Overexpression of GRP78 in complete hydatidiform moles.

OBJECTIVE: Hydatidiform moles, subdivided into partial moles (PM) and complete moles (CM), are abnormal pregnancies with a disturbed invasive behavior. We had previously shown that MMP-2 and p53 proteins are overexpressed in CM versus PM, and that in primary cytotrophoblasts p53 protein is stabilized by complexing to the 78kDa glucose-regulated protein (GRP78) which is involved in cytotrophoblasts invasion process. The present study aims to compare the transcript expression profile of p53, MMP-2 and GRP78 in hydatidiform moles. METHODS: A retrospective study was performed by RT-qPCR and immunostaining on paraffin-embedded tissues of 19 PM, 16 CM and 16 control (CTRL) samples of gestational age 8-12 weeks. RESULTS: Expression of MMP-2 transcript was significantly overexpressed in CM compared to CTRL samples (p=0.031). In contrast, expression of p53 transcript was similar among the samples. This suggests a regulation of p53 in CM at the protein level. GRP78 cDNA was significantly overexpressed in CM compared to CTRL (p=0.021) and to PM (p=0.011). At the protein level, immunostaining of GRP78 was on average stronger in CM than PM samples. CONCLUSIONS: Collectively, present data suggest that in CM, p53 is normally expressed at the mRNA level but probably complexes at the protein level with the overexpressed GRP78, leading to accumulation of p53 protein. Moreover, since GRP78 and MMP-2 are increased in CM and known to play key roles in invasion, our results suggest that GRP78 and MMP-2 should be investigated as prognostic markers of hydatidiform moles.

Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

[Expression of the elastic fibers components during the fœtal liver development]. / Expression des composants de la matrice élastique au cours du développement hépatique fœtal.

Elastic fibers are composed of microfibrils containing fibrillin-1 and an elastic component, elastin. Microfibrils may not be associated with elastin. In the adult liver, fibrillin-1 and elastin are coexpressed within the stroma and portal tracts vessel walls. Fibrillin-1 is expressed alone around the bile ducts and within the Disse space. There is little work that has studied the elastic fiber organization during the fœtal liver development. Here, we studied the expression of fibrillin-1 and elastin by immunohistochemistry on 20 cases of fœtal liver. During the development of the portal tract, the two components are coexpressed on interstitial elastic fibers and within vessel walls. Fibrillin-1 is expressed alone around the bile structures during their maturation. Unlike adult liver, fibrillin-1 is expressed on thin and very irregular microfibrils within the Disse space. Our study shows that the elastic matrix development in the portal tract follows the development of the different structures, notably biliary structures. In the Disse space, microfibrils are not continuous. Their maturation may be in relation with the change of the hepatic blood flow after birth.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

[Perinatal prognosis of pregnancies complicated by placental chronic intervillitis]. / Pronostic périnatal des grossesses compliquées d'intervillites chroniques placentaires.

UNLABELLED: SUBJECT. Massive Chronic Intervillositis is an infrequent inflammation lesion of the placenta, characterized by lymphohistiocytic intervillous infiltration, associated with fibrinoid deposition. The purpose of this study was to evaluate the perinatal outcome of pregnancies complicated by such lesions. MATERIAL AND METHODS: We conducted a descriptive retrospective multicentric analysis of a series of pregnancies for which placenta or products of abortion were analyzed between January 1995 and September 2005, at the University Hospital of Bordeaux. After re-examining the histology slides, we performed a semi-quantitative graduation of the cell infiltration and fibrinoid deposition. RESULTS: Twenty-five women were included (one twin-pregnancy and two histologic recurrences). We found three spontaneous abortions before 22 weeks, four intrauterine fetal deaths and three neonatals deaths. Seven of eight elective inductions pregnancies, were performed for intrauterine growth restriction less than 2.5 percentile. The rate of pregnancy loss was 55% and the perinatal mortality was 29%. 77% of fetuses are small for gestational age. Three mothers were pre-eclamptic. 21% of the fetuses had a congenital malformation. Only 32% of the fetuses were alive one week after birth. Histologically, 25% were associated with lesions of Villitis of Unknown Etiology. 77% of the cell infiltration was grade 3 and seemed to be correlated with severe growth restriction. We describe 3 cases of antenatal diagnosis of Chronic Intervillositis, realised after immunofixation on chorionic villous sampling. CONCLUSION: Massive Chronic Intervillositis is a recurrent lesion with a poor prognosis complicated by spontaneous abortion, intrauterine growth restriction and perinatal fetal death. Currently, there is no treatment. Chorionic villous sampling in severe growth restriction might be useful in order to obtain at the same time the fetal karyotype and an histological probe of the placenta.

[DiGeorge syndrome, a review of 52 patients]. / Syndrome de Di George, étude rétrospective de 52 cas.

UNLABELLED: The deletion of chromosome 22q11.2 is involved in the majority of DiGeorge or velo-cardiofacial syndrome. The phenotypic variability was noted in the "CATCH 22" acronym. This acronym doesn't recapitulate the full spectrum of the symptoms. The diagnosis of this syndrome can be done with the prenatal diagnosis, with fetal pathology or with a child alive. METHODS: Review of 52 cases with the microdeletion 22q11. Six cases were diagnosed during the prenatal period, 12 cases at fetal pathology examination, and 34 cases during infancy. RESULTS: Cardiac malformations were the major indications (75%) to search for the microdeletion. The facial dysmorphy was difficult to diagnose during the antenatal period or in dead foetus, thereby it was not often recognized. The renal anomalies usually present in 35% of cases, were diagnosed in only 6 to 16% of the cases in our study. CONCLUSION: Phenotypic diversity of the DiGeorge syndrome is important. Its knowledge allows to better determine the indications of the research of the microdeletion. 22q11.2.

Molecular anatomy of the development of the human substantia nigra.

A series of 15 fetal and perinatal human brains (from week 12 of fetal life to day 2 after birth) was studied in order to describe the anatomical and molecular correlates of the substantia nigra ontogeny. In situ hybridization, immunohistochemistry and binding studies were used to detect D2 dopamine receptor (D2R) mRNA, D2R binding sites, dopamine membrane transporter (DAT) mRNA, tyrosine hydroxylase (TH) protein D1 dopamine receptor (D1R) protein and D1R binding sites. Dopaminergic (DA) neurons of the substantia nigra were detected through TH immunoreactivity from week 12. At week 16, the substantia nigra was clearly delineated as a compact group of intermingled neurons and fibers. From week 19, groups of DA neurons were segregated from the pars reticulata. These groups have been divided into the substantia nigra pars compacta, the ventral tegmental area and the retrorubral area. The DA neurons exhibited a gradual increase in size and branching development until birth. From week 12 onward they expressed several other markers of dopamine transmission, i.e., D2R mRNA, D2R binding sites and DAT mRNA. The ventral tegmental area expressed lower levels of mRNA for DAT and D2R than the pars compacta. From week 12, D1R immunoreactivity and D1R binding sites were also present in the substantia nigra pars reticulata. This suggests that projecting striatonigral neurons, known to express the D1R gene, have developed pathways connecting with the substantia nigra by week 12. Our results demonstrate that the developing substantia nigra in human displays early transcriptional and translational activity for the main constituents of dopaminergic transmission from week 12 and receives at this time dopaminoceptive inputs bearing D1 receptors from the striatum.

Ontogeny of the striatal neurons expressing neuropeptide genes in the human fetus and neonate.

The distribution patterns of neurons expressing mRNAs for four neuropeptides in the human striatum were studied during ontogeny by the use of in situ hybridization. The results of our study demonstrate that somatostatin, enkephalin, dynorphin, and substance P mRNAs are present in striatal neuronal populations from week 12 of fetal life. Each neuronal population undergoes a specific differentiation. Neurons containing somatostatin mRNA are scattered throughout the caudate-putamen up until birth. Neurons containing enkephalin, dynorphin, or substance P mRNAs evolve throughout fetal life in relation to caudate-putamen and patch-matrix compartmentalization. Neurons containing enkephalin mRNA (distinct from those containing substance P or dynorphin mRNAs) are present in the matrix from week 12 of fetal life. These neurons are preferentially distributed in the matrix and, at birth, display higher enkephalin mRNA content in the matrix than in the patches. Dynorphin mRNA is found in the caudate and putamen, preferentially in the patch neurons; nevertheless, a low level of dynorphin mRNA is also present in neurons of the caudate matrix. Substance P mRNA is initially restricted to caudate neurons. At birth, both substance P and dynorphin mRNAs are expressed at high levels in the patches. These results demonstrate that each neuropeptide gene is expressed during human fetal life in neurons with a specific topology and pace of development in relation to caudate-putamen and patch-matrix differentiation. These results also contribute evidence that neurochemical evolution of the striatal neuronal populations is not complete at birth in humans.

Ontogeny of the striatal neurons expressing the D1 dopamine receptor in humans.

We studied D1 dopamine receptor (D1R) gene expression in the human striatum during ontogeny by in situ hybridization, immunohistochemistry, and D1R ligand autoradiography. D1R mRNA, protein, and binding sites ([3H]SCH 23390) were detected in the striatum from week 12 of fetal life. At this time, D1R mRNA was predominant in the striosomal neurons; D1R immunoreactivity (D1R-IR) and D1R binding sites displayed a pattern similar to D1R mRNA. D1R-IR was essentially present in striosomal cell bodies and neuropil, whereas only a few cell bodies were detected in the matrix. From week 20 of fetal life, D1R gene expression developed in the matrix neurons as well, thus leading to an even D1R mRNA expression throughout striosomes and matrix compartments at birth. Comparative analysis of the expression of D1R and dynorphin mRNA show the same developmental patchy pattern up to week 26. Indeed, neurons expressing the D1R gene contain dynorphin mRNA; in contrast, they do not express the preproenkephalin A gene. At birth, the pattern of D1R mRNA expression level was sharply different from that of dynorphin (DYN) gene expression. High DYN mRNA expression was restricted to the striosomes, whereas high D1R mRNA expression was present in the whole striatum. These results demonstrate that, during human ontogeny, functional D1 receptors are expressed as early as week 12 in the striatum, developing initially in the striosomal neurons containing high dynorphin mRNA content. Toward the end of fetal life, there is a dissociation between D1R and DYN expression levels, suggesting that neuroanatomical or neurochemical modifications occur at this period, which may contribute to the regulation of the tone of the striatal D1R and DYN gene with topological specificity.

Expression of NGF receptors in normal and pathological human thymus.

The expression of NGF receptors was investigated in normal human thymus and in thymic hyperplasias, thymomas and thymic carcinomas. By RT-PCR, we detected TrkAI transcripts encoding for the high-affinity NGF receptor. Western blot analysis showed the presence of both TrkA and p75NGFR proteins. In normal thymuses, epithelial subcapsular and medullar cells were TrkA immunoreactive. Interdigitated medullar cells were stained for both TrkA and p75NGFR. While epithelial cells of normal thymuses or benign thymomas exhibited a TrkA positive-p75NGFR negative phenotype, a switch to a TrkA negative-p75NGFR positive phenotype was observed in malignant epithelial cell tumours and was associated with cell proliferation-associated MIB1 expression. Our results argue for a local role of NGF and its receptors on thymic stromal cells both in normal and neoplastic conditions.

Differential expression of the nm23 genes in the developing human trophoblast.

NDP kinases are the non-specific enzymes which catalyse the synthesis of the NTPs through a transfer reaction using ATP as phosphoryl donor. In addition to their enzymatic activity, they display other not yet explained functions related to cell growth, differentiation and apoptosis, embryonic development, tumour progression and metastasis. In this study, the expression patterns of the three highly related NDP kinases A, B and C isoforms were investigated in the developing human trophoblast. Both NDP kinase A and B were found to be primarily present in the villous and extravillous cytotrophoblasts, while NDP kinase C was found almost exclusively in the syncytiotrophoblast layer. This suggests that NDP kinase A and B could be a marker for the mononuclear stage of differentiation of villous trophoblasts, while NDP kinase C could be a marker of the syncytiotrophoblast layer.

Splenogonadal fusion limb defect syndrome: report of five new cases and review.

Splenogonadal fusion (SGF) is a rare congenital malformation in which the spleen is abnormally connected to the gonad. SGF may occur as an isolated condition or may be associated with other malformations, especially with terminal limb defects in what is called splenogonadal fusion limb defect (SGFLD) syndrome. In this article, we report on 5 new cases of SGFLD and we review the 25 cases reported since 1889. Most cases reviewed here have a combination of severe limb and oro-mandibular defects, suggesting that SGFLD may be related to the broader group of Hanhart complex. In addition, several cases have limb malformations and facial anomalies, which suggest that SGFLD overlaps with both femur-fibula-ulna dysostosis and femoral-facial syndrome. The hypothesis of a vascular disruptive event, occurring between the 5th and the 7th weeks of gestation, could explain the limb defects, the mandibular hypoplasia, and the fusion of the spleen to the gonad observed in SGFLD. However, this heterogenous and polytopic condition could also be the consequence of a primary field defect. All the cases to date reported have been sporadic and the recurrence risk is probably low. However, a recent case of Roberts syndrome with SGF was reported that suggests careful examination of chromosomal status.

Ventricular patch endocarditis caused by Propionibacterium acnes: advantages of gallium scanning.

Propionibacterium acnes is a weakly pathogenic commensal of the skin. When isolated from blood cultures it is often considered a contaminant. However, P. acnes may be responsible for severe infections and its role in certain cases of infectious endocarditis has now been definitely established.(1) We report a case of endocarditis due to P. acnes stemming from a ventricular patch and revealed by a gallium 67 scan.

Idiopathic arterial calcification in a stillborn complicated by pleural hemorrhage and hydrops fetalis.

We report a case of idiopathic arterial calcification in a stillborn. As usually noted in this rare entity, the pregnancy was complicated by a polyhydramnios. The postmortem examination showed generalized arterial calcification, periarticular calcific deposits, and a large pleural hemorrhage. The causes of fetal hydrops in idiopathic infantile calcification are discussed, and, in the present case, the absence of myocardial ischemic lesion suggests that the fetal hydrops and the fetal death could have been caused by the bulky blood clot that was present in the right pleural cavity. The pathogenesis remains undetermined, but a primitive inherent defect of the elastic elements seems to initiate this disorder.

Laryngomucocele as an unusual late complication of subtotal laryngectomy. Case report.

We report an unusual case of laryngomucocele occurring after subtotal laryngectomy. Laryngoceles generally have a congenital origin in a long-preexisting saccule, and their association with laryngeal carcinoma is well known. Laryngocele is usually favored by the increase of intraglottic pressure caused by the laryngeal carcinoma. However, an iatrogenic secondary laryngomucocele occurring after a surgical procedure is uncommon. We report in detail the physiopathologic conditions leading to the creation of this lesion.

Trisomy 22 with thyroid isthmus agenesis and absent gall bladder.

This manuscript reports a fetus of 24 weeks gestation, detected on echography to have congenital anomalies: intra-uterine growth retardation, facial dysmorphism, ventricular septal defect with aortic displacement and 8-mm nuchal skinfold thickness. Karyotype was performed. Post termination of pregnancy autopsy showed additionnal internal organ anomalies included: absent gall bladder and thyroid isthmus agenesis. To our knowledge, these anomalies have never been described in trisomic 22 fetuses. This case suggests that chromosome 22 could play a role in thyroid development.

Horizontal glottectomy: functional and oncological results.

The authors report on their experience with 25 cases of horizontal glottectomy and discuss the functional and oncological results of this operation. Indications for this procedure are T1a and T1b glottic carcinomas. The overall three-year and five-year survival was respectively 94 and 88 per cent. Distant metastasis appears to be the major long-term failure, three patients dying of lung carcinoma. Short functional rehabilitation was observed in all cases. Decannulation was achieved in 100 per cent of the cases and none of our patients had laryngeal stenosis. The average time of removal of the nasogastric tube was 11.8 days. Because of its high local control and reduced functional after effects, horizontal glottectomy appears to be a reliable and safe procedure for limited glottic carcinomas and must be included in their therapeutic management.

[Anatomo-pathological diagnosis of neonatal malformations of the urinary tract. II. Excreto-urinary tract malformations]. / Diagnostic anatomo-pathologique des malformations néo-natales de l'appareil urinaire. II. Malformations des voies excréto-urinaires.

Congenital anomalies of the urinary tract are of great pathological importance and account for about 10.9 per cent of all fetal and neonatal autopsies. This paper reports 17 cases of such lesions compiled from 156 consecutive autopsies of newborn infants performed during 33 months at C.H.R. de Bordeaux. Each malformation is discussed, using embryological classification. These lesions can occur independently but usually they are associated with other organ abnormalities. Whenever, an hereditary syndrome must be seek after. In a first part, we have presented the anomalies of the kidney proper. In a second part, we shall present the anomalies of the excretory apparatus, bladder, and urethra.

[Anatomo-pathologic diagnosis of neonatal malformations of the urinary tract. 1: Malformations of the kidney parenchyma]. / Diagnostic anatomo-pathologique des malformations néo-natales de l'appareil urinaire. 1re partie: Malformations du parenchyme rénal.

Congenital anomalies of the urinary tract are of great pathological importance and account for about 10,9 per cent of all fetal and neonatal autopsies. This paper reports 17 cases of such lesions compiled from 156 consecutive autopsies of newborn infants performed during 33 months at C.H.R. de Bordeaux (France). Each malformation is discussed, using embryological classification. These lesions can occur independently but usually they are associated with other organ abnormalities. Whenever, an hereditary syndrome must be seek after. In a first part, we present the anomalies of the kidney proper. In a second part, we shall present the anomalies of the excretory apparatus, bladder and urethra.