Distinguishing grade I meningioma from higher grade meningiomas without biopsy

BACKGROUND: Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas. METHODS: Patients with a pathologic diagnosis of meningioma from 2002-2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades. RESULTS: Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi \u3c 4, no CVA. 4. Postmenopausal, vi \u3c 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas. CONCLUSIONS: Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Analysis of the presynaptic zytomatrix proteins at the photoreceptor ribbon synapses of the mouse retina

Synapsen sind Kontaktstellen von Nervenzellen, an denen die Informations-übertragung von einer Nervenzelle auf die Zielzelle stattfindet. Als erste Synapse im Sehsystem vermittelt die Bandsynapse der Photorezeptoren die Weitergabe von Lichtsignalen an nachgeschaltete Neurone. Sie ist auf die kontinuierliche Transmitter-Freisetzung spezialisiert und eine der leistungsfähigsten und komplexesten chemischen Synapsen des Zentralnervensystems. An der präsynaptischen Seite gewährleistet ein dichtes Proteinnetzwerk – die Zytomatrix der aktiven Zone (CAZ) - die exakte Transmitter-Freisetzung. Die CAZ wird an der Photorezeptor-Bandsynapse in die beiden Module arciforme Dichte und synaptisches Band unterteilt. Anhand einer Bassoon-mutanten Maus konnten diesen beiden Modulen die entsprechenden molekularen Komponenten zugeordnet werden. Bassoon verbindet die beiden Module der Bandsynapse miteinander (Dick et al. 2003; tom Dieck et al. 2005). Unklar ist, welche Protein-Interaktionen für die Stabilität der Bandsynapse sorgen. Kandidaten für einen Komplex mit Bassoon waren Piccolo und RIBEYE am synaptischen Band und CAST an der arciformen Dichte. Zur Klärung dieser Fragestellung wurden im Rahmen dieser Arbeit die Retinae der Piccolo-DeltaEx16-Maus, der Bassoon-mutanten Maus und der CAST-Knockout-Maus auf morphologische und funktionelle Veränderungen untersucht. Bei allen drei Mauslinien wurde eine gestörte Morphologie und Funktion der Bandsynapse erwartet. Überraschenderweise konnten in der Retina der Piccolo-DeltaEx16-Maus weder synaptische noch zelluläre Veränderungen festgestellt werden. Mit Hilfe von Piccolo-Antikörpern, deren antigene Epitope an unterschiedlichen Stellen im Piccolo-Protein lokalisiert sind, wurde biochemisch (Western Blot-Analysen) und immunzytochemisch eine Bandsynapsen-spezifische Piccolo-Isoform identifiziert. Diese Piccolo-Isoform ist in der Piccolo-DeltaEx16-Maus noch vorhanden, wodurch es zu keinem Bandsynapsen-Phänotyp kommt. Im Gegensatz zur Piccolo-DeltaEx16-Maus zeigten die Retinae der Bassoon-mutanten und der CAST-Knockout-Maus zelluläre und synaptische Veränderungen. Bei beiden Mauslinien wachsen die Horizontal- und die Bipolarzellen fortschreitend in die ONL aus. Dabei bilden sich entlang der auswachsenden Fortsätze ektopische Synapsen. Funktionelle ERG-Analysen ergaben eine gestörte Transmission der Photorezeptoren auf die nachfolgenden Bipolar- und Horizontal-Zellen. In der CAST-Knockout-Maus ist die Struktur der Bandsynapse größtenteils erhalten. Sie ist lediglich in ihrer dreidimensionalen Ausdehnung nicht voll entwickelt. Keines der untersuchten Proteine ist bei der CAST-Knockout-Maus in seiner Menge reduziert oder umverteilt. Eine strukturelle Funktion von CAST an der Bandsynapse kann aufgrund dieser Ergebnisse weitgehend ausgeschlossen werden. Es wirkt möglicherweise regulierend auf den Prozess des Dockings und/oder Primings der Transmitter-gefüllten Vesikel. Im Unterschied zur CAST-Knockout-Maus hat die Bandsynapse der Bassoon-mutanten Maus einen dramatischen Phänotyp - die Struktur der Bandsynapse ist gestört und viele der Proteine der arciformen Dichte sind nicht mehr detektierbar oder umverteilt. Aus diesen Ergebnissen wurde für Bassoon eine Struktur- und Bandsynapsen-erhaltende Funktion abgeleitet. Mittels in vitro-Versuchen zu zustandsabhängigen Veränderungen des synaptischen Bandes wurde die Struktur-erhaltende Funktion von Bassoon an der Photorezeptor-Bandsynapse bestätigt. Die Proteine der Bandsynapse konnten anhand dieser Versuche, bei denen die Kalziumkonzentration experimentell erhöht oder verringert wurde, in Proteine mit einem stabilen Verteilungsmuster und solche, deren Verteilung dynamisch veränderlich ist, unterschieden werden. Die Kenntnis des molekularen Aufbaus und die funktionellen Interaktionen der einzelnen Komponenten der Bandsynapse ist eine Grundvoraussetzung für die Erforschung des Wirkungsmechanismus der Bandsynapse in sensorischen Systemen. Weiterführende Analysen wie beispielsweise live imaging-Untersuchungen werden unbedingt notwendig sein, um die Funktion des synaptischen Bandes und seine molekulare Struktur zu ergründen.Signals from neuron to neuron or to other cells are transmitted via synapses. In the visual system the first synapse that conveys the light signal from the photoreceptors to second order neurons is the photoreceptor ribbon synapse. This synapse is one of the most complex and powerful synapses in the central nervous system and specialized for tonic transmitter release. At the presynaptic side a dense network of synaptic proteins called cytomatrix at the active zone (CAZ) assures the high accuracy of synaptic transmission. The CAZ at the photoreceptor ribbon synapse is subdivided into two compartments, the arciform density and the synaptic ribbon compartment. The proteins of the synaptic ribbon and the arciform density were separated with the help of a mutant mouse, which lacks a functional Bassoon protein. The CAZ protein Bassoon links the two compartments at the active zone. The protein interactions ensuring the stability of the ribbon complex are still unknown. Putative molecular links for anchoring the synaptic ribbon to the plasma membrane are between Piccolo and Bassoon and between RIBEYE and Bassoon at the synaptic ribbon side and between CAST and Bassoon at the arciform density side. This thesis addresses the question of molecular interactions at the ribbon synaptic complex by investigating morphological and functional changes in retinae of a Piccolo-DeltaEx16 mouse, a Bassoon mutant mouse and a CAST knockout mouse. In all three mouse lines a disturbed ribbon synapse morphology and function was expected. Surprisingly, the retina of the Piccolo-DeltaEx16 mouse showed neither synaptic nor cellular alterations. Using antibodies against different Piccolo epitopes, a new ribbon specific Piccolo isoform was identified by biochemical and immunocytochemical methods. This isoform is still expressed in the Piccolo-DeltaEx16 mouse and explains why no ribbon synapse phenotype was observed. In contrast to the Piccolo-DeltaEx16 mouse, the Bassoon and the CAST knockout mouse showed cellular and synaptic alterations. Throughout the lifetime of the mice, the horizontal cells and the bipolar cells of both genotypes sprout progressively into the ONL and form ectopic synapses with photoreceptors. Functional ERG analyses showed a perturbed synaptic transmission from the photoreceptors to the second order neurons in the Bassoon mutant and the CAST knockout. The retinal CAST phenotype, however, is not a phenocopy of the Bassoon mutant. Interestingly, the structure of the ribbon synapse is mainly preserved. The ribbon synaptic proteins are correctly localized, although the three dimensional synapse architecture is not fully developed. Obviously, CAST has no structural function at the ribbon synapse. More likely CAST plays a role in the process of vesicle priming and/or docking. In contrast to the CAST knockout the ribbon synapse of the Bassoon mutant mouse shows a dramatic phenotype. The ribbon synaptic structure is completely altered and many of the arciform density proteins are not visibly clustered anymore. These results suggest a structural and maintaining function for Bassoon at the ribbon synapse. Bassoons role in the structural maintenance of the ribbon synapse was confirmed by an in vitro assay investigating state dependent structural changes. By experimentally increasing or decreasing the calcium concentration, the ribbon synaptic proteins were classified into stable proteins or proteins which undergo dynamic changes. Bassoon and the active zone calcium channel subunit alpha1F proved to be the most stably localized proteins at the ribbon synaptic complex. The knowledge of the molecular structure and the functional interactions of the ribbon synaptic components is the basis to unravel the mechanisms of ribbon synapse function in the retina