[Value of MRI in the evaluation of congenital anomalies of the heart and great vessels]. / Apport de l'IRM dans l'exploration des anomalies cardiaques congénitales et des gros vaisseaux.

Management of congenital heart diseases (CHD) frequently is a diagnostic challenge. MRI, as a complement to echocardiography, plays an important role in the non-invasive evaluation of these anomalies. MRI allows high resolution anatomical evaluation of these structures in multiple planes as well as functional evaluation. These features are helpful to further characterize extra-cardiac anomalies that may be difficult to assess at US and even angiography. MRI is thus a valuable imaging tool in the evaluation of CHD.

[Role of gastroesophageal reflux in asthma in infants and young children]. / Rôle du reflux gastro-oesophagien dans l'asthme du nourrisson et du jeune enfant.

Gastroesophageal reflux (GER) occurs more frequently in asthmatic children than in general population. Esophageal pH recording data may be somewhat particular. The debate on GER increasing bronchial obstruction or GER being a parallel phenomenon remains controversial. Hypotheses are: acid microaspirations giving bronchospasm, vagally-transmitted reflex, or more probably coexisting phenomena. Pulmonary contamination is rarely seen during esophageal scintigraphy. Asthma symptoms are rarely clearly correlated to acid reflux episodes in pH-recording studies. However the esophageal acid infusion test may increase bronchial obstruction in adult asthmatics. Basically, when should one seek GER in asthmatic children? Many authors keep this for asthmatic children not responding to conventional treatment, also keeping in mind that GER-specific therapy efficacy is often difficult to appreciate in such patients. Briefly, one may speculate that GER improves with bronchodilator treatment in most cases.

[Thoracic aortic coarctation: MRI evaluation and follow-up]. / Coarctation de l'aorte thoracique: évaluation et suivi en IRM.

PURPOSE: Report our experience in the evaluation and follow-up of thoracic aortic coarctation with MRI and describe its role to estimate trans-stenotic flow. MATERIAL AND METHODS: 43 MR examinations were performed in 30 patients (age range 15 days to 73 years) referred to our institution in the last 7 years. RESULTS: MRI visualized the ascending, horizontal and descending portions of the aorta and the supra-aortic vessels in 42/43 patients. MRI clearly identified preoperatively an aortic coarctation in 11/12 cases confirmed by surgery. Postoperatively MRI depicted 4 restenosis and one aneurysm. In 5 patients MRI demonstrated pseudo-coarctation. A significant correlation was established between the maximal trans-stenotic pressure gradient when measured by Doppler US or angiography and the size of the signal void measured on cine-MR images (r=0.72; p<0.01). CONCLUSION: MRI is a reliable non invasive investigation method for the diagnosis and semi-quantitative evaluation of aortic coarctation particularly when colour Doppler US is not satisfactory.

[Tetralogy of Fallot in monozygotic twins]. / Tétralogie de Fallot chez un couple de jumeaux monozygotes.

UNLABELLED: The causative mechanisms of congenital heart defects remain unclear and little is known about the respective implication of chance, genetics and environment, though recent findings in molecular biology may provide further insight into understanding the pathophysiologic basis of congenital heart diseases. CASE REPORT: We report the exceptional but significant case of monozygotic twins both affected by tetralogy of Fallot, for whom prenatal diagnosis ruled out 22q11 microdeletion. CONCLUSION: We discuss how far this observation is consistent with the latest hypothesis, which emphasizes the leading role of genetic factors. Several genes indeed, either separately or in combination, could be responsible for those defects, even if other influences may still come into play.

Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha.

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-kappaB (NFkappaB). We investigated the effect of NGF on the expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1-10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFkappaB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFkappaB p65 subunit. NGF-induced NFkappaB activity and Bcl-xL expression were inhibited in cells overexpressing the NFkappaB inhibitor, IkappaBalpha. Unlike tumor necrosis factor-alpha (TNF-alpha), however, NGF-induced NFkappaB activation occurred without significant degradation of IkappaBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein-tagged IkappaBalpha. Moreover, in contrast to TNF-alpha, NGF failed to phosphorylate IkappaBalpha at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IkappaBalpha potently suppressed NFG-, but not TNF-alpha-induced NFkappaB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-alpha-, but not NGF-induced NFkappaB activation. We conclude that NGF and TNF-alpha induce different signaling pathways in neurons to activate NFkappaB and bcl-x gene expression.

Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.

Phosphorylation of the N-terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF-kappa B. Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of I kappa B-alpha, little is known about the mechanisms that lead to release of active NF-kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B-alpha [Imbert, V., Rupec, R.A., Livolsi, A., Pahl, H.L., Traenckner, B.M., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auberger, P., Baeuerle, P. & Peyron, J.F. (1996) Cell 86, 787--798]. The involvement of the tyrosine kinases p56(lck) and ZAP-70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases. Although the inhibitors prevented both pervanadate-induced phosphorylation of I kappa B-alpha on Tyr42 and NF-kappa B activation, we observed that, in p56(lck)-deficient Jurkat mutants, NF-kappa B could still associate with I kappa B-alpha despite phosphorylation on Tyr42. Furthermore, the SH2 domain of p56(lck) appeared to be required for pervanadate-induced NF-kappa B activation but not for Tyr42 phosphorylation. These results show that p56(lck) and ZAP-70 are key components of the signaling pathway that leads to phosphotyrosine-dependent NF-kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF-kappa B. Finally, we show that H(2)O(2), which stimulates p56(lck) and ZAP-70 in T cells, is an activator of NF-kappa B through tyrosine phosphorylation of I kappa B-alpha.

Cleavage and relocation of the tyrosine kinase P59FYN during Fas-mediated apoptosis in T lymphocytes.

Ligation of Fas with its natural ligand or with anti-Fas antibodies induces an apoptotic program in Fas sensitive cells. We report here the identification of the tyrosine kinase p59Fyn as a substrate for CPP32-like proteinases and more particularly caspase 3 during Fas-mediated apoptosis in Jurkat T cells. Inhibition of CPP32-like proteinases by Ac-Asp-Glu-Val-Asp-aldehyde but not by Ac-Tyr-Val-Ala-Asp-aldehyde prevents CPP32, PARP and p59Fyn cleavage indicating that CPP32 or CPP32-like proteinases are responsible for the cleavage of p59Fyn. Cleavage occurs in the N-terminal domain of p59Fyn between Asp19 and Gly20 and is accompanied by relocation of an active p57Fyn kinase to cytoplasm of Fas-stimulated Jurkat cells as judged by both biochemical and confocal microscopy experiments. Thus, p59Fyn relocation and activity may play an important role during Fas-mediated cell death in human T lymphocytes.

Structural analysis, expression, and chromosomal localization of the mouse ikba gene.

The pleiotropic transcription factor NF-kappaB is localized in the cytoplasm bound to its inhibitory subunit IkappaB. The predominant form of NF-kappaB is a p50/p65 heterodimer which can be released from IkappaB-alpha and migrate to the nucleus. Previous studies have shown that IkappaB-alpha-/- mice die 8 to 10 days postnatally, showing runting and a severe dermatitis. However, the organ distribution of mouse IkappaB-alpha, the exon-intron structure, and the chromosomal localization of ikba have not been determined so far. A mouse Sv129 genomic DNA library was screened with a human IkappaB-alpha/MAD-3 cDNA probe. One clone (P1) was isolated, spanning the complete ikba gene and the promoter/enhancer region. We show that the exon-intron structure between mouse and pig ikba is completely conserved. In contrast to human ikba, the ankyrin repeat 5 is not interrupted by an intron. Furthermore, the mouse ikba promoter contains 6 putative NF-kappaB binding sequences, which are conserved in mouse, pig, and human, underlining the importance of NF-kappaB as a key regulator of ikba transcription. The deduced amino acid sequence shows >90% similarity between mouse, pig, and human ikba. Chromosome mapping localized the mouse ikba gene to chromosome 12. Northern blot analysis demonstrated predominant expression in lymphoid tissue (lymph node and thymus). However, IkappaB-alpha mRNA was detected as well in liver tissue, the gastrointestinal tract, and the reproductive tract. The cloning and determination of the structure are a prerequisite for the construction of vectors for conditional gene targeting experiments.

Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation.

Melanogenesis is a physiological process resulting in the synthesis of melanin pigments which play a crucial protective role against skin photocarcinogenesis. In vivo, solar ultraviolet light triggers the secretion of numerous keratinocyte-derived factors that are implicated in the regulation of melanogenesis. Among these, tumor necrosis factor alpha (TNFalpha), a cytokine implicated in the pro-inflammatory response, down-regulates pigment synthesis in vitro. In this report, we aimed to determine the molecular mechanisms by which this cytokine inhibits melanogenesis in B16 melanoma cells. First, we show that TNFalpha inhibits the activity and protein expression of tyrosinase which is the key enzyme of melanogenesis. Further, we demonstrate that this effect is subsequent to a down-regulation of the tyrosinase promoter activity in both basal and cAMP-induced melanogenesis. Finally, we present evidence indicating that the inhibitory effect of TNFalpha on melanogenesis is dependent on nuclear factor kappa B (NFkappaB) activation. Indeed, overexpression of this transcription factor in B16 cells is sufficient to inhibit tyrosinase promoter activity. Furthermore, a mutant of inhibitory kappa B (IkappaB), that prevents NFkappaB activation, is able to revert the effect of TNFalpha on the tyrosinase promoter activity. Taken together, our results clarify the mechanisms by which TNFalpha inhibits pigmentation and point out the key role of NFkappaB in the regulation of melanogenesis.

Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.

Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappaB). NF-kappaB is sequestered in the cytosol by Ikappa Balpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappaB in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and activated upon TNF exposure. Within the same time frame, TNF induced c-Src associates with Ikappa Balpha in a long lived complex. The proto-oncogene, when associated with Ikappa Balpha phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced Ikappa Balpha tyrosine phosphorylation, NF-kappaB activation, by the cytokine, is markedly delayed and reduced in c-src-/- BMMs. Underscoring the physiological significance of c-Src activation of NF-kappaB, TNF induction of IL-6, which is an NF-kappaB mediated event, is substantially diminished in c-src-/- BMMs.

Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.

The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-kappa B activation through tyrosine phosphorylation but not degradation of I kappa B-alpha. Pervanadate-induced I kappa B-alpha phosphorylation and NF-kappa B activation required expression of the T cell tyrosine kinase p56ick. Reoxygenation of hypoxic cells appeared as a physiological effector of I kappa B-alpha tyrosine phosphorylation. Tyrosine phosphorylation of I kappa B-alpha represents a proteolysis-independent mechanism of NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase.

Mediastinal stabilization by an expansion prosthesis in postoperative congenital diaphragmatic hernia with severe pulmonary hypoplasia.

The authors illustrate a case of right neonatal congenital diaphragmatic hernia (CDH) of Bochdalek with major pulmonary hypoplasia and postoperative massive mediastinal displacement to the right, leading to tracheal compression and recurrent respiratory distress at every attempt to wean the infant from the ventilator. Mediastinal stabilization was obtained by placing an expansion prosthesis (of the cutaneous type) in the right hemithorax, to prevent mediastinal obstruction of the main airways. This procedure may prove to be an original and efficient solution for the critical postoperative respiratory obstruction due to severe pulmonary hypoplasia and mediastinal mass effect in the newborn with CDH. However, this may not prevent progressive scoliosis, a serious problem frequently seen in the absence of one lung.

[Cantrell syndrome or the "shagreen skin" pentalogy. Apropos of 3 cases]. / Le syndrome de Cantrell ou la pentalogie "peau de chagrin". A propos de trois observations.

Three patients with incomplete forms of Cantrell syndrome underwent surgical therapy at the Department of Infantile Surgery in Strasbourg, France, between 1979 and 1990. One patient had a giant omphalocele. Another had a ventricular septal defect. Two of the three patients are alive and doing well. The nosology and prognostic factors in Cantrell syndrome are discussed.

[Tracheal compression by an aberrant brachiocephalic trunk: diagnosis by magnetic resonance]. / Compression trachéale par un tronc artériel brachio-céphalique aberrant: diagnostic par résonance magnétique.

In a full-term infant who underwent surgery for type III esophageal atresia, attempts to remove the tracheal tube postoperatively failed. Bronchoscopy disclosed external compression of the trachea in the chest. Selection of the investigations most likely to provide the etiologic diagnosis was discussed. Because of the patient's poor general condition, MRI of the mediastinal area was performed first and showed an abnormal origin of the brachiocephalic trunk which was the cause of tracheal compression. No attempt at corrective surgery was made and the patient was successfully extubated at four months of age.

Contribution of MRI in supracardiac total anomalous pulmonary venous drainage.

A case of supracardiac total anomalous pulmonary venous drainage (TAPVD) in an infant aged 2 1/2 months is presented. Diagnosis was established non invasively by magnetic resonance image (MRI). Not only did MRI precisely depict the anomalous venous pathway but it moreover securely excluded pulmonary venous obstruction.

[Mediastinal bronchogenic cyst of the carina in an infant: contribution of magnetic resonance]. / Kyste bronchogénique médiastinal de la carène chez un nourrisson: apport de la résonance magnétique.

The case of a young child who demonstrated extrinsic narrowing of the thoracich trachea related to a mediastinal bronchogenic cyst is reported. Diagnosis was made by magnetic resonance imaging. About this case report, the authors review the possible causes of tracheal narrowing at this age of life and suggest a simple diagnostic management protocol.

MR diagnosis of subdiaphragmatic anomalous pulmonary venous drainage in a newborn.

Our report describes a case of infradiaphragmatic total anomalous pulmonary venous return diagnosed by MR in a newborn with an interruption of the aortic arch with ventricular septum defect and anomalous pulmonary venous drainage. The severity of the congenital cardiopathy did not permit surgical treatment and the infant died soon after. Pathology confirmed the MR findings. Magnetic resonance not only complements echocardiography but also can be used for patients in intensive care and can in our case avoid angiography.

[Indications of magnetic resonance imaging in congenital cardiopathies in neonatal period. Apropos of 54 cases]. / Indications de l'imagerie par résonance magnétique dans les cardiopathies congénitales en période néonatale. A propos de cinquante-quatre cas.

Between February 1988 and July 1989, the authors used magnetic resonance imaging (MRI) to study 54 newborn infants aged between 2 and 35 days and suspected of congenital heart disease. All children also underwent echocardiography and 7 angiography during the neonatal period (13% of children studied). MRI was well tolerated and there were no adverse events. MRI proved to be complementary to echocardiography in several lesions affecting the great vessels of the base and the left atrial region. Agreement between angiography and MRI results was very good, with MRI being more useful in one case. MRI enables full and non-invasive postoperative follow-up. In conclusion, despite the great heterogenicity of the cardiac malformations studied and which requires a degree of caution, the authors feel that MRI is a second line investigation after echocardiography. It may limit the indications of angiography. Its own indications are the retrocardiac region, the main arteriovenous vessels of the base and postoperative follow-up in congenital heart disease. The development of techniques such as angio RM will further modify data in the future.