Report on the Fourth Excavation Season (2011) of the Madâ'in Sâlih Archaeological Project

This volume is the report on the results of the fourth excavation season of the Saudi-French Archaeological Project at Madâ'in Sâlih, ancient Hegra in the Nabataean kingdom, in north-west Saudi Arabia (MAEE, SCTA, CNRS, Univ Paris 1, IFPO). Apart from the results obtained in the different excavation areas (both in the residential area and in tomb IGN 117), the reader will find a study on the cairns/tumuli of the site (W. Abu-Azizeh) as well as intermediary reports on the geophysical detection (Chr. Benech), the fauna (J. Studer) and the pottery (C. Durand).Ce volume constitue le rapport sur les résultats de la quatrième campagne de fouilles de la mission archéologique franco-saoudienne de Madâ'in Sâlih, l'ancienne Hégra des Nabatéens, dans le nord-ouest de l'Arabie Saoudite (MAEE, SCTA, CNRS, Univ. Paris 1, IFPO). Outre les résultats obtenus dans les différents chantiers (dans la zone résidentielle et dans le tombeau IGN 117), le lecteur trouvera une étude synthétique sur les cairns/tumuli du site (W. Abu-Azizeh) ainsi que des rapports intermédiaires sur la détection géophysique (Chr. Benech), la faune (J. Studer) et la céramique (C. Durand)

Complete Ascertainment of Intragenic Copy Number Mutations (CNMs) in the CFTR Gene and its Implications for CNM Formation at Other Autosomal Loci

Over the last 20 years since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than 1,600 different putatively pathological CFTR mutations have been identified. Until now, however, copy number mutations (CNMs) involving the CFTR gene have not been methodically analyzed, resulting almost certainly in the under-ascertainment of CFTR gene duplications compared with deletions. Here, high-resolution array comparative genomic hybridization (averaging one interrogating probe every 95 bp) was used to analyze the entire length of the CFTR gene (189 kb) in 233 cystic fibrosis chromosomes lacking conventional mutations. We succeeded in identifying five duplication CNMs that would otherwise have been refractory to analysis. Based upon findings from this and other studies, we propose that deletion and duplication CNMs in the human autosomal genome are likely to be generated in the proportion of approximately 2-3:1. We further postulate that intragenic gene duplication CNMs in other disease loci may have been routinely underascertained. Finally, our analysis of +/-20 bp flanking each of the 40 CFTR breakpoints characterized at the DNA sequence level provide support for the emerging concept that non-B DNA conformations in combination with specific sequence motifs predispose to both recurring and nonrecurring genomic rearrangements. Hum Mutat 31:421-428, 2010. (C) 2010 Wiley-Liss, Inc

Rapport préliminaire sur les activités de la mission syro-française de Ras Shamra-Ougarit en 2007 et 2008 (67e et 68e campagnes)

Ce rapport présente les résultats préliminaires des travaux de terrain de la mission archéologique syro-française de Ras Shamra – Ougarit pour les campagnes de 2007 et 2008 qui se sont déroulées à Ras Shamra et sur plusieurs sites côtiers. Sur le tell de Ras Shamra, quatre opérations de fouilles ont été menées  : la poursuite du chantier du «  Rempart » et de celui de la «  Grand-rue », la reprise du dégagement du «  pont-barrage » sur le Nahr ed-Delbé et un nouveau chantier conjoint dans le secteur du «  Temple de Dagan ». Deux autres opérations ont commencé en 2008  : la prospection géomagnétique du tell et l’étude des techniques de taille de la pierre à Ougarit. Les travaux de la mission se sont portés également sur les sites côtiers du royaume d’Ougarit dans le cadre d’un nouveau programme conjoint visant à reconstituer l’évolution des paléo-environnements portuaires et la mobilité des paysages littoraux. La présentation des activités de terrain est complétée par une réflexion sur le plan de l’antique cité d’Ougarit et les premiers résultats de l’étude d’un atelier de travail du silex (Bronze récent final) mis au jour dans le chantier «  Grand-rue ».This report presents preliminary results from the Syrian-French archaeological excavations at Ras Shamra-Ugarit for the field seasons of 2007 and 2008, which took place at Ras Shamra and a number of coastal sites. At Ras Shamra tell, four excavations were undertaken : work continued at the sites of “Rempart” and “Grand-rue”, with further investigations of the “pont-barrage” on the Nahr ed-Delbe, in addition to a new joint site in the area of the “Temple de Dagan”. Two other projects began in 2008 : the geomagnetic survey of the tell and a study of the techniques of stone quarrying at Ugarit. The expedition’s work also extended to the coastal sites of the Kingdom of Ugarit within the framework of a new program looking to reconstruct the evolution of its harbours and mobility of the coastal landscapes. The presentation of the fieldwork activities is complemented by a piece looking at the plan of the ancient city of Ugarit and the first results of a study investigating a flint workshop (Late Bronze Age) unearthed at the “Grand-rue” site.خلاصة – يقدم هذا التقرير النتائج الأولية للبعثة الأثرية السورية-الفرنسية العاملة في موقع رأس شمرا- أوغاريت عن الأعمال تاميدانية في رأس شمرا خلال عامي 2007 و2008 وعدد من المواقع الساحلية. في موقع تل رأس شمرا، تمّ تنفيذ أربع عمليات حفر : إستكمال الحفريات في حقل « الأسوار» وحقل « الشارع الكبير»، ومتابعة أعمال الكشف على « الجسر-السد» على نهر الدلبة، بالإضافة الى المباشرة في تنفيذ تنقيب مشترك في حقل معبد « داغان». بالمقابل ثم المباشرة بتنفيذ عمليتين في أوغاريت خلال عام 2008 : عمليات مسح جيومغناطيسية للتل، ودراسة تقنية تتعلّق بطرق تقصيب وتشذيب أحجار البناء. تضمّنت أعمال البعثة أيضاً، العمل على المواقع الساحلية لمملكة أوغاريت وذلك ضمن إطار برنامج جديد مشترك يهدف إلى وضع تصوّر لتطوّر الظروف البيئية للمرافئ بالأضافة إلى تصوّر عام لكينونة الشريط الساحلي. إستكمال عرض الأعمال الميدانية بوضع تصوّر لمخطط المدينة القديمة لأوغاريت والنتائج الأولية لمشغل للأدوات الصوانية إكتشف في حقل « الشارع الكبير» يعود إلى عصر البرونز الحديث النهائي

High-Throughput Analysis of Promoter Occupancy Reveals New Targets for Arx, a Gene Mutated in Mental Retardation and Interneuronopathies

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

International audienceBackground and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and theABCB1 3435 C>T(rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation

Interval between planning and frameless stereotactic radiotherapy for brain metastases: are our margins still accurate?

International audienceAbstractBackgroundAdvances in intracranial stereotactic radiosurgery (SRS) have led to dramatically reduced planning target volume (PTV) margins. However, tumor growth between planning and treatment may lead to treatment failure. Our purpose was to assess the kinetics of tumor growth before SRS for brain metastases.MethodsThis retrospective, monocentric study included all consecutive patients (pts) treated for brain metastases secondary to melanoma (ML) and non-small cell lung cancer (NSCLC) between June 2015 and May 2016. All pts underwent diagnostic brain imaging and a radiosurgery planning MRI, during which gross tumor volume (GTV) was delineated. Linear and exponential models were used to extrapolate a theoretical GTV at first day of treatment, and theoretical time to outgrow the PTV margins.ResultsTwenty-three ML and 31 NSCLC brain metastases (42 pts, 84 brain imaging scans) were analyzed. Comparison of GTV at diagnosis and planning showed increased tumor volume for 20 ML pts (96%) and 22 NSCLC pts (71%). The shortest time to outgrow a 1 mm margin was 6 days and 3 days for ML and 14 and 8 days for NSCLC with linear and exponential models, respectively.ConclusionsPhysicians should bear in mind the interval between SRS planning and treatment. A mathematical model could screen rapidly progressing tumors

Low-dose erythromycin in pediatrics: Formulation and stability of 20 mg hard gelatin capsules.

ObjectiveErythromycin is a macrolide antibiotic that is also prescribed off-label in premature neonates as a prokinetic agent. There is no oral formulation with dosage and/or excipients adapted for these high-risk patients.MethodsClinical studies of erythromycin as a prokinetic agent were reviewed. Capsules of 20 milligrams of erythromycin were compounded with microcrystalline cellulose. Erythromycin capsules were analyzed using the chromatographic method described in the United States Pharmacopoeia which was found to be stability-indicating. The stability of 20 mg erythromycin capsules stored protected from light at room temperature was studied for one year.Results20 mg erythromycin capsules have a beyond use date not lower than one year.Conclusion20 milligrams erythromycin capsules can be compounded in batches of 300 unities in hospital pharmacy with a beyond-use-date of one year at ambient temperature protected from light