Benchmarking clinical management of spinal and non-spinal disorders using quality of life: results from the EPI3-LASER survey in primary care

Concerns have been raised regarding sub-optimal utilization of analgesics and psychotropic drugs in the treatment of patients with chronic musculoskeletal disorders (MSDs) and their associated co-morbidities. The objective of this study was to describe drug prescriptions for the management of spinal and non-spinal MSDs contrasted against a standardized measure of quality of life. A representative population sample of 1,756 MSDs patients [38.5% with spinal disorder (SD) and 61.5% with non-spinal MSDs (NS-MSD)] was drawn from the EPI3-LASER survey of 825 general practitioners (GPs) in France. Physicians recorded their diagnoses and prescriptions on that day. Patients provided information on socio-demographics, lifestyle and quality of life using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than 12 weeks duration of the current episode. Chronic SD and NS-MSD patients were prescribed less analgesics and non-steroidal anti-inflammatory drugs than their non-chronic counterpart [odds ratios (OR) and 95% confidence intervals (CI), respectively: 0.4, 0.2–0.7 and 0.5, 0.3–0.6]. They also had more anxio-depressive co-morbidities reported by their physicians (SD: 16.1 vs.7.4%; NS-MSD: 21.6 vs. 9.5%) who prescribed more antidepressants and anxiolytics with a difference that was statistically significant only for spinal disorder patients (OR, 95% CI: 2.0, 1.1–3.6). Psychotropic drugs were more often prescribed in patients in the lower quartile of SF-12 mental score and prescriptions of analgesics in the lower quartile of SF-12 physical score (P < 0.001). In conclusion, anxiety and depressive disorders were commonly reported by GPs among chronic MSD patients. Their prescriptions of psychotropic and analgesic drugs were consistent with patients’ self-rated mental and physical health

Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415

Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice

Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients. Keywords: citrullinemia; gene therapy; hyperammonemia; rAAV; urea cycl

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4-/- mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients

L’enfant et la mort dans l’Antiquité III. Le matériel associé aux tombes d’enfants

Ce volume rassemble les communications presentées à la troisième et dernière réunion scientifique organisée dans le cadre du programme « L’enfant et la mort dans l’Antiquité : des pratiques funéraires à l’identité sociale » (EMA), financé par l’Agence nationale de la recherche (ANR) de novembre 2007 à novembre 2011. Les 26 contributions - rédigées en français, en italien ou en anglais - envisagent la question du matériel associé aux tombes d’enfants. Dépose-t-on autant d’objets auprès des tout-petits, des enfants de 6-7 ans et de 12-13 ans ? La nature de ces offrandes varie-t-elle en fonction du sexe ? Dans quelle mesure certaines d’entre elles - « biberons », vases miniatures, astragales, figurines en terre cuite sont-elles caractéristiques des sépultures d’immatures ? Ces questions se posent-elles de la même façon dans les différentes régions du monde méditerranéen et tout au long des douze siècles environ que couvre notre enquête ? Les articles réunis ici envisagent ces problèmes dans un cadre plus large que celui du monde méditerranéen classique - Grèce et Rome -, en intégrant des études relatives à l’Égypte préhellénistique, à Carthage, au monde celtique du Midi et à la Gaule non méditerranéenne. Certaines de ces contributions présentent des découvertes récentes, partiellement ou entièrement inédites.Ce volume rassemble les communications presentées à la troisième et dernière réunion scientifique organisée dans le cadre du programme « L’enfant et la mort dans l’Antiquité : des pratiques funéraires à l’identité sociale » (EMA), financé par l’Agence nationale de la recherche (ANR) de novembre 2007 à novembre 2011. Les 26 contributions - rédigées en français, en italien ou en anglais - envisagent la question du matériel associé aux tombes d’enfants. Dépose-t-on autant d’objets auprès des tout-petits, des enfants de 6-7 ans et de 12-13 ans ? La nature de ces offrandes varie-t-elle en fonction du sexe ? Dans quelle mesure certaines d’entre elles - « biberons », vases miniatures, astragales, figurines en terre cuite sont-elles caractéristiques des sépultures d’immatures ? Ces questions se posent-elles de la même façon dans les différentes régions du monde méditerranéen et tout au long des douze siècles environ que couvre notre enquête ? Les articles réunis ici envisagent ces problèmes dans un cadre plus large que celui du monde méditerranéen classique - Grèce et Rome -, en intégrant des études relatives à l’Égypte préhellénistique, à Carthage, au monde celtique du Midi et à la Gaule non méditerranéenne. Certaines de ces contributions présentent des découvertes récentes, partiellement ou entièrement inédites

Incidence and risk factors for striae gravidarum

International audienc

Two functionally distinct domains generated by invivo cleavage of Nup145p: a novel biogenesis pathway for nucleoporins

International audienceNup145p is an essential yeast nucleoporin involved in nuclear export of polyadenylated RNAs. We demonstrate here that Nup145p is cleaved in vivo to yield two functionally distinct domains: a carboxy‐terminal domain (C‐Nup145p) which is located at the nuclear pore complex (NPC) and assembles into the Nup84p complex, and a GLFG‐containing amino‐terminal domain (N‐Nup145p) which is not part of this complex. Whereas the essential C‐Nup145p accomplishes the functions required for efficient mRNA export and normal NPC distribution, N‐Nup145p, which is homologous to the GLFG‐containing nucleoporins Nup100p and Nup116p, is not necessary for cell growth. However, the N‐Nup145p becomes essential in a nup188 mutant background. Strikingly, generation of a free N‐domain is a prerequisite for complementation of this peculiar synthetic lethal mutant. These data suggest that N‐ and C‐domains of Nup145p perform independent functions, and that the in vivo cleavage observed is of functional importance

Management of Upper Respiratory Tract Infections by Different Medical Practices, Including Homeopathy, and Consumption of Antibiotics in Primary Care: The EPI3 Cohort Study in France 2007–2008

International audienceBackgroundPrescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care.ObjectivesTo describe and compare antibiotic and antipyretic/anti-inflammatory drugs use, URTI symptoms' resolution and occurrence of potentially-associated infections in patients seeking care from general practitioners (GPs) who exclusively prescribe conventional medications (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho).MethodThe EPI3 survey was a nationwide population-based study of a representative sample of 825 GPs and their patients in France (2007–2008). GP recruitment was stratified by self-declared homeopathic prescribing preferences. Adults and children with confirmed URTI were asked to participate in a standardized telephone interview at inclusion, one-, three- and twelve-month follow up. Study outcomes included medication consumption, URTI symptoms' resolution and potentially-associated infections (sinusitis or otitis media/externa) as reported by patients. Analyses included calibration to account for non-respondents and groups were compared using multivate analyses adjusting for baseline differences with a propensity score.Results518 adults and children with URTI (79.3% rhinopharyngitis) were included (36.9% response rate comparable between groups). As opposed to GP-CM patients, patients in the GP-Ho group showed significantly lower consumption of antibiotics (Odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.27–0.68) and antipyretic/anti-inflammatory drugs (OR = 0.54, 95% CI: 0.38–0.76) with similar evolution in related symptoms (OR = 1.16, 95% CI: 0.64–2.10). An excess of potentially-associated infections (OR = 1.70, 95% CI: 0.90–3.20) was observed in the GP-Ho group (not statistically significant). No difference was found between GP-CM and GP-Mx patients.ConclusionPatients who chose to consult GPs certified in homeopathy used less antibiotics and antipyretic/anti-inflammatory drugs for URTI than those seen by GPs prescribing conventional medications. No difference was observed in patients consulting GPs within mixed-practice. A non-statistically significant excess was estimated through modelling for associated infections in the GP-Ho group and needs to be further studied