Lung Hypoplasia Research Articles

Lung Perfusion MRI After Congenital Diaphragmatic Hernia Repair in 2-Year-Old Children With and Without Extracorporeal Membrane Oxygenation Therapy.

In severe cases of congenital diaphragmatic hernia (CDH), extracorporeal membrane oxygenation (ECMO) therapy improves survival. Later on, lung morbidity mainly defines development. The purpose of this study was to investigate whether 2-year-old children who need ECMO therapy after delivery have reduced perfusion MRI values as a sign of more severe lung hypoplasia than do children who do not need ECMO. After CDH repair, 38 children underwent dynamic contrast-enhanced MRI with a 3D time-resolved angiography with stochastic trajectories sequence. Fifteen (39%) of the children had received ECMO therapy in the neonatal period. Pulmonary blood flow (PBF), pulmonary blood volume (PBV), and mean transit time were calculated for both lungs. In addition, the ratio of ipsilateral to contralateral lung was calculated for all parameters. In all children, those with and those without ECMO requirement, PBF and PBV were significantly reduced on the ipsilateral side (p < 0.05). Children who had received ECMO therapy had significantly reduced PBF and PBV values on the ipsilateral side (p < 0.05) compared with children who had not needed ECMO therapy. The ratios of ipsilateral to contralateral lung for PBF and PBV were also significantly reduced after ECMO. Two-year-old children undergoing CDH repair who had needed neonatal ECMO had significantly reduced perfusion MRI values in the ipsilateral lung in comparison with children who had not needed ECMO. Perfusion MRI measurements are associated with the severity of lung hypoplasia and may therefore be helpful in follow-up investigations.

Effect of Perflubron-induced lung growth on pulmonary vascular remodeling in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) involves lung hypoplasia and pulmonary hypertension (PH). Post-natal Perflubron ventilation induces lung growth. This phenomenon is called Perflubon-induced lung growth (PILG). However, it does not appear to ameliorate PH in CDH. We aim to determine the effect of PILG on pulmonary vascular remodeling in neonates with CDH and PH requiring extracorporeal membrane oxygenation (ECMO). Lung tissue from four patients was obtained, three treated with PILG+ECMO, and one maintained on conventional ventilation+ECMO (control). The distribution of collagen was assessed with Masson's trichrome stain. Immunohistochemistry was done to assess cell proliferation and immunofluorescence to assess vascular morphology. Comparing PILG vs. control, there was an increase in vessel wall diameter (6.85μm, 10.28μm, and 10.35μm vs. 4.34μm), increase in collagen thickness in two PILG patients (35.66μm, 14.23μm, and 38.46μm vs. 22.16μm), and decrease in lumen diameter despite similar total area (48.99μm, 41.74μm, and 36.32μm vs. 51.56μm) for each PILG patient vs. the control patient, respectively. PILG does not appear to improve pulmonary vascular remodeling that occurs with PH. The findings are descriptive and will require larger samples to validate the significance of the findings. Overall, further studies will be required to identify the mechanistic causes of PH in CDH to create effective treatments.

Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia

IntroductionThe management of congenital diaphragmatic hernia (DH) would benefit from an antenatal medical therapy, which addresses both lung hypoplasia and persistent pulmonary hypertension. We aimed at evaluating the pulmonary effects...

Decreased expression of miR-33 in fetal lungs of nitrofen-induced congenital diaphragmatic hernia rat model

BackgroundThe pathogenesis of congenital diaphragmatic hernia (CDH) and the causes of pulmonary hypoplasia and hypertension remain unclear. miRNAs have been identified to play important regulatory roles in pulmonary pathological processes and lung development. We carried out the study to investigate the hypothesis that specific miRNAs are expressed differently in the lungs of nitrofen-induced rats, and to explore the possible targeting genes and roles of miR-33 in the pathological process of CDH. MethodsPregnant rats were divided into nitrofen and control group, and were exposed to nitrofen or vehicle respectively on D9. Fetuses were harvested on D21 and left lungs were dissected. 4 samples from each group underwent miRNAs microarray analysis using Agilent miRNA Array. Quantitative real-time polymerase chain reaction (qRT-PCR) was further performed to validate the miR-33 expression. Results11 miRNAs exhibited increased expression in nitrofen group compared with control (p<0.05): miR-3588, miR-382*, miR-363, miR-375, miR-487b, miR-483, miR-382, miR-495, miR-434, miR-181a, and miR-99a. 14 miRNAs showed decreased expression (p<0.05): miR-33, miR-193, miR-338, miR-30c-2*, miR-22, miR-18a, miR-532-5p, miR-28, miR-96, miR-551b, miR-141, miR-362*, miR-30a*, and miR-3559-5p. Among them, miR-33 expression was markedly decreased in CDH lungs compared to controls and the result was confirmed by qRT-PCR. ConclusionDecreased expression of miR-33 was found in the nitrofen-induced hypoplastic lung on D21. This finding suggests that pathogenesis of lung hypoplasia and CDH in the nitrofen model involve epigenetic layer of regulation.

MiR-449a Affects Epithelial Proliferation during the Pseudoglandular and Canalicular Phases of Avian and Mammal Lung Development.

Congenital diaphragmatic hernia is associated with pulmonary hypoplasia and respiratory distress, which result in high mortality and morbidity. Although several transgenic mouse models of lung hypoplasia exist, the role of miRNAs in this phenotype is incompletely characterized. In this study, we assessed microRNA expression levels during the pseudoglandular to canalicular phase transition of normal human fetal lung development. At this critical time, when the distal respiratory portion of the airways begins to form, microarray analysis showed that the most significantly differentially expressed miRNA was miR-449a. Prediction algorithms determined that N-myc is a target of miR-449a and identified the likely miR-449a:N-myc binding sites, confirmed by luciferase assays and targeted mutagenesis. Functional ex vivo knock-down in organ cultures of murine embryonic lungs, as well as in ovo overexpression in avian embryonic lungs, suggested a role for miR-449a in distal epithelial proliferation. Finally, miR-449a expression was found to be abnormal in rare pulmonary specimens of human fetuses with Congenital Diaphragmatic Hernia in the pseudoglandular or canalicular phase. This study confirms the conserved role of miR-449a for proper pulmonary organogenesis, supporting the delicate balance between expansion of progenitor cells and their terminal differentiation, and proposes the potential involvement of this miRNA in human pulmonary hypoplasia.

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1(Δ/Δ)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Δ/Δ) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1(Δ/Δ) macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1(Δ/Δ) mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1(Δ/Δ) mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.

Why do we need more data on MR volumetric measurements of the fetal lung?

Fetal lung hypoplasia is associated with a series of congenital anomalies, particularly the congenital diaphragmatic hernia. Evaluation of the severity of the lung hypoplasia is important for parental counseling, assessment of prognosis and planning of postnatal management. Although a large number of studies have been performed to measure fetal lung volumes in order to predict outcome, there are little data on fetuses younger than 24weeks of gestation, the age when parental counseling is crucial if termination is considered. Few studies have evaluated prognosis of lung hypoplasia in fetuses with congenital chest anomalies other than congenital diaphragmatic hernia. We review the studies on measurements of the fetal lung volumes by MRI.

Non-cardiovascular findings in clinical cardiovascular magnetic resonance imaging in children.

With increasing use of pediatric cardiovascular MRI, it is important for all imagers to become familiar with the spectrum of non-cardiovascular imaging findings that can be encountered. This study aims to ascertain the prevalence and nature of these findings in pediatric cardiovascular MRIs performed at our institution. We retrospectively evaluated reports of all cardiovascular MRI studies performed at our institute from January 2008 to October 2012 in patients younger than18 years. Most studies (98%) were jointly interpreted by a pediatric cardiologist and a radiologist. We reviewed the electronic medical records of all cases with non-cardiovascular findings, defined as any imaging finding outside the cardiovascular system. Non-cardiovascular findings were classified into significant and non-significant, based on whether they were known at the time of imaging or they required additional workup or a change in management. In 849 consecutive studies (mean age 9.7 ± 6.3 years), 145 non-cardiovascular findings were found in 140 studies (16.5% of total studies). Overall, 51.0% (74/145) of non-cardiovascular findings were in the abdomen, 30.3% (44/145) were in the chest, and 18.6% (27/145) were in the spine. A total of 19 significant non-cardiovascular findings were observed in 19 studies in individual patients (2.2% of total studies, 47% male, mean age 5.9 ± 6.7 years). Significant non-cardiovascular findings included hepatic adenoma, arterially enhancing focal liver lesions, asplenia, solitary kidney, pelvicaliectasis, renal cystic diseases, gastric distention, adrenal hemorrhage, lung hypoplasia, air space disease, bronchial narrowing, pneumomediastinum and retained surgical sponge. Non-cardiovascular findings were seen in 16.5% of cardiovascular MRI studies in children, of which 2.2% were clinically significant findings. Prevalence and nature of these non-cardiovascular findings are different from those reported in adults. Attention to these findings is important during interpretation.

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia.

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. 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. 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. Nitrofen-induced hypoplastic lungs have an abnormal transcriptome that may lead to impaired development.

Prolonged latency period of 70 days in a diamniotic and dichorionic twin pregnancy complicated by early second trimester rupture of membrane in one sac and its outcome

A patient with diamniotic dichorionic twin (DADC) pregnancy was on regular antenatal checkup from conception, admitted to emergency department at 21 weeks with leaking PV. On per speculum and pervaginal examination it was found that clear liquor was draining from os &amp;amp; cervix was long and os was closed. USG revealed twin A sac having live fetus of 20 weeks with no liquor and twin B sac having live fetus with plenty of liquor. Considering the emotional aspect of parents we decided for conservative management which includes combination of antibiotics, micronized progesterone as tocolytic, probiotics, L- arginine and absolute bed rest. Caesarean section was performed at 31 weeks as she entered in labour and had cord prolapse. She delivered two live twin babies after a long latency period of 70 days. Twin ‘A’ baby could not be saved because of lung hypoplasia due to prolonged Oligohydraminous but twin ‘B’ was discharged safely along with mother. Since last decade assisted reproduction technique has increased in numbers of twin pregnancies and its complications. The most important are preterm labour and PPROM. On literature review there is no clear cut guide line for management of PPROM in early second trimester in twin pregnancies. This case is reported because of its long latency period of 70 days from PPROM in early 2&lt;sup&gt;nd&lt;/sup&gt; trimester in a twin pregnancy to delivery by conservative management and can save the baby in intact sac. Also we can add our experience to currently available limited literature regarding management of such patient.

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Imaging findings of bronchial atresia in fetuses, neonates and infants.

Congenital lung malformations are increasingly detected before birth. However, bronchial atresia is rarely identified in utero and not always recognized in neonates. There are two types of atresia: 1) proximal, located at the level of the mainstem or the proximal lobar bronchi, which is extremely rare and usually lethal during pregnancy, causing a tremendous volume increase of the distal involved lung with secondary hypoplasia of the normal lung, and 2) peripheral, located at the segmental/subsegmental bronchial level, which may present as an isolated lesion or as part of a complex congenital malformation. Prenatal findings are mostly nonspecific. Postnatal exams show overinflated lung areas and focal bronchial dilations. The typical fluid-filled bronchoceles are not always observed in neonates but develop progressively in the first months of life. This pictorial essay describes the spectrum of imaging findings of bronchial atresia in fetuses, neonates and infants.

Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is often secondary to parenchymal lung disease (such as meconium aspiration syndrome) or lung hypoplasia (with congenital diaphragmatic hernia) but can also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance, resulting in right-to-left shunting of blood and hypoxemia. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis and confirmed by echocardiography. Lung volume recruitment with optimal use of positive end-expiratory pressure or mean airway pressure and/or surfactant is very important in secondary PPHN due to parenchymal lung disease. Other management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation, and pulmonary vasodilator therapy. Failure of these measures leads to consideration of extracorporeal membrane oxygenation, although this rescue therapy is needed less frequently with advances in medical management. Randomized clinical trials with long-term follow-up are required to evaluate various therapeutic strategies in PPHN.

Unique Tracheal Fluid MicroRNA Signature Predicts Response to FETO in Patients With Congenital Diaphragmatic Hernia.

Our objective was to determine the fetal in vivo microRNA signature in hypoplastic lungs of human fetuses with severe isolated congenital diaphragmatic hernia (CDH) and changes in tracheal and amniotic fluid of fetuses undergoing fetoscopic endoluminal tracheal occlusion (FETO) to reverse severe lung hypoplasia due to CDH. We profiled microRNA expression in prenatal human lungs by microarray analysis. We then validated this signature with real-time quantitative polymerase chain reaction in tracheal and amniotic fluid of CDH patients undergoing FETO. We further explored the role of miR-200b using semiquantitative in situ hybridization and immunohistochemistry for TGF-β2 in postnatal lung sections. We investigated miR-200b effects on TGF-β signaling using a SMAD-luciferase reporter assay and Western blotting for phospho-SMAD2/3 and ZEB-2 in cultures of human bronchial epithelial cells. CDH lungs display an increased expression of 2 microRNAs: miR-200b and miR-10a as compared to control lungs. Fetuses undergoing FETO display increased miR-200 expression in their tracheal fluid at the time of balloon removal. Future survivors of FETO display significantly higher miR-200 expression than those with a limited response. miR-200b was expressed in bronchial epithelial cells and vascular endothelial cells. TGF-β2 expression was lower in CDH lungs. miR-200b inhibited TGF-β-induced SMAD signaling in cultures of human bronchial epithelial cells. Human fetal hypoplastic CDH lungs have a specific miR-200/miR-10a signature. Survival after FETO is associated with increased miR-200 family expression. miR-200b overexpression in CDH lungs results in decreased TGF-β/SMAD signaling.

Abstract 13158: Impact of Enhancing Fetal Lung Vascular and Alveolar Development by Slow-release Novel Synthetic Prostacyclin Agonist for Treatment of Fetal Lung Hypoplasia

Background: Lung hypoplasia and persistent pulmonary hypertension associated with critical pathologies, such as congenital diaphragmatic hernia (CDH), is the major cause of mortality in the neonates. Although prostaglandins pathway is known to play a pivotal role in the lung development, effectiveness of postnatal treatment by prostaglandin agonists was reported to be suboptimal. We hypothesized that prenatal treatment by ONO-1301SR, slow-release form of a novel synthetic prostacyclin agonist with thromboxane inhibitory activity, might promote development of lungs having hypoplasia in the fetal period. Methods: On embryonic day (E) 9.5, nitrofen was given to pregnant Sprague-Dawley rats to produce a CDH-relating lung hypoplasia model, while normal rats (n=4) received vehicle only. At the same day, either ONO-1301SR or placebo was randomly given to the nitrofen-treated rats (placebo; n=7, ONO; n=5). On E21.5, the normal fetuses, and the fetuses having CDH were analyzed. Results: Prenatal ONO-1301SR administration had no influence on incidence of nitrofen-induced CDH. One-seventh of maternal blood concentration of ONO-1301 was transferred to fetal blood at E21.5, warranting efficient placental permeability of this molecule. Prostacyclin receptor was expressed in pulmonary arterial smooth muscle cells in the fetus. Lung-to-body weight ratio (%) in the ONO group (1.88±0.07) was greater than that in the placebo group (1.60±0.04, p&lt;0.01). Histologically, medial wall thickness in the ONO group was two-third thinner than that in the placebo group (p&lt;0.01). In addition, the number of Ttf-1-positive cells and capillary density were 1.5 times or more greater in the ONO group than that in the placebo group (p&lt;0.05), associated with a greater expression of VEGF and SDF-1 in the ONO group, suggesting enhanced development of the alveolar and capillary network. Conclusions: Prenatal ONO-1301SR administration promoted efficient development of hypoplastic lungs associated with CDH in the nitrofen-induced rat model, indicating potential of this treatment for pathologies having lung hypoplasia.

Possible role of increased oxidative stress in pulmonary hypertension in experimental diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is one of the causes of respiratory failure in newborns due to lung hypoplasia and pulmonary abnormalities leading to pulmonary hypertension (PH). NAD(P)H oxidase (Nox) is a family of isoenzymes that generate reactive oxygen species (ROS) which can contribute to PH-induced vascular dysfunction. On the other hand, superoxide dismutase (SOD) 1-2 and catalase are the antioxidant enzymes that eliminate the excess of ROS in pulmonary vascular cells. Our aim is to examine whether PH-associated with CDH is due to a dysregulation of ROS production in lungs from CDH fetuses. Pregnant rats received either 100mg nitrofen or vehicle on E9.5. Fetuses were recovered on E21. (1) Nox activity, (2) H2O2 production and (3) mRNA levels of Nox1, Nox2, Nox4, SOD1, SOD2 and catalase were analyzed in fetal lungs. Nox activity and Nox1 and Nox2 mRNA levels were increased in the lungs of fetuses with CDH. However, there were no changes in H2O2 production and Nox4 mRNA levels. SOD1, SOD2 and catalase were decreased. The raised oxidative stress due to increase in ROS generation by Nox isoenzymes and dysfunction of antioxidant enzymes seems to be a potential mechanism responsible on PH-associated with CDH.

Scimitar Syndrome a Rare Cause of Isolated Esophgeal Varices

We present a rare case of isolated esophageal varices arising from Scimitar syndrome, an anomalous connection of the right pulmonary vein to the Inferior vena cava (IVC). A 53 year old female with past medical history of Scimitar syndrome repaired at age 20, with dissection of the anomalous right pulmonary vein and connecting it to the right atrium, and then creating an intra-atrial pericardial baffle directing venous flow to the left atrium presented with epigastric pain. She denied history of gastrointestinal bleeding or chest pain. Vital signs and exam were normal. Labs were normal. CT Chest, abdomen and pelvis showed mild mediastinal enlargement, a small right pulmonary artery, loss of right lung volume and diffuse distal esophageal wall prominence. The liver, spleen & pancreas were unremarkable. For epigastric pain, she underwent an EGD showing H.pylori gastritis and grade III esophageal varices in the mid and distal esophagus. She was treated for H. pylori gastritis. Endoscopic US showed esophageal varices, a lymph node in the aortopulmonary region and normal flow in the portal and splenic veins. For further workup of her esophageal varices in the setting of Scimitar syndrome and in the absence of portal hypertension, she underwent a cardiac catheterization. The cardiac catheterization showed normal right atrial and left ventricular end diastolic pressures. Also right pulmonary venous hypertension was noted, with the pulmonary venous collaterals draining into the azygous venous system, intercostal veins and then into the para esophageal venous system producing esophageal varices. Blood flow in the baffle from the right lower pulmonary vein into left atrium was not visualized, suggestive of obstruction of the surgical baffle. The study concluded that the right pulmonary venous flow drained into the systemic circulation via the paraesophageal veins. Scimitar syndrome aka pulmonary venolobar syndrome is a rare congenital heart malformation, with a prevalence of 0.5-1%. It is characterized by partial or complete anomalous drainage of the right pulmonary vein into the IVC, right lung hypoplasia and mediastinal shift. The ‘Scimitar sign' is a curvilinear shadow resembling a curved Turkish sword ‘scimitar' created by an abnormal right pulmonary vein draining into the IVC. The common causes of esophageal varices in an adult are portal vein thrombosis, liver cirrhosis, SVC obstruction, mediastinal tumors, thymoma or chronic fibrosing mediastinitis. Esophageal varices arising from an anomalous pulmonary venous return is very rare. In this case, obstruction of the surgical baffle resulted in esophageal varices without portal hypertension. Patient was referred to surgery for evaluation of right lower lobe pneumonectomy or creation of another surgical baffle which may diminish the esophgeal varices.Figure 1Figure 2Figure 3

PP‐10 CHARACTERIZATION OF ESOPHAGEAL MOTILITY IN INFANTS BORN WITH CONGENITAL DIAPHRAGMATIC HERNIA USING HIGH RESOLUTION MANOMETRY

Purpose:Congenital diaphragmatic hernia (CDH) is a rare condition characterized by a congenital defect in the diaphragm. Abdominal organs are displaced into the thorax through the diaphragmatic defect, hereby causing lung hypoplasia. Survivors also present with long‐term functional gastro‐intestinal morbidity such as gastro‐esophageal reflux, esophageal dysfunction and poor nutritional status. Congenital esophageal dysmotility and surgical disruption of the esophago‐gastric junction (EGJ) may contribute to this esophageal dysfunction. The aim of this study was to characterize esophageal function in young infants born with CDH.Methods:High resolution solid state manometry was used to investigate the esophageal function in 9 postoperative infants born with CDH (6 M, median age 23 days). A total of 416 liquid swallows were analyzed (range 27–70 swallows per patient; mean 46 swallows). All data are presented as median (IQR).Results:We included 9 patients: 8 with a left diaphragmatic defect, 5 with a “liver up” defect, 4 underwent a fetal tracheal occlusion procedure because of severe lung hypoplasia, 8 needed a patch to close a large diaphragmatic defect. Across patients, length of peristaltic defects was 0.4 (0.3,0.6) cm. Distal contractile integral (DCI) was 357 (249,428) mmHg.sec.cm. Distal Latency (DL) was 4.9 (3.6,5.6) sec, whereby 5/9 patients had a DL less than 4.5 sec. EGJ resting pressure was 37 (17,60) mmHg. The integrated relaxation pressure (IRP4) was 14 (9,19) mmHg with IRP4 over 15 mmHg in 4 patients.Conclusion:We investigated the esophageal body and EGJ function in 9 patients with CDH using high resolution manometry. This pilot study shows that the distal contractile integral is reduced in all infants with CDH. This reflects weak esophageal contractile strength and supports the congenital foregut dysmotility hypothesis. Surprisingly, deglutitive relaxation pressures were increased in only 4/9 patients suggesting that EGJ outflow obstruction post hernia repair of the crural diaphragm, is only partially contributing to the esophageal motor dysfunction observed in patients with CDH.

High-Resolution (1)H NMR Spectroscopy Discriminates Amniotic Fluid of Fetuses with Congenital Diaphragmatic Hernia from Healthy Controls.

Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, although defining those to benefit remains challenging. Metabonomics of (1)H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF embodies lung secretions and hence might contain pulmonary next to general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests that explore spectral variability, similarity, and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with up to 92% accuracy. Within the identified spectral regions, isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine, and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with 12 spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from CDH fetuses versus healthy controls independent of gestational age.

Scimitar syndrome. Correlation anatomo-embryological

To describe morphologically a toracoabdominal visceral block of a scimitar's syndrome case. We propose a pathogenetic theory wich explains the development of the pulmonary venous connection in this syndrome. The anatomic specimen was described with the segmental sequential system. The situs was solitus, the connections between the cardiac segments and the associated anomalies were determined. The anatomy of both lungs, including the venous pulmonary connection, was described. A pathogenetic hypothesis was made, which explains the pulmonary venous connection throw a correlation between the pathology of this syndrome and the normal development of the pulmonary veins. The situs was solitus, the connections of the cardiac chambers were normal; there were hypoplasia and dysplasia of the right lung with sequestration of the inferior lobe; the right pulmonary veins were connected with a curved collector which drainaged into the suprahepatic segment of the inferior vena cava; the left pulmonary veins were open into the left atrium. The sequestered inferior lobe of the right lung received irrigation throw a collateral aortopulmonary vessel. There was an atrial septal defect. The pathogenetic hypothesis propose that the pulmonary venous connection in this syndrome represent the persistent of the Streeter's horizon xiv (28-30 days of development), period in which the sinus of the pulmonary veins has double connection, with the left atrium and with a primitive collector into the right viteline vein which forms the suprahepatic segment of the inferior vena cava.