Essential role of the N-terminal region of TFII-I in viability and behavior

Background: GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice. Methods: By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients. Results: Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs. Conclusion: Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

Incorporating features of distribution and progression for automatic Makam classification

Automatic classification of makams from symbolic data is a rarely studied topic. In this paper, first a review of an n-gram based approach is presented using various representations of the symbolic data. While a high degree of precision can be obtained, confusion happens mainly for makams using (almost) the same scale and pitch hierarchy but differ in overall melodic progression, seyir. To further improve the system, first n-gram based classification is tested for various sections of the piece to take into account a feature of the seyir that melodic progression starts in a certain region of the scale. In a second test, a hierarchical classification structure is designed which uses n-grams and seyir features in different levels to further improve the system.

Neuroretinitis: review of the literature and new observations.

Neuroretinitis (NR) is an inflammatory disorder characterized by optic disc edema and subsequent formation of a macular star figure. The underlying pathophysiology involves increased permeability of disc vasculature, but the etiology is not fully defined. In some cases, NR is probably due to an infectious process involving the disc; in others, a postviral or autoimmune mechanism is more likely. Cases can be divided into those in which a specific infectious agent has been identified, those considered idiopathic, and those with recurrent attacks. Some reports have not distinguished among these subgroups, and it is unclear if their clinical features vary. We reviewed the literature and our own patients looking particularly at features that might better distinguish these subtypes. Features common to all 3 groups included age, absence of pain, and fundus appearance. Preceding systemic symptoms were more common in patients with cat scratch disease (CSD) and uncommon in those with recurrence. The pattern and magnitude of visual field loss differed, more commonly confined to the central field in CSD cases and more severe in recurrent cases. Recovery of visual acuity and field was less substantial in recurrent cases even after the initial episode. MRI was usually normal in all 3 groups. Enhancement confined to the optic disc was found in all 3 groups, but enhancement of the retrobulbar optic nerve was seen only in recurrent cases. Findings that are strongly suggestive of CSD include very young age, preceding systemic symptoms, and poor visual acuity but with a small or absent relative afferent pupil defect (RAPD). In contrast, the following are suggestive of idiopathic NR with a high risk of recurrence: absence of systemic symptoms, visual field defect outside the central field, preserved visual acuity with a large RAPD, and poor recovery of vision. Decisions regarding evaluation and treatment should be made with these features in mind.

Development of the first disease activity index for eosinophilic esophagitis: update on the EEsAI in 2012

Background and Aims: The international E EsAI s tudy g roup is currently d eveloping the first activity index ( EEsAI) specific for E osinophilic Esophagitis (EoE). G oal: T o develop, e valuate and validate the EEsAI. Methods: T he development c omprises three p hases: 1. Selection of c andidate items ( completed); 2. Evaluation of t he activity index i n a first patient cohort (in progress, p atient recruitment completed); and 3. Validation in a s econd EoE patient cohort. F ocus group interviews with patients were used in p hase 1 to g enerate patient r eported outcomes (PRO) according to g uidelines o f regulatory authorities (FDA a nd EMA), whereas the section of biologic items was developed by Delphi rounds o f international E oE experts from E urope and North America. Results: T he EEsAI has a modular c omposition to a ssess the following components o f EoE activity: p atient r eported outcomes, e ndoscopic activity, histologic activity, laboratory activity, a nd quality of l ife (QoL). Definitions for a ll aspects o f endoscopic and histologic appearance were e stablished by consensus r ounds a mong E oE experts. S ymptom a ssessment tools were c reated that t ake into account d ifferent food consistencies as w ell as f ood avoidance and specific processing strategies. The EEsAI i s currently e valuated in a cohort of a dult EoE patients since M arch 2 011 (patient recruitment completed). Conclusions: The EEsAI standardizes outcome assessment in EoE t rials. T he collaboration with i nternational E oE e xperts a s well as f ollowing o f the guidelines f rom regulatory authorities will lead to its wide applicability.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.