Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson's disease patients.

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[18F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (Ki), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA Ki (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA Ki loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.

Effects of cottonseed hull levels in the diet and ageing time on visual and sensory meat acceptability from young bulls finished in feedlot.

Cottonseed hulls are co-product of agribusiness that can be used in beef cattle rations, decreasing the cost of feed. The aim of this study was to evaluate the effects of different cottonseed hull levels, display and ageing times on visual and sensorial meat acceptability. Longissimus thoracis muscle from 30 crossbred young bulls finished on three high-grain diets (210, 270 or 330 g/kg of cottonseed hulls on dry matter, respectively) were visually evaluated during 10 days of display by 37 appraisers. Tenderness, flavour and overall acceptability from the three diets and three ageing times (1, 7 and 14 days) were evaluated by 120 consumers. On the visual study, time of display (P⩽0.001) was a more significant factor than diet. Cottonseed hull level had no effect on sensorial analyses, with tenderness acceptability improving with ageing time (P⩽0.001). Results indicate the possibility of using the three studied levels of cottonseed without damaging consumer meat acceptability.

Functional and structural brain connectivity of young binge drinkers: a follow-up study.

Adolescence is a period of ongoing brain maturation characterized by hierarchical changes in the functional and structural networks. For this reason, the young brain is particularly vulnerable to the toxic effects of alcohol. Nowadays, binge drinking is a pattern of alcohol consumption increasingly prevalent among adolescents. The aim of the present study is to evaluate the evolution of the functional and anatomical connectivity of the Default Mode Network (DMN) in young binge drinkers along two years. Magnetoencephalography signal during eyes closed resting state as well as Diffusion Tensor Imaging (DTI) were acquired twice within a 2-year interval from 39 undergraduate students (22 controls, 17 binge drinkers) with neither personal nor family history of alcoholism. The group comparison showed that, after maintaining a binge drinking pattern along at least two years, binge drinkers displayed an increased brain connectivity of the DMN in comparison with the control group. On the other hand, the structural connectivity did not show significant differences neither between groups nor over the time. These findings point out that a continued pattern of binge drinking leads to functional alterations in the normal brain maturation process, even before anatomical changes can be detected.

Magnetic properties of epitaxial discontinuous Fe/MgO multilayers.

We report magnetic, dynamic and transport properties of discontinuous metal-insulator multilayers Fe/MgO grown on amorphous Corning glass and single-crystalline MgO (001) substrates. The films of structure Substrate/MgO (3 nm)/[Fe (0.6 nm)/MgO (3.0 nm)] x 10 were prepared in ultra-high vacuum conditions using Pulsed Laser Deposition. It was shown that conditions of epitaxial growth are favorable for MgO substrates. As a result a substantial increase of tunneling magnetoresistance caused by spin-filtering effect was observed and reasonably theoretically explained. The value of TMR - 9.2% at room temperature in 18 kOe magnetic field is three times higher comparing to that for the samples grown on Corning glass substrates.

Determination of the percolation threshold in Fe/MgO magnetic granular multilayers.

The evolution of the morphology, magnetic and transport properties of Fe(t nm)/MgO(3.0 nm) multilayers with respect to the nominal metallic layer thickness was investigated. A comparison with existing experimental data on discontinuous metal-insulator multilayers, ultrathin epitaxial Fe films on MgO substrates and granular cermet films is made. It is confirmed that the deposition conditions and the material composition play a crucial role in the percolation process. Nominal thicknesses of Fe layers at which an infinite metallic cluster is formed and the conditions for continuous Fe coverage were determined. Different methods of percolation threshold detection were analysed. We show that investigation of the temperature dependence of resistance in nanostructures could lead to an overestimation of the percolation threshold value, while magnetic measurements alone could lead to its underestimation.

[Prognostic factors in pediatric liver transplantation. Multivariate analysis]. / Factores pronósticos del trasplante hepático pediátrico. Análisis multivariante.

AIM: To analyze independent risk factors associated with poor graft and patient survival in a series of 292 pediatric liver transplants (PLT) performed in 234 children during a 15 years period. MATERIAL AND METHODS. 1. Univariate graft and patient survival analysis in 45 variables related to pretransplant patient status, surgical technique and donor conditions. 2. Variables found with univariate analysis to be associated with outcome were entered into a stepwise backward proportional hazard model (Cox), to determine independent prediction of outcome. RESULTS: 11 variables influence the graft survival: recipient age, z-score recipient height, UNOS status, recipient and donor weight, transplant for immune hepatitis, platelet transfusion during the transplant, blood index > 4 during the surgery, type of arterial reconstruction, retransplantation and era of the transplant (first er: 1986-1990; 2nd. era: 1991-1995; 3rd. era: 1996-2000). Four of those variables are independent in the multivariate analysis: UNOS 1 status (Odds Ratio, OR = 2.82, 95% confidence interval = 1.36-5.85), recipient < 3 years (OR = 3.76, 95% CI = 2.13-6.63), transplants for autoimmune hepatitis and era (OR of first and second versus third era respectively 3.93 and 2.81). The independent variables influencing the patient survival were: children receiving more than one graft children less than 3 years old and transplant era. CONCLUSIONS: Liver transplant in small children is associated with an increased risk of graft loss and patient dead. The experience of the hospital in pediatric liver transplantation improves the results, particularly in small children.

Prenatal vitamin E improves lung and heart hypoplasia in experimental diaphragmatic [correction of diaphragamatic] hernia.

Nitrofen induces in rats diaphragmatic hernia (CDH) with heart and lung hypoplasia by a mechanism involving oxidation. The aim of this study was to examine if prenatal administration of the anti-oxidant agent vitamin E (VitE) prevents to some extent heart and lung hypoplasia. Pregnant rats received on E9.5 either 100 mg of nitrofen alone or followed by 150 IU of VitE on E16.5-E20.5. Control animals received either vehicle or VitE alone. The fetuses were recovered on E21. The hearts and lungs were weighed and DNA and proteins were measured. Sections of the heart and lung were immunohistochemically stained for ki-67, Tunel and TTF-1, and the proportions of proliferating, apoptotic and TTF-1-expressing cells were determined. Cultured human pneumocytes were exposed to the same agents and similarly processed. TTF-1 expression and the proportion of proliferating cells were quantitated. The ANOVA or Kruskall-Wallis tests were used for comparison with p<0.05 as threshold of significance. Nitrofen-exposed rats had decreased lung and heart weight/body weight ratios, lung and heart DNA and protein, lung TTF-1 expression and proportion of proliferating cells in lung and heart. Additional treatment with VitE ameliorated these decreases except for lung TTF-1 and heart weight. In cultured pneumocytes, TTF-1 expression was decreased by nitrofen and rescued by VitE. Cell proliferation followed the same pattern. Antioxidant VitE partially reverses the effects of nitrofen on the heart and lungs of exposed rats. The same effects are observed in cultured human pneumocytes. These results further substantiate the oxidative nature of the effects of nitrofen and suggest that anti-oxidant agents could have a potential clinical application.

The adrenal cortex in experimental congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Adrenal cortical malfunction was found recently in patients with severe congenital diaphragmatic hernia (CDH). The current study tests the hypothesis that the development and function of the adrenal cortex could be abnormal in an experimental model of CDH. METHODS: Pregnant rats were exposed on day 9.5 of gestation to 100 mg of 2-4-dichlorophenyl-p-nitrophenyl ether (nitrofen) diluted in olive oil. The sham group was treated only with oil. Fetuses were recovered on the 21st day, bled, and examined for the presence or absence of CDH. Adrenal glands from sham and CDH animals were dissected, weighed, and prepared for histologic, biochemical, and immunohistochemical studies (ki-67) aimed at measuring total DNA, total protein, and the proportion of proliferating cells. Serum corticosterone levels were assayed. The results in both groups were compared with parametric tests with a significance level of P <.05. RESULTS: The adrenal weight was not different in CDH animals versus controls (0.049 +/- 0.014 v 0.052 +/- 0.012% of body weight; not significant). Total DNA was reduced significantly (1.180 +/- 0.481 v 1.909 +/- 0.893 microgram P <.05) with unchanged DNA to protein ratio. Proliferation index in both groups was 20.1 +/- 3.1% and 26.5 +/- 7.5%, respectively (not significant), and the proliferating cells were mainly located in the glomerular areas of the glands. Corticosterone levels were similar in both groups. CONCLUSIONS: Nitrofen induces very slight changes in the development of adrenal glands of fetal rats, expressed by reduced cell proliferation especially in glomerular areas, reduced total DNA with preservation of cell sizes (constant DNA to protein ratio), with no change in function because corticosterone levels remained unchanged. It is doubtful that primary adrenal malformation/malfunction contributes to the severity of CDH in this model.

Situación actual del trasplante renal en el niño / Overview of renal Transplant in children

El Trasplante Renal (TR) es el tratamiento de elección para todos los niños en Insuficiencia Renal Terminal (IRT). Realizamos un análisis de varios factores que influyen de forma significativa en los resultados del TR en el niño: Receptor, donante, inmunosupresión, tratamiento quirúrgico y complicaciones quirúrgicas. También mostramos las curvas de supervivencia del injerto al año y a los 5 años. Desde 1966 los resultados del TR en el niño han mejorado de forma llamativa. El TR ofrece al niño en IRT una excelente rehabilitación y una supervivencia aceptable del injerto a largo plazo (AU)

Modelo experimental de embriopatía por ácido retinoico en ratas para el estudio de las malformaciones craneofaciales / Experimental model of retinoid embryopathy in rats for craneofacial malformations study

El objetivo de este trabajo es demostrar que la exposición de ratas gestantes al ácido retinoico induce malformaciones craneofaciales a sus embriones. Se trataron 45 ratas hembra Sprague-Dawley con 125 mg/Kg de ácido all-trans-retinoico en el día 10 de gestación, produciéndose malformaciones craneofaciales en el 100 por ciento de los embriones. Se realizó un estudio morfológico de los defectos craneofaciales. Nuestros datos confirman la hipótesis de que el ácido retinoico altera el desarrollo craneofacial. Un defecto en la migración de las células de la cresta neural podría explicar esta alteración (AU)

Neural crest-derived defects in experimental congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is often associated with other malformations. This study tests the hypothesis that the heart and great vessels, thymus, parathyroids, and thyroid might be abnormal in the rat model of CDH as a result of disturbed neural-crest development. Time-mated pregnant rats were fed either 100 mg 2-4-dichlorophenyl-p-nitrophenyl ether (nitrofen) or vehicle on gestational day 9.5. Diaphragm, lung, heart, and thymic malformations were sought after dissection and the parathyroids and thyroid were histologically investigated in term fetuses. Ten control fetuses had no malformations, whereas 22 of 32 nitrofen fetuses had CDH and 20 had cardiovascular defects like narrow pulmonary outflow tract (n = 7), aberrant right subclavian artery (n = 7), ventricular septal defect (n = 4), atrial septal defect (n = 4), tetralogy of Fallot (n = 2), double-outflow right ventricle (n = 2), right ductus arteriosus (n = 2), and others. The thymus was present but was significantly hypoplastic in all nitrofen fetuses and was ectopic or single-lobed in 28% of them while the parathyroid glands were unilaterally absent or ectopic in 50%. The thyroid was only minimally malformed or ectopic. In conclusion, malformations of structures derived from the pharyngeal arches are likely neural-crest related in rats exposed to nitrofen.

Prenatal dexamethasone rescues heart hypoplasia in fetal rats with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Patients and rats with congenital diaphragmatic hernia (CDH) have lung and heart hypoplasia. Prenatal steroids improve lung hypoplasia in CDH rats. The current study tests the hypothesis that prenatal dexamethasone could rescue heart hypoplasia in rats with CDH. METHODS: Timed pregnant rats received intragastrically either 100 mg nitrofen or oil on day 9.5, and other animals had the same treatment with, in addition, either 0.25 mg/kg dexamethasone intraperitoneally or no treatment on days 19 and 20. Fetuses were recovered on day 21, and heart weight to body weight ratios, heart DNA, protein, and glycogen were measured in fresh specimens. Left-to-right ventricular diameter and aortic-to-pulmonary diameter ratios were measured after formalin fixation. RESULTS: Wet heart weight to body weight, left-to-right ventricular diameter, and aortic-to-pulmonary root diameter ratios, which were lower in fetuses exposed only to nitrofen than in their oil controls, were similar in those exposed to nitrofen plus dexamethasone than in their corresponding oil plus dexamethasone controls. Total heart DNA, which was decreased in fetuses exposed to nitrofen with CDH in comparison with their controls, was increased in those receiving nitrofen and dexamethasone in comparison with theirs. Protein to DNA ratio was decreased in all rats with CDH irrespective of their exposure or not to dexamethasone. Glycogen to DNA ratio was higher in all dexamethasone-treated fetuses than in those without this treatment. No gross histologic differences were seen among groups. CONCLUSIONS: Heart hypoplasia in rats with CDH is in part rescued by prenatal dexamethasone treatment as expressed by increased number of smaller myocytes with higher glycogen content. Prenatal steroids could modify heart involvement in human fetuses with CDH as well.

Down-regulation of thyroid transcription factor-1 gene expression in fetal lung hypoplasia is restored by glucocorticoids.

The thyroid transcription factor (TTF)-1 has an essential role in lung morphogenesis and development. It is involved in the transcription of surfactant proteins (SP), which are critical in respiratory function. Neonates with congenital diaphragmatic hernia die of respiratory failure caused by pulmonary hypoplasia with associated biochemical immaturity. To gain new insights into the causes of this disorder and the effect of prenatal hormonal treatment on reducing mortality in these infants, we evaluated the expression of TTF-1 as marker of lung morphogenesis and SP-B as marker of lung maturity. Using a rat model of lung immaturity, we show that TTF-1 and SP-B messenger RNA (mRNA) levels are drastically reduced in congenital lung hypoplasia. Interestingly, prenatal dexamethasone (Dex) treatment increased both TTF-1 and SP-B mRNAs over control levels when administered to rats with lung hypoplasia, but it had no effect on TTF-1 or a moderate effect on SP-B mRNA when administered to control rats. TRH alone also increases TTF-1 and SP-B mRNA levels but to a lesser extent than Dex. When administered together with Dex, TRH counteracts the induction observed with the glucocorticoid. The decrease in TTF-1 mRNA levels in lung hypoplasia is paralleled by a down-regulation of TTF-1 protein levels, as well as by a decrease in the TTF-1/DNA complex when the TTF-1-binding site of the SP-B promoter was used as a probe. Both parameters were reestablished after glucocorticoid treatment. Moreover, the regulation of TTF-1 gene expression described in this report is accompanied by the same regulation in its promoter activity, as demonstrated in transfection experiments performed in H-441 human lung-derived adenocarcinoma cells. In conclusion, our data demonstrate, for the first time, that lung hypoplasia and the associated respiratory dysfunction caused by SP-B deficiency are caused, in part, by down-regulation of TTF-1 gene expression. The observations that prenatal glucocorticoid treatment induces the expression of TTF-1 supports routine in utero glucocorticoid treatment of patients expected to have lung hypoplasia.

Neural crest-derived defects in experimental esophageal atresia.

Esophageal atresia (EA) is often associated with cardiovascular and other malformations that are likely neural crest derived. The present study tests the hypothesis that the heart and great vessels and the thymus and parathyroids may be abnormal in the rat model of EA as a result of disturbed neural crest development. Time-mated pregnant rats received intraperitoneally on d 8 and 9 of gestation either 2 mg/kg adriamycin or vehicle. Esophageal, heart, and thymic malformations were sought under the microscope in term fetuses. The parathyroids were histologically investigated. Control fetuses had no malformations, whereas 69 of 109 fetuses exposed to adriamycin had EA and 45 of 69 had 15 right aortic arches, nine aberrant right subclavia, eight ventricular septal defects, six narrow pulmonary outflow tracts, five tetralogies of Fallot, three double outflow right ventricles, three double aortic arches, three atrial septal defects, three right ductus arteriosus, and two truncus. The thymus was absent in 19, hypoplastic in 12, and ectopic in five out of 36 fetuses with EA in which it was studied, whereas the parathyroid glands were absent in 16, single in four, and ectopic in one of the 23 fetuses with EA in which they were studied. In conclusion, the nature of the cardiovascular, thymic, and parathyroid malformations associated with EA in rats is consistent with the hypothesis of neural crest participation in their pathogenesis. Mechanisms simultaneously disturbing foregut septation, somitic segmentation, and neural crest development should be sought to explain the combined occurrence of malformations in EA.

Skeletal malformations associated with congenital diaphragmatic hernia: experimental and human studies.

BACKGROUND/PURPOSE: Skeletal malformations are seen occasionally in infants with congenital diaphragmatic hernia (CDH). This study examines whether nitrofen, able to produce CDH in fetal rats, also induces skeletal anomalies and, if so, whether these are similar to those seen in CDH patients. METHODS: Pregnant rats received either nitrofen (100 mg, n = 7) or no treatment (n = 2) on gestational day 9.5. Skeletal anatomy was studied in fetuses recovered on day 21 after alcian blue-alizarin red staining. The charts and postmortem records of 117 stillborns or newborns who died of CDH were investigated retrospectively for skeletal defects. The proportions of anomalies found in the different groups were compared. RESULTS: The 15 control rat fetuses were normal, whereas 57 of 90 nitrofen-exposed animals (63%) had CDH accompanied by other malformations. Skeletal defects limited to vertebral segmentation or identity anomalies (split vertebra or absent, hypoplastic, or fused ribs) were seen at low thoracic and high lumbar levels in 68% of animals with CDH and in 57% of those without. Delayed ossification of limbs was seen in treated animals. There were skeletal malformations in 31.6% of the 117 human patients with CDH. Costovertebral defects (malformed, extra or defective vertebral bodies or ribs and spina bifida) were comparably frequent in infants with syndromes and in those without them (31.2% v 17.8%, not significant), whereas limb defects were significantly more frequent in those with syndromes (56.2% v 13.9%, P<.05). CONCLUSION: The nature and location of costovertebral malformations found in both CDH patients and nitrofen-exposed rats suggest that the diaphragmatic defect and the associated organ malformations might be caused by the same early embryonal disturbance involving axial and para-axial mesoderm.

[Respiratory malformations associated with esophageal atresia]. / Malformaciones respiratorias asociadas a la atresia de esófago.

AIMS: Since trachea, lungs and esophagus develop from foregut and esophageal atresia is a defect of its normal division, we examined the occurrence of respiratory malformations in a large clinical series of esophageal atresia. MATERIALS AND METHODS: The records of 415 patients born with esophageal atresia between 1965 and 1996 and 129 autopsies of the same patients were retrospectively reviewed. The presence of other associated anomalies was carefully studied and noted. RESULTS: Of 415 patients with esophageal atresia, 25 (6%) had one or more associated respiratory malformations. Only 8 patients (2.8%) having bronchopulmonary malformations were diagnosed clinically (8/286) while 17 (13.2%) were diagnosed at autopsy (17/129). The most frequent malformations were: lung segmentation defects (n = 14), pulmonary hypoplasia (n = 9) and tracheomalacia (n = 4). Eighty percent of esophageal atresia patients had another associated malformations specially of the cardiovascular system. CONCLUSIONS: Esophageal atresia patients have a high incidence of associated bronchopulmonary malformations that are frequently not diagnosed.

[Tissue adhesives in closing of fistulas after surgery of esophageal atresia]. / Adhesivos tisulares en la refistulización de la atresia de esófago.

AIMS: Recurrent tracheoesophageal fistula is a severe postoperative complication after esophageal atresia repair. Endoscopic obliteration with tissue adhesives has been used as an alternative to reoperation. The aim of this study is to review our experience with such procedure. MATERIAL AND METHODS: The medical records of 415 esophageal atresia patients were retrospectively reviewed in order to analyze the incidence of complications and the outcome of patients in whom tissue adhesives were used to close a recurrent tracheoesophageal fistula. RESULTS: 334 patients underwent an esophageal anastomosis and fistula closure or fistula division alone, 41 (12.3%) of them had recurrent tracheoesophageal fistula. In eight of these patients and one having an H type tracheoesophageal fistula, endoscopic obliteration using tissue adhesives was attempted. None of these nine children cured after this procedure and all required an open procedure for their recurrent tracheoesophageal fistula. CONCLUSIONS: Contrary to some published cases, we have not succeeded with endoscopic obliteration of recurrent tracheoesophageal fistula using tissue adhesives; therefore, we do not recommend this treatment.

Gastroesophageal reflux after combined lower esophageal sphincter and diaphragmatic crural sling inactivation in the rat.

This study tests the hypothesis that either selective or combined destruction of the lower esophageal sphincter and the diaphragmatic crural sling should induce reflux in the rat. Pull-through perfusion manometry was performed before and after lower esophageal myectomy, crural myotomy, or both. pH monitoring was used to detect reflux. Unmanipulated rats served as controls. Paired t tests were used for comparison of pre- and postoperative pressure values and contingency tables with Fisher's tests for examining the association between the interventions and the appearance of reflux. Esophageal myectomy decreased only sphincteric pressure from 25.9+/-15.5 to 9+/-6 mm Hg (P < 0.01), whereas crural myotomy decreased only sling pressure from 26.2+/-13.3 to 7.3+/-3.9 mm Hg (P < 0.01). Simultaneous performance of both procedures decreased sphincteric and crural pressures from 20.4+/-7.5 to 7.6+/-4.3 mm Hg (P < 0.01) and from 45.9+/-20.6 to 18.2+/-7.4 mm Hg (P < 0.01), respectively. None of the control, myectomy, or myotomy animals showed reflux upon pH-metry but 5/8 rats in which both procedures were performed had prolonged acid exposure. No esophagitis was seen. In conclusion, normal rats do not have reflux. Selective destruction of either the sphincter or the crural sling does not induce reflux, despite causing flattening of their respective manometric profiles. Conversely, combined inactivation of both components is significantly associated with reflux.

Cardiovascular malformations in congenital diaphragmatic hernia: human and experimental studies.

BACKGROUND/PURPOSE: Cardiovascular malformations (CVM) associated with congenital diaphragmatic hernia (CDH) account in part for the high mortality caused by this defect. The aim of this study is to examine the nature of these malformations in a large series of autopsies and to assess if similar defects are also present in rat fetuses with experimental CDH. METHODS: The incidence of CVM and their nature were examined in the autopsy records of 136 stillborns and neonates with CDH admitted to our institution in the last 30 years. Experimental CDH was induced in rat fetuses by giving 100 mg of nitrofen to their mothers on gestational day 9.5, and the fetuses were harvested on day 21 (near full term). The presence of CDH and the anatomy of the heart and great vessels were studied under dissecting microscope after formalin fixation. Unexposed fetuses were used as controls. RESULTS: Thirty-three newborns with CDH (24%) had CVM, either isolated or associated with other defects, and 7 had heart hypoplasia. Most CVM (ventricular septal defect, tetralogy of Fallot, transposition of the great vessels, double-outlet right ventricle) involved the outflow tract. In our animal experiments, no malformations were found in 21 control pups. Conversely, 80 of 130 nitrofen-exposed fetuses (61%) had CDH, and 59 of them (74%) had CVM. A significant association (Fisher's Exact test, P<.01) was found between CDH and CVM because only 25 of the 50 exposed animals without CDH (50%) had CVM. Again, most defects involved the outflow tract and were similar to those seen in human CDH (tetralogy of Fallot, persistent truncus, ventricular septal defect, double-outlet right ventricle, aberrant right subclavian artery, agenetic ductus, and interrupted aortic arch). Animals with CDH had significantly decreased heart weight to fetal weight ratio in comparison with controls and with those without CDH. CONCLUSIONS: The similar nature of the cardiovascular defects found in babies succumbing to CDH and in nitrofen-exposed rats suggests that a similar disturbance of the regional organogenesis related to the neural crest might be involved in both settings, and further validates the use of this animal model for clarifying the cellular and molecular pathogenetic mechanisms.

Skeletal malformations associated with esophageal atresia: clinical and experimental studies.

BACKGROUND/PURPOSE: Patients with esophageal atresia (EA) often have skeletal malformations. The purpose of this study is to examine if similar defects occur in rat fetuses prenatally exposed to Adriamycin, a chemical capable of causing EA in these animals. METHODS: The charts of 443 babies with EA were reviewed to assess the incidence and nature of these defects in them. Time-mated female rats were given either 2 mg/kg intraperitoneal Adriamycin (experimental group, n = 16) or no treatment (control group, n = 4) on gestational days 8 and 9, and the fetuses were removed near term. Skeletal anatomy was studied after alcian blue and alizarin red staining. RESULTS: A total of 528 skeletal malformations, mainly abnormal segmentation and vertebral identity (extra or defective bodies or ribs), mishaped vertebral bodies, and limb malformations like radial aplasia or hypoplasia were found in 245 babies (55%). Costal fusion and sternal anomalies were present in 17 and 4 babies, respectively. In the animal study, all control fetuses were normal, whereas 83 of 134 experimental fetuses (62%) had EA accompanied by other malformations. No segmentation or vertebral identity anomalies were seen, but butterfly, wedged, and asymmetric vertebral bodies were found at various levels in all animals with EA and in about half of those without it. Three fetuses had rib anomalies, and 3 more had sternal malformations. Ossification of limbs was delayed in treated fetuses and short, thick, and crooked bones were seen in 4 of 31 fetuses with EA and in none of the Adriamycin-exposed ones without EA. CONCLUSIONS: Adriamycin exposure induces in fetal rats, in addition to esophageal, duodenal, and anorectal atresias, high proportions of vertebral malformations and some limb defects of nature not identical but quite similar to that of babies with EA. This further validates this model for investigating the nature of the processes leading to EA and its associated malformations.