Severity of Retrognathia and Glossoptosis Does Not Predict Respiratory and Feeding Disorders in Pierre Robin Sequence

Pierre Robin sequence (PRS) may lead to life-threatening respiratory and feeding disorders. With the aim to analyse the association of the severities of retrognathia and glossoptosis with those of respiratory and feeding disorders, we retrospectively studied a series of 50 infants with retrognathia, glossoptosis, cleft palate, and airway obstruction. The patients were managed from birth to at least 6 years of age by a single pediatric team at the Armand Trousseau Hospital in Paris within a 12 years period (2000–2012). Retrognathia and glossoptosis were graded in the neonatal period according to a specific clinical examination. Ventilation assistance was required for 32/50 (64%) patients, and enteral feeding for 41/50 (82%). The grades of retrognathia and glossoptosis and the severity of respiratory disorders did not differ between patients with isolated PRS and syndromic PRS. Severe respiratory disorders were more common and long-lasting feeding (>12 months) was more frequently required in patients with syndromic PRS compared with isolated PRS (42 vs. 13%, p = 0.04 and 42 vs. 4%, p < 0.01 respectively). Using univariate analysis, neurological impairments and laryngomalacia were associated with severe respiratory disorders [Odds ratio (OR) 5.0, 95% CI 1.3–19.6; and OR 14.6, 95% CI 1.3–161.4; p < 0.05] as well as with long-lasting feeding (>12 months) disorders (OR 18.6, 95% CI 3.9–89.2 and OR 20.4, 95% CI 3,4–122.8; p < 10−2). Syndromic SPR status was also associated with severe respiratory disorders (OR 4.9, 95% CI 1–32.5; p < 0.05). Using multivariate analysis, only syndromic PRS status was predictive for severe respiratory disorders (adjusted OR 8, 95% CI 1.47–44.57; p < 0.05); and only neurological impairments remained a significant risk for long lasting feeding disorders (>12 months) (adjusted OR 21.72, 95% CI 3.4–138.63; p < 10−2). The grades of retrognathia and glossoptosis were not predictive factors for the severity of respiratory and feeding disorders.Conclusion: In children with PRS, the severity of clinical conditions may not correlate with anatomic variables but rather with laryngeal abnormalities, neurological impairement and syndromic PRS status

Characterization of the Interactions between Fluoroquinolone Antibiotics and Lipids: a Multitechnique Approach

Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and intracellular activity between two fluoroquinolones, ciprofloxacin and moxifloxacin, that may actually result from their differential susceptibility to efflux by the ciprofloxacin transporter. In view of the critical role of lipids for the drug cellular uptake and differences observed for the two closely related fluoroquinolones, we investigated the interactions of these two antibiotics with lipids, using an array of complementary techniques. Moxifloxacin induced, to a greater extent than ciprofloxacin, an erosion of the DPPC domains in the DOPC fluid phase (atomic force microscopy) and a shift of the surface pressure-area isotherms of DOPC/DPPC/fluoroquinolone monolayer toward lower area per molecule (Langmuir studies). These effects are related to a lower propensity of moxifloxacin to be released from lipid to aqueous phase (determined by phase transfer studies and conformational analysis) and a marked decrease of all-trans conformation of acyl-lipid chains of DPPC (determined by ATR-FTIR) without increase of lipid disorder and change in the tilt between the normal and the germanium surface (also determined by ATR-FTIR). All together, differences of ciprofloxacin as compared to moxifloxacin in their interactions with lipids could explain differences in their cellular accumulation and susceptibility to efflux transporters

Functional Assessment of Disease-Associated Regulatory Variants <i>In Vivo</i> Using a Versatile Dual Colour Transgenesis Strategy in Zebrafish

Disruption of gene regulation by sequence variation in non-coding regions of the genome is now recognised as a significant cause of human disease and disease susceptibility. Sequence variants in cis-regulatory elements (CREs), the primary determinants of spatio-temporal gene regulation, can alter transcription factor binding sites. While technological advances have led to easy identification of disease-associated CRE variants, robust methods for discerning functional CRE variants from background variation are lacking. Here we describe an efficient dual-colour reporter transgenesis approach in zebrafish, simultaneously allowing detailed in vivo comparison of spatio-temporal differences in regulatory activity between putative CRE variants and assessment of altered transcription factor binding potential of the variant. We validate the method on known disease-associated elements regulating SHH, PAX6 and IRF6 and subsequently characterise novel, ultra-long-range SOX9 enhancers implicated in the craniofacial abnormality Pierre Robin Sequence. The method provides a highly cost-effective, fast and robust approach for simultaneously unravelling in a single assay whether, where and when in embryonic development a disease-associated CRE-variant is affecting its regulatory function

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

CHIRURGIE PRECOCE DES HEMANGIOMES IMMATURES A L'AIDE D'UN DISSECTEUR A ULTRASONS (ETUDE RETROSPECTIVE)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etiopathogénie des hémangiomes infantiles et des hémangiomes congénitaux

Parmi les tumeurs vasculaires de l enfant, les hémangiomes immatures infantiles (HI) sont les plus fréquentes car observées chez 5 à 10% des enfants. Ces lésions à développement postnatal ont un profil de croissance et d involution connu. Les hémangiomes infantiles sont caractérisé par une importante prolifération de cellules endothéliales (Hemangioma endothelial cells, Hem EC) exprimant le Glucose-Transporter-1. Des travaux récents ont démontré la présence de cellules endothéliales progénitrices (hemangioma endothelial progenitor cell, Hem EPC) au sein des hémangiomes infantiles caractérisées par l expression du marqueur CD133 associée aux marqueurs endothéliaux. Nous avons également envisagé l existence d une cellule progénitrice CD133+ non différenciée impliquée dans le développement de l HI. Cette cellule a été isolée et caractérisée et définie comme Hemangioma Multipotent cell (Hem MPC). Plus récemment, ont été décrits également des hémangiomes congénitaux (HC), tumeurs vasculaires très rares, ayant une croissance prénatale, pleinement développés à la naissance, subdivisés en 2 types : le RICH ou Rapidly Involuting Congenital Hemangioma, et le NICH ou Non Involuting Congenital Hemangioma. Les HC et HI appartiennent probablement au même spectre clinique, bien que les HC n expriment pas GLUT-1. Sachant que les HI expriment fortement L Insulin-like growth factor-2 (IGF-2), nous avons étudié l expression de IGF2 dans les HI et comparé les résultats aux HI. Nous avons étudié les niveaux d expression des récepteurs au VEGF dans l HC et comparé ceux-ci à l HI. A partir d hémangiomes immatures infantiles opérés, les Hem MPC présentes au sein de la tumeur ont été isolés et caractérisées. La localisation des cellules CD133+ a été étudiée par immunofluorescence. Afin d étudier les le rôle des HemMPC dans la croissance de l HI, l analyse de l expression de GLUT-1 a été étudié par PCR en temps réel à partir de l ARN des Hem EPC en coculture avec les Hem MPC. Par ailleurs, des Hem MPC ont été implantées dans du Matrigel en sous cutané chez la souris nu/nu. Concernant les HC, une analyse quantitative de l expression de l ARN IGF2, et l ARN des récepteurs au VEGF par real time PCR ainsi qu une analyse comparative de l expression de la protéine IGF2 en immunofluorescence entre hémangiomes congénitaux et hémangiomes immatures ont été effectuées. Concernant l HI, les résultats ont montré que les Hem MPC n induisaient pas une augmentation de l expression de GLUT-1 dans les cellules endothéliales en coculture. En revanche, les Hem MPC induisent la formation de vaisseaux sanguins in vivo laissant supposer une différenciation en cellules endothéliales. Les hypothèses concernant l implication de ces cellules dans la genèse de l hémangiome sont discutées. Les hémangiomes congénitaux, qui se distinguent des hémangiomes infantiles par l absence d expression de GLUT1, expriment IGF2 permettant d établir un lien entre hémangiomes congénitaux et hémangiomes infantiles et d aborder différentes hypothèses concernant le rôle d IGF2 dans la croissance des tumeurs vasculaires. Enfin, l expression du FLT-1 membranaire est plus importante dans l HC que dans l HI.Infantile Hemangiomas (HI) are the most common tumors of infancy, affecting 5 to 10% of children. Initial proliferation of hemangioma is characterized by a high proliferation of endothelial cells (Hem EC). These cells show an immunoreactivity for GLUT-1. Recent studies have shown the presence of endothelial progenitor cells (Hem EPC), expressing a stem cell marker CD133 and endothelial markers. We suggested the existence of a undifferentiated cell CD133+. These cells have been isolated and characterized and called Hemangioma multipotent cell (Hem MPC). We could localize the CD133+ cells in proliferating hemangioma by indirect immunofluorescence. To test the effect of Hem MPC on Hem EPC, we analysed the ARNm GLUT-1 expression in Hem EPC by quantitative real time PCR when Hem MPC and Hem EPC are cultured together. Then, to test the role of Hem MPC, we injected a clonal population of Hem MPC in Matrigel into immunodeficient mice. Recently, Congenital Hemangiomas (HC) have been described. HC are characterized by a prenatal growth, and the lack of postnatal proliferation. 2 subtypes have been described: the NICH or Non Involuting Congenital Hemangioma and the RICH or Rapidly Involuting Congenital Hemangioma. These tumors have some overlapping histologic features with HI, although HC are negative for GLUT-1.To gain further insight into the molecular differences and similarities between HC and HI, we analyzed expression of IGF-2 and Vascular endothelial growth factor (VEGF)-receptors, by quantitative real time PCR. Concerning HI, we show that the Hem MPC plays a crucial role in the hemangioma development. In effect, Hem MPC can give rise to human blood vessels in nude mice, indicating a differentiation of the Hem MPC into endothelial cells, GLUT-1 positive. The Hem MPC in a coculture system, do not increase GLUT-1 expression in Hem EPC. Concerning HC, we show that IGF-2 mRNA was expressed in both RICH and NICH at a level comparable to that detected in HI over 4 years of age. In contrast, FLT-1 (VEGF-R1) was uniformly increased in HC compared to HI.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Les fentes orbito-faciales (analyse et discussion)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Alveolar Cleft Closure Managed by Primary Alveoloplasty

International audienc

Outcomes of Neonatal Bulbar Weakness

International audienceBACKGROUND AND OBJECTIVE: Neonatal bulbar weakness (BW) has various etiologies and a broad prognostic range. We aimed to report outcomes in a large series of children with neonatal BW and explore the association of orofacial electrodiagnostic data with outcome.METHODS: We retrospectively reviewed the files of children who presented with facial, lingual, laryngeal, or pharyngeal weakness at birth and who underwent electrodiagnostic studies combining conventional needle electromyography (EMG) of orofacial muscles, blink responses, and EMG during bottle-feeding. Outcome measures included the need for prolonged respiratory assistance and enteral feeding, as well as sensorimotor and cognitive impairments.RESULTS: Of 175 patients, 73% had developmental disorders, 25% suffered from acquired brain damage, and 2% had no apparent underlying disorders. Motor or mental impairment was observed in 71%; death occurred in 16%. Outcomes were not significantly different when comparing developmental disorders versus acquired brain damage or neurogenic versus normal detection EMG. Abnormal blink responses were associated with higher frequencies of respiratory assistance (P = .03), gastrostomy (P = .025), and death (P = .009); moderate or severe oropharyngeal incoordinations were associated with higher frequencies of respiratory assistance (P = .006), prolonged enteral feeding (P < .0001), and gastrostomy (P = .0002).CONCLUSIONS: Orofacial electrodiagnostic studies provide supplementary information to help the pediatrician anticipate the management and prognosis of young infants with BW