58 results on '"Hernias, Diaphragmatic, Congenital pathology"'
Search Results
2. Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.
- Author
-
Antounians L, Figueira RL, Kukreja B, Litvack ML, Zani-Ruttenstock E, Khalaj K, Montalva L, Doktor F, Obed M, Blundell M, Wu T, Chan C, Wagner R, Lacher M, Wilson MD, Post M, Kalish BT, and Zani A
- Subjects
- Animals, Rats, Humans, Stem Cells metabolism, Inflammation metabolism, Inflammation pathology, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital therapy, Female, Macrophages metabolism, Disease Models, Animal, Cell Differentiation, Fetus, Pregnancy, Stem Cell Transplantation methods, Extracellular Vesicles metabolism, Amniotic Fluid cytology, Amniotic Fluid metabolism, Lung pathology, Lung metabolism
- Abstract
Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.
- Published
- 2024
- Full Text
- View/download PDF
3. The brain of fetuses with congenital diaphragmatic hernia shows signs of hypoxic injury with loss of progenitor cells, neurons, and oligodendrocytes.
- Author
-
Biouss G, Antounians L, Aguet J, Kopcalic K, Fakhari N, Baranger J, Mertens L, Villemain O, and Zani A
- Subjects
- Animals, Rats, Humans, Female, Stem Cells pathology, Fetus pathology, Disease Models, Animal, Pregnancy, Male, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital diagnostic imaging, Neurons pathology, Neurons metabolism, Oligodendroglia pathology, Oligodendroglia metabolism, Brain pathology, Brain diagnostic imaging, Brain embryology
- Abstract
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
4. Review of the Evaluation of Pulmonary Hypoplasia as an Important Determinant of Clinical Outcomes in Infants with Congenital Diaphragmatic Hernia.
- Author
-
Kuchnowska D, Luterek K, Węgrzyn P, and Kosiński P
- Subjects
- Pregnancy, Female, Infant, Newborn, Humans, Prenatal Diagnosis methods, Lung pathology, Fetoscopy methods, Hernia, Ultrasonography, Prenatal, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology
- Abstract
Pulmonary hypoplasia is one of main causes of neonatal mortality and morbidity in patients with congenital diaphragmatic hernia. With most cases diagnosed prenatally, the emphasis is put on prediction of the severity of this defect. Several attempts are made to reduce the mortality and provide optimal prenatal and postnatal care. Appropriate estimation of risk of pulmonary hypoplasia also provides an important inclusion criterion for prenatal intervention. The main tool used for the detection and prediction of pulmonary hypoplasia is ultrasound, with an increasing number of available formulas to estimate the risk of occurrence of this phenomenon and complication associated with it. For most of the formulas used in this measurement method, the main limitations are either gestational-age dependency or limited research. Other imaging methods used to assess the risk of pulmonary hypoplasia involve magnetic resonance imaging and vascular assessment of affected lungs. The limitation in these remains the limited accessibility. Currently, the most widely used indexes are observed-to-expected lungs-to-head ratio and presence of liver herniation. These are the 2 most commonly used measurement methods, as they are the basis for patient qualification for fetoscopic endoluminal tracheal occlusion. This article aims to review the evaluation of pulmonary hypoplasia or hypoplastic lung disease as an important determinant of clinical outcomes in infants with congenital diaphragmatic hernia. In this review, we emphasize the importance of early prenatal diagnosis of congenital diaphragmatic hernia and present a summary of different methods of prenatal risk assessment of lung hypoplasia in congenital diaphragmatic hernia.
- Published
- 2024
- Full Text
- View/download PDF
5. Single-cell transcriptomic profiling of microvascular endothelial cell heterogeneity in congenital diaphragmatic hernia.
- Author
-
Robertson JO, Bazeley P, Erzurum SC, and Asosingh K
- Subjects
- Humans, Rats, Animals, Endothelial Cells, Transcriptome, Rats, Sprague-Dawley, Lung pathology, Disease Models, Animal, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital pathology
- Abstract
Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that microvascular endothelial cell (EC) heterogeneity is different in CDH lungs and related to lung underdevelopment and remodeling. To test this, we evaluated rat fetuses at E21.5 in a nitrofen model of CDH to compare lung transcriptomes among healthy controls (2HC), nitrofen-exposed controls (NC) and nitrofen-exposed subjects with CDH. Single-cell RNA sequencing with unbiased clustering revealed 3 distinct microvascular EC clusters: a general population (mvEC), a proliferative population and a population high in hemoglobin. Only the CDH mvEC cluster had a distinct inflammatory transcriptomic signature as compared to the 2HC and NC endothelial cells, e.g. greater activation and adhesion of inflammatory cells and production of reactive oxygen species. Furthermore, CDH mvECs had downregulated Ca4, Apln and Ednrb gene expression. Those genes are markers for ECs important to lung development, gas exchange and alveolar repair (mvCa4+). mvCa4+ ECs were reduced in CDH (2HC [22.6%], NC [13.1%] and CDH [5.3%], p < 0.0001). Overall, these findings identify transcriptionally distinct microvascular endothelial cell clusters in CDH, including the distinctly inflammatory mvEC cluster and the depleted group of mvCa4+ ECs, which together may contribute to pathogenesis., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
6. The myocardial capillary network is altered in congenital diaphragmatic hernia in the fetal rabbit model.
- Author
-
Nour ALA, Fabro AT, Batah SS, Oria M, Peiro JL, and Sbragia L
- Subjects
- Pregnancy, Female, Rabbits, Animals, Ki-67 Antigen, Lung pathology, Myocardium, Fetus, Hernias, Diaphragmatic, Congenital complications, Hernias, Diaphragmatic, Congenital pathology
- Abstract
Congenital diaphragmatic hernia (CDH) is associated with thoracic compression of the lungs and heart caused by the herniated abdominal content, leading to cardiac modifications including pressure and vascular changes. Our aim was to investigate the experimental immunoexpression of the capillary proliferation, activation, and density of Ki-67, VEGFR2, and lectin in the myocardium after surgical creation of a diaphragmatic defect. Pregnant New Zealand rabbits were operated on the 25th gestational day in order to create left-sided CDH (LCDH, n=9), right-sided CDH (RCDH, n=9), and Control (n=9), for a total of 27 fetuses in 19 pregnant rabbits. Five days after the procedure, animals were sacrificed, and histology and immunohistochemistry studies of the harvested hearts were performed. Total body weight and heart weight were not significantly different among groups (P=0.702 and 0.165, respectively). VEGFR2 expression was increased in both ventricles in the RCDH group (P<0.0001), and Ki-67 immunoexpression was increased in the left ventricle in the LCDH group compared to Control and RCDH groups (P<0.0001). In contrast, capillary density was reduced in the left ventricle in the LCDH compared to the Control and RCDH groups (P=0.002). Left and right ventricles responded differently to CDH in this model depending on the laterality of the diaphragmatic defect. This surgical model of diaphragmatic hernia was associated with different expression patterns of capillary proliferation, activation, and density in the myocardium of the ventricles of newborn rabbits.
- Published
- 2023
- Full Text
- View/download PDF
7. Cubilin-, megalin-, and Dab2-dependent transcription revealed by CRISPR/Cas9 knockout in kidney proximal tubule cells.
- Author
-
Long KR, Rbaibi Y, Bondi CD, Ford BR, Poholek AC, Boyd-Shiwarski CR, Tan RJ, Locker JD, and Weisz OA
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Agenesis of Corpus Callosum genetics, Agenesis of Corpus Callosum metabolism, Agenesis of Corpus Callosum pathology, Animals, Apoptosis Regulatory Proteins genetics, Cells, Cultured, Databases, Genetic, Gene Regulatory Networks, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural metabolism, Hearing Loss, Sensorineural pathology, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Humans, Kidney Tubules, Proximal pathology, Low Density Lipoprotein Receptor-Related Protein-2 genetics, Male, Mice, Knockout, Monodelphis, Myopia genetics, Myopia metabolism, Myopia pathology, Proteinuria genetics, Proteinuria metabolism, Proteinuria pathology, Receptors, Cell Surface genetics, Renal Tubular Transport, Inborn Errors genetics, Renal Tubular Transport, Inborn Errors metabolism, Renal Tubular Transport, Inborn Errors pathology, Mice, Adaptor Proteins, Signal Transducing metabolism, Apoptosis Regulatory Proteins metabolism, CRISPR-Associated Protein 9 genetics, CRISPR-Cas Systems, Gene Knockout Techniques, Kidney Tubules, Proximal metabolism, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Receptors, Cell Surface metabolism, Transcription, Genetic
- Abstract
The multiligand receptors megalin ( Lrp2 ) and cubilin ( Cubn ) and their endocytic adaptor protein Dab2 ( Dab2 ) play essential roles in maintaining the integrity of the apical endocytic pathway of proximal tubule (PT) cells and have complex and poorly understood roles in the development of chronic kidney disease. Here, we used RNA-sequencing and CRISPR/Cas9 knockout (KO) technology in a well-differentiated cell culture model to identify PT-specific transcriptional changes that are directly consequent to the loss of megalin, cubilin, or Dab2 expression. KO of Lrp2 had the greatest transcriptional effect, and nearly all genes whose expression was affected in Cubn KO and Dab2 KO cells were also changed in Lrp2 KO cells. Pathway analysis and more granular inspection of the altered gene profiles suggested changes in pathways with immunomodulatory functions that might trigger the pathological changes observed in KO mice and patients with Donnai-Barrow syndrome. In addition, differences in transcription patterns between Lrp2 and Dab2 KO cells suggested the possibility that altered spatial signaling by aberrantly localized receptors contributes to transcriptional changes upon the disruption of PT endocytic function. A reduction in transcripts encoding sodium-glucose cotransporter isoform 2 was confirmed in Lrp2 KO mouse kidney lysates by quantitative PCR analysis. Our results highlight the role of megalin as a master regulator and coordinator of ion transport, metabolism, and endocytosis in the PT. Compared with the studies in animal models, this approach provides a means to identify PT-specific transcriptional changes that are directly consequent to the loss of these target genes. NEW & NOTEWORTHY Megalin and cubilin receptors together with their adaptor protein Dab2 represent major components of the endocytic machinery responsible for efficient uptake of filtered proteins by the proximal tubule (PT). Dab2 and megalin expression have been implicated as both positive and negative modulators of kidney disease. We used RNA sequencing to knock out CRISPR/Cas9 cubilin, megalin, and Dab2 in highly differentiated PT cells to identify PT-specific changes that are directly consequent to knockout of each component.
- Published
- 2022
- Full Text
- View/download PDF
8. Decreased neonatal morbidity in 'stomach-down' left congenital diaphragmatic hernia: implications of prenatal ultrasound diagnosis for counseling and postnatal management.
- Author
-
Didier RA, Oliver ER, Rungsiprakarn P, Debari SE, Adams SE, Hedrick HL, Adzick NS, Khalek N, Howell LJ, and Coleman BG
- Subjects
- Adult, Cephalometry, Female, Fetus diagnostic imaging, Fetus pathology, Head diagnostic imaging, Head pathology, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital embryology, Humans, Infant, Newborn, Infant, Newborn, Diseases diagnostic imaging, Infant, Newborn, Diseases embryology, Lung diagnostic imaging, Lung embryology, Lung pathology, Male, Morbidity, Pregnancy, Retrospective Studies, Stomach diagnostic imaging, Stomach embryology, Hernias, Diaphragmatic, Congenital pathology, Infant, Newborn, Diseases pathology, Magnetic Resonance Imaging, Stomach pathology, Ultrasonography, Prenatal
- Abstract
Objective: To evaluate the influence of stomach position on postnatal outcome in cases of left congenital diaphragmatic hernia (CDH) without liver herniation, diagnosed and characterized on prenatal ultrasound (US), by comparing those with ('stomach-up' CDH) to those without ('stomach-down' CDH) intrathoracic stomach herniation., Methods: Infants with left CDH who underwent prenatal US and postnatal repair at our institution between January 2008 and March 2017 were eligible for inclusion in this retrospective study. Detailed prenatal US examinations, fetal magnetic resonance imaging (MRI) studies, operative reports and medical records of infants enrolled in the pulmonary hypoplasia program at our institution were reviewed. Cases with liver herniation and those with an additional anomaly were excluded. Cases in which bowel loops were identified within the fetal chest on US while the stomach was intra-abdominal were categorized as having stomach-down CDH. Cases in which bowel loops and the stomach were visualized within the fetal chest on US were categorized as having stomach-up CDH. Prenatal imaging findings and postnatal outcomes were compared between the two groups., Results: In total, 152 patients with left CDH were initially eligible for inclusion. Seventy-eight patients had surgically confirmed liver herniation and were excluded. Of the 74 included CDH cases without liver herniation, 28 (37.8%) had stomach-down CDH and 46 (62.2%) had stomach-up CDH. Of the 28 stomach-down CDH cases, 10 (35.7%) were referred for a suspected lung lesion. Sixty-eight (91.9%) cases had postnatal outcome data available for analysis. There was no significant difference in median observed-to-expected (o/e) lung-area-to-head-circumference ratio (LHR) between cases with stomach-down CDH and those with stomach-up CDH (41.5% vs 38.4%; P = 0.41). Furthermore, there was no difference in median MRI o/e total lung volume (TLV) between the two groups (49.5% vs 44.0%; P = 0.22). Compared with stomach-up CDH patients, stomach-down CDH patients demonstrated lower median duration of intubation (18 days vs 9.5 days; P < 0.01), median duration of extracorporeal membrane oxygenation (495 h vs 223.5 h; P < 0.05), rate of supplemental oxygen requirement at 30 days of age (20/42 (47.6%) vs 3/26 (11.5%); P < 0.01) and rate of pulmonary hypertension at initial postnatal echocardiography (28/42 (66.7%) vs 9/26 (34.6%); P = 0.01). No neonatal death occurred in stomach-down CDH patients and one neonatal death was seen in a patient with intrathoracic stomach herniation., Conclusions: In infants with left CDH without liver herniation, despite similar o/e-LHR and o/e-TLV, those with stomach-down CDH have decreased neonatal morbidity compared to those with stomach herniation. Progressive or variable physiological distension of the stomach over the course of gestation may explain these findings. Stomach-down left CDH is mistaken for a lung mass in a substantial proportion of cases. Accurate prenatal US characterization of CDH is crucial for appropriate prenatal counseling and patient management. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)
- Published
- 2021
- Full Text
- View/download PDF
9. Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.
- Author
-
Qiao L, Xu L, Yu L, Wynn J, Hernan R, Zhou X, Farkouh-Karoleski C, Krishnan US, Khlevner J, De A, Zygmunt A, Crombleholme T, Lim FY, Needelman H, Cusick RA, Mychaliska GB, Warner BW, Wagner AJ, Danko ME, Chung D, Potoka D, Kosiński P, McCulley DJ, Elfiky M, Azarow K, Fialkowski E, Schindel D, Soffer SZ, Lyon JB, Zalieckas JM, Vardarajan BN, Aspelund G, Duron VP, High FA, Sun X, Donahoe PK, Shen Y, and Chung WK
- Subjects
- Animals, Case-Control Studies, Cohort Studies, Craniofacial Abnormalities pathology, Eye Abnormalities pathology, Female, Growth Disorders pathology, Hernias, Diaphragmatic, Congenital pathology, Hip Dislocation, Congenital pathology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteochondrodysplasias pathology, Pedigree, Tooth Abnormalities pathology, ATP-Dependent Proteases genetics, ATP-Dependent Proteases physiology, Craniofacial Abnormalities genetics, DNA Copy Number Variations, Eye Abnormalities genetics, Growth Disorders genetics, Hernias, Diaphragmatic, Congenital genetics, Hip Dislocation, Congenital genetics, Mitochondrial Proteins genetics, Mitochondrial Proteins physiology, Mutation, Missense, Osteochondrodysplasias genetics, Tooth Abnormalities genetics
- Abstract
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
10. Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia.
- Author
-
Miura M, Imai K, Tsuda H, Miki R, Tano S, Ito Y, Hirako-Takamura S, Moriyama Y, Ushida T, Iitani Y, Nakano-Kobayashi T, Toyokuni S, Kajiyama H, and Kotani T
- Subjects
- Animals, Animals, Newborn, Antioxidants pharmacology, Deuterium Oxide pharmacology, Disease Models, Animal, Female, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Hydrogen metabolism, Hypertension, Pulmonary metabolism, Lung pathology, Male, Organogenesis drug effects, Phenyl Ethers adverse effects, Phenyl Ethers pharmacology, Pregnancy, Pulmonary Artery, Pulmonary Surfactants metabolism, Rats, Rats, Sprague-Dawley, Vascular Remodeling drug effects, Hernias, Diaphragmatic, Congenital drug therapy, Hydrogen pharmacology
- Abstract
Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H
2 ), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2'-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.- Published
- 2021
- Full Text
- View/download PDF
11. Isolated congenital diaphragm hernia associated with homozygous SLIT3 gene variant in dizygous twins.
- Author
-
Kaya TB, Aydemir O, Ceylaner S, Ceylaner G, and Tekin AN
- Subjects
- Female, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology, Humans, Infant, Newborn, Male, Mutation, Twins, Dizygotic, Hernias, Diaphragmatic, Congenital genetics, Membrane Proteins genetics
- Abstract
Congenital diaphragmatic hernia (CDH) is a serious life-threatening birth defect characterized by abnormal development in the muscular or tendinous portion of the diaphragm during embryogenesis. Despite its high incidence, the etiology of CDH hasn't been fully understood. Genetic factors are important in pathogenesis; however, few single genes have been definitively implicated in human CDH. SLIT1, SLIT2, and SLIT3 (slit guidance ligand) are three human homologs of the drosophila Slit gene. They interact with roundabout (Robo) homolog receptors to affect cell migration, adhesion, cell motility, and angiogenesis and play important roles in cell signaling pathways including the guidance of axons. In this report, we presented dizygous twin babies with CDH related to the SLIT3 gene variant. Previous studies showed that Slit3 null mice had congenital diaphragmatic hernias on or near the ventral midline portion of the central tendon. This is the first report of homozygous SLIT3 variant associated with CDH in humans., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
12. Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics.
- Author
-
Cannata G, Caporilli C, Grassi F, Perrone S, and Esposito S
- Subjects
- Diaphragm embryology, Diaphragm pathology, Genetic Predisposition to Disease, Hernias, Diaphragmatic, Congenital classification, Hernias, Diaphragmatic, Congenital diagnosis, Hernias, Diaphragmatic, Congenital pathology, High-Throughput Nucleotide Sequencing, Humans, Prognosis, Hernias, Diaphragmatic, Congenital genetics
- Abstract
Congenital diaphragmatic hernia (CDH) is a relatively common major life-threatening birth defect that results in significant mortality and morbidity depending primarily on lung hypoplasia, persistent pulmonary hypertension, and cardiac dysfunction. Despite its clinical relevance, CDH multifactorial etiology is still not completely understood. We reviewed current knowledge on normal diaphragm development and summarized genetic mutations and related pathways as well as cellular mechanisms involved in CDH. Our literature analysis showed that the discovery of harmful de novo variants in the fetus could constitute an important tool for the medical team during pregnancy, counselling, and childbirth. A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.
- Published
- 2021
- Full Text
- View/download PDF
13. Computed tomography based measurements to evaluate lung density and lung growth after congenital diaphragmatic hernia.
- Author
-
Stoll-Dannenhauer T, Schwab G, Zahn K, Schaible T, Wessel L, Weiss C, Schoenberg SO, Henzler T, and Weis M
- Subjects
- Case-Control Studies, Child, Child, Preschool, Female, Hernias, Diaphragmatic, Congenital complications, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital surgery, Humans, Image Interpretation, Computer-Assisted, Infant, Male, Pulmonary Emphysema etiology, Pulmonary Emphysema pathology, Pulmonary Emphysema surgery, Tomography, X-Ray Computed, Hernias, Diaphragmatic, Congenital diagnostic imaging, Pulmonary Emphysema diagnostic imaging
- Abstract
Emphysema-like-change of lung is one aspect of lung morbidity in children after congenital diaphragmatic hernia (CDH). This study aims to evaluate if the extent of reduced lung density can be quantified through pediatric chest CT examinations, if side differences are present and if emphysema-like tissue is more prominent after CDH than in controls. Thirty-seven chest CT scans of CDH patients (mean age 4.5 ± 4.0 years) were analyzed semi-automatically and compared to an age-matched control group. Emphysema-like-change was defined as areas of lung density lower than - 950 HU in percentage (low attenuating volume, LAV). A p-value lower than 0.05 was regarded as statistically significant. Hypoattenuating lung tissue was more frequently present in the ipsilateral lung than the contralateral side (LAV 12.6% vs. 5.7%; p < 0.0001). While neither ipsilateral nor contralateral lung volume differed between CDH and control (p > 0.05), LAV in ipsilateral (p = 0.0002), but not in contralateral lung (p = 0.54), was higher in CDH than control. It is feasible to quantify emphysema-like-change in pediatric patients after CDH. In the ipsilateral lung, low-density areas are much more frequently present both in comparison to contralateral and to controls. Especially the ratio of LAV ipsilateral/contralateral seems promising as a quantitative parameter in the follow-up after CDH.
- Published
- 2021
- Full Text
- View/download PDF
14. Three-dimensional reconstruction model in the diagnosis of Morgagni's hernia.
- Author
-
Zhang Z, Fu Y, and Hu B
- Subjects
- Aged, Diagnostic Errors, Diaphragmatic Eventration diagnosis, Diaphragmatic Eventration surgery, Female, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital surgery, Humans, Laparoscopy, Preoperative Care methods, Hernias, Diaphragmatic, Congenital diagnostic imaging, Imaging, Three-Dimensional, Tomography, X-Ray Computed
- Abstract
Morgagni's hernia (MH) can be diagnosed by different utilities, but all these methods are not always 100% accurate. Three-dimensional (3D) reconstruction model could be helpful in better understanding the important anatomical structures. We report a case of MH who was once misdiagnosed as diaphragmatic eventration at the other institution and we offered laparoscopic repair according to the 3D reconstruction model. Our case highlights that 3D reconstruction model could be a useful supplementary tool in the diagnosis and preoperative assessment for patients with MH especially when it is confused in diagnosis in clinical practice., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
- Full Text
- View/download PDF
15. Early behavioral and developmental interventions in ADNP-syndrome: A case report of SWI/SNF-related neurodevelopmental syndrome.
- Author
-
Shillington A, Pedapati E, Hopkin R, and Suhrie K
- Subjects
- Antipsychotic Agents administration & dosage, Antipsychotic Agents therapeutic use, Autism Spectrum Disorder genetics, Autism Spectrum Disorder pathology, Behavioral Symptoms genetics, Behavioral Symptoms pathology, Child, Preschool, Female, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital pathology, Humans, Risperidone administration & dosage, Risperidone therapeutic use, Syndrome, Autism Spectrum Disorder drug therapy, Behavioral Symptoms drug therapy, Early Medical Intervention, Hernias, Diaphragmatic, Congenital drug therapy, Homeodomain Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
Background: Autism spectrum disorder (ASD) affects approximately one in 59 children. Variants in the activity-dependent neuroprotector homeobox ADNP (OMIM #611386) gene may be one of the most common single-gene causes of syndromic ASD. Most patients diagnosed with ADNP syndrome have ASD as a comorbidity, and all patients have mild-to-severe intellectual disability., Methods/case Report: We present a case report of a patient diagnosed with ADNP syndrome at 2.5 years of age. The patient has many of the key features of the syndrome, including ASD, global developmental delay, behavioral problems, congenital heart defect, early tooth eruption, and vision problems. The patient's initial presentation included congenital diaphragmatic hernia (CDH), which has not been previously reported in this condition., Results: The patient exhibited frequent behavioral outbursts and was initiated on antipsychotic medication with near-complete resolution of symptoms allowing her to engage more fully in early intervention therapies leading to progress in language acquisition., Conclusion: This short report provides guidance for antipsychotic medication dosing to improve early intervention outcomes. This is the first report of CDH in this syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2020
- Full Text
- View/download PDF
16. Neonatal lung growth in congenital diaphragmatic hernia: evaluation of lung density and mass by pulmonary MRI.
- Author
-
Adaikalam SA, Higano NS, Tkach JA, Yen Lim F, Haberman B, Woods JC, and Kingma PS
- Subjects
- Female, Hernias, Diaphragmatic, Congenital diagnostic imaging, Humans, Infant, Newborn, Lung diagnostic imaging, Male, Hernias, Diaphragmatic, Congenital pathology, Lung growth & development, Magnetic Resonance Imaging methods
- Abstract
Background: Outcomes of infants with congenital diaphragmatic hernia (CDH) are primarily dependent on the severity of pulmonary hypoplasia. It is previously unknown whether postnatal lung growth in infants with CDH represents true parenchymal lung growth or merely an expansion in volume of the existing tissue. We hypothesized that lung volume growth in CDH infants will be accompanied by an increase in lung mass and that CDH infants will demonstrate accelerated catch-up growth of the more hypoplastic lung., Methods: We used fetal and post-CDH repair MRI of 12 infants to measure lung volume and density, which was used to calculate lung mass., Results: The average increase in right lung mass was 1.1 ± 1.1 g/week (p = 0.003) and the average increase in left lung mass was 1.8 ± 0.7 g/week (p < 0.001). When the ratio of left-to-right lung mass of the prenatal MRI was compared to post-repair MRI, the ratio significantly increased in all infants with average prenatal and post-repair ratios of 0.30 and 0.73, respectively (p = 0.002)., Conclusion: Lung growth in infants with CDH is indeed growth in lung mass (i.e. parenchyma), and the lungs demonstrate catch-up growth (i.e., increased rate of growth in the more hypoplastic ipsilateral lung).
- Published
- 2019
- Full Text
- View/download PDF
17. Inhibition of retinoic acid signaling induces aberrant pericyte coverage and differentiation resulting in vascular defects in congenital diaphragmatic hernia.
- Author
-
Kool HM, Bürgisser PE, Edel GG, de Kleer I, Boerema-de Munck A, de Laat I, Chrifi I, Cheng C, van Cappellen WA, Kremers GJ, Tibboel D, and Rottier RJ
- Subjects
- Animals, Disease Models, Animal, Endothelial Cells pathology, Hernias, Diaphragmatic, Congenital drug therapy, Humans, Hypertension, Pulmonary drug therapy, Hypertension, Pulmonary pathology, Lung drug effects, Lung pathology, Mice, Pericytes drug effects, Pericytes pathology, Signal Transduction drug effects, Cell Differentiation drug effects, Endothelial Cells drug effects, Hernias, Diaphragmatic, Congenital pathology, Tretinoin pharmacology
- Abstract
The mortality and morbidity of patients with congenital diaphragmatic hernia (CDH) is primarily caused by treatment-resistant, persistent pulmonary hypertension. Structural vascular changes, exemplified by extensive muscularization, are already present early in gestation, but the origin of these abnormalities is unknown. Understanding the origin of the vascular defects is important to improve treatment modalities. Here, we show that the distribution of pericytes is different and may thereby potentially initiate the vascular pathology in CDH. Transient inhibition of retinoic acid (RA) signaling early during pregnancy, the basis of the CDH mouse model, led to an increase in the number of pericytes, thereby affecting the angiogenic potential of pericytes in the fetuses. Pericytes of CDH lungs showed reduced proliferation and an increased ACTA2 expression, which indicates that these pericytes are more contractile than in control lung pericytes. This resulted in increased pericyte coverage of pulmonary vessels and reduced expansion of the capillary bed, the earliest pathological sign of the structural changes in CDH. Furthermore, the pericytes had reduced and altered collagen IV deposition in CDH, pointing to a loss of basal membrane integrity between pericytes and endothelial cells. Inhibition of RA signaling in vitro resulted in reduced migration of pericytes, reduced angiogenesis, and loss of collagen IV expression. Importantly, we confirmed our findings in lungs of human CDH patient samples. In summary, inhibition of RA signaling affects the lung pericyte population, leading to increased contractility, reduced pulmonary angiogenesis, and aberrant lung development, as observed in CDH.
- Published
- 2019
- Full Text
- View/download PDF
18. Bochdalek hernia in an adult female with intrathoracic left kidney and splenic flexure of the colon: a rare case report with literature review.
- Author
-
Kumar N, Gupta A, and Rajput D
- Subjects
- Adult, Female, Hernias, Diaphragmatic, Congenital pathology, Humans, Kidney diagnostic imaging, Kidney surgery, Kidney Diseases, Tomography, X-Ray Computed, Ureteral Obstruction diagnostic imaging, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital surgery, Kidney pathology, Ureteral Obstruction pathology, Ureteral Obstruction surgery
- Abstract
Congenital diaphragmatic hernia (CDH) is extremely rare in adults. Bochdalek hernia (BH) is the most common one among all congenital diaphragmatic hernias. This is due to incomplete fusion of pleuroperitoneal folds during early fetal development. It remains asymptomatic in many adults. It usually occurs on the left side and is common in males (62%). Open or laparoscopic surgical repair is the treatment of choice. We reported on a rare case of BH in an adult female with intra-thoracic left kidney and splenic flexure of the colon, who presented with non-specific abdominal symptoms. Key message: BH in adults is usually present with vague abdominal symptoms. We advocate the use of the CECT scan of the abdomen in the management of all cases with non-specific abdominal symptoms.
- Published
- 2019
- Full Text
- View/download PDF
19. Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia.
- Author
-
Kipfmueller F, Heindel K, Geipel A, Berg C, Bartmann P, Reutter H, Mueller A, and Holdenrieder S
- Subjects
- Extracorporeal Membrane Oxygenation, Fetal Blood chemistry, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital therapy, Humans, Infant, Newborn, Intensive Care Units, Neonatal, Liver pathology, Prospective Studies, Receptor for Advanced Glycation End Products biosynthesis, Receptor for Advanced Glycation End Products genetics, Respiration, Artificial, Hernias, Diaphragmatic, Congenital pathology, Hypertension, Pulmonary pathology, Lung pathology, Receptor for Advanced Glycation End Products blood
- Abstract
Pulmonary hypertension (PH) and lung hypoplasia are major contributors to morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). The soluble receptor for advanced glycation end products (sRAGE) is a marker of endothelial function and might be associated with disease severity in CDH newborns. In a cohort of 30 CDH newborns and 20 healthy control newborns, sRAGE concentration was measured at birth and at 6 h, 12 h, 24 h, 48 h, and 7-10 days. In healthy newborns, sRAGE was significantly higher at birth and at 48 h compared with CDH newborns (both P < 0.001). Among CDH newborns, sRAGE was significantly lower at birth ( P = 0.033) and at 7-10 days ( P = 0.035) in patients receiving extracorporeal membrane oxygenation (ECMO) compared with patients not receiving ECMO. In contrast, CDH newborns receiving ECMO had significantly higher values at 6 h ( P = 0.001), 12 h ( P = 0.004), and 48 h (0.032). Additionally, sRAGE correlated significantly with PH severity, intensity and duration of mechanical ventilation, and prenatally assessed markers of CDH severity (lung size, liver herniation). The probability to receive ECMO therapy was five times higher in CDH newborns with sRAGE concentrations below the calculated cutoff of 650 pg/ml at birth ( P = 0.002) and nine times higher in CDH newborns with sRAGE concentrations above the cutoff of 3,500 pg/ml at 6 h ( P = 0.001). These findings suggest a potential involvement of sRAGE in the pathophysiology of CDH and may act as a therapeutic target in future treatment approaches.
- Published
- 2019
- Full Text
- View/download PDF
20. Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling.
- Author
-
Montalva L, Antounians L, and Zani A
- Subjects
- Animals, Animals, Newborn, Disease Models, Animal, Endothelial Cells drug effects, Endothelial Cells pathology, Endothelial Cells physiology, Female, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital physiopathology, Humans, Hypertension, Pulmonary pathology, Hypertension, Pulmonary physiopathology, Infant, Newborn, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle pathology, Myocytes, Smooth Muscle physiology, Phenyl Ethers toxicity, Pregnancy, Pulmonary Artery drug effects, Pulmonary Artery pathology, Pulmonary Artery physiopathology, Rats, Risk Factors, Vascular Remodeling drug effects, Vascular Remodeling physiology, Hernias, Diaphragmatic, Congenital complications, Hypertension, Pulmonary etiology
- Abstract
Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.
- Published
- 2019
- Full Text
- View/download PDF
21. The proportion of alveolar type 1 cells decreases in murine hypoplastic congenital diaphragmatic hernia lungs.
- Author
-
Nguyen TM, Jimenez J, Rendin LE, Müller C, Westergren-Thorsson G, Deprest J, and Toelen J
- Subjects
- Alveolar Epithelial Cells metabolism, Animals, Cell Count, Cell Differentiation, Diamines toxicity, Disease Models, Animal, Embryonic Stem Cells metabolism, Embryonic Stem Cells pathology, Female, Hernias, Diaphragmatic, Congenital chemically induced, Hernias, Diaphragmatic, Congenital embryology, Lung embryology, Lung pathology, Mice, Organ Size, Phenyl Ethers toxicity, Pregnancy, Teratogens toxicity, Alveolar Epithelial Cells pathology, Hernias, Diaphragmatic, Congenital pathology, Lung abnormalities
- Abstract
Background: Pulmonary hypoplasia, characterized by incomplete alveolar development, remains a major cause of mortality and morbidity in congenital diaphragmatic hernia. Recently demonstrated to differentiate from a common bipotent progenitor during development, the two cell types that line the alveoli type 1 and type 2 alveolar cells have shown to alter their relative ratio in congenital diaphragmatic hernia lungs., Objective: We used the nitrofen/bisdiamine mouse model to induce congenital diaphragmatic hernia and accurately assess the status of alveolar epithelial cell differentiation in relation to the common bipotent progenitors., Study Design: Pregnant Swiss mice were gavage-fed with nitrofen/bisdiamine or vehicle at embryonic day 8.5. The administered dose was optimized by assessing the survival, congenital diaphragmatic hernia and facial abnormality rates of the exposed mouse pups. NanoCT was performed on embryonic day 11.5 and 16.5 to assess the embryonic and early canalicular stages of lung development. At embryonic day 17.5 corresponding to late canalicular stage, congenital diaphragmatic hernia lungs were characterized by measuring the lung weight/body weight ratio, morphometry, epithelial cell marker gene expression levels and alveolar cell type quantification., Results: Nitrofen/bisdiamine associated congenital diaphragmatic hernia lungs showed delayed development, hypoplasia with morphologic immaturity and thickened alveolar walls. Expression levels of distal epithelial progenitor marker Id2 increased, alveolar type 1 cell markers Pdpn and Hopx decreased, while type 2 cell markers pro-SPC and Muc1 remained constant during the canalicular stage. The number of Pdpn+ type 1 alveolar cells also decreased in congenital diaphragmatic hernia lungs., Conclusion: The mouse nitrofen/bisdiamine model is a potential model allowing the study of congenital diaphragmatic hernia lung development from early stages using a wide array of methods. Based on this model, the alveolar epithelium showed a decrease in the number of alveolar type 1 cell in congenital diaphragmatic hernia lungs while type 2 cell population remains unchanged., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
- Full Text
- View/download PDF
22. MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.
- Author
-
Perveen S, Ayasolla K, Zagloul N, Patel H, Ochani K, Orner D, Benveniste H, Salerno M, Vaska P, Zuo Z, Alabed Y, Nasim M, Miller EJ, and Ahmed M
- Subjects
- Animals, Animals, Newborn, Body Weight, Disease Models, Animal, Female, Hemodynamics, Hernias, Diaphragmatic, Congenital chemically induced, Hernias, Diaphragmatic, Congenital pathology, Hypertension, Pulmonary etiology, Immunity, Innate, Inflammation, Lung growth & development, Maternal Exposure, Phenyl Ethers, Pregnancy, Pregnancy, Animal, Rats, Systole, Tomography, X-Ray Computed, Vascular Remodeling, Ventricular Function, Right, Hernias, Diaphragmatic, Congenital therapy, Intramolecular Oxidoreductases antagonists & inhibitors, Lung drug effects, Macrophage Migration-Inhibitory Factors antagonists & inhibitors, Neovascularization, Physiologic drug effects
- Abstract
Background: Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development., Methods: Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology., Results: Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1., Conclusion: Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.
- Published
- 2019
- Full Text
- View/download PDF
23. Rare right congenital diaphragmatic hernia with ileum and colon herniated into thoracic cavity in an 18-year-old adult.
- Author
-
Chen HH, Chen Y, Zhu JH, Chen YD, and Zhou JJ
- Subjects
- Adolescent, Humans, Male, Tomography, X-Ray Computed, Colon diagnostic imaging, Colon pathology, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology, Ileum diagnostic imaging, Ileum pathology, Thoracic Cavity diagnostic imaging, Thoracic Cavity pathology
- Published
- 2019
- Full Text
- View/download PDF
24. Hepatopulmonary fusion associated with right-sided congenital diaphragmatic hernia: management of this rare anomaly and a review of the literature.
- Author
-
Almaramhy HH
- Subjects
- Female, Humans, Infant, Newborn, Prognosis, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital surgery
- Abstract
Hepatopulmonary fusion is a rare malformation that is often discovered during operative repair of right-sided congenital diaphragmatic defects. Based on a search using medical search engines, we only found 22 cases of hepatopulmonary fusion in the English literature worldwide to date. We describe herein a case of hepatopulmonary fusion with right-sided congenital diaphragmatic hernia in a female neonate who presented with respiratory distress. We discuss management of this case and review the relevant literature.
- Published
- 2018
- Full Text
- View/download PDF
25. Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia.
- Author
-
Gosemann JH, Friedmacher F, Hofmann A, Zimmer J, Kuebler JF, Rittinghausen S, Suttkus A, Lacher M, Alvarez L, Corcionivoschi N, and Puri P
- Subjects
- Animals, Chemokine CCL2 blood, Chemokine CCL2 genetics, Chemokine CCL2 metabolism, Disease Models, Animal, Female, Gene Expression, Hernias, Diaphragmatic, Congenital drug therapy, Hernias, Diaphragmatic, Congenital pathology, Immunohistochemistry, Lung pathology, Macrophages immunology, Macrophages metabolism, Phenyl Ethers adverse effects, Pregnancy, Prenatal Care, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Hernias, Diaphragmatic, Congenital etiology, Hernias, Diaphragmatic, Congenital metabolism, Lung metabolism, Monocytes drug effects, Monocytes metabolism, Rosiglitazone pharmacology, Vascular Remodeling drug effects
- Abstract
Introduction: Extensive vascular remodeling causing pulmonary hypertension (PH) represents a major cause of mortality in patients with congenital diaphragmatic hernia (CDH). The chemokine monocyte chemoattractant protein-1 (MCP-1) is a biomarker for the severity of PH and its activation is accompanied by pulmonary influx of monocytes and extensive vascular remodeling. MCP-1 activation can be reversed by application of rosiglitazone (thiazolidinedione). We performed this study to evaluate the role of MCP-1 for the pathogenesis of PH in experimental CDH. We hypothesized that vascular remodeling and MCP-1 activation is accompanied by pulmonary influx of fetal monocytes and can be attenuated by prenatal treatment with rosiglitazone., Methods: In a first set of experiments pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blot (WB), and immunohistochemistry (IHC) were used to evaluate MCP-1 expression, activation, and localization. Quantification and localization of pulmonary monocytes/macrophages were carried out by IHC. In a second set of experiments nitrofen-exposed dams were randomly assigned to prenatal treatment with rosiglitazone or placebo on D18+D19. Fetal lungs were harvested on D21, divided into control, CDH+rosiglitazone, and CDH+placebo and evaluated by WB as well as IHC., Results: Increased thickness of pulmonary arteries of CDH fetuses was accompanied by increased systemic and perivascular MCP-1 protein expression and significantly higher amounts of pulmonary monocytes/macrophages compared to controls (p<0.01). These effects were reversed by prenatal treatment with rosiglitazone (p<0.01 vs. CDH+P; control)., Conclusion: Prenatal treatment with rosiglitazone has the potential to attenuate activation of pulmonary MCP-1, pulmonary monocyte influx, and vascular remodeling in experimental CDH. These results provide a basis for future research on prenatal immunomodulation as a novel treatment strategy to decrease secondary effects of PH in CDH., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
- Full Text
- View/download PDF
26. Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism.
- Author
-
Li Q, Lei F, Tang Y, Pan JS, Tong Q, Sun Y, and Sheikh-Hamad D
- Subjects
- Agenesis of Corpus Callosum genetics, Agenesis of Corpus Callosum metabolism, Agenesis of Corpus Callosum pathology, Amyloid beta-Peptides metabolism, Animals, Brain metabolism, Brain pathology, Cell Membrane genetics, Glycoproteins genetics, HEK293 Cells, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural metabolism, Hearing Loss, Sensorineural pathology, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Humans, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Mice, Mitochondria metabolism, Myopia genetics, Myopia metabolism, Myopia pathology, Oculocerebrorenal Syndrome genetics, Oculocerebrorenal Syndrome metabolism, Oculocerebrorenal Syndrome pathology, Proteinuria genetics, Proteinuria metabolism, Proteinuria pathology, RAW 264.7 Cells, Renal Tubular Transport, Inborn Errors genetics, Renal Tubular Transport, Inborn Errors metabolism, Renal Tubular Transport, Inborn Errors pathology, Signal Transduction, Sirtuin 3 genetics, Transforming Growth Factor beta genetics, rab GTP-Binding Proteins metabolism, Amyloid beta-Peptides genetics, Low Density Lipoprotein Receptor-Related Protein-2 genetics, Mitochondria genetics, rab GTP-Binding Proteins genetics
- Abstract
Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain. Megalin mutations underlie the pathogenesis of Donnai-Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-β to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.
- Published
- 2018
- Full Text
- View/download PDF
27. Treatment of rat congenital diaphragmatic hernia with sildenafil and NS-304, selexipag's active compound, at the pseudoglandular stage improves lung vasculature.
- Author
-
Mous DS, Kool HM, Burgisser PE, Buscop-van Kempen MJ, Nagata K, Boerema-de Munck A, van Rosmalen J, Dzyubachyk O, Wijnen RMH, Tibboel D, and Rottier RJ
- Subjects
- Animals, Drug Therapy, Combination, Humans, Rats, Rats, Sprague-Dawley, Acetamides pharmacology, Hernias, Diaphragmatic, Congenital drug therapy, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital physiopathology, Lung blood supply, Lung metabolism, Lung pathology, Lung physiopathology, Pyrazines pharmacology, Sildenafil Citrate pharmacology
- Abstract
Patients with congenital diaphragmatic hernia (CDH) often suffer from severe pulmonary hypertension, and the choice of current vasodilator therapy is mostly based on trial and error. Because pulmonary vascular abnormalities are already present early during development, we performed a study to modulate these pulmonary vascular changes at an early stage during gestation. Pregnant Sprague-Dawley rats were treated with nitrofen at day 9.5 of gestation (E9.5) to induce CDH in the offspring, and subsequently, the phosphodiesterase-5 inhibitor sildenafil and/or the novel prostaglandin-I receptor agonist selexipag (active compound NS-304) were administered from E17.5 until E20.5. The clinical relevant start of the treatment corresponds to week 20 of gestation in humans, when CDH is usually detected by ultrasound. CDH pups showed increased density of air saccules that was reverted after the use of only sildenafil. The pulmonary vascular wall was thickened, and right ventricular hypertrophy was present in the CDH group and improved both after single treatment with sildenafil or selexipag, whereas the combination therapy with both compounds did not have additive value. In conclusion, antenatal treatment with sildenafil improved airway morphogenesis and pulmonary vascular development, whereas selexipag only acted positively on pulmonary vascular development. The combination of both compounds did not act synergistically, probably because of a decreased efficiency of both compounds caused by cytochrome- P450 3A4 interaction and induction. These new insights create important possibilities for future treatment of pulmonary vascular abnormalities in CDH patients already in the antenatal period of life.
- Published
- 2018
- Full Text
- View/download PDF
28. Congenital diaphragmatic hernia as a part of Nance-Horan syndrome?
- Author
-
Kammoun M, Brady P, De Catte L, Deprest J, Devriendt K, and Vermeesch JR
- Subjects
- Animals, Cataract genetics, Cataract pathology, Codon, Nonsense, Diaphragm embryology, Diaphragm metabolism, Genetic Diseases, X-Linked pathology, Hernias, Diaphragmatic, Congenital pathology, Humans, Infant, Newborn, Loss of Function Mutation, Male, Membrane Proteins, Mice, Nuclear Proteins genetics, Nuclear Proteins metabolism, Tooth Abnormalities pathology, Cataract congenital, Genetic Diseases, X-Linked genetics, Hernias, Diaphragmatic, Congenital genetics, Phenotype, Tooth Abnormalities genetics
- Abstract
Nance-Horan syndrome is a rare X-linked developmental disorder characterized by bilateral congenital cataract, dental anomalies, facial dysmorphism, and intellectual disability. Here, we identify a patient with Nance-Horan syndrome caused by a new nonsense NHS variant. In addition, the patient presented congenital diaphragmatic hernia. NHS gene expression in murine fetal diaphragm was demonstrated, suggesting a possible involvement of NHS in diaphragm development. Congenital diaphragmatic hernia could result from NHS loss of function in pleuroperitoneal fold or in somites-derived muscle progenitor cells leading to an impairment of their cells migration.
- Published
- 2018
- Full Text
- View/download PDF
29. Prognosis of isolated congenital diaphragmatic hernia using lung-area-to-head-circumference ratio: variability across centers in a national perinatal network.
- Author
-
Senat MV, Bouchghoul H, Stirnemann J, Vaast P, Boubnova J, Begue L, Carricaburu E, Sartor A, Jani J, Benachi A, and Bouyer J
- Subjects
- Adult, Female, Fetal Diseases mortality, France, Gestational Age, Head embryology, Head pathology, Hernias, Diaphragmatic, Congenital embryology, Hernias, Diaphragmatic, Congenital mortality, Hernias, Diaphragmatic, Congenital pathology, Humans, Lung embryology, Lung pathology, Predictive Value of Tests, Pregnancy, Reproducibility of Results, Retrospective Studies, Survival Analysis, Cephalometry methods, Fetal Diseases diagnostic imaging, Head diagnostic imaging, Hernias, Diaphragmatic, Congenital diagnostic imaging, Lung diagnostic imaging, Ultrasonography, Prenatal
- Abstract
Objective: Congenital diaphragmatic hernia (CDH) is a severe anomaly. The observed-to-expected lung-area-to-head-circumference ratio (o/e-LHR) has been shown to provide a useful prediction of subsequent survival of fetuses with CDH in referral centers with expertise and a large caseload. However, the accuracy of o/e-LHR measurements in general fetal medicine units with less expertise is not well known. The aim of this study was to evaluate the capacity of o/e-LHR to provide a useful prediction of mortality of fetuses with CDH when the measurement is performed in fetal medicine units with different levels of expertise., Methods: Between January 2008 and November 2013, 305 live births with expectantly managed left-sided isolated CDH were recorded in the database of the French National Center for Rare Diseases (31 centers) and followed up after birth. Centers were grouped into two categories according to their mean annual CDH caseload over the study period: large centers with an average of ≥ 14 cases and smaller centers with < 14 cases per year. The relationship between o/e-LHR and 28-day and 6-month mortality was modeled using fractional polynomials and the predictive value of o/e-LHR was quantified using the area under the receiver-operating characteristics curve. Comparisons between the two center categories were carried out. Analyses were adjusted for potential confounders such as thoracic herniation of the liver and gestational age at birth and at diagnosis., Results: During the study period, two large centers managed a total of 82 CDH cases and 29 smaller centers a total of 223 CDH cases. Overall, there was a significant inverse relationship between 28-day mortality rate and o/e-LHR, which decreased from 54% when o/e-LHR was 20% to 6% when o/e-LHR was 75% (P < 0.01). When the category of center was considered, adjusted associations between o/e-LHR and 28-day mortality were significantly different (P = 0.032) between large and smaller centers. The ability to predict survival at 28 days postpartum based on o/e-LHR was better in large centers; for a specificity of 0.30, the sensitivity was 0.71 in large centers and 0.55 in smaller ones. The results were similar for 6-month mortality., Conclusions: Our results show that o/e-LHR measured on two-dimensional ultrasound is a good indicator of neonatal prognosis in cases of CDH that may be used even in fetal medicine centers with a small caseload. However, our results also suggest that LHR measurement may be difficult to perform correctly. Therefore, appropriate training should be offered to professionals. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
30. Three-dimensional assessment of umbilical vein deviation angle for prediction of liver herniation in left-sided congenital diaphragmatic hernia.
- Author
-
Volpe N, Mazzone E, Muto B, Suprani A, Fanelli T, Kaihura CT, Dall'Asta A, Pedrazzi G, Del Rossi C, Silini EM, Magnani C, Volpe P, Ghi T, and Frusca T
- Subjects
- Adult, Female, Fetal Diseases pathology, Genetic Testing, Gestational Age, Hernias, Diaphragmatic, Congenital embryology, Hernias, Diaphragmatic, Congenital pathology, Humans, Italy, Liver embryology, Liver Diseases embryology, Liver Diseases pathology, Pregnancy, Prospective Studies, ROC Curve, Umbilical Veins abnormalities, Umbilical Veins diagnostic imaging, Echocardiography, Three-Dimensional, Fetal Diseases diagnostic imaging, Hernias, Diaphragmatic, Congenital diagnostic imaging, Liver diagnostic imaging, Liver Diseases diagnostic imaging, Ultrasonography, Prenatal
- Abstract
Objectives: To introduce a new sonographic marker of intrathoracic liver herniation in fetuses with left-sided congenital diaphragmatic hernia (CDH)., Methods: In a consecutive series of fetuses with isolated CDH, an ultrasound volume of the fetal abdomen was acquired. On this volume, offline calculation of the angle formed by the midline of the abdomen (joining the center of the vertebral body to the abdominal insertion of the umbilical cord) and a second line joining the center of the vertebral body to the intra-abdominal convexity of the umbilical vein was carried out to give the umbilical vein deviation angle (UVDA). The UVDA was measured in a group of normal fetuses selected as controls. At follow-up, the presence of liver herniation was investigated in all cases of CDH. UVDA values were compared between the CDH group and controls, and between CDH 'liver-up' vs 'liver-down' cases. A receiver-operating characteristics (ROC) curve was constructed to identify a cut-off value of the UVDA with the highest accuracy in predicting liver herniation in the CDH group., Results: Between 2009 and 2015, 22 cases of left-sided CDH were included in the study group, of which nine cases had liver herniation. Eighty-eight normal fetuses were recruited as controls. The UVDA was significantly higher in the cases vs controls (15.25 ± 7.91° vs 7.68 ± 1.55°; P < 0.0001). Moreover, the UVDA was significantly increased in CDH fetuses with liver-up vs liver-down (21.77 ± 8.79° vs 10.75 ± 2.10°; P < 0.0001). On ROC curve analysis the UVDA showed good prediction of liver herniation (area under the ROC curve, 0.94; P < 0.0001) with the best cut-off of 15.2°, yielding a sensitivity of 89% and a specificity of 100% (P < 0.0001)., Conclusions: In fetuses with CDH, umbilical vein bowing may be quantified by measuring the UVDA using three-dimensional ultrasound. This sonographic marker seems to be an accurate predictor of liver herniation in left-sided CDH. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
31. Spontaneous prematurity in fetuses with congenital diaphragmatic hernia: a retrospective cohort study about prenatal predictive factors.
- Author
-
Barbosa BML, Rodrigues AS, Carvalho MHB, Bittar RE, Francisco RPV, and Bernardes LS
- Subjects
- Chi-Square Distribution, Female, Fetus diagnostic imaging, Fetus pathology, Head diagnostic imaging, Head embryology, Head pathology, Hernias, Diaphragmatic, Congenital embryology, Hernias, Diaphragmatic, Congenital pathology, Humans, Infant, Newborn, Lung diagnostic imaging, Lung embryology, Lung pathology, Organ Size, Pregnancy, Premature Birth pathology, ROC Curve, Retrospective Studies, Sensitivity and Specificity, Statistics, Nonparametric, Ultrasonography, Prenatal, Hernias, Diaphragmatic, Congenital complications, Premature Birth etiology
- Abstract
Background: To evaluate possible predictive factors of spontaneous prematurity in fetuses with congenital diaphragmatic hernia (CDH)., Methods: A retrospective cohort study was performed. Inclusion criteria were presence of CDH; absence of fetoscopy; absence of karyotype abnormality; maximum of one major malformation associated with diaphragmatic hernia; ultrasound monitoring at the Obstetrics Clinic of Clinicas Hospital at the University of São Paulo School of Medicine, from January 2001 to October 2014. The data were obtained through the electronic records and ultrasound system of our fetal medicine service. The following variables were analyzed: maternal age, primiparity, associated maternal diseases, smoking, previous spontaneous preterm birth, fetal malformation associated with hernia, polyhydramnios, fetal growth restriction, presence of intrathoracic liver, invasive procedures performed, side of hernia and observed-to- expected lung to head ratio (o/e LHR). On individual analysis, variables were assessed using the Chi-square test and the Mann-Whitney test. A multiple logistic regression model was applied to select variables independently influencing the prediction of preterm delivery. A ROC curve was constructed with the significant variable, identifying the values with best sensitivity and specificity to be suggested for use in clinical practice., Results: Eighty fetuses were evaluated, of which, 21 (26.25%) were premature. O/e LHR was the only factor associated with prematurity (p = 0.020). The ROC curve showed 93% sensitivity with 48.4% specificity for the cutoff of 40%., Conclusion: O/e LHR was the only predictor of prematurity in this sample.
- Published
- 2018
- Full Text
- View/download PDF
32. STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia.
- Author
-
Piairo P, Moura RS, Baptista MJ, Correia-Pinto J, and Nogueira-Silva C
- Subjects
- Animals, Female, Fetal Development drug effects, Gene Expression drug effects, Hernias, Diaphragmatic, Congenital chemically induced, Hernias, Diaphragmatic, Congenital pathology, Immunohistochemistry, Lung metabolism, Phenyl Ethers toxicity, Rats, Rats, Sprague-Dawley, STAT Transcription Factors antagonists & inhibitors, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, STAT6 Transcription Factor antagonists & inhibitors, STAT6 Transcription Factor metabolism, Stilbenes pharmacology, Suppressor of Cytokine Signaling 3 Protein metabolism, Lung growth & development, STAT Transcription Factors metabolism
- Abstract
Background: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival., Methods: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis., Results: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth., Conclusion: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH., (© 2018 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2018
- Full Text
- View/download PDF
33. Scimitar syndrome associated with aberrant right subclavian artery, diaphragmatic hernia, and urinary anomalies - case report and review of the literature.
- Author
-
Youssef T, Mahmoud H, Ionescu NS, Stoica DM, Grigore CA, Nicolescu AM, Bălgrădean M, and Cinteză EE
- Subjects
- Adult, Cardiovascular Abnormalities pathology, Female, Hernias, Diaphragmatic, Congenital pathology, Humans, Scimitar Syndrome, Subclavian Artery pathology, Urogenital Abnormalities pathology, Young Adult, Cardiovascular Abnormalities etiology, Echocardiography methods, Hernias, Diaphragmatic, Congenital etiology, Subclavian Artery abnormalities, Urogenital Abnormalities etiology
- Abstract
Scimitar syndrome is a form of a partially or totally right pulmonary venous return to the inferior vena cava, which may associate variably right lung hypoplasia, right pulmonary artery hypoplasia, pulmonary sequestration together with the presence of aortopulmonary collaterals from the descending aorta towards the right lung. In many cases, there are also other cardiac anomalies associated. We present a unique association of a partially anomalous pulmonary venous return to the inferior vena cava with other vascular and thoracic anomalies: inferior sinus venosus and secundum atrial septal defect, retroesophageal right subclavian artery, obstructed accessory right bronchus, diaphragmatic hernia with ectopic liver, "S"-type thoracic scoliosis and malformations of the urinary tract (duplication of the right ureter and of the left basinet). The patient had a reimplantation of the "scimitar" vein to the left atrium and closure of the inferior sinus venosus and secundum atrial septal defect.
- Published
- 2018
34. Morphological Characterization of Diaphragm in Common Squirrel Monkey (Saimiri sciureus).
- Author
-
Souza Neto JRN, Branco É, Giese EG, and Lima AR
- Subjects
- Animals, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital veterinary, Male, Monkey Diseases pathology, Muscle Fibers, Skeletal, Organ Size, Reference Values, Diaphragm anatomy & histology, Saimiri anatomy & histology
- Abstract
The wall of the diaphragm can be affected by congenital or acquired alterations which allow the passage of viscera between the abdominal and chest cavities, allowing the formation of a diaphragmatic hernia. We characterized morphology and performed biometrics of the diaphragm in the common squirrel monkey Saimiri sciureus. After fixation, muscle fragments were collected and processed for optical microscopy. In this species the diaphragm muscle is attached to the lung by phrenopericardial ligament. It is also connected to the liver via the coronary and falciform ligaments. The muscle is composed of three segments in total: 1) sternal; 2) costal, and 3) a segment consisting of right and left diaphragmatic pillars. The anatomical structures analyzed were similar to those reported for other mammals. Histological analysis revealed stable, organized muscle fibers with alternation of light and dark streaks, indicating transverse striation.
- Published
- 2018
- Full Text
- View/download PDF
35. Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy.
- Author
-
Mous DS, Buscop-van Kempen MJ, Wijnen RMH, Tibboel D, and Rottier RJ
- Subjects
- Animals, Bronchodilator Agents administration & dosage, Female, Hernias, Diaphragmatic, Congenital drug therapy, Humans, Hypertension, Pulmonary drug therapy, Infant, Newborn, Male, Nitric Oxide administration & dosage, Pregnancy, Rats, Rats, Sprague-Dawley, Vasoconstriction drug effects, Vasodilation drug effects, Hernias, Diaphragmatic, Congenital metabolism, Hernias, Diaphragmatic, Congenital pathology, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary pathology, Vasoconstriction physiology, Vasodilation physiology
- Abstract
Background: Patients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients., Methods: The expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients., Results: CDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I
2 receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model., Conclusions: Together, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally.- Published
- 2017
- Full Text
- View/download PDF
36. Lung hypoplasia in newborn rabbits with a diaphragmatic hernia affects pulmonary ventilation but not perfusion.
- Author
-
Flemmer AW, Thio M, Wallace MJ, Lee K, Kitchen MJ, Kerr L, Roehr CC, Fouras A, Carnibella R, Jani JC, DeKoninck P, Te Pas AB, Pearson JT, and Hooper SB
- Subjects
- Animals, Animals, Newborn, Female, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology, Pregnancy, Rabbits, Regional Blood Flow, Tidal Volume, Hernias, Diaphragmatic, Congenital physiopathology, Lung blood supply, Pulmonary Ventilation
- Abstract
BackgroundA congenital diaphragmatic hernia (DH) can result in severe lung hypoplasia that increases the risk of morbidity and mortality after birth; however, little is known about the cardiorespiratory transition at birth.MethodsUsing phase-contrast X-ray imaging and angiography, we examined the cardiorespiratory transition at birth in rabbit kittens with DHs. Surgery was performed on pregnant New Zealand white rabbits (n=18) at 25 days' gestation to induce a left-sided DH. Kittens were delivered at 30 days' gestation, intubated, and ventilated to achieve a tidal volume (V
t ) of 8 ml/kg in control and 4 ml/kg in DH kittens while they were imaged.ResultsFunctional residual capacity (FRC) recruitment and Vt in the hypoplastic left lung were markedly reduced, resulting in a disproportionate distribution of FRC into the right lung. Following lung aeration, relative pulmonary blood flow (PBF) increased equally in both lungs, and the increase in pulmonary venous return was similar in both control and DH kittens.ConclusionThese findings indicate that nonuniform lung hypoplasia caused by DH alters the distribution of ventilation away from hypoplastic and into normally grown lung regions. During transition, the increase in PBF and pulmonary venous return, which is vital for maintaining cardiac output, is not affected by lung hypoplasia.- Published
- 2017
- Full Text
- View/download PDF
37. [Advances in fetal surgery].
- Author
-
Mesas Burgos C, Conner P, Papatziamos G, and Tiblad E
- Subjects
- Airway Obstruction pathology, Airway Obstruction surgery, Female, Fetal Therapies trends, Fetus surgery, Head and Neck Neoplasms surgery, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital surgery, Humans, Meningomyelocele surgery, Pregnancy, Treatment Outcome, Fetal Diseases surgery, Fetal Therapies methods
- Abstract
Advances in fetal surgery Fetal surgery is a subspeciality that is evolving rapidly with focus on improving the natural history of congenital malformations and conditions that are either life threatening or cause severe disability. Fetal surgery for myelomeningocele has been shown to improve neurologic outcome, motor function and to reduce the need of ventriculo-peritoneal shunting after birth compared to postnatal care. However, it conveys an increased risk of preterm birth and maternal morbidity. The role of prenatal intervention with endoscopic tracheal occlusion in congenital diaphragmatic hernia is currently the focus of an ongoing multicenter randomized controlled trial. The trial is comparing the effect of fetal surgery as an alternative to standard postnatal management. The main, but not sole, indication for an Ex-utero intrapartum treatment (EXIT) is airway obstruction due to laryngeal atresia and tumors in the head and neck region. It is a complex procedure that should be performed only in experienced centers with a multidisciplinary team.
- Published
- 2017
38. Video-assisted thoracoscopic surgery for adult Bochdalek hernia: a case report.
- Author
-
Shen YG, Jiao NN, Xiong W, Tang Q, Cai QY, Xu G, and Liang GY
- Subjects
- Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital pathology, Humans, Male, Middle Aged, Rare Diseases diagnostic imaging, Rare Diseases pathology, Rare Diseases surgery, Tomography, X-Ray Computed, Hernias, Diaphragmatic, Congenital surgery, Thoracic Surgery, Video-Assisted
- Abstract
Background: Bochdalek hernia is a type of congenital diaphragmatic hernia that typically presents in childhood, while this diseases is extremely rare in adults., Case Presentation: We review a case of a 63-year-old man with a left-sided Bochdalek hernia who was experiencing occasional pain at the left side of his chest for 8 months. The diagnosis of Bochdalek hernia was made by chest computed tomography. A part of the retroperitoneal adipose tissue was herniated into the left thoracic cavity through the diaphragmatic defect. The hernia was treated via video-assisted thoracoscopic surgery and he made an uneventful recovery., Conclusions: We report a rare case of a left-sided Bochdalek hernia for which our patient was treated successfully via video-assisted thoracoscopic surgery. Even though rare, this disorder should be recognised, examined and treated appropriately to avoid complications.
- Published
- 2016
- Full Text
- View/download PDF
39. Polygenic Causes of Congenital Diaphragmatic Hernia Produce Common Lung Pathologies.
- Author
-
Donahoe PK, Longoni M, and High FA
- Subjects
- Animals, Diaphragm embryology, Diaphragm pathology, Disease Models, Animal, Female, Hernias, Diaphragmatic, Congenital therapy, Humans, Infant, Lung embryology, Lung pathology, Mice, Mice, Knockout, Chromosome Aberrations, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital pathology
- Abstract
Congenital diaphragmatic hernia (CDH) is one of the most common and lethal congenital anomalies, and significant evidence is available in support of a genetic contribution to its etiology, including single-gene knockout mice associated with diaphragmatic defects, rare monogenetic disorders in humans, familial aggregation, and association of CDH with chromosomal abnormalities. Structural lung defects in the form of lung hypoplasia are almost invariably seen in patients with CDH and frequently in animal models of this condition. Better understanding of the mechanisms of pulmonary defects in CDH has the potential for creating targeted therapies, particularly in postnatal stages, when therapeutics can have maximum clinical impact on the surviving cohorts. Successful treatment of CDH is dependent on the integration of human genomic and genetic data with developmental expression profiling, mouse knockouts, and gene network and pathway modeling, which have generated a large number of candidate genes and pathways for follow-up studies. In particular, defective alveolarization appears to be a common and potentially actionable phenotype in both patients and animal models., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
40. Understanding Lung Development, Injury, and Repair.
- Author
-
Chauhan C and Roth KA
- Subjects
- Fibroblasts physiology, Hernias, Diaphragmatic, Congenital pathology, Humans, Organogenesis, Pericytes physiology, Stem Cells physiology, Wound Healing, Lung embryology, Lung Injury therapy
- Abstract
This Editorial introduces the Lung Ontogeny and Injury Theme Issue, which provides critical insights into lung development, injury, and repair as well as key pulmonary diseases., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
41. Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia.
- Author
-
Fujinaga H, Fujinaga H, Watanabe N, Kato T, Tamano M, Terao M, Takada S, Ito Y, Umezawa A, and Kuroda M
- Subjects
- Case-Control Studies, Cell Movement, Cell Proliferation, Cells, Cultured, Chemokine CXCL12 blood, Fetal Blood, Hernias, Diaphragmatic, Congenital metabolism, Humans, Infant, Newborn, Neovascularization, Physiologic, Nitric Oxide, Vascular Endothelial Growth Factor A physiology, Endothelial Progenitor Cells physiology, Hernias, Diaphragmatic, Congenital pathology
- Abstract
Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1-3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
42. The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia.
- Author
-
Mahood TH, Johar DR, Iwasiow BM, Xu W, and Keijzer R
- Subjects
- Animals, Female, Gene Expression Regulation, Developmental, Hernias, Diaphragmatic, Congenital pathology, Humans, Lung drug effects, Lung embryology, MicroRNAs metabolism, Phenyl Ethers adverse effects, Phosphatidylinositol 3-Kinases metabolism, Polymerase Chain Reaction, RNA, Messenger metabolism, Rats, Sequence Analysis, DNA, Signal Transduction genetics, Transforming Growth Factor beta metabolism, Hernias, Diaphragmatic, Congenital metabolism, Lung pathology, Transcriptome
- Abstract
Background: We currently do not know how the herbicide nitrofen induces lung hypoplasia and congenital diaphragmatic hernia in rats. Our aim was to compare the differentially expressed transcriptome of nitrofen-induced hypoplastic lungs to control lungs in embryonic day 13 rat embryos before the development of embryonic diaphragmatic defects., Methods: Using next-generation sequencing technology, we identified the expression profile of microRNA (miRNA) and mRNA genes. Once the dataset was validated by both RT-qPCR and digital-PCR, we conducted gene ontology, miRNA target analysis, and orthologous miRNA sequence matching for the deregulated miRNAs in silico., Results: Our study identified 186 known mRNA and 100 miRNAs which were differentially expressed in nitrofen-induced hypoplastic lungs. Sixty-four rat miRNAs homologous to known human miRNAs were identified. A subset of these genes may promote lung hypoplasia in rat and/or human, and we discuss their associations. Potential miRNA pathways relevant to nitrofen-induced lung hypoplasia include PI3K, TGF-β, and cell cycle kinases., Conclusion: Nitrofen-induced hypoplastic lungs have an abnormal transcriptome that may lead to impaired development.
- Published
- 2016
- Full Text
- View/download PDF
43. Prenatal diagnosis of unilateral agenesis of diaphragm and associated anomalies.
- Author
-
Morosanu C, Cioca A, Stamatian F, and Crisan D
- Subjects
- Adult, Female, Humans, Hernias, Diaphragmatic, Congenital diagnosis, Hernias, Diaphragmatic, Congenital pathology, Prenatal Diagnosis
- Published
- 2016
- Full Text
- View/download PDF
44. Pulmonary transcriptome analysis in the surgically induced rabbit model of diaphragmatic hernia treated with fetal tracheal occlusion.
- Author
-
Engels AC, Brady PD, Kammoun M, Finalet Ferreiro J, DeKoninck P, Endo M, Toelen J, Vermeesch JR, and Deprest J
- Subjects
- Animals, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital surgery, Rabbits, Disease Models, Animal, Hernias, Diaphragmatic, Congenital pathology, Lung metabolism, Trachea embryology, Transcriptome
- Abstract
Congenital diaphragmatic hernia (CDH) is a malformation leading to pulmonary hypoplasia, which can be treated in utero by fetal tracheal occlusion (TO). However, the changes of gene expression induced by TO remain largely unknown but could be used to further improve the clinically used prenatal treatment of this devastating malformation. Therefore, we aimed to investigate the pulmonary transcriptome changes caused by surgical induction of diaphragmatic hernia (DH) and additional TO in the fetal rabbit model. Induction of DH was associated with 378 upregulated genes compared to controls when allowing a false-discovery rate (FDR) of 0.1 and a fold change (FC) of 2. Those genes were again downregulated by consecutive TO. But DH+TO was associated with an upregulation of 157 genes compared to DH and controls. When being compared to control lungs, 106 genes were downregulated in the DH group and were not changed by TO. Therefore, the overall pattern of gene expression in DH+TO is more similar to the control group than to the DH group. In this study, we further provide a database of gene expression changes induced by surgical creation of DH and consecutive TO in the rabbit model. Future treatment strategies could be developed using this dataset. We also discuss the most relevant genes that are involved in CDH., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
45. Coexistence of congenital diaphragmatic hernia and abdominal wall closure defect with chromosomal abnormality: two case reports.
- Author
-
Inoue S, Odaka A, Muta Y, Beck Y, Sobajima H, and Tamura M
- Subjects
- Fatal Outcome, Heart Defects, Congenital pathology, Heart Defects, Congenital therapy, Heart Failure etiology, Hernia, Umbilical complications, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital therapy, Humans, Infant, Newborn, Karyotyping, Male, Ultrasonography, Prenatal, Abdominal Wall abnormalities, Chromosome Aberrations, Down Syndrome diagnosis, Heart Defects, Congenital complications, Hernia, Umbilical diagnostic imaging, Hernias, Diaphragmatic, Congenital complications
- Abstract
Background: We reported two rare cases of congenital diaphragmatic hernia with abdominal wall closure defect, which were not associated with septum transversum diaphragmatic defects or Fryns syndrome., Case Presentation: Case 1: a Japanese baby boy was delivered at 37 weeks' gestation by urgent cesarean section because of the diagnosis of severe fetal distress. Congenital diaphragmatic hernia with omphalocele was prenatally diagnosed with fetal ultrasound. A ruptured omphalocele was confirmed at delivery. A silo was established on the day of his birth; direct closure of his diaphragmatic defect and abdominal wall closure was performed on the fifth day after his birth. Trisomy 13 was confirmed by genetic examination. His postoperative course was uneventful and he was discharged 5 months postnatally with home oxygen therapy. He was readmitted because of heart failure and died at 6 months. Case 2: a Japanese baby boy, who was prenatally diagnosed with gastroschisis, was delivered at 35 weeks' gestation by urgent cesarean section because of the diagnosis of fetal distress. Silo construction using a wound retractor was performed on the day of his birth and direct abdominal closure was performed on the tenth day after his birth. Trisomy 21 was confirmed by genetic examination. Treatment for his respiratory distress was continued after surgery. A retrosternal hernia was revealed at 6 months and direct closure of retrosternal diaphragm with the resection of hernia sac was performed. His postoperative course was uneventful and he was discharged with home oxygen therapy., Conclusions: Attention should be paid to chromosomal abnormality in cases in which the coexistence of congenital diaphragmatic hernia and abdominal wall closure defect are observed.
- Published
- 2016
- Full Text
- View/download PDF
46. RIGHT-SIDED BOCHDALEK HERNIA IN ADULT ASSOCIATED WITH CHOLESTATIC SYNDROME: CASE REPORT.
- Author
-
dos Santos-Netto JM, Oliveira CV, and Sousa MG
- Subjects
- Female, Hernias, Diaphragmatic, Congenital pathology, Humans, Middle Aged, Syndrome, Cholestasis etiology, Hernias, Diaphragmatic, Congenital complications
- Published
- 2015
- Full Text
- View/download PDF
47. Quantification of liver herniation in fetuses with isolated congenital diaphragmatic hernia using two-dimensional ultrasonography.
- Author
-
Werneck Britto IS, Olutoye OO, Cass DL, Zamora IJ, Lee TC, Cassady CI, Mehollin-Ray A, Welty S, Fernandes C, Belfort MA, Lee W, and Ruano R
- Subjects
- Adult, Cohort Studies, Extracorporeal Membrane Oxygenation methods, Female, Fetal Diseases therapy, Hernias, Diaphragmatic, Congenital pathology, Hernias, Diaphragmatic, Congenital surgery, Hernias, Diaphragmatic, Congenital therapy, Humans, Infant, Newborn, Liver Diseases therapy, Magnetic Resonance Imaging methods, Predictive Value of Tests, Pregnancy, Retrospective Studies, Fetal Diseases diagnostic imaging, Fetal Diseases pathology, Hernias, Diaphragmatic, Congenital diagnostic imaging, Liver Diseases diagnostic imaging, Liver Diseases embryology, Liver Diseases pathology, Ultrasonography, Prenatal methods
- Abstract
Objectives: To describe a method of quantifying the amount of liver herniation in fetuses with isolated congenital diaphragmatic hernia (CDH) using two-dimensional ultrasonography and to correlate this finding with neonatal outcome., Methods: Ultrasound images obtained from 77 consecutive fetuses that presented with isolated CDH between January 2004 and July 2012 were reviewed. Liver herniation and thoracic area were measured in a cross-sectional plane of the fetal chest at the level of the four-chamber view of the heart (the same section as is used to measure the lung area-to-head circumference ratio) and the ultrasound-derived liver-to-thoracic area ratio (US-LiTR) was calculated by dividing the liver herniation area by the thoracic area. Receiver-operating characteristics (ROC) curve analysis was used to evaluate the performance of US-LiTR in predicting neonatal outcome (survival to 6 months after delivery and need for extracorporeal membrane oxygenation (ECMO)). In addition, the US-LiTR was compared with the magnetic resonance imaging (MRI)-derived volume ratio (MRI-LiTR) and percentage of liver herniation (MRI-%LH)., Results: The overall neonatal mortality in the 77 cases with isolated CDH was 20.8% (16/77). ECMO was needed in 35.5% (27/76) of the newborns, with a survival rate of 52%. The US-LiTR was associated statistically with mortality (P < 0.01) and with the need for ECMO (P < 0.01). Good correlations were observed between US-LiTR and MRI-LiTR (r = 0.87; P < 0.001) and between US-LiTR and MRI-%LH (r = 0.90; P < 0.001). Based on ROC curve analysis, all three parameters had similar accuracy in predicting mortality (US-LiTR: area under the ROC curve (AUC), 0.78 (95% CI, 0.65-0.92), P < 0.01; MRI-LiTR: AUC, 0.77 (95% CI, 0.63-0.90), P < 0.01; MRI-%LH: AUC, 0.79 (95% CI, 0.65-0.92), P < 0.01, respectively) as well as the need for ECMO (US-LiTR: AUC, 0.72 (95% CI, 0.60-0.84), P < 0.01; MRI-LiTR: AUC, 0.73 (95% CI, 0.60-0.88), P < 0.01; MRI-%LH: AUC, 0.77 (95% CI, 0.64-0.89), P < 0.01, respectively)., Conclusions: Two-dimensional ultrasound measurement of the amount of liver herniation in fetuses with isolated CDH is feasible and demonstrates a predictive accuracy for neonatal outcome similar to that of MRI., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
48. Correlation of observed-to-expected total fetal lung volume with intrathoracic organ herniation on magnetic resonance imaging in fetuses with isolated left-sided congenital diaphragmatic hernia.
- Author
-
Nawapun K, Eastwood M, Sandaite I, DeKoninck P, Claus F, Richter J, Rayyan M, and Deprest J
- Subjects
- Abnormalities, Multiple diagnosis, Female, Humans, Liver anatomy & histology, Liver pathology, Liver Diseases diagnosis, Lung embryology, Lung Diseases diagnosis, Pregnancy, Prenatal Diagnosis methods, Reproducibility of Results, Retrospective Studies, Stomach pathology, Fetal Diseases pathology, Hernias, Diaphragmatic, Congenital pathology, Liver Diseases congenital, Lung abnormalities, Magnetic Resonance Imaging methods
- Abstract
Objectives: To assess using fetal magnetic resonance imaging (MRI) the relationship between the position of the stomach as well as the volume of herniation of organs into the thorax, and the observed-to-expected total fetal lung volume (o/e-TFLV), as a measure of pulmonary hypoplasia, in fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH)., Methods: This was a single-center retrospective study using archived MR images from fetuses > 20 weeks' gestation evaluated for isolated LCDH over an 11-year period between July 2002 and September 2013. We retrieved data on the gestational age at MRI, o/e-TFLV and liver position. Images were also reviewed by a single operator to determine retrospectively the position of the stomach as well as the proportion of the total thorax volume occupied by the herniated fetal liver, stomach and other viscera. Following confirmation of reproducibility, we assessed the correlation of intrathoracic organ volumes and stomach position with o/e-TFLV., Results: The study included 205 fetuses which underwent a total of 259 MR examinations. The reproducibility of organ volume measurements was excellent (intraclass correlation coefficient range, 0.928-0.997). The average time spent to obtain intrathoracic organ volumes ranged from 2.28 to 5.13 min. Of all herniated organ-to-thoracic volume ratios, the liver-to-thoracic volume ratio had the strongest correlation with o/e-TFLV (ρ = -0.429, P<0.0001). Stomach volume did not correlate, although, when categorized by the position and extent of stomach herniation, there was an inverse relationship to o/e-TFLV. No intrathoracic organ-to-thoracic volume ratio was related to gestational age., Conclusions: We observed in fetuses with isolated LCDH an inverse relationship between lung volume and the amount of liver herniated as well as the position of the stomach in the chest., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
49. Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH.
- Author
-
Rhodes J, Saxena D, Zhang G, Gittes GK, and Potoka DA
- Subjects
- Animals, Calcium Channel Blockers pharmacology, Carbachol pharmacology, Cardiotonic Agents pharmacology, Disease Models, Animal, Embryo, Mammalian drug effects, Female, Hernias, Diaphragmatic, Congenital chemically induced, Hernias, Diaphragmatic, Congenital embryology, Humans, Immunoenzyme Techniques, Lung drug effects, Mice, Parasympathetic Nervous System embryology, Parasympathetic Nervous System metabolism, Pesticides toxicity, Phenyl Ethers toxicity, Respiratory System drug effects, Respiratory System embryology, Stem Cells drug effects, Verapamil pharmacology, Embryo, Mammalian pathology, Hernias, Diaphragmatic, Congenital pathology, Lung abnormalities, Lung pathology, Parasympathetic Nervous System pathology, Respiratory System pathology
- Abstract
Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
50. Longitudinal assessment of lung area measurements by two-dimensional ultrasound in fetuses with isolated left-sided congenital diaphragmatic hernia.
- Author
-
Ruano R, Britto IS, Sangi-Haghpeykar H, Bussamra LC, Da Silva MM, Belfort MA, Deter RL, Lee W, Tannuri U, and Zugaib M
- Subjects
- Female, Gestational Age, Head embryology, Hernias, Diaphragmatic, Congenital embryology, Hernias, Diaphragmatic, Congenital pathology, Humans, Lung embryology, Lung growth & development, Predictive Value of Tests, Pregnancy, Prenatal Diagnosis, Prognosis, Head diagnostic imaging, Hernias, Diaphragmatic, Congenital diagnostic imaging, Lung diagnostic imaging, Lung Volume Measurements methods, Ultrasonography, Prenatal
- Abstract
Objective: To evaluate lung growth in healthy fetuses and those with congenital diaphragmatic hernia (CDH) using two-dimensional (2D) ultrasound., Methods: Fetal right lung measurements obtained by 2D ultrasound between 19 and 37 weeks' gestation were evaluated longitudinally in 66 healthy fetuses and 52 fetuses with isolated left-sided CDH. Right lung areas were determined by the 'tracing' and 'longest-diameters' methods and, subsequently, lung area-to-head circumference ratios (LHRs) were calculated. Functions fitted to these size parameters with respect to gestational age were evaluated for three sets of group-wise comparisons: (1) healthy vs CDH fetuses; (2) different degrees of severity of CDH; and (3) CDH fetuses that survived vs those that died by 6 months postpartum., Results: There was a significantly slower increase in right lung areas and LHRs with advancing gestational age in CDH fetuses than in healthy individuals (P < 0.05). Compared to those with milder forms of CDH, lung areas and LHRs of fetuses with more severe forms displayed a smaller increase (P < 0.05) and LHRs of fetuses with severe CDH did not increase during pregnancy (P > 0.05). Individuals who died postpartum did not show any increase in LHR (P > 0.05) throughout gestation., Conclusions: The right lung area and LHR, calculated using either the longest-diameters or tracing method, display reduced growth rates during gestation in cases of isolated left-sided CDH as compared with healthy fetuses. The growth curve characteristics of fetal lung areas and LHRs may be useful for predicting neonatal mortality., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.