Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the β-isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.

Reflux vésico-­‐urétéral et atteinte rénale: rôle de l'albuminurie

Introduction :¦Le reflux vésico-urétéral (RVU) touche environs 1% des nouveau-nés et est retrouvé chez 25 à 30 % des enfants ayant une pyélonéphrite. Le RVU peut être associé à une hypoplasie/dysplasie rénale ou/et à des cicatrices rénales causées par les pyélonéphrites. Ces changements morphologiques sont plus ou moins importants selon le grade du reflux et peuvent conduire à une insuffisance rénale chronique et potentiellement évoluer en une insuffisance rénale terminale.¦La microalbuminurie (MA) reflète une augmentation anormale de la perméabilité capillaire glomérulaire et est un indicateur prédictif de la péjoration de la fonction rénale vers l'insuffisance chronique. La MA est également un facteur de risque cardiovasculaire.¦Objectif :¦Le but de cette recherche transversale est d'évaluer la présence de MA chez des patients atteints de RVU et de voir s'il est possible de corréler la MA avec le degré de reflux, la présence d'une hyperfiltration et le degré de l'insuffisance rénale.¦Patients et méthode :¦Une base de données de 160 dossiers médicaux du service de pédiatrie du CHUV, portant sur les années 2007, 2008, 2009 et 2010, va être investiguée. Ces dossiers regroupent tous les patients atteints de RVU ayant eu une exploration fonctionnelle rénale, dont l'âge varie du nouveau-né au jeune adulte âgé de 21 ans. Les variables suivantes seront considérées et analysées en détail: âge, sexe, taille, type de RVU, taux de filtration glomérulaire (TFG), flux plasmatique rénal (FPR), fraction de filtration (FF), albuminurie, rapport albumine/créatinine.¦- Les RVU sont classés en cinq grades (I, II, III, IV, V) et peuvent être uni- ou bilatéraux¦- Le TFG est calculé avec la clairance à l'inuline, un polymère de glucose filtré, non réabsorbé, ni sécrété, qu'on perfuse au patient. TFG = Uin V/Pin (ml/min)¦- Le FPR est calculé avec la clairance au PAH (acide para-amino-hippurique), une substance entièrement filtrée et sécrétée au premier passage et qu'on injecte au patient. FPR = UPAHV / PPAH (ml/min)¦- La FF est la proportion du FPR qui est filtrée.¦FF= TGF / FPR ou FF = Cl in / Cl PAH¦- La MA a été mesurée par la méthode Immulite (Siemens) jusqu'en fin août 2010 et par la méthode ALBT2 (Roche Diagnostics) à partir d'octobre 2010. Le taux normal d'albuminurie est de moins de 20 mg/l sur un échantillon d'urine.¦- Le rapport albumine urinaire / créatinine urinaire permet d'éviter les problèmes de variation de volume urinaire lors de l'analyse d'échantillon urinaire d'une seule miction. Le rapport normal est de moins de 2,5 g/mol de créatinine.¦Un questionnaire sera envoyé aux patients pour obtenir des précisions sur la fréquence et la sévérité des infections urinaires éventuellement survenues depuis.¦Les dossiers seront revus pour connaître l'évolution du RVU.¦Résultats attendus et discussion: Les résultats nous permettront :¦1) De savoir si les patients avec un RVU ont une MA¦2) De savoir si la MA varie en fonction du grade de leur reflux¦3) De savoir si la MA varie en fonction de l'hyperfiltration mesurée par la FF.¦Interprétation :¦Si la MA varie en fonction de la FF cela indiquera que la MA est la conséquence directe de l'hyperfiltration compensatrice de la perte de la masse néphronique et qu'elle est ainsi le reflet d'une cause principalement mécanique. Si la MA ne varie pas en fonction de la FF cela indiquera qu'elle est liée à l'hypoplasie/dysplasie ou/et aux cicatrices dues aux pyélonéphrites. Elle pourra alors être par exemple la conséquence d'une néphropathie glomérulotubulointerstitielle.¦Du point de vue pratique, cette étude permettra de déterminer si la simple mesure da la MA peut aider à prédire le degré de l'atteinte rénale et/ou le degré de l'hyperfiltration dans ce groupe de patients atteints de RVU.¦Bibliographie¦1. Silbernagl S, Despopoulos A. Atlas de poche de physiologie. Paris : Flammarion médecine-sciences; 2004.¦2. Brenner BM, Rector FC. The Kidney . Philadelphia : WB Saunders Company; 1996.¦3. Brandström P, Esbjörner E, Herthelius M, Holmdahl G, Läckgren G, Nevéus T, et al. The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics. The Journal of Urology. 2010;184:274-279.¦4. Holmdahl G, Brandström P, Läckgren G, Sillén U, Stokland E, Jodal U, et al. The Swedish Reflux Trial in Children: II. Vesicoureteral Reflux Outcome. The Journal of Urology. 2010;184:280-285.¦5. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish Reflux Trial in Children: III. Urinary Tract Infection Pattern. The Journal of Urology. 2010;184:286-291.¦6. Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish Reflux Trial in Children: IV. Renal Damage. The Journal of Urology. 2010;184:292-297.¦7. Ruggenenti P, Remuzzi G. Time to abandon microalbuminuria? Kidney Int. 2006;70:1214-1222.¦8. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J. Am. Soc. Nephrol. 2001;12:1315-1325.¦9. Basic J, Golubovic E, Miljkovic P, Bjelakovic G, Cvetkovic T, Milosevic V. Microalbuminuria in children with vesicoureteral reflux. Ren Fail. 2008:639-643.¦10. González E, Papazyan JP, Girardin E. Impact of vesicoureteral reflux on the size of renal lesions after an episode of acute pyelonephritis. The Journal of Urology. 2005;173:571-575.

IVA in addition to BMD can change the osteoporosis management in 25% of clinical routine patients

Introduction Vertebral fracture is one of the major osteoporoticfractures which are unfortunately very often undetected. In addition,it is well known that prevalent vertebral fracture increases dramaticallythe risk of future additional fracture. Instant Vertebral Assessment(IVA) has been introduced in DXA device a couple of years ago toease the detection of such fracture when routine DXA are performed.To correctly use such tool, ISCD provided clinical recommendationon when and how to use it. The aim of our study was to evaluate theISCD guidelines in clinical routine patients and see how often itmay change of patient management.Methods During two months (March and April 2010), a medicalquestionnaire was systematically given to our clinical routine patientto check the validity of ISCD IVA recommendations in our population.In addition, all women had BMD measurement at AP spine,femur and 1/3 radius using a Discovery A System (Hologic, Waltham,USA). When appropriate, IVA measurement had been performedon the same DXA system and had been centrally evaluated by twotrained doctors for fracture status according to the semi-quantitativemethod of Genant. The reading had been performed when possiblebetween L5 and T4.Results Out of 210 women seen in the consultation, 109 (52 %)of them (mean age 68.2 ± 11.5 years) fulfilled the necessary criteriato have an IVA measurement. Out of these 109 women, 43 (incidence39.4 %) had osteoporosis at one of the three skeletal sitesand 31 (incidence 28.4 %) had at least one vertebral fracture. 14.7 %of women had both osteoporosis and at least one vertebral fractureclassifying them as "severe osteoporosis" while 46.8 % did not haveosteoporosis and no vertebral fracture. 24.8 % of the women hadosteoporosis but no vertebral fracture while 13.8 % of women didhave osteoporosis but vertebral fracture (clinical osteoporosis).Conclusions In 52 % of our patients, IVA was needed accordingto ISCD criteria. In half of them the IVA test influenced of patientmanagement either may changing the type of treatment of simplyby classifying patient as "clinical osteoporosis". IVA appears to bean important tool in clinical routine but unfortunately is not yetvery often use in most of the centers.

Revue des cas d'intoxication aux champignons dans un service d'urgence entre 2005 et 2011

Introduction: Les services d'urgences sont régulièrement confrontés à des intoxications par ingestion de champignons. Ces situations, souvent banales, peuvent nécessiter une prise en charge intensive et comporter un risque réel de morbi-mortalité, en particulier lors de cytolyse hépatique aiguë. La prévalence, ainsi que la fréquence réelle des complications liées à l'ingestion de champignons sont mal connues. Méthodes: Etude rétrospective dans un service d'urgence universitaire entre décembre 2004 et octobre 2011. Les codes diagnostics «intoxication aux champignons», ainsi que les termes «amanite» ou «champignons» ont été extraits de la base de données des urgences. Les caractéristiques des patients, leurs présentations cliniques, durées de séjour et complications ont été analysées. Résultats: 72 cas ont été répertoriés et revus, âge 44,3 ± 2,0 ans (moy ± SE, 95%CI 40,2-48,4), ratio H:F 1:1,2 (33H, 39F). 81% des cas sont survenus entre août et décembre. 14 cas sont arrivés sous forme de clusters familiaux (35 patients, moyenne = 2,6 cas/cluster, min: 2, max: 7). Un spécialiste en mycologie a été contacté dans 25 cas pour identifier les champignons. 69 patients (96%) sont rentrés à domicile depuis les urgences (séjour de 10,8 ± 1,3 heures, 95%CI 8,2-13,4 h). Lorsque les symptômes survenaient <= 4 heures après l'ingestion, les patients restaient moins longtemps (N = 57, durée séjour médiane 6,1 h, P25-P75 3,2-11,8 h) que les cas avec des symptômes plus tardifs (N = 15, durée séjour médiane 13,3 h, P25-P75 10,2-36,2) (p = 0,0001 selon Mann-Whitney). Une patiente a nécessité un transfert dans un centre spécialisé (intoxication par amanite phalloïde, avec dosage positif de l'alpha-amanitine). Elle a bénéficié de silibinine et d'une hospitalisation (9 jours), avec une évolution favorable sans nécessité de transplantation. Les symptômes étaient apparus tardivement (7 h). Conclusions: Sur les 72 cas, un seul (1,4%) a nécessité une prise en charge spécialisée. Les autres patients ont pu rentrer à domicile dans les heures qui ont suivi leur admission. Une grande partie des cas est survenue entre août et décembre, période favorable pour la récolte ou la consommation de champignons. Cette analyse confirme que la plupart des cas sont bénins et que les patients peuvent rentrer rapidement à domicile une fois les symptômes passés. Le seul cas potentiellement grave a présenté des symptômes tardifs et une longue hospitalisation, ce qui réaffirme les données de la littérature.

Arsenic(V) adsorption onto α-Al2O3 between 25 and 70°C

The adsorption of As(V) onto alpha -Al2O3 was investigated at 25, 50 and 70 degreesC using batch adsorption experiments. Results indicate that As is strongly adsorbed at low pH and gets progressively released to the fluid with increasing pH above 7. At any pH, increasing temperature favors aqueous species of As over surface species. Surface complexation constants were determined at the experimental temperatures by fitting the adsorption data. Adsorption reactions were then converted to semi-isocolumbic reactions, i.e, reactions with balanced like-charged aqueous species. Intrinsic adsorption constants of semi-isocolumbic reactions change linearly when plotted against inverse temperature, suggesting that the heat capacity of these reactions remains constant over the temperature range considered. This permitted thermodynamic parameters of intrinsic surface complexation constants to be determined. Changes in surface complexation constants result in a change in the surface speciation with increasing temperature. This change is similar to the one observed for aqueous species, i.e. increasing temperature favors less negatively charged species below a pH of 9 and more negatively charged species above a pH of 10. Comparison with the stability of As surface complexes with Fe suggests that surface complexes with Al are more stable. (C) 2001 Elsevier Science Ltd. All rights reserved.

Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naïve HIV-1-positive individuals: 96 week results from FLAMINGO.

INTRODUCTION: Dolutegravir (DTG) 50 mg once daily was superior to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL (p=0.025) [1]. We present data through Week 96. MATERIAL AND METHODS: FLAMINGO is a multicentre, randomized, open-label, Phase IIIb non-inferiority study, in which HIV-1-positive ART-naïve adults with HIV-1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator-selected backbone NRTIs (TDF/FTC or ABC/3TC). Participants were stratified by screening HIV-1 RNA (≤100K c/mL) and NRTI backbone. RESULTS: A total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002). Secondary analyses supported primary results: per-protocol [(DTG 83% vs. DRV/r 70%), 95% CI 12.9 (5.3, 20.6)] and treatment-related discontinuation = failure [(98% vs. 95%), 95% CI 3.2 (-0.3, 6.7)]. Overall virologic non-response (DTG 8%; DRV/r 12%) and non-response due to other reasons (DTG 12%; DRV/r 21%) occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96) and in the TDF/FTC stratum (79% vs. 64%); consistent responses were seen in the ABC/3TC stratum (82% vs. 75%). Six participants (DTG 2, none post-Week 48; DRV/r 4, two post-Week 48) experienced protocol-defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24); none had treatment-emergent resistance to study drugs. Most frequent drug-related adverse events (AEs) were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24%) than DTG (10%). Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22%) vs. DTG (7%), p<0.001; mean changes in creatinine for DTG (~0.18 mg/dL) observed at Week 2 were stable through Week 96. CONCLUSIONS: Once-daily DTG was superior to once-daily DRV/r in treatment-naïve HIV-1-positive individuals, with no evidence of emergent resistance to DTG in virologic failure and relatively similar safety profiles for DTG and DRV/r through 96 Weeks.

25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients.

BACKGROUND: Circulating 25-hydroxyvitamin D [25(OH)D] concentration is inversely associated with peripheral arterial disease and hypertension. Vascular remodeling may play a role in this association, however, data relating vitamin D level to specific remodeling biomarkers among ESRD patients is sparse. We tested whether 25(OH)D concentration is associated with markers of vascular remodeling and inflammation in African American ESRD patients.METHODS: We conducted a cross-sectional study among ESRD patients receiving maintenance hemodialysis within Emory University-affiliated outpatient hemodialysis units. Demographic, clinical and dialysis treatment data were collected via direct patient interview and review of patients records at the time of enrollment, and each patient gave blood samples. Associations between 25(OH)D and biomarker concentrations were estimated in univariate analyses using Pearson's correlation coefficients and in multivariate analyses using linear regression models. 25(OH) D concentration was entered in multivariate linear regression models as a continuous variable and binary variable (<15 ng/ml and =15 ng/ml). Adjusted estimate concentrations of biomarkers were compared between 25(OH) D groups using analysis of variance (ANOVA). Finally, results were stratified by vascular access type.RESULTS: Among 91 patients, mean (standard deviation) 25(OH)D concentration was 18.8 (9.6) ng/ml, and was low (<15 ng/ml) in 43% of patients. In univariate analyses, low 25(OH) D was associated with lower serum calcium, higher serum phosphorus, and higher LDL concentrations. 25(OH) D concentration was inversely correlated with MMP-9 concentration (r = -0.29, p = 0.004). In multivariate analyses, MMP-9 concentration remained negatively associated with 25(OH) D concentration (P = 0.03) and anti-inflammatory IL-10 concentration positively correlated with 25(OH) D concentration (P = 0.04).CONCLUSIONS: Plasma MMP-9 and circulating 25(OH) D concentrations are significantly and inversely associated among ESRD patients. This finding may suggest a potential mechanism by which low circulating 25(OH) D functions as a cardiovascular risk factor.

Intraoperative angiography reloaded: a new hybrid operating theater for combined endovascular and surgical treatment of cerebral arteriovenous malformations: a pilot study on 25 patients.

BACKGROUND: Multimodality treatment suites for patients with cerebral arteriovenous malformations (AVM) have recently become available. This study was designed to evaluate feasibility, safety and impact on treatment of a new intraoperative flat-panel (FP) based integrated surgical and imaging suite for combined endovascular and surgical treatment of cerebral AVM. METHODS: Twenty-five patients with AVMs to treat with combined endovascular and surgical interventions were prospectively enrolled in this consecutive case series. The hybrid suite allows combined endovascular and surgical approaches with intraoperative scanner-like imaging (XperCT®) and intraoperative 3D rotational angiography (3D-RA). The impact of intraoperative multimodal imaging on feasibility, workflow of combined interventions, surgery, and unexpected imaging findings were analyzed. RESULTS: Twenty-five patients (mean age 38 ± 18.6 year) with a median Spetzler-Martin grade 2 AVM (range 1-4) underwent combined endovascular and surgical procedures. Sixteen patients presented with a ruptured AVM and nine with an unruptured AVM. In 16 % (n = 4) of cases, intraoperative imaging visualized AVM remnants ≤3 mm and allowed for completion of the resections in the same sessions. Complete resection was confirmed in all n = 16 patients who had follow-up angiography one year after surgery so far. All diagnostic and therapeutical steps, including angiographic control, were performed without having to move the patients CONCLUSION: The hybrid neurointerventional suite was shown to be a safe and useful setup which allowed for unconstrained combined microsurgical and neuroradiological workflow. It reduces the need for extraoperative angiographic controls and subsequent potential surgical revisions a second time, as small AVM remnants can be detected with high security.