Diffuse intrinsic pontine glioma: clinical aspects and imaging

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Background for a New Standard on Pass-By Measurement of Combined Roughness, Track Decay Rate and Vibroacoustic Transfer Functions

A measurement method for combined roughness, track decay rates and transfer functions derived from rail vibration during a train pass-by was initially developed in the late nineties [1]. This method was later implemented in software tools [2] and applied in several countries for various purposes [3, 4, 5]. Due to the broad application potential and the need for a common approach, standardisation work has been undertaken since 2011 within the framework of CEN /TC256/WG3. This resulted in a draft CEN Technical Report [6] in 2013, describing the method and providing background information on benchmarks that could serve as a basis for a new standard. In this paper, the scope and the main elements of the method are presented and performance aspects are discussed

Evaluation of the interim measurement protocol for railway noise source description

The Dutch national calculation scheme for railway noise has been declared the default interim method for railway noise calculation by the EU, until the introduction of results from the Harmonoise project. It includes a measurement protocol for determining emission input data in the format suitable for the present calculation scheme. The calculation scheme contains a fixed database of emission data for common Dutch rolling stock. The measurement protocol provides for the addition of emission data of new or foreign rolling stock. This is relevant for the Netherlands, as such rolling stock increasingly appears on the network, but also for other European countries that are going to use the interim method, since emission data for their rolling stock have to be established. The protocol features two procedures. Procedure A allows using the existing fixed database of emission data. Selection of a particular dataset (or 'category') can be based on external appearance of rolling stock (without measurements) or pass-by sound pressure level measurements at a site with known rail roughness. If a user finds that none of the existing data sets properly represent its rolling stock, the optional procedure B is available. This procedure assesses pass-by levels, track and wheel roughness levels. The measurement protocol is based on a type-test-like procedure requiring controlled conditions for the vehicle and track. A measurement campaign has been undertaken to test procedures A and B. This campaign coincided with a Swiss campaign to establish the sound emission of freight vehicles equipped with composite block brakes. The test of the protocol was focussed both on the practicability of the required measurements and on the unambiguity and comprehensiveness of the test. Open questions, findings, resulting conclusions and recommendations regarding the protocol are discussed here

Diffuse intrinsic pontine gliomas: A systematic update on clinical trials and biology

Patients with diffuse intrinsic pontine gliomas (DIPG) have a poor prognosis. Although DIPG constitute only 10-15% of all pediatric brain tumors, they are the main cause of death in this group. Despite 26 clinical trials in newly diagnosed DIPG in the past 5 years (including several targeted agents), there is no clear improvement in prognosis. However, knowledge on DIPG biology is increasing, mainly due to the (re)introduction of biopsies and autopsies, the possibility of gene expression profiling, and the development of in vivo models. Translation of this knowledge into clinical trials in combination with improved drug distribution methods may eventually lead to more effective treatment of this devastating disease. (C) 2011 Elsevier Ltd. All rights reserve

Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8

Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T3and T4uptake, T3metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T3uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity.RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T3; L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations. Copyrigh

Convection enhanced delivery of carmustine to the murine brainstem: A feasibility study

Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG model