Development of a pediatric eosinophilic esophagitis activity index (ped-EEsAI): International experts propose dysphagia, whitish exudates on endoscopy , and intraepithelial eosinophili count as major items related to EoE activity

Background and Aims: The international EEsAI study group aims to develop, validate and evaluate the first pediatric EoE activity index (ped-EEsAI). We report on results of phase 1, which aims to generate candidate items. Methods: This study involves 3 phases: (1) item generation, (2) index derivation and testing on a first patient cohort, and (3) validation in a second cohort. In phase 1, item generation, weighting and reduction are achieved through a Delphi process with an international EoE expert group. The experts proposed and ranked candidate items on a 7-point Likert scale (0 = no, 6 = perfect relationship with EoE activity). Results: 23 international EoE experts proposed and ranked 39 items (20 clinical, 6 endoscopic, 8 histologic, 5 laboratory items). Rank order for clinical items: dysphagia related to food consistencies (median 5, range 2-6), severity of dysphagia (5, 3-6), frequency of dysphagia episodes (5, 3-6), regurgitation and vomiting (4, 2-5), response to dietary restrictions (4, 1-6); endoscopic items: whitish exudates (5, 3-6), furrowing (4, 3-6), corrugated rings (4, 2-6), linear shearing (4, 2-6), strictures (3, 2-6); histologic items: intraepithelial eosinophil count (5, 4-6), lamina propria fibrosis (3, 2-6), basal layer enlargement (3, 1-5); laboratory items: % blood eosinophils (3, 0-5). Conclusions: These items will now be reduced in further Delphi rounds, tested on a cohort of 100 pediatric EoE patients and validated in a second independent cohort, resulting in a robust, broadly accepted disease activity index for use in clinical trials and daily care.

Characteristics of eyes with secondary loss of visual acuity receiving variable dosing ranibizumab for neovascular age-related macular degeneration.

PURPOSE: The aim of this work is to investigate the characteristics of eyes failing to maintain visual acuity (VA) receiving variable dosing ranibizumab for neovascular age-related macular degeneration (nAMD) after three initial loading doses. METHODS: A consecutive series of patients with nAMD, who, after three loading doses of intravitreal ranibizumab (0.5 mg each), were re-treated for fluid seen on optical coherence tomography. After exclusion of eyes with previous treatment, follow-up less than 12 months, or missed visits, 99 patients were included in the analysis. The influence of baseline characteristics, initial VA response, and central retinal thickness (CRT) fluctuations on the VA stability from month 3 to month 24 were analyzed using subgroups and multiple regression analyses. RESULTS: Mean follow-up duration was 21.3 months (range 12-40 months, 32 patients followed-up for ≥24 months). Secondary loss of VA (loss of five letters or more) after month 3 was seen in 30 patients (mean VA improvement from baseline +5.8 letters at month 3, mean loss from baseline -5.3 letters at month 12 and -9.7 at final visit up to month 24), while 69 patients maintained vision (mean gain +8.9 letters at month 3, +10.4 letters at month 12, and +12.8 letters at final visit up to month 24). Secondary loss of VA was associated with the presence of pigment epithelial detachment (PED) at baseline (p 0.01), but not with baseline fibrosis/atrophy/hemorrhage, CRT fluctuations, or initial VA response. Chart analysis revealed additional individual explanations for the secondary loss of VA, including retinal pigment epithelial tears, progressive fibrosis, and atrophy. CONCLUSIONS: Tissue damage due to degeneration of PED, retinal pigment epithelial tears, progressive fibrosis, progressive atrophy, or massive hemorrhage, appears to be relevant in causing secondary loss of VA despite vascular endothelial growth factor suppression. PED at baseline may represent a risk factor.

When should clinicians search for GLUT1 deficiency syndrome in childhood generalized epilepsies?

UNLABELLED: GLUT1 deficiency (GLUT1D) has recently been identified as an important cause of generalized epilepsies in childhood. As it is a treatable condition, it is crucial to determine which patients should be investigated. METHODS: We analyzed SLC2A1 for mutations in a group of 93 unrelated children with generalized epilepsies. Fasting lumbar puncture was performed following the identification of a mutation. We compared our results with a systematic review of 7 publications of series of patients with generalized epilepsies screened for SLC2A1 mutations. RESULTS: We found 2/93 (2.1%) patients with a SLC2A1 mutation. One, carrying a novel de novo deletion had epilepsy with myoclonic-atonic seizures (MAE), mild slowing of head growth, choreiform movements and developmental delay. The other, with a paternally inherited missense mutation, had childhood absence epilepsy with atypical EEG features and paroxysmal exercise-induced dyskinesia (PED) initially misdiagnosed as myoclonic seizures. Out of a total of 1110 screened patients with generalized epilepsies from 7 studies, 2.4% (29/1110) had GLUT1D. This rate was higher (5.6%) among 303 patients with early onset absence epilepsy (EOAE) from 4 studies. About 50% of GLUT1D patients had abnormal movements and 41% a family history of seizures, abnormal movements or both. CONCLUSION: GLUT1D is most likely to be found in MAE and in EOAE. The probability of finding GLUT1D in the classical idiopathic generalized epilepsies is very low. Pointers to GLUT1D include an increase in seizures before meals, cognitive impairment, or PED which can easily be overlooked.

Registries in rheumatological and musculoskeletal conditions. Paediatric Behçet's disease: an international cohort study of 110 patients. One-year follow-up data.

OBJECTIVE: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children. METHODS: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database. RESULTS: At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria. CONCLUSION: The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.

Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial.

OBJECTIVES: To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis. METHODS: Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria. RESULTS: In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration > 1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index > 1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index > 1.14 (OR 2.18) and a parent's evaluation of child's overall well-being < or = 4.69 (OR 2.2). CONCLUSION: The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.

Surgical complications due to postnatal cytomegalovirus infection in a preterm infant with malrotation.

We report a case of an extremely preterm infant with intestinal malrotation who contracted postnatal systemic cytomegalovirus (CMV) infection with a complicated intestinal evolution requiring repeated surgical interventions and antiviral treatment. This report is to emphasize that prolonged gastrointestinal symptoms in extremely preterm infants fed with non-pasteurized breast milk should lead to suspicion of CMV infection. The importance of preventive measures when feeding very preterm infants with breast milk needs to be considered. Furthermore, the indications for antiviral treatment, in particular in preterm infants, need to be clarified.

Factors Influencing the Treatment Response of Pigment Epithelium Detachment in Age-Related Macular Degeneration.

PURPOSE: To study the effect of various baseline factors, particularly the type of drug (ranibizumab vs aflibercept), on the functional and anatomic response of treatment-naïve pigment epithelial detachment (PED) associated with neovascular age-related macular degeneration (neovascular AMD), after 3 intravitreal injections. DESIGN: Retrospective consecutive case series. METHODS: This study included 102 patients (n = 115 eyes) with treatment-naïve neovascular AMD and PED (>150 μm), who were treated with either ranibizumab (n = 68 eyes) or aflibercept (n = 47 eyes). A multivariate analysis using stepwise linear regression was performed in order to assess factors influencing visual acuity improvement, as well as treatment response of PED height after 3 monthly injections. RESULTS: Multivariate analysis revealed that better visual improvement was associated with lower best-corrected visual acuity (BCVA) at baseline (P = .001), presence of subretinal fluid (P = .001), and retinal angiomatous proliferation (P = .001); PED reduction was associated with higher PED at baseline (P = .001), predominantly serous PED (P = .003), and the use of aflibercept (P = .022). Drug type was not associated with change in BCVA at 3 months. CONCLUSION: Eyes with neovascular AMD and PED showed significant functional and anatomic response after 3 monthly intravitreal anti-VEGF injections. The functional response depended on baseline BCVA, presence of subretinal fluid, and retinal angiomatous proliferation, while anatomic response was influenced by baseline PED height, degree of vascularization, and drug type. Drug type was not associated with change in BCVA, but had a weak effect on anatomic response.

PEC1/AtABCG32 transport function in cuticle biosynthesis

Most aerial parts of the plants are covered by a hydrophobic coating called cuticle. The cuticle is formed of cutin, a complex mixture of esterified fatty acids that are embedded and associated with waxes. The cuticle often appears as a superposition of layers of different composition: The cuticle proper formed of cutin and a mixture of waxes and underneath, the cuticle layer containing cutin, intracuticular waxes and polysaccharides of the cell wall. In addition to its involvement in plant development by preventing organ fusions, the cuticle acts as a barrier to prevent water loss and protect plants against environmental aggressions such as excessive radiation or pathogens attacks. PEC1/AtABCG32 is an ABC transporter from the PDR family involved in cutin biosynthesis. Characterization of the peci mutant in Arabidopsis thaliana showed that PEC1 plays a significant role in the diffusion barrier formation in leaves and petals. The cuticles of leaves and flowers of peci are permeable and the cuticular layer rather than the cuticular proper was altered in the petals, underlining the importance of this particular layer in the maintenance of the diffusion barrier. Chemical analysis on the flower cutin monomer composition of ped mutant revealed a decrease in hydroxylated cutin monomers, suggesting a function of PEC1 in the incorporation of these monomers in the polymer cutin. However, the exact nature of the substrates of PEC1 remained elusive. PEC1 homologues in barley and rice, respectively HvABCG31/EIBI1 and OsABCG31, are also implicated in cuticle biosynthesis. Interestingly, the rice mutant displays more severe phenotypes such as dwarfism and spreading necrosis conducting to the seedling death. In this work, we further characterized osabcg31 mutant and hairpin-RNAi downregulated OsABCG31 plant lines showing reduced growth and cuticle permeability. Our analysis showed a decrease in hydroxylated cutin monomers and severe disruptions in the cuticle, which explain the permeability. Further insights into the function of the cuticle in rice resistance/susceptibility to Pathogens were obtained after inoculation with Magnaporthe oryzae, the fungus responsible for the rice blast disease. Osabcg31 as well as the transgenic lines downregulating OsABCG31 showed increased resistance to the fungus. However, only later steps of infection are reduced . and no impact is obseived on the germination or penetration stages, suggesting that the cuticle disruption per se is not responsible for the resistance. We further investigated the cause of the resistance by analyzing the expression of defense related gene in osabcg31 prior to infection. We found that osabcg31 constitutively express defense related genes, which may explain the resistance, the dwarfism and the cell death. osabcg31 is thus a tool to study the connection between cuticle, plant development and defense signaling networks in rice. The transport function of PEC1 family members is still unknown. In order to link cutin biosynthesis and transport activity, we combined ped mutation with mutations in cutin synthesis related genes. Here, we show that PEC1 acts independently from GPAT4 and GPAT8 pathway and partially overlaps with GPAT6 biosynthesis pathway that leads to the production of hydroxylated C16 cutin precursor 2-Mono(10,16-dihydroxyhexadecanoylJglycerol (2-MHG). In addition, we noticed that despite a comparable cutin monomer composition, ped mutant leaves cuticle are permeable while that of gpat6 mutant are not. This finding raises the possibility of PEC1 being required for the incorporation of C16 hydroxylated monomers and their structural arrangement rather than their direct transport towards the cuticle. A careful investigation of the cuticle permeability, cutin composition and ultrastructure during leave development in Wt plants and ped mutants revealed a possible different regulation of several pathways of cutin biosynthesis and showed the importance of PEC1 function early during leave cuticle maturation. In order to elucidate the transport activity of PEC1, we successfully expressed PEC1 in Nicotiana benthamiana plant system for direct transport experiments. This system will be used to test the PEC 1-dependent transport of potential substrates such as sn-2-monoacylglycerol loaded with a hydroxylated C16 fatty acid. -- Toutes les parties aériennes des plantes sont recouvertes d'une couche hydrophobe appelée «cuticule». Cette cuticule est composée de cutine, un polymère d'acides gras estérifiés, et de cires. La cuticule apparaît souvent sous forme de couches superposées: une première couche extérieure appelée «cuticle proper» formée de cutine et d'un mélange de cires, et une deuxième couche, la «cuticle layer», formée de cutine associée à des cires intracuticulaires et des polysaccharides pariétaux. La cuticule joue le rôle de barrière prévenant contre la perte d'eau et les agressions environnementales. AtABCG32/PEC1 est un transporteur ABC de la famille des PDR impliqué dans la synthèse de la cutine. L'étude du mutant peci d'Arabidopsis thaliana a révélé une fonction de PEC1 dans la formation de la barrière de diffusion. La cuticule des feuilles et fleurs de peci est perméable. Des altérations de la «cuticle layer» ont été démontrées, soulignant son importance dans le maintien de la barrière. L'analyse de la composition de la cutine de peci a montré une réduction spécifique en monomères hydroxylés, suggérant un rôle de PEC1 dans leur incorporation dans la cuticule. Cependant, la nature exacte des substrats de PEC1 n'a pas été identifiée. PEC1 possède deux homologues chez l'orge et le riz, respectivement HvABCG31 et OsABCG31, et qui sont impliqués dans la biosynthèse de la cuticule. Chez le riz, des phénotypes plus sévères ont été observés tels que nanisme et nécroses conduisant à la mort des jeunes plants. Dans cette étude, nous avons continué la caractérisation de osabcg31 ainsi que des lignées de riz sous exprimant le gène OsABCG31 et présentant une cuticule perméable tout en ayant une meilleure croissance. Notre étude a démontré une réduction des monomères hydroxylés de cutine et une désorganisation de la structure de la cuticule, aggravée dans le mutant osabcg31. Ce résultat explique la perméabilité observée. Des mformations P|us approfondies sur l'implication de la cuticule dans la résistance aux pathogènes ont été obtenues après inoculation du mutant osabcg31 et les lignées sous- exprimant OsABCG31 avec une souche virulente de Magnaporthe Oryzae, le champignon responsable de la pyriculariose du riz. Les différentes lignées testées ont démontré une résistance au pathogène. Cependant, seules les étapes tardives de l'infection sont réduites et aucun impact n'est observé sur la germination des spores ou la pénétration du champignon, suggérant que les modifications de la cuticule ne sont pas directement à l'origine de la résistance. L'analyse de l'expression de gènes impliqués dans la résistance à Magnaporthe.oryzae a mis en évidence l'expression constitutive de ces gènes en l'absence de tout contact avec le pathogène. Ceci explique la résistance, le nanisme et la mort cellulaire observés. Ainsi, osabcg31 représente un outil efficace pour l'étude intégrée des systèmes de régulation de la défense, de développement des plantes et la cuticule. La nature des substrats transportés par PEC1/AtABCG32 reste inconnue. Dans le but d'établir une liaison entre biosynthèse de cutine et transport des précurseurs par PEC1, la mutation peci a été combinée avec des mutants impliqués dans différentes voies de biosynthèse. Cette étude a démontré une fonction indépendante de PEC1 de la voie de biosynthèse impliquant les enzymes GPAT4 et GPAT8, et une fonction partiellement indépendante de la voie impliquant GPAT6 qui mène à la production de précurseurs sn-2- monoacylglycerol chargés en acides gras en C16 (2-MHG). De plus, malgré un profil similaire en monomères de cutine, gpat6 conserve une cuticule imperméable alors que celle de PEC1 est perméable. Ceci suggère que PEC1 est nécessaire à l'incorporation des monomères en C16 et leur arrangement structurel plutôt que simplement à leur transport direct. L'étude approfondie de la perméabilité cuticulaire, de la structure ainsi que de la composition en cutine pendant le développement des feuilles de peci et la plante sauvage a révélé l'existence de différentes régulations des voies de biosynthèses des monomères et a démontré l'importance de PEC1 dans les premières étapes de la mise en place de la cuticule. Pour identifier les substrats transportés, l'expression de PEC1 chez le système hétérologue Nicotiana benthamiana a été conduite avec succès. Ce système sera utilisé pour tester le transport de substrats potentiels tels que le sn-2-monoacylglycerol chargé en acide gras en C16.