anastomose em-Y de Roux/reabilitação , Dieta Redutora/métodos , Derivação Gástrica/reabilitação , Obesidade Mórbida , Tempo , Perda de Peso/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Intestino Delgado/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Obesidade Mórbida/dietoterapia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Transcriptoma
6.
Birth Defects Res ; 109(18): 1430-1441, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28898573

RESUMO

BACKGROUND: Although autopsy is a key component of the etiologic evaluation following fetal and early neonatal death, and traditionally has been the preferred method to determine the cause of death, an alternative may be suitable when traditional autopsy by a perinatal pathologist is not available or declined. METHODS: Among 3137 cases evaluated through the Wisconsin Stillbirth Service Program (WiSSP), a community-based program for etiologic evaluation of second trimester miscarriage, stillbirth, and early neonatal death, most diagnoses are based on multiple types of data including placental pathology, clinical examination, photographs, maternal records, radiographs, and laboratory testing. RESULTS: Cases in the WiSSP cohort without autopsy have nearly the same overall rate of diagnosis as those with traditional autopsy (56% vs. 58%). Review of the literature shows that although recent systematic protocols including autopsy, placental pathology and genetic studies yield a definite or probable diagnosis in 70% or more, both healthcare providers and families desire less invasive options. Several minimally invasive protocols substituting imaging, primarily MRI, for traditional autopsy have been proposed, but the numbers of deaths evaluated are still very small. CONCLUSION: We join others who have promoted the benefits of a targeted or less invasive protocol to study perinatal deaths, and emphasize integration of clinical data, selective imaging, genetic testing, and parental counseling. Birth Defects Research 109:1430-1441, 2017.© 2017 Wiley Periodicals, Inc.


Assuntos
Autopsia/métodos , Morte Fetal/etiologia , Natimorto/epidemiologia , Causas de Morte , Morte , Feminino , Feto/patologia , Humanos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Parto , Morte Perinatal/etiologia , Placenta/patologia , Gravidez , Cuidado Pré-Natal , Wisconsin
7.
J Pediatr Gastroenterol Nutr ; 62(5): 687-91, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26913756

RESUMO

OBJECTIVE: Alterations in intestinal function, often characterized as a "leaky gut," have been attributed to children who are on the autism spectrum. Disaccharidase activity, intestinal inflammation, and permeability were analyzed in 61 children with autism and 50 nonautistic individuals with gastrointestinal symptoms. METHODS: All patients had duodenal biopsies assayed for lactase, sucrase, maltase, and palatinase activity. Intestinal permeability was evaluated by rhamnose/lactulose test and measured by high-performance liquid chromatography-mass spectrometry. Intestinal inflammation was evaluated by fecal calprotectin and lactoferrin levels using enzyme-linked immunosorbent assay and histology. RESULTS: Some children with autism had mild levels of mucosal inflammation on intestinal biopsy. Disaccharidase activity was not different in autistic and nonautistic individuals. Fecal calprotectin and lactoferrin were similar in both groups. Differences between lactulose and rhamnose recovery and lactulose/rhamnose ratio in urine were not statistically different in patients with and without autism. CONCLUSIONS: The present study supports the observation that children with autism who have symptoms of gastrointestinal disorders have objective findings similar to children without autism. Neither noninvasive testing nor endoscopic findings identify gastrointestinal pathology specific to autism, but may be of benefit in identifying children with autism who have atypical symptoms.


Assuntos
Transtorno Autístico , Doenças Inflamatórias Intestinais/patologia , Adolescente , Biópsia , Estudos de Casos e Controles , Criança , Serviços de Saúde da Criança , Duodenoscopia , Duodeno/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Mucosa Intestinal/patologia , Lactoferrina/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino
8.
Science ; 341(6144): 406-10, 2013 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-23888041

RESUMO

The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB.


Assuntos
Glicemia/metabolismo , Derivação Gástrica , Glucose/metabolismo , Jejuno/metabolismo , Adaptação Fisiológica , Animais , Colesterol/biossíntese , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/cirurgia , Digestão , Metabolismo Energético , Fluordesoxiglucose F18/metabolismo , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Masculino , Redes e Vias Metabólicas , Metabolômica , Imagem Multimodal , Via de Pentose Fosfato , Tomografia por Emissão de Pósitrons , Ratos , Ratos Long-Evans , Transdução de Sinais , Distribuição Tecidual , Tomografia Computadorizada por Raios X , Regulação para Cima
9.
J Surg Res ; 179(1): e91-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22504136

RESUMO

BACKGROUND: Gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective treatment for severe obesity. RYGB is associated with a remarkable decrease in the rate of death from obesity-related complications, such as diabetes mellitus, coronary artery disease, and cancer. Dissecting the mechanisms of RYGB effects could augment our understanding about the pathogenesis of obesity and its complications. OBJECTIVES AND METHODS: In this study, we describe in detail a mouse model of RYGB that closely reproduces the surgical steps of the human procedure. RESULTS: We show that RYGB in mice has the same effects as in human patients, proving the high translational validity of this model system. We present an intraoperative video to facilitate the widespread use of this complex and difficult method. CONCLUSIONS: The study of the mechanisms of RYGB using this model system can greatly facilitate our understanding about the effects of RYGB in human patients. The reverse engineering of the physiological mechanisms of RYGB could lead to discovery of new, effective, and less invasive treatments.


Assuntos
Cirurgia Bariátrica , Derivação Gástrica , Metabolismo/fisiologia , Modelos Animais , Obesidade/cirurgia , Animais , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
10.
Endocrinology ; 153(5): 2234-44, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22416083

RESUMO

Although the prevalence of obesity has increased dramatically throughout the world during the last 25 yr, its long-term control remains poor. Currently, only gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is associated with substantial and sustained weight loss and resolution or significant improvement of diabetes mellitus and other metabolic obesity-induced complications. Clinical observations and recent studies have suggested that RYGB induces its effects by changing the physiology of weight regulation. Understanding the underlying mechanisms of these profound and sustainable effects could facilitate the development of novel and less invasive treatments against obesity and its complications. To study the physiological mechanisms of RYGB, we have developed a mouse RYGB model that replicates the human operation. The aims of this study were to develop a roadmap for assessing energy expenditure (EE) in animal models of weight loss surgery and to examine the effects of RYGB on EE. We first measured EE by indirect calorimetry in groups of animals that underwent RYGB or a sham operation. Calorimetry data were analyzed using three different methods: normalization by total body mass, allometric scaling, and analysis of covariance modeling. RYGB in mice induced a significant increase in EE that was independent of the method used. An energy balance analysis was then performed, which also confirmed that RYGB-treated animals have higher energy maintenance needs. Finally, we determined the EE components that account for the observed increase in EE, and we found that resting EE and postprandial thermogenesis are the major contributors to this increase.


Assuntos
Metabolismo Basal/fisiologia , Ingestão de Alimentos/fisiologia , Obesidade/metabolismo , Animais , Peso Corporal/fisiologia , Calorimetria Indireta , Derivação Gástrica , Camundongos , Camundongos Obesos , Obesidade/cirurgia
11.
Pediatr Nephrol ; 23(2): 221-31, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18060435

RESUMO

Current evidence implicates a prothrombotic state in the development of Shiga-toxin (Stx)-mediated hemolytic uremic syndrome (HUS). We recently reported that Stx modulates procoagulant activity by enhancing functional tissue factor (TF) activity on cytokine-activated human glomerular endothelial cells (HGECs). Since angiotensin II (Ang II), the key effector of the renin angiotensin system (RAS), has been shown to increase TF expression in vascular tissue, we examined the possible involvement of Ang II in TF expression in HGECs. HGECs were exposed to tumor necrosis factor (TNF)-alpha +/- Stx-1 +/- Ang II. Exogenous Ang II significantly increased TF activity and TF mRNA in TNF-alpha- +/- Stx-1-activated HGECs. This increase was mediated via Ang II type I receptor (AT(1)R), as losartan, an AT(1)R inhibitor, attenuated Ang-II-induced TF activity. To study the effect of endogenous Ang II in TF expression by TNF-alpha +/- Stx-1, HGECs were incubated with losartan or an AT(2)R inhibitor (PD 123319) or an angiotensin-converting enzyme inhibitor (enalapril). Losartan but not PD 123319 decreased TF activity induced by TNF-alpha +/- Stx-1 (P < 0.05). Enalapril, also, dose dependently, downregulated TF expression in HGECs exposed to TNF-alpha +/- Stx-1 (P < 0.05). AT(1)R mRNA was upregulated in TNF-alpha- +/- Stx-1-activated HGECs (P < 0.05). These data indicate that TF expression in TNF-alpha- and Stx-1-activated HGECs is enhanced by exogenous Ang II and that endogenous Ang II production may be upregulated by TNF-alpha +/- Stx-1. Hence, local RAS activation may be important in the development of the thrombotic microangiopathy observed in HUS.


Assuntos
Sistema Renina-Angiotensina/fisiologia , Toxina Shiga I/farmacologia , Tromboplastina/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Enalapril/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Imidazóis/farmacologia , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Losartan/farmacologia , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Toxina Shiga I/metabolismo , Tromboplastina/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Pediatr Nephrol ; 22(6): 813-24, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17357786

RESUMO

Both paired homeo box-2 (Pax-2) and N-myc genes play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation, but whether and how they interact have not been addressed. In the present study, we investigated such a potential interaction using embryonic renal cells in vitro. Mouse embryonic mesenchymal (MK4) cells stably transfected with Pax-2 cDNA in sense (+) or antisense (-) orientation were used for experiments. Pax-2 promoter activity was monitored by luciferase assay. Reactive oxygen species (ROS) generation, cell proliferation, and cell apoptosis were evaluated. We found that Pax-2 and N-myc gene expression were upregulated and downregulated in Pax-2 (+) and Pax-2 (-) stable transformants, respectively. ROS generation and apoptosis were significantly reduced both in Pax-2 (+) transformants compared with Pax-2 (-) transformants and in naïve MK4 cells cultured in either normal- (5 mM) or high-glucose (25 mM) medium. Transient transfection of N-myc cDNA into Pax-2 (-) stable transformants restored Pax-2 gene expression and prevented ROS generation induced by high glucose. Our data demonstrate that Pax-2 gene overexpression prevents hyperglycemia-induced apoptosis, and N-myc appears to provide a positive autocrine feedback on Pax-2 gene expression in embryonic mesenchymal cells.


Assuntos
Apoptose/genética , Proliferação de Células , Células Epiteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Fator de Transcrição PAX2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Comunicação Autócrina/fisiologia , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Retroalimentação Fisiológica , Rim/embriologia , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Fator de Transcrição PAX2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transfecção
13.
Thromb Res ; 116(5): 409-19, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16122554

RESUMO

INTRODUCTION: Cytokine activation of endothelial cell monolayers is associated with cell detachment, microparticle shedding from plasma membranes, and phosphatidylserine appearance in the plasma membrane outer leaflets. While tissue factor expression on activated endothelial cells and microparticles is well documented, the contribution of detached endothelial cells to tissue factor activity is less clear. We studied tissue factor expression and the role of tissue factor pathway inhibitor on adherent and detached endothelial cells and on microparticles following endothelial cell activation with TNF-alpha. MATERIALS AND METHODS: Detached endothelial cells and microparticles were obtained from cultures of human umbilical vein endothelial cells by differential centrifugation of cell culture supernatant. For microparticle capture, an antibody directed against CD146 was used. Functional tissue factor activity was measured by chromogenic assay and tissue factor antigen by ELISA. Endothelial cell and microparticle morphology was examined by light and transmission electron microscopy. RESULTS: After cell activation for 22 h, functional tissue factor activity was distributed as follows: 60%, adherent endothelial cells; 35%, detached cells; and 5%, microparticles. Tissue factor protein followed a similar distribution. Cell detachment was 47%. Electron microscopy demonstrated shedding of microparticles with a diameter of 0.1-0.6 mum. Cy3-annexin V revealed increased phosphatidylserine on activated adherent endothelial cells and microparticles. Pre-incubation of adherent and detached endothelial cells and microparticles with anti-tissue factor antibody blocked factor Xa production. Pre-incubation with anti-tissue factor pathway inhibitor antibody increased tissue factor activity of adherent endothelial cells 2.8-fold, detached cells 1.4-fold, and microparticles 45-fold. CONCLUSIONS: Detached endothelial cells as well as microparticles from activated endothelial cell monolayers express tissue factor activity, and this activity on microparticles is markedly inhibited by microparticle-associated tissue factor pathway inhibitor.


Assuntos
Endotélio Vascular/metabolismo , Tromboplastina/metabolismo , Adesão Celular , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Separação Celular , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/ultraestrutura , Humanos , Microscopia Eletrônica , Tamanho da Partícula , Tromboplastina/isolamento & purificação
14.
Kidney Int ; 67(6): 2254-66, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15882267

RESUMO

BACKGROUND: The pathophysiology of hemolytic uremic syndrome (HUS) is incompletely established. Based on clinical studies demonstrating the presence of prothrombotic plasma markers in patients with HUS, we hypothesized that Shiga toxin might cause activation of the coagulation pathway by augmenting tissue factor, the major initiator of coagulation. METHODS: Human proximal tubular epithelial cells (PTECs) [human kidney-2 (HK-2 cells)] were exposed to Shiga toxin-1, and expression of tissue factor, cell detachment, protein synthesis, caspase-3 activity, and Shiga toxin-1 binding were examined. Results. HK-2 cells expressed constitutive surface tissue factor activity and increased their tissue factor expression upon exposure to Shiga toxin-1. Shiga toxin-1 bound to HK-2 cells and inhibited protein synthesis. The up-regulation of tissue factor was dose- and time-dependent and strongly correlated with cell detachment and increase in caspase-3 activity caused by Shiga toxin-1 exposure. A general caspase inhibitor simultaneously inhibited HK-2 cell detachment and tissue factor up-regulation while mutant Shiga toxin-1 neither caused cell detachment, protein synthesis inhibition, nor increase in tissue factor activity. Tissue factor activity elicited by Shiga toxin-1 was abrogated by a monoclonal antitissue factor antibody. Calphostin C, a protein kinase C (PKC) inhibitor, partially blocked tissue factor up-regulation, indicating possible involvement of PKC-dependent mechanism. CONCLUSION: These data, taken together, suggest a strong link between Shiga toxin-induced up-regulation of tissue factor activity, cytotoxicity, and apoptosis in HK-2 cells. The proximal tubule is a target of Shiga toxin in HUS, and it seems plausible that injured proximal tubular cells trigger the activation of the coagulation system, the formation of intrarenal platelet-fibrin thrombi, and the development of acute renal failure in HUS.


Assuntos
Túbulos Renais Proximais/efeitos dos fármacos , Toxina Shiga I/toxicidade , Tromboplastina/biossíntese , Clorometilcetonas de Aminoácidos/farmacologia , Caspase 3 , Caspases/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/metabolismo , Humanos , Túbulos Renais Proximais/metabolismo , Lipoproteínas/fisiologia , Biossíntese de Proteínas/efeitos dos fármacos , Proteína Quinase C/fisiologia , Toxina Shiga I/metabolismo , Tromboplastina/análise , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
15.
Curr Opin Neurol ; 15(2): 139-44, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11923626

RESUMO

The role of plasma-phase risk factors for stroke in the pediatric age group is presently unclear due to the lack of sufficiently large prospective studies, and due to the fact that these risk factors do not apply uniformly to newborns, children with sickle cell disease, and older children. Available evidence indicates that factor V Leiden, prothrombin 20210A, and lipoprotein (a) are all important in the pathogenesis of arterial ischemic stroke in older children, but the role of other plasma-phase risk factors remains uncertain. The contribution of these risk factors to newborn stroke and the stroke of children with sickle cell disease is similarly unclear, likely because the ischemia in affected children is predominantly due to nonhematologic perinatal events and erythrocyte adhesion to endothelium with obstruction of flow in the cerebral microcirculation, respectively. Evaluation of childhood stroke should, in our view, always be performed from the standpoint of the presenting clinical symptoms, diagnostic imaging, and determination of plasma-phase risk factors. Therapeutic anticoagulation and use of antiplatelet agents at present focus on the older child.


Assuntos
Isquemia Encefálica/etiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Anticoagulantes/metabolismo , Isquemia Encefálica/sangue , Criança , Fator V/genética , Fator V/metabolismo , Humanos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Imagem por Ressonância Magnética , Protrombina/genética , Protrombina/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA