Prenatal prediction of pulmonary arterial hypertension in congenital diaphragmatic hernia.

OBJECTIVE: To evaluate the role of prenatal prognostic markers obtained routinely by ultrasound examination and magnetic resonance imaging (MRI) in the prediction of development of postnatal pulmonary arterial hypertension (PAH) in isolated congenital diaphragmatic hernia (CDH). METHODS: One hundred and ten cases of isolated CDH were referred to our fetal medicine unit between January 2004 and April 2013. Mortality and morbidity rates were reviewed for those presenting with postnatal PAH. The following prenatal markers were evaluated as potential predictive factors of PAH: liver position, side of the CDH defect, lung area to head circumference ratio (LHR) and observed/expected LHR (o/e-LHR), which were measured by ultrasound, and observed/expected total fetal lung volume (o/e-TFLV), which was measured by MRI. Univariable logistic regression was used to assess associations. RESULTS: PAH was significantly associated with perinatal mortality and morbidity (P < 0.001). The occurrence of PAH decreased significantly with an increasing LHR, o/e-LHR and o/e-TFLV and was significantly increased for cases with an intrathoracic liver, but not for those with right-sided defects. Univariable regression revealed that o/e-TFLV (odds ratio (OR), 0.9 (95% CI, 0.86-0.95); P < 0.05 for percentage unit change in o/e), LHR (OR, 0.19 (95% CI, 0.09-0.40); P < 0.05 for unit change), o/e-LHR (OR, 0.95 (95% CI, 0.93-0.98); P < 0.05 for percentage unit change in o/e) and liver position (OR, 2.82 (95% CI, 1.13-7.00); P < 0.05 for intrathoracic liver) were significant predictors of subsequent PAH. No differences were found after adjusting for gestational age at delivery. The areas under the receiver-operating characteristics curve were 0.80 and 0.75 for o/e-TFLV and o/e-LHR, respectively. CONCLUSION: In cases of CDH, PAH is associated with high rates of mortality and morbidity. Routinely obtained prenatal markers, usually used for the assessment of pulmonary hypoplasia, are also relevant for the postnatal prediction of PAH.

Is complex gastroschisis predictable by prenatal ultrasound?

OBJECTIVE: To establish a correlation between prenatal ultrasound findings and postnatal outcome in neonates with gastroschisis (GS). DESIGN: Retrospective case-control study. SETTING: Prenatal ultrasound reports, labour and neonatal intensive care unit notes, and paediatric surgical clinic records were reviewed. POPULATION: Neonates with an antenatal diagnosis of isolated GS. METHODS: The neonates were divided into two groups: one with associated bowel complications including intestinal atresia, perforation, necrosis or volvulus ('complex' GS), and the second without bowel complication ('simple' GS). Prenatal ultrasound markers: small-for-gestational-age, intra-abdominal and extra-abdominal bowel dilatation (>6 mm), thickened intestinal wall and stomach dilatation were correlated with outcome. MAIN OUTCOME MEASURES: Fetal or neonatal death in complex versus simple GS. Time on parenteral nutrition and duration of hospital stay were also noted. RESULTS: In all, 105 cases were eligible for analysis. Survival rate was 101/105 (96.2%). None of the ultrasound markers was predictive of fetal or neonatal death. Fourteen of 103 live-born babies (14.6%) had complex GS, which was associated with longer time on parenteral nutrition [8.0 (51.5-390) versus 33.5 (25.3-53.3) days, P<0.001] and longer duration of hospital stay [85.3 (55.5-210) versus 41.5 (33.0-64.8) days, P<0.001]. Infants with complex GS were more likely to require bowel resection and stoma placement (P<0.05). Intra-abdominal bowel dilatation was the only predictive ultrasound marker of complex GS (odds ratio 4.13, 95% CI 1.32-12.90; P=0.018). Receiver operating characteristic curve for observed/expected bowel diameter yielded 6 as the cutoff value for predicting complex GS (odds ratio 7.9, 95% CI 2.3-27.3; P=0.001) with 54% and 88% for sensibility and specificity, respectively. CONCLUSIONS: Intra-abdominal bowel dilatation is the only ultrasound marker predictive of complex GS but it is a strong marker.

Secondary bladder herniation in isolated gastroschisis justifies increased surveillance.

OBJECTIVES: To assess the perinatal outcome of fetuses with gastroschisis complicated by secondary bladder herniation. POPULATION AND MATERIALS: This was a retrospective study of all cases of isolated gastroschisis associated with bladder herniation managed at our institution. Prenatal ultrasound, obstetrical and perinatal information were collected. Pathology reports were also gathered. RESULTS: Out of 105 cases of gastroschisis managed at our institution, six (5.7%) were associated with secondary bladder herniation, two of them being diagnosed postnatally. Median gestational age at diagnosis of bladder herniation was 33.6 weeks (range 31-36) in five female and one male fetuses. Bladder herniation was associated with bowel dilatation in four cases (67%) and with pyelic dilatation in one case (17%). Despite increased surveillance, one male fetus died in utero. In four other cases, cesarean section was performed for fetal distress (three cases) or hyperechogenic bowels (one case). The five survivors had primary abdominal closure (n = 2) or staged repair (n = 3) with uneventful follow-up. CONCLUSION: Bladder herniation was present in 6% of apparently isolated gastroschisis. There was one intrauterine fetal death and four other cases were delivered for fetal distress. Increased surveillance seems justified.

[Prenatal path of care following the diagnosis of a malformation for which a novel prenatal therapy is available]. / Parcours prénatal devant une malformation pour laquelle un traitement in utero émergent est disponible.

OBJECTIVES: Fetal therapy is part of the available care offer for several severe malformations. The place of these emergent prenatal interventions in the prenatal path of care is poorly known. The objective of this study is to describe the decision-making process of patients facing the option of an emergent in utero intervention. METHODS: We have conducted a retrospective monocentric descriptive study in the department of maternal-fetal medicine of Necker Hospital. We collected data regarding eligibility or not for fetal surgery and the pregnancy outcomes of patients referred for myelomeningocele, diaphragmatic hernia, aortic stenosis and low obstructive uropathies. RESULTS: All indications combined, 70% of patients opted for fetal surgery. This rate was lower in the case of myelomeningocele with 21% consent, than in the other pathologies: 69% for diaphragmatic hernias, 90% for aortic stenoses and 76% for uropathy. When fetal intervention was declined, the vast majority of patients opted for termination of pregnancy: 86%. In 14% of the considering fetal surgery, the patient was referred too far. CONCLUSION: The acceptance rate for fetal surgeries depends on condition. It offers an additional option and is an alternative for couples for which termination of pregnancy (TOP) is not an option. Timely referral to an expert center allows to discuss the place of a fetal intervention and not to deprive couples of this possibility.

The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells.

BACKGROUND: The G-protein-coupled formylpeptide receptor (FPR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides is selectively expressed by highly malignant human gliomas and contributes to tumour growth and angiogenesis. As invasion of surrounding normal tissues is one of the important features of tumour malignancy, we investigated the function of FPR in the invasive behaviour of human glioblastoma cells. METHODS: Cells (FPR(+) and FPR(-)) were isolated by single-cell cloning from a human glioblastoma cell line U-87MG. The FPR expression was assayed by flow cytometry and reverse transcription PCR. The function of FPR was investigated by chemotaxis and calcium flux induced by FPR agonist fMLF. Tumour cell motility was assayed by a wound-healing model in vitro. The growth and invasive phenotype were observed with subcutaneous implantation of tumour cells in nude mice. Over-expression of FPR in FPR(-) cells was performed by transfection of a plasmid vector-containing human FPR gene. RESULTS: One of the glioma clones F9 that expressed high level of FPR showed a more 'motile' phenotype in vitro as compared with a clone G3 without FPR expression. Although F9 and G3 clones both formed subcutaneous tumours in nude mice, only F9 tumours invaded surrounding mouse connective tissues. Over-expression of FPR in G3 clone (G3F) increased the cell motility in vitro and the capacity of the cells to form more rapidly growing and invasive tumours in nude mice. We further found that, in addition to supernatant of necrotic tumour cells, foetal calf serum and human serum used in culture media contained FPR agonist activity and increased the motility of FPR-expressing glioblastoma cells. CONCLUSION: The expression of FPR is responsible for increased motility of human glioblastoma cells and their formation of highly invasive tumours.

Genomic masking of nondefective recombinant murine leukemia virus in Moloney virus stocks.

HIX virus cloned from Moloney leukemia virus stocks is a nondefective, leukemogenic, and amphotropic murine oncornavirus with a recombinant-type major glycoprotein. Although Moloney leukemia virus stocks generally contain little or no free amphotropic virus, dilution analysis of several virus stocks and the examination of virus progeny from individual foci revealed that HIX virus is present and functionally coated with ecotropic Moloney virus envelopes. Because most mice have serum factors that inactivate recombinant viruses, masking may represent a general survival mechanism for HIX as well as other analogous recombinant viruses.

Retinyl acetate: effect on cellular content of RNA in epidermis in cell culture in chemically defined medium.

Cell cultures of epidermis from newborn mice were established in chemically defined medium. Additions of retinyl acetate to these cultures caused a significant increase in cellular RNA content. Addition of insulin and hydrocortisone to the cultures potentiated the effect of retinyl acetate on cellular RNA content.

Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity.

Synthetic peptide segments of the CD4 molecule were tested for their ability to inhibit infection of CD4+ cells by the human immunodeficiency virus (HIV) and to inhibit HIV-induced cell fusion. A peptide mixture composed of CD4(76-94), and synthesis side products, blocked HIV-induced cell fusion at a nominal concentration of 125 micromolar. Upon high-performance liquid chromatography, the antisyncytial activity of the peptide mixture was found not in the fraction containing the peptide CD4(76-94) itself, but in a side fraction containing derivatized peptide products generated in the automated synthesis. Derivatized deletion and substitution peptides in the region CD4(76-94) were used to demonstrate sequence specificity, a requirement for benzyl derivatization, and a core seven-residue fragment required for antisyncytial activity. A partially purified S-benzyl-CD4(83-94) peptide mixture inhibited HIV-induced cell fusion at a nominal concentration of less than or equal to 32 micromolar. Derivatized CD4 peptides blocked cell fusion induced by several HIV isolates and by the simian immunodeficiency virus, SIV, and blocked infection in vitro by four HIV-1 isolates with widely variant envelope gene sequences. Purified CD4(83-94) dibenzylated at cysteine 86 and glutamate 87 possessed antisyncytial activity at 125 micromolar. Derivatization may specifically alter the conformation of CD4 holoreceptor peptide fragments, increasing their antiviral efficacy.

Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody.

The ability of antibodies to neutralize diverse primary isolates of human immunodeficiency virus-type 1 in vitro has been questioned, with implications for the likely efficacy of vaccines. A recombinant human antibody to envelope glycoprotein gp120 was generated and used to show that primary isolates are not refractory to antibody neutralization. The recombinant antibody neutralized more than 75 percent of the primary isolates tested at concentrations that could be achieved by passive immunization, for example, to interrupt maternal-fetal transmission of virus. The broad specificity and efficacy of the antibody implies the conservation of a structural feature on gp120, which could be important in vaccine design.

[Early diagnosis of omphalocele: Prognostic value of the herniated viscera for associated anomalies]. / Omphalocèle au premier trimestre : valeur pronostique du contenu extériorisé pour le risque d'anomalie associée.

OBJECTIVES: Prognosis of infants with omphalocele depends on many factors, including associated anomalies. "Small" omphaloceles are believed to have more often WB syndrome, but so far no prenatal criterion has been demonstrated to predict associated anomalies. The aim of this study was to assess the outcomes of omphaloceles with prenatal diagnosis, and to seek for any correlation between the herniated viscera in the first trimester and the risk of associated anomalies. METHODS: We conducted a retrospective study at the Necker Enfants Malades Hospital between 2008 and 2018. Pregnancy outcomes and post natal data were collected and compared to the omphalocele content in the first trimester. RESULTS: One hundred and ninety-one women with antenatal diagnosis of omphalocele were included. Twenty-eight percent were isolated at birth, 32% had a polymalformative syndrome with chromosomal anomaly, 13% had a polymalformative syndrome without genetic anomaly, 9% had a Wiedemann-Beckwith syndrome, 7% had an association with cardiopathy, 6% had a limb body wall complex, 3% had OEIS complex and one case had a Cantrell pentalogy. The presence of the liver in the omphalocele during the first trimester was a predictive factor of heart disease (85.7% vs 48.6% P=0.01). The presence of bowel in the omphalocele during the first trimester was a predictor of chromosomal abnormalities (69.6% vs 37.2% P<0.001). Omphalocele content in the first trimester was not predictive of Wiedemann-Beckwith syndrome. CONCLUSION: Ultrasound analysis in the first trimester of omphalocele content is a valuable clue for prenatal counseling and diagnosis of associated abnormalities.

Bowel obstruction due to ingestion of a water-absorbing bead.

Foreign body ingestion is a common pediatric complaint. Most foreign bodies pass spontaneously through the gastrointestinal tract, but bowel obstruction is a rare complication that can occur. We report a case of a 14-month-old infant with complete bowel obstruction due to ingestion of a polymer bead used for botanical arrangements. A laparotomy was performed to remove the object, resolving the symptoms. Polymer beads are brightly coloured and are of a size that is easy to swallow by very young children, increasing the risk of accidental ingestion. They increase in size over a short period of time during their passage through the gastrointestinal tract, causing significant morbidity.

Prenatal factors associated with neonatal survival of infants with congenital chylothorax.

OBJECTIVES: Congenital chylothorax is a rare disease and prognostic factors are key element in properly informing parents. This study aimed at determining the prenatal factors associated with neonatal survival in a cohort of liveborn infants with congenital chylothorax. STUDY DESIGN: Observational monocentric cohort study including all liveborn neonates consecutively admitted for congenital chylothorax. RESULTS: Neonatal mortality was 32% (16/50). Prematurity (or birth weight), persistence of hydrops at birth and the absence of thoracoamniotic shunt procedure were significantly associated with mortality, whereas prenatal diagnosis of pleural effusion, side of pleural effusion, hydrops fetalis and amniodrainage were not. In case of prenatal diagnosis of hydrops fetalis, the reversal in utero of hydrops fetalis was significantly associated with survival (P=0.001). In case of thoracoamniotic shunting, the interval between thoracoamniotic shunting intervention and delivery was significantly longer for patients who survived (P=0.03). CONCLUSIONS: Thoracoamniotic shunting and reversal of hydrops significantly improves survival, whereas prematurity worsened outcome of liveborn infants with congenital chylothorax. Our data also suggest that the interval between thoracoamniotic shunting and birth appears to be crucial; the longer the interval, the more likely is the reversal of antenatal hydrops and neonatal survival.

Lipoprotein-associated oncornavirus-inactivating factor in the genus Mus: effects on murine leukemia viruses of laboratory and exotic mice.

High titers of oncornavirus-inactivating factor (OIF) were found previously in sera of laboratory mice. OIF is highly active against mouse xenotropic and polytropic envelope recombinant murine leukemia viruses (MuLVs) but not against ecotropic MuLVs. Of the 20 different mouse species or subspecies currently tested, that represent 4 subgenera, no OIF was found in the 3 subgenera more distant to the laboratory mouse. In the subgenus Mus, 7 of the 8 most distant species had no OIF, whereas all the ancestral species and subspecies of the laboratory mouse (Mus musculus musculus, Mus musculus domesticus), including a more distant member (Mus musculus cookii), had ample titers of OIF. A new separation technique was devised so that potential virus-neutralizing immunoglobulins could be separated by electrophoresis from OIF in small-volume serum samples. Active OIF was recovered from serum high-density lipoprotein, from very-low-density lipoprotein, as well as from chylomicron fractions. Murine sarcoma virus pseudotypes were made with several available exotic MuLV types. These pseudotype MuLVs were not susceptible to standard OIF preparations. The sera of exotic mice also had no factor analogous to OIF which would inactivate their own homologous or heterologous exotic MuLVs. It appears that, with one exception, OIF activity is limited to two subspecies of M. musculus and may be correlated in these subspecies with the presence of endogenous xenotropic MuLVs.

[Prenatal discovery of Joubert syndrome associated with small bowel volvulus]. / Découverte anténatale d'un syndrome de Joubert associé à un volvulus du grêle.

Joubert syndrome and prenatal volvulus are difficult to diagnose during pregnancy. Joubert syndrome and related diseases should be considered in case of prenatal abnormal features of the fourth ventricle. Small bowel volvulus is also a surgical emergency because of the risk of intestinal necrosis before or after delivery. This type of condition justifies the transfer of pregnant women to a specialized hospital where the newborn may receive appropriate care. We report the case of a 31-week and 4-day gestational-age fetus in whom intrauterine growth retardation and small-bowel volvulus were diagnosed. Additional imaging revealed associated Joubert syndrome. This highlights the need for regular ultrasound monitoring during pregnancy and the comanagement of obstetricians and pediatricians to provide appropriate care before and after delivery.

Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1.

Amyloid beta (Abeta) is a major contributor to the pathogenesis of Alzheimer's disease (AD). Although Abeta has been reported to be directly neurotoxic, it also causes indirect neuronal damage by activating mononuclear phagocytes (microglia) that accumulate in and around senile plaques. In this study, we show that the 42 amino acid form of beta amyloid peptide, Abeta(42), is a chemotactic agonist for a seven-transmembrane, G-protein-coupled receptor named FPR-Like-1 (FPRL1), which is expressed on human mononuclear phagocytes. Moreover, FPRL1 is expressed at high levels by inflammatory cells infiltrating senile plaques in brain tissues from AD patients. Thus, FPRL1 may mediate inflammation seen in AD and is a potential target for developing therapeutic agents.

Synthetic peptide MMK-1 is a highly specific chemotactic agonist for leukocyte FPRL1.

Human phagocytic leukocytes express the seven-transmembrane G-protein-coupled receptors formyl peptide receptor (FPR) and FPR-like 1 (FPRL1). MMK-1, a synthetic peptide derived from a random peptide library, is reported to induce calcium mobilization specifically in human FPRL1 gene-transfected cells. However, its actions on human phagocytic leukocytes remain poorly defined. We found that MMK-1 is a potent chemotactic and calcium-mobilizing agonist for human monocytes, neutrophils, and FPRL1-transfected human embryonic kidney (HEK) 293 cells but is inactive in cells transfected with FPR. MMK-1 also activated HEK 293 cells transfected with FPR2, a mouse counterpart of human FPRL1. Furthermore, MMK-1 increased pertussis toxin-sensitive production of inflammatory cytokines in human monocytes. MMK-1 signaling in human phagocytes was completely desensitized by a well-defined FPRL1 agonist, suggesting that FPRL1 is likely a receptor that mediates the action of MMK-1 in primary cells. Since MMK-1 is one of the most potent FPRL1-specific agonists identified so far, it can serve as a modulator of the host defense and a useful agent for further studying the signaling and function of FPRL1.

[Does prenatal diagnosis modify neonatal management and early outcome of children with esophageal atresia type III?]. / Le diagnostic anténatal modifie-t-il la prise en charge néonatale et le devenir à 1 an des enfants suivis pour atrésie de l'œsophage de type III ?

OBJECTIVE: Evaluate neonatal management and outcome of neonates with either a prenatal or a post-natal diagnosis of EA type III. STUDY DESIGN: Population-based study using data from the French National Register for EA from 2008 to 2010. We compared children with prenatal versus post-natal diagnosis in regards to prenatal, maternal and neonatal characteristics. We define a composite variable of morbidity (anastomotic esophageal leaks, recurrent fistula, stenosis) and mortality at 1 year. RESULTS: Four hundred and eight live births with EA type III were recorded with a prenatal diagnosis rate of 18.1%. Transfer after birth was lower in prenatal subset (32.4% versus 81.5%, P<0.001). Delay between birth and first intervention was not significantly different. Defect size (2cm vs 1.4cm, P<0.001), gastrostomy (21.6% versus 8.7%, P<0.001) and length in neonatal unit care were higher in prenatal subset (47.9 days versus 33.6 days, P<0.001). The composite variables were higher in prenatal diagnosis subset (38.7% vs 26.1%, P=0.044). CONCLUSION: Despite the excellent survival rate of EA, cases with antenatal detection have a higher morbidity related to the EA type (longer gap). Even if it does not modify neonatal management and 1-year outcome, prenatal diagnosis allows antenatal parental counseling and avoids post-natal transfer.

HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients.

OBJECTIVE: A phase I trial was conducted to evaluate the safety and immunogenicity of an HIV synthetic peptide vaccine in HIV-seropositive individuals. The immunogens used in this study were PCLUS 3-18MN and PCLUS 6.1-18MN envelope peptides. METHODS: Eight HIV-infected patients received six subcutaneous injections of 160 microg PCLUS 3-18MN in Montanide ISA 51 and were followed longitudinally for a year after the first immunization. Peripheral blood mononuclear cells (PBMC) were tested for peptide-specific T helper and cytotoxic T cell (CTL) responses, HIV-1MN neutralizing antibodies and antibodies against HIV PCLUS 3 and P18 MN peptides. RESULTS: PCLUS 3-1 8MN-specific T helper responses were significantly increased at 36 weeks (P < 0.05, after adjustment for multiple comparisons) following initial immunization with PCLUS 3-18MN. A P18MN-specific CTL response, not present prior to vaccination, was observed after immunization in one patient. Serum HIV-1 MN-neutralizing antibody titers increased in each of the three patients who had low titers prior to immunization. Plasma HIV RNA levels and CD4 cell counts did not change appreciably during the study period. CONCLUSIONS: This trial demonstrates that both peptides can be safely administered to HIV-infected individuals and that PCLUS 3-18MN induces increases in HIV peptide-specific immune responses.

Heat-labile, complement-like factor(s) of animal sera prevent(s) HIV-1 infectivity in vitro.

We studied inactivation of HIV-1 by fresh sera of animals. We found that while fresh sera of humans and chimpanzees (among others) did not have antiviral activity, fresh sera of several other mammals, especially those of rodents and felines, showed a dose-dependent viral-inactivating property against cell-free HIV-1; these sera were also capable of inactivating virus preadsorbed to cells, similar to neutralizing antibody. The activity was destroyed by heating to 56 degrees C, required Ca2+ but no antiviral antibody, and therefore apparently involves the classical complement pathway. The activity could not be ascribed to any single fraction of sera separated on a size exclusion HPLC column. Mouse serum (the only one tested) also inactivated HIV-2. The data are consistent with classical C-mediated pathway inactivation of HIV-1 and HIV-2 by animal sera and is the first report of any "complement-like" antilentiviral serum factor. Elucidation of this mechanism may aid in understanding the lack of activity of human serum against HIV-1 and may prove useful in combined interventive strategies against HIV-1.