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1.
Cell Death Dis ; 9(5): 474, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29700293

RESUMO

DNA methylation is a key epigenetic modification that can regulate gene expression. Genomic DNA hypomethylation is commonly found in many gastrointestinal (GI) diseases. Dysregulated gene expression in GI smooth muscle cells (GI-SMCs) can lead to motility disorders. However, the consequences of genomic DNA hypomethylation within GI-SMCs are still elusive. Utilizing a Cre-lox murine model, we have generated SMC-restricted DNA methyltransferase 1 (Dnmt1) knockout (KO) mice and analyzed the effects of Dnmt1 deficiency. Dnmt1-KO pups are born smaller than their wild-type littermates, have shortened GI tracts, and lose peristaltic movement due to loss of the tunica muscularis in their intestine, causing massive intestinal dilation, and death around postnatal day 21. Within smooth muscle tissue, significant CpG hypomethylation occurs across the genome at promoters, introns, and exons. Additionally, there is a marked loss of differentiated SMC markers (Srf, Myh11, miR-133, miR-143/145), an increase in pro-apoptotic markers (Nr4a1, Gadd45g), loss of cellular connectivity, and an accumulation of coated vesicles within SMC. Interestingly, we observed consistent abnormal expression patterns of enzymes involved in DNA methylation between both Dnmt1-KO mice and diseased human GI tissue. These data demonstrate that DNA hypomethylation in embryonic SMC, via congenital Dnmt1 deficiency, contributes to massive dysregulation of gene expression and is lethal to GI-SMC. These results suggest that Dnmt1 has a necessary role in the embryonic, primary development process of SMC with consistent patterns being found in human GI diseased tissue.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Gastroenteropatias/embriologia , Miócitos de Músculo Liso/enzimologia , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/patologia
2.
Ultrasound Q ; 32(1): 15-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26086457

RESUMO

Prenatal detection of a wide variety of anomalies and masses of the gastrointestinal tract is now possible. Prenatal imaging with ultrasonography and in selected cases magnetic resonance imaging provides invaluable information to the referring obstetrician, the maternal fetal medicine specialist, the neonatologist and pediatrician who will care for the child after birth, the surgeons and pediatric specialists who will repair or manage a prenatally detected anomaly, and of course to the parents, allowing them to prepare psychologically and financially for the specific interventions that may be needed for their child. Additional screening for associated anomalies can take place, route of delivery can be decided, and arrangements for delivery in an appropriate setting can be made. Prenatal detection also allows for consideration for pregnancy termination. This article will give a broad overview of anomalies of the gastrointestinal tract that can be detected prenatally and their imaging appearance postnatally.


Assuntos
Gastroenteropatias/diagnóstico por imagem , Gastroenteropatias/embriologia , Trato Gastrointestinal/diagnóstico por imagem , Trato Gastrointestinal/embriologia , Imageamento por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Idoso , Feminino , Humanos , Aumento da Imagem/métodos , Recém-Nascido , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como Assunto
3.
Am J Physiol Gastrointest Liver Physiol ; 306(5): G382-93, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24458021

RESUMO

Intra-amniotic exposure to proinflammatory agonists causes chorioamnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO(+), CD3(+), and FoxP3(+) cells), tumor necrosis factor-α, and interferon-γ expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.


Assuntos
Corioamnionite/patologia , Doenças Fetais/etiologia , Gastroenteropatias/etiologia , Pneumonia/complicações , Líquido Amniótico , Animais , Diferenciação Celular , Proliferação de Células , Corioamnionite/induzido quimicamente , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Doenças Fetais/induzido quimicamente , Gastroenteropatias/embriologia , Gastroenteropatias/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Ileíte/induzido quimicamente , Ileíte/embriologia , Ileíte/patologia , Íleo/embriologia , Íleo/patologia , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/patologia , Mucosa Intestinal/citologia , Lipopolissacarídeos/toxicidade , Pneumonia/induzido quimicamente , Pneumonia/patologia , Gravidez , Distribuição Aleatória , Ovinos , Linfócitos T Reguladores , Receptores Toll-Like
4.
Nat Rev Gastroenterol Hepatol ; 10(1): 43-57, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23229326

RESUMO

The enteric nervous system (ENS) arises from neural crest-derived cells that migrate into and along the gut, leading to the formation of a complex network of neurons and glial cells that regulates motility, secretion and blood flow. This Review summarizes the progress made in the past 5 years in our understanding of ENS development, including the migratory pathways of neural crest-derived cells as they colonize the gut. The importance of interactions between neural crest-derived cells, between signalling pathways and between developmental processes (such as proliferation and migration) in ensuring the correct development of the ENS is also presented. The signalling pathways involved in ENS development that were determined using animal models are also described, as is the evidence for the involvement of the genes encoding these molecules in Hirschsprung disease-the best characterized paediatric enteric neuropathy. Finally, the aetiology and treatment of Hirschsprung disease in the clinic and the potential involvement of defects in ENS development in other paediatric motility disorders are outlined.


Assuntos
Sistema Nervoso Entérico/embriologia , Gastroenteropatias/embriologia , Doença de Hirschsprung/embriologia , Crista Neural/embriologia , Transdução de Sinais/fisiologia , Animais , Movimento Celular , Proliferação de Células , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/fisiologia , Gastroenteropatias/patologia , Gastroenteropatias/fisiopatologia , Doença de Hirschsprung/patologia , Doença de Hirschsprung/fisiopatologia , Humanos , Camundongos , Modelos Animais , Crista Neural/citologia , Crista Neural/fisiologia
6.
Postgrad Med J ; 86(1011): 42-51; quiz 50, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20065340

RESUMO

Improvements in magnetic resonance (MR) imaging now permit diagnostic images of the fetus to be obtained. Ultrasound remains vital in all aspects of fetal imaging but MR provides a useful second line imaging test. Its value is best researched in fetal central nervous system disorders but it can be applied in other areas too. This pictorial review shows many of the commonly encountered problems. The pictures have a powerful impact on parental understanding. Future research must involve determination of the prognosis of abnormalities found at MR.


Assuntos
Feto/anatomia & histologia , Imageamento por Ressonância Magnética , Diagnóstico Pré-Natal/métodos , Sistema Nervoso Central/embriologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/embriologia , Hérnia Diafragmática/diagnóstico , Hérnia Diafragmática/embriologia , Humanos , Ilustração Médica , Disrafismo Espinal/diagnóstico , Disrafismo Espinal/embriologia , Doenças Urológicas/diagnóstico , Doenças Urológicas/embriologia
7.
Dev Dyn ; 238(12): 3111-25, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19924810

RESUMO

During digestive organogenesis, the primitive gut tube (PGT) undergoes dramatic elongation and forms a lumen lined by a single-layer of epithelium. In Xenopus, endoderm cells in the core of the PGT rearrange during gut elongation, but the morphogenetic mechanisms controlling their reorganization are undetermined. Here, we define the dynamic changes in endoderm cell shape, polarity, and tissue architecture that underlie Xenopus gut morphogenesis. Gut endoderm cells intercalate radially, between their anterior and posterior neighbors, transforming the nearly solid endoderm core into a single layer of epithelium while concomitantly eliciting "radially convergent" extension within the gut walls. Inhibition of Rho/ROCK/Myosin II activity prevents endoderm rearrangements and consequently perturbs both gut elongation and digestive epithelial morphogenesis. Our results suggest that the cellular and molecular events driving tissue elongation in the PGT are mechanistically analogous to those that function during gastrulation, but occur within a novel cylindrical geometry to generate an epithelial-lined tube.


Assuntos
Endoderma/embriologia , Gástrula/embriologia , Morfogênese/genética , Miosina não Muscular Tipo IIB/fisiologia , Quinases Associadas a rho/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologia , Animais , Animais Geneticamente Modificados , Padronização Corporal/genética , Polaridade Celular/genética , Forma Celular/genética , Embrião não Mamífero , Endoderma/citologia , Endoderma/metabolismo , Gastroenteropatias/congênito , Gastroenteropatias/embriologia , Trato Gastrointestinal/anormalidades , Trato Gastrointestinal/embriologia , Gástrula/metabolismo , Modelos Biológicos , Miosina não Muscular Tipo IIB/genética , Miosina não Muscular Tipo IIB/metabolismo , Transdução de Sinais/genética , Xenopus/embriologia , Xenopus/genética , Xenopus/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Best Pract Res Clin Obstet Gynaecol ; 23(6): 765-77, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19666240

RESUMO

Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. A complex and dynamic interaction of maternal, placental and fetal environment is involved in ensuring normal fetal growth. An imbalance or lack of coordination in this complex system may lead to IUGR. Animal studies have given us an insight into some aspects of the basic pathophysiology of IUGR, and recent technologies such as Doppler studies of maternal and fetal vessels have added further information. The aetiologies of IUGR are diverse, involving multiple complex mechanisms, which make understanding of the pathophysiology difficult. However, particular focus is placed on the mechanisms involved in uteroplacental insufficiency as a cause of IUGR, as (1) it is common, (2) outcome can be good if timing of delivery is optimal and (3) it may be amenable to therapy in the future. While the research into the pathophysiology of IUGR continues, there have been interesting discoveries related to the genetic contribution to IUGR and the intrauterine programming of adult-onset diseases attributed to IUGR.


Assuntos
Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/etiologia , Encefalopatias/embriologia , Doenças Cardiovasculares/embriologia , Doenças do Sistema Endócrino/embriologia , Feminino , Gastroenteropatias/embriologia , Doenças Genéticas Inatas/embriologia , Idade Gestacional , Humanos , Nefropatias/embriologia , Pneumopatias/embriologia , Doenças Musculares/embriologia , Doenças Placentárias/fisiopatologia , Circulação Placentária/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia
9.
J Pediatr Surg ; 43(4): 647-53, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18405710

RESUMO

PURPOSE: In the setting of gastroschisis, the clinical significance of prenatal ultrasound findings of secondary changes in bowel appearance remains unknown. The purpose of this study was to correlate prenatal identification of additional gastrointestinal sonographic abnormalities with postnatal clinical outcome. METHODS: A retrospective review was conducted on 64 fetuses with a prenatal diagnosis of gastroschisis treated at the Children's Hospital of Philadelphia from 2000 to 2007. Postnatal outcomes were compared between newborns with additional sonographic gastrointestinal abnormalities and those without secondary changes to the bowel appearance. RESULTS: Thirty (47%) patients had at least one gastrointestinal abnormality (eg, bowel dilatation, echogenic bowel, thickened bowel, matted bowel, herniation of the stomach through the abdominal wall defect, or segmental loss of bowel peristalsis) on prenatal ultrasound. There were no significant differences between groups with respect to the time to initial and full enteral nutrition, total hospital stay, requirement for ventilator support, central line infection rates, reoperation rates, or mortality. CONCLUSIONS: In the setting of gastroschisis, isolated findings of gastrointestinal abnormalities on prenatal ultrasound do not correlate with adverse postnatal outcome.


Assuntos
Gastroenteropatias/congênito , Trato Gastrointestinal/anormalidades , Trato Gastrointestinal/diagnóstico por imagem , Gastrosquise/diagnóstico por imagem , Ultrassonografia Pré-Natal , Cesárea/estatística & dados numéricos , Nutrição Enteral/estatística & dados numéricos , Seguimentos , Gastroenteropatias/embriologia , Gastroenteropatias/terapia , Gastrosquise/mortalidade , Humanos , Recém-Nascido , Tempo de Internação , Nutrição Parenteral Total/estatística & dados numéricos , Philadelphia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
11.
Ultrasound Obstet Gynecol ; 27(5): 537-44, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16538610

RESUMO

OBJECTIVES: To evaluate the potential of a single-shot thick-slab RARE (rapid acquisition with relaxation enhancement) sequence in fetal thoracoabdominal magnetic resonance (MR) examinations compared with multislice T2-weighted sequence and postnatal imaging. METHODS: RARE sequence is rapid and provides very heavily T2-weighted images. Twenty-seven fetal thoracoabdominal MR imaging examinations were performed at 23-38 weeks using our conventional protocol. This included thin multislice T2-weighted half-Fourier acquired single-shot turbo spin-echo (HASTE) sequence and thin-slice GE (gradient echo) T1-weighted images with a 1.5-T MR unit. A single-shot thick-slab (60 mm) RARE sequence was added to all MR examinations. The acquisitions were obtained with the mother breath-holding. The thick-slab heavily T2-weighted images were compared with HASTE sequence images and with postnatal imaging in all cases. RESULTS: The thick-slab RARE sequence did not show additional abnormalities compared with the conventional protocol but displayed an overall view of the urinary tract, tracheobronchial tract and small bowel. It gave information that was highly correlated with postnatal imaging, such as abdominal plain films, chest film or cystography. The quality of the thick-slab RARE images was considered as good in 13 cases (48%), moderate in 12 cases (45%) and poor in two cases (7%). CONCLUSION: Although thick-slab RARE sequence does not show additional abnormalities compared with the conventional protocol, it illustrates very nicely static fluids such as those in urinary dilatation, the esophagus and small bowel (normal or dilated) and thoracic cystic masses. It is very rapid (5 s) to perform, allows fetal hydrography, and correlates well with postnatal imaging.


Assuntos
Doenças Fetais/diagnóstico , Imageamento por Ressonância Magnética/métodos , Diagnóstico Pré-Natal/métodos , Adulto , Feminino , Doenças Urogenitais Femininas/diagnóstico , Doenças Urogenitais Femininas/embriologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/embriologia , Humanos , Gravidez , Sensibilidade e Especificidade
12.
Turk J Pediatr ; 46(4): 388-92, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15641280

RESUMO

Meckel-Gruber syndrome (MGS) is rare autosomal recessive disorder characterized by occipital encephalocele, postaxial polydactyly and polycystic kidneys. A one-day-old girl was admitted to our clinic with occipital encephalocele, polydactyly, ulnar deviation of left hand and failure to thrive. Patient's parents were first-degree relatives. It was learned that the patient's two sisters had died from similar anomalies. In our case, prenatal sonographic examination revealed oligohydramnios and hydrocephaly in the 33rd week of gestation. At birth her weight was 2200 g. Both physical and radiological examinations diagnosed MGS. Cranial computed tomography (CT) showed agenesis of cerebellar vermis and corpus callosum, and cystic dilatation of the 4th ventricle and lateral ventricles. The case died due to severe respiratory distress in the Intensive Care Unit on day 38. In the postmortem examination, longitudinally located intestine-like stomach was determined without a fundus. In conclusion, intestinal malrotation and hepatic portal fibrosis have been reported in MGS in the literature. In this case, a longitudinally located intestine-like stomach in MGS is reported for the first time. No such association to our knowledge has been previously reported.


Assuntos
Anormalidades Múltiplas/patologia , Trato Gastrointestinal/anormalidades , Hidrocefalia/patologia , Anormalidades Múltiplas/embriologia , Evolução Fatal , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/embriologia , Mãos/diagnóstico por imagem , Mãos/patologia , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/embriologia , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Oligo-Hidrâmnio/patologia , Gravidez , Radiografia , Síndrome , Ultrassonografia Pré-Natal
13.
Am J Med Genet ; 115(4): 221-30, 2002 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-12503117

RESUMO

This review describes recent advances using animal models in the analysis of the molecular controls of gastrointestinal development, with specific attention to mutations causing maldevelopment similar to those seen in human gut malformations. By focusing on specific human gut pathologic conditions and maldevelopment, we describe the probable roles of signaling pathways, including the hedgehog pathway, the bone morphogenic protein pathway, and the role of the homeotic genes.


Assuntos
Sistema Digestório , Modelos Animais de Doenças , Gastroenteropatias/etiologia , Animais , Sistema Digestório/embriologia , Sistema Digestório/inervação , Anormalidades do Sistema Digestório , Sistema Nervoso Entérico , Gastroenteropatias/embriologia , Gastroenteropatias/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Humanos , Morfogênese , Transativadores
14.
Ultrasound Obstet Gynecol ; 19(5): 467-70, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11982979

RESUMO

OBJECTIVE: The aim of this observational study was to construct an ultrasound index of fetal gastric size for the prenatal detection of congenital digestive tract obstruction. SUBJECTS: A total of 386 fetal measurements were performed in routine ultrasonographic examinations of women with normal singleton pregnancies between 18 and 39 weeks of gestation. Gastric measurements were also performed in 13 fetuses with digestive tract obstruction. METHODS: The ultrasound plane which included the pylorus and which provided the largest stomach area was used for definition and measurement of gastric area and maximal longitudinal dimension. The transverse section at the center of the gastric corpus was used for transverse and anteroposterior dimensions. Gastric volumes were calculated as a prolate ellipsoid. The gastric area ratio was defined as the gastric area divided by the transverse abdominal area. Biparietal diameter (BPD) and abdominal transverse area were also measured. RESULTS: The fetal gastric area was significantly correlated with fetal gastric volume (r = 0.91) and gestational age (r = 0.74). However, the correlation coefficient for gastric area with gestational age was smaller than those of the BPD (r = 0.97) with gestational age and abdominal transverse area with gestational age (r = 0.97). Gastric area ratio decreased slightly towards term. The gastric area ratio was below the 95% confidence intervals for the predicted values in all five fetuses with esophageal atresia, and exceeded the 95% confidence intervals in seven of the eight fetuses with duodenal atresia or intestinal tract obstruction. CONCLUSION: Fetal gastric area correlates with ultrasound-determined gastric volume measurements and appears to be useful in the assessment of digestive tract anomalies.


Assuntos
Gastroenteropatias/diagnóstico por imagem , Estenose Pilórica/diagnóstico por imagem , Estômago/embriologia , Ultrassonografia Pré-Natal/métodos , Estudos de Casos e Controles , Intervalos de Confiança , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Gastroenteropatias/embriologia , Idade Gestacional , Humanos , Gravidez , Probabilidade , Estenose Pilórica/embriologia , Valores de Referência , Sensibilidade e Especificidade , Estômago/anatomia & histologia , Estômago/diagnóstico por imagem
16.
Early Hum Dev ; 40(1): 1-11, 1994 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-7712956

RESUMO

To reveal which fetal life-threatening diseases significantly contribute to impairment of in-utero urine production and also to determine the gestational age at which time aberrant urine production becomes manifest, we observed 376 compromised fetuses (subject group) at 21-42 weeks' gestation using ultrasonography. A total of 358 uncomplicated fetuses, aged 21-40 weeks, were separately chosen as a control group. Statistical differences in the urine production rate between subject- and control-group fetuses were analysed using the Grubbs-Smirnoff test at corresponding gestational ages. Significant decreases were evident in: bilateral renal agenesis (100%) at 21-23 weeks; bilateral infantile polycystic kidney (100%) at 21-28 weeks; bilateral multicystic kidney disease (100%) at 21-31 weeks; donor fetuses with twin transfusion syndrome (TTS) (100%) at 21-28 weeks; post-term fetuses (100%) at 42 weeks; bilateral hydronephrosis (60%) at 21-38 weeks; non-immunologic hydrops fetalis (42%) at 21-35 weeks; intrauterine growth retardation (41%) at 29-40 weeks; and upper gastrointestinal tract obstruction (36%) at 30-38 weeks. Significant increases were noted in: recipient fetuses with TTS (100%) at 21-28 weeks, and unilateral hydronephrosis (36%) at 27-32 weeks. All indicate that urine production clearly delineates various fetal conditions in utero, in a closely disease-dependent relation to gestational age.


Assuntos
Diurese , Doenças Fetais/fisiopatologia , Feto/fisiologia , Idade Gestacional , Feminino , Retardo do Crescimento Fetal/embriologia , Retardo do Crescimento Fetal/fisiopatologia , Transfusão Feto-Fetal/fisiopatologia , Gastroenteropatias/embriologia , Gastroenteropatias/fisiopatologia , Humanos , Hidronefrose/embriologia , Hidronefrose/fisiopatologia , Hidropisia Fetal/embriologia , Hidropisia Fetal/fisiopatologia , Rim/anormalidades , Doenças Renais Císticas/embriologia , Doenças Renais Císticas/fisiopatologia , Doenças Renais Policísticas/embriologia , Doenças Renais Policísticas/fisiopatologia , Gravidez
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