Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: Implication for neuroprotective therapies

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD. Cell Death and Disease (2013) 4, e595; doi:10.1038/cddis.2013.116; published online 18 April 201

A Novel and Freely Available Interactive 3d Model of the Internal Carotid Artery

We describe a new and freely available 3D interactive model of the intracranial internal carotid artery (ICA) and the skull base that also allows to display and compare its main segment classifications. High-resolution 3D human angiography (isometric voxel's size 0.36 mm) and Computed Tomography angiography images were exported to Virtual Reality Modeling Language (VRML) format for processing in a 3D software platform and embedding in a 3D Portable Document Format (PDF) document that can be freely downloaded at http://diposit.ub.edu/dspace/handle/2445/112442 and runs under Acrobat Reader on Mac and Windows computers and Windows 10 tablets. The 3D-PDF allows for visualisation and interaction through JavaScript-based functions (including zoom, rotation, selective visualization and transparentation of structures or a predefined sequence view of the main segment classifications if desired). The ICA and its main branches and loops, the Gasserian ganglion, the petrolingual ligament and the proximal and distal dural rings within the skull base environment (anterior and posterior clinoid processes, silla turcica, ethmoid and sphenoid bones, orbital fossae) may be visualized from different perspectives. This interactive 3D-PDF provides virtual views of the ICA and becomes an innovative tool to improve the understanding of the neuroanatomy of the ICA and surrounding structures

Three-dimensional Magnetic Resonance Image of structures enclosed in the spinal canal relevant to anesthetists and estimation of the lumbosacral CSF volume

Three-dimensional (3D) image-reconstruction of structures inside the spinal canal certainly produces relevant data of interest in regional anesthesia. Nowadays, all hospital MRI equipment is designed mainly for clinical diagnostic purposes. In order to overcome the limitations we have produced more accurate images of structures contained inside the spinal canal using different software, validating our quantitative results with those obtained with standard hospital MRI equipment. Neuroanatomical 3D reconstruction using Amira® software, including detailed manual edition was compared with semi-automatic 3D segmentation for CSF volume calculations by commonly available software linked to the MR equipment (MR hospital). Axial sections from seven patients were grouped in two aligned blocks (T1 Fast Field Eco 3D and T2 Balance Fast Field Eco 3D - resolution 0,65 x 0,65 x 0,65 mm, 130 mm length, 400 sections per case). T2 weighted was used for CSF volume estimations. The selected program allowed us to reconstruct 3D images of human vertebrae, dural sac, epidural fat, CSF and nerve roots. The CSF volume, including the amount contained inside nerve roots, was calculated. Different segmentation thresholds were used, but the CSF volume estimations showed high correlation between both teams (Pearson coefficient = 0.98, p = 0.003 for lower blocks ; Pearson 0.89, p = 0.042 for upper blocks). The mean estimated value of CSF volume in lower blocks (L 3-S1) was 15.8 ± 2.9 ml (Amira® software) and 13.1 ± 1.9 ml (software linked to the MR equipment) and in upper blocks (T11-L2) was 21 ± 4.47 ml and 18.9 ± 3.5 ml, respectively. A high variability was detected among cases, without correlation with either weight, height or body mass index. Aspects concerning the partial volume effect are also discussed. Quick semi-automatic hospital 3D reconstructions give results close to detailed neuroanatomical 3D reconstruction and could be used in the future for individual quantification of lumbosacral CSF volumes and other structures for anesthetic purposes

Modulation of dopamine d1 receptors via histamine h3 receptors is a novel therapeutic target for huntington’s disease

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1 R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1 R over-activation, we present a strategy based on targeting complexes of D1 R and histamine H3 receptors (H3 R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1 R-induced cell death signaling and neuronal degeneration, are mitigated by an H3 R antagonist. We demonstrate that the D1 R-H3 R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3 R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R-H3 R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD

La atención al paciente con patología linfática y lipedema en la pandemia COVID-19. Recomendaciones del Grupo Español de Linfología (GEL)

La pandemia de COVID-19 es un desafío para el manejo de las patologías no COVID como la enfermedad linfática y el lipedema. La telemedicina puede evitar la propagación del coronavirus. Se necesita un sistema que nos ayude a determinar la prioridad clínica y la selección de la asistencia presencial o telemática para cada paciente y la forma de realizarlas durante la pandemia. El Grupo Español de Linfología ha realizado un documento de consenso con recomendaciones basadas en la bibliografía y experiencia clínica, como guía de práctica clínica en el manejo de anomalías linfáticas y lipedema durante la pandemia de COVID-19. Estas recomendaciones deben adaptarse a las características del paciente, las condiciones locales de los centros y las decisiones de los profesionales de la salud. Es un documento de criterios mínimos, sujeto a modificaciones según evolucione la pandemia, los conocimientos científicos y las instrucciones de las autoridades sanitarias