[Validation of identification criteria for patients having surgery for rhegmatogenous retinal detachment at Toulouse University Hospital]. / Validation des critères d'identification des patients opérés d'un décollement de rétine rhegmatogène au CHU de Toulouse.

INTRODUCTION: Seasonal variations seem to modify the incidence of rhegmatogenous retinal detachment (RRD), with a summer peak, although the meteorological parameters involved have not been studied in France. In order to conduct a national study evaluating the association between the occurrence of RRD and various climatological variables (METEO-POC study), we need to establish a national cohort of patients having undergone surgery for RRD. The data of the National Health Data System (SNDS) allow the realization of epidemiological studies concerning various pathologies. However, as these databases were initially intended for medical administrative use, the identification of the pathologies coded in these databases must be validated before any use for research purposes. In order to carry out a cohort study using SNDS data, the objective of this study is to validate the identification criteria for patients having undergone RRD surgery at Toulouse University Hospital. METHODS: We compared the cohort of RRD surgery patients at Toulouse University Hospital from January to December 2017 assembled from SNDS data with the cohort of patients meeting the same selection criteria assembled from Softalmo software data. RESULTS: With a positive predictive value of 82.0%, a sensitivity of 83.8%, a specificity of 69.9%, and a negative predictive value of 72.5%, we can consider that our eligibility criteria are performing well. CONCLUSION: Since the selection of patients via SNDS data is reliable at Toulouse University Hospital, we can use it at the national level for the METEO-POC study.

[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.

Acute ischaemic lesions are associated with cortical superficial siderosis in spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) commonly detects acute ischaemic lesions in patients with acute intracerebral hemorrhage (ICH), especially with cerebral amyloid angiopathy (CAA). We investigated the relationship between cortical superficial siderosis (cSS), a neuroimaging marker of CAA, and DWI lesions in patients with acute ICH. METHODS: We conducted a retrospective analysis of prospectively collected data from consecutive patients with acute supratentorial ICH who underwent brain magnetic resonance imaging within 10 days after symptom onset. Magnetic resonance imaging scans were analyzed for DWI lesions, cSS and other markers for small-vessel disease. Univariate and multivariate analyses were performed to assess the association between cSS and DWI lesions. RESULTS: Among 246 ICH survivors (mean age 71.4 ± 12.6 years) who were enrolled, 126 had lobar ICH and 120 had deep ICH. Overall, DWI lesions were observed in 38 (15.4%) patients and were more common in patients with lobar ICH than deep ICH (22.2% vs. 8.3%; P = 0.003). In multivariate logistic regression analysis, the extent of white matter hyperintensities [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05-1.58; P = 0.02] and cSS severity (focal cSS: OR, 3.54; 95% CI, 1.28-9.84; disseminated cSS: OR, 4.41; 95% CI, 1.78-10.97; P = 0.001) were independently associated with the presence of DWI lesions. CONCLUSIONS: Diffusion-weighted imaging lesions are more frequently observed in patients with acute lobar ICH than in those with deep ICH. cSS severity and white matter hyperintensity extent are independent predictors for the presence of DWI lesions, suggesting that CAA may be involved in the pathogenesis of DWI lesions associated with acute ICH.

Management and outcome of neonates with a prenatal diagnosis of esophageal atresia type A: A population-based study.

OBJECTIVE: Evaluate the neonatal management and outcomes of neonates with prenatal diagnosis of esophageal atresia (EA) type A. METHODS: This population-based study was conducted using data from the French National Register for infants with EA born from 2008 to 2014, including all cases of EA type A. We compared prenatal and neonatal characteristics and outcomes in children with prenatal diagnosis of EA type A with those with a postnatal diagnosis until the age of 1. RESULTS: A total of 1118 live births with EA were recorded among which 88 (7.9%) were EA type A. Prenatal diagnoses were performed in 75 cases (85.2%), and counselling with a prenatal specialist was conducted in 84.8% of the prenatal group. Still within that group, the gestational age at delivery was significantly higher than in the postnatal group (36 [35-38] versus 34 [32-36] weeks; P = .048). Inborn births were more frequent in the prenatal group (86.1% vs 7.7%, P < .0001), and mortality and outcome were similar in both groups. CONCLUSION: Prenatal diagnosis is high in EA type A, which enables to offer an antenatal parental counseling and which avoids postnatal transfers. Prognosis of EA types A does not appear to be influenced by the prenatal diagnosis.

Cognitive complaint in early Parkinson's disease: A pilot study.

BACKGROUND: Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD. MATERIALS AND METHODS: We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one-month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing. RESULTS: VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 ± 1.9 vs 0.8 ± 1.1; P < .001), language (2.3 ± 2.5 vs 1.0 ± 1.3, P < .001), and attention (2.1 ± 2.2 vs 1.2 ± 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing. CONCLUSIONS: SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated.

Abnormal pain perception in patients with Multiple System Atrophy.

INTRODUCTION: Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. METHODS: We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. RESULTS: Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). CONCLUSION: Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy.

Epidermal-specific deletion of CD44 reveals a function in keratinocytes in response to mechanical stress.

CD44, a large family of transmembrane glycoproteins, plays decisive roles in physiological and pathological conditions. CD44 isoforms are involved in several signaling pathways essential for life such as growth factor-induced signaling by EGF, HGF or VEGF. CD44 is also the main hyaluronan (HA) receptor and as such is involved in HA-dependent processes. To allow a genetic dissection of CD44 functions in homeostasis and disease, we generated a Cd44 floxed allele allowing tissue- and time-specific inactivation of all CD44 isoforms in vivo. As a proof of principle, we inactivated Cd44 in the skin epidermis using the K14Cre allele. Although the skin of such Cd44Δker mutants appeared morphologically normal, epidermal stiffness was reduced, wound healing delayed and TPA induced epidermal thickening decreased. These phenotypes might be caused by cell autonomous defects in differentiation and HA production as well as impaired adhesion and migration on HA by Cd44Δker keratinocytes. These findings support the usefulness of the conditional Cd44 allele in unraveling essential physiological and pathological functions of CD44 isoforms.

CD44: More than a mere stem cell marker.

CD44 is a cell adhesion molecule that plays an important role in tumor progression and metastasis. The role of CD44 in tumorigenesis is due to its binding to extracellular matrix components, including hyaluronan (HA) and osteopontin (OPN), and to messenger molecules, such as growth factors present in the tumor microenvironment. HA and OPN are highly abundant in the leukemic stem cell niche and in solid tumors of various cancer types, where they contribute to the maintenance of the stemness of malignant cells. CD44 has consequently been recognized as a cancer stem cell marker in several types of cancers, which has been a topic of much recent research. In this review we have addressed the question of how CD44 might promote cancer cell stemness by interacting with extracellular matrix components, growth factors and cytokines.

Feshbach-stabilized insulator of bosons in optical lattices.

Feshbach resonances-namely, resonances between an unbound two-body (atomic) state and a bound (molecular) state, differing in magnetic moment-are a unique tool to tune the interaction properties of ultracold atoms. Here we show that the spin-changing interactions, coherently coupling the atomic and molecular states, can act as a novel mechanism to stabilize an insulating phase-the Feshbach insulator-for bosons in an optical lattice close to a narrow Feshbach resonance. Making use of quantum Monte Carlo simulations and mean-field theory, we show that the Feshbach insulator appears around the resonance, preventing the system from collapsing when the effective atomic scattering length becomes negative. On the atomic side of the resonance, the transition from condensate to Feshbach insulator has a characteristic first-order nature, due to the simultaneous loss of coherence in the atomic and molecular components. These features appear clearly in the ground-state phase diagram of, e.g., ^{87}Rb around its 414 G resonance, and they are therefore directly amenable to experimental observation.

[Hospital readmission induced by adverse drug reaction: a pilot study in a post-emergency unit of a French university hospital]. / Réhospitalisations d'origine médicamenteuse : étude pilote dans un service de post-urgences médicales d'un hôpital universitaire français.

PURPOSE: Adverse Drug Reactions (ADRs) leading to hospital admission was estimated to 3.6 to 21.7%. Despite its importance in terms of patients care, readmission to hospital due to ADRs remains poorly documented. The aim of our study was to investigate the rate and main characteristics of readmission for ADRs. METHODS: We undertook a retrospective study during two years (2011-2012) in the post-emergency unit of Toulouse university hospital (south western, France). We selected all unplanned hospitalization for acute disease and included all cases of patients admitted twice fold or more for ADRs. Characteristics of drug-induced ADRs were assessed according to appropriate use or not. RESULTS: Out of the 197 readmitted patients, 71 was related to ADRs (3.6%) corresponding to 17.8‰ patients-year. Mean age was 82.3 years and 67% were women. The most frequent ADRs found were vascular (n=41, 18.4%), gastro-intestinal (n=28, 12.6%), cardiac (n=28, 12.6%), neurologic (n=26, 11.7%), metabolic (n=26, 10.3%) and psychiatric (n=24, 9.9%). The drugs mainly involved were psychoactive, cardiovascular, digestive or antithrombotic agents. The context of occurrence of ADRs was related to inappropriate drug prescription in 56% of cases. A total of 24 patients were admitted twice for the same ADR and 2 others three times. For 22 patients (30.9%), the same drugs were involved. CONCLUSION: Our data show hospital readmission was due to ADRs in 3.6% of cases. In 1.1% of cases, the same couple "drug-ADR" was involved. Furthermore, in 56% of cases, repeated admissions are related to an inappropriate drug prescription.

Perspectives of CD44 targeting therapies.

CD44 is a family of single-span transmembrane glycoproteins. Members of this family differ in the extracellular domain where ten variant exons are either excluded or included in various combinations. CD44 isoforms participate in many physiological processes including hematopoiesis, regeneration, lymphocyte homing and inflammation. Most importantly, they are involved in pathological processes and in particular in cancer. In several types of tumors, CD44 together with other antigens specifies for cancer stem cell populations. Mechanistically, CD44 proteins act as receptors for hyaluronan, co-receptor for receptor tyrosine kinases (RTKs) or G-protein-coupled receptors or provide a platform for metalloproteinases. For all these reasons, targeting CD44 may be a successful approach in cancer therapy. In this review, we discuss the various possibilities of targeting CD44. Among these are the production of CD44 ectodomains, antibodies, peptides or aptamers. Also inhibition of CD44 expression has been proposed. Finally, the function of CD44 as a hyaluronan receptor was also taken advantage of. We are convinced that the success of these therapies will depend on an increased understanding of the molecular functions of specific CD44 isoforms in particular in cancer stem cells.

CD44 functions in Wnt signaling by regulating LRP6 localization and activation.

Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration-dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing brain of Xenopus laevis embryos as shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants.

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital.

PURPOSE: The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Médicalisation des Systèmes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. METHODS: The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs. RESULTS: During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4 %) and central (11.3 %) ADRs in PMSI database versus cutaneous (22.4 %) and general (17.5 %) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1 %) in PMSI database versus anti-infectives (38.2 %) in FPVDB. The estimated number of ADRs was 717 [95 % confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6 % (95 % CI 0.4, 0.8). CONCLUSIONS: Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.

[Evaluation of transit in vivo dosimetry using portal imaging and comparison with measurements using diodes]. / Évaluation d'une dosimétrie in vivo de transit utilisant l'imageur portal et comparaison avec les mesures par diodes.

PURPOSE: In vivo dosimetry transit using portal imaging is a promising approach for quality assurance in radiotherapy. A comparative evaluation was conducted between a commercial solution, EPIgray(®) and an in vivo dosimetry control reference using semiconductors diodes. MATERIAL AND METHODS: The performance of the two in vivo dosimetry methods was assessed. The primary endpoint was the dose deviation between the reconstructed dose at the prescription point and the measured dose using the ionization chamber in phantoms or the calculated predictive dose by the treatment planning system with patients. The deviation threshold was set to ±5%. In total, 107 patients were prospectively included and treated with 3D-conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques for tumours of the brain, chest and head and neck. RESULTS: The dosimetric accuracy of EPIgray(®) in phantom were comparable to diodes in terms of repeatability (0.11%), reproducibility (0.29-0.51%) with a mean dose deviation of 0.17% (SD: 1.11). The rates of radiotherapy sessions out of the tolerance for the brain (3D-CRT and IMRT), thorax (3D-CRT) and the head and neck (IMRT) were respectively 0%, 9.6% and 5.3% with a mean dose deviation ranging between 0.49% and 1.53%. The mean of dose deviation between three consecutive sessions with EPIgray(®) validates 99.1% of treatments. CONCLUSION: The performance of EPIgray(®) in in vivo dosimetry is consistent with the recommendations of the European Society for Radiotherapy and Oncology (ESTRO) and equivalent to semiconductor diodes for 3D-CRT. It also allows adequate control for IMRT, which is technically difficult to perform with the diodes.

[Evaluation and implementation of in vivo transit dosimetry with an electronic portal imaging device]. / Évaluation et mise en œuvre de la dosimétrie in vivo de transmission par imageurs portals.

PURPOSE: In vivo dosimetry is now widely recommended to avoid major treatment error. Transit dosimetry using portal imagers allows fast and accurate in vivo dose verifications. Several teams have published clinical studies but no recommendation has been proposed to define tolerance levels and validation criteria. This study proposes a simple methodology to assess the overall standard deviation of transit dosimetry and was applied to our transit dosimetry method. MATERIAL AND METHODS: In a first step, the uncertainties due to the dose reconstruction method are evaluated. Their estimation is based on a set of geometries, representative of clinical situations for which 45 points of measurement have been defined. In a second step, we studied the variations of our method in clinical situations. During the treatment session of the patient, the dose was reconstructed and the differences between reconstructed dose and prescribed dose were used to define a realistic tolerance level, adapted to the clinical routine. Then, a methodology is proposed to determine if the transit dosimetry method, with the defined tolerance level allows detecting significant treatment errors (>5% of the prescribed dose). RESULTS -  CONCLUSION: Applying this methodology we concluded that a tolerance level of 6.5% (k=2) can be associated with our method. With this value, it is demonstrated that in many cases differences of 5% (or less) on the prescribed dose can be detected. This study demonstrates clearly that in vivo transit dosimetry is not able to detect all the treatment errors but remains an ultimate and efficient tool in many situations.

Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44.

The tumor microenvironment makes a decisive contribution to the development and dissemination of cancer, for example, through extracellular matrix components such as hyaluronan (HA), and through chemokines that regulate tumor cell behavior and angiogenesis. Here we report a molecular link between HA, its receptor CD44 and the chemokine CXCL12 in the regulation of cell motility and angiogenesis. High-molecular-weight HA (hHA) was found to augment CXCL12-induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility. The augmentation of CXCR4 signaling translated into increased vessel sprouting and angiogenesis in a variety of assays. Small HA oligosaccharides (sHA) efficiently inhibited these effects. Both siRNA-mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12-induced CXCR4 signaling depends on the binding of hHA to CD44. Consistently, CD44 and CXCR4 were found to physically interact in the presence of CXCL12, an interaction that could be inhibited by sHA. These findings provide novel insights into how microenvironmental components interact with cell surface receptors in multi-component complexes to regulate key aspects of tumor growth and progression.

[Anorectal malformations]. / Malformations ano-rectales.

Anorectal malformations (ARM) are the result of an abnormal development of the terminal part of the digestive tract interesting anus and/or rectum that occur early between the sixth and tenth week of embryonic development. They carry a malformation spectrum of severity depending on the level of disruption of the anorectal canal and of the associated caudal malformations (sacrum and spine). ARM are associated in over half the cases with other malformations that can be integrated in some cases in known syndromes. If surgical treatment to restore anatomy as normal as possible is indispensable, post-operative care is essential for these patients whose defecation mechanisms are altered, to reach if not continence, at least a socially acceptable cleanliness.

Competing supersolid and Haldane insulator phases in the extended one-dimensional bosonic Hubbard model.

The Haldane insulator is a gapped phase characterized by an exotic nonlocal order parameter. The parameter regimes at which it might exist, and how it competes with alternate types of order, such as supersolid order, are still incompletely understood. Using the stochastic Green function quantum Monte Carlo algorithm and density matrix renormalization group, we study numerically the ground state phase diagram of the one-dimensional bosonic Hubbard model with contact and near neighbor repulsive interactions. We show that, depending on the ratio of the near neighbor to contact interactions, this model exhibits charge density waves, superfluid, supersolid, and the recently identified Haldane insulating phases. We show that the Haldane insulating phase exists only at the tip of the unit-filling charge density wave lobe and that there is a stable supersolid phase over a very wide range of parameters.