Diffusion Tensor Imaging in Sport-Related Concussion: A Systematic Review Using an a priori Quality Rating System

Diffusion tensor imaging (DTI) of brain white matter (WM) may be useful for characterizing the nature and degree of brain injury after sport-related concussion (SRC) and assist in establishing objective diagnostic and prognostic biomarkers. This study aimed to conduct a systematic review using an a priori quality rating strategy to determine the most consistent DTI-WM changes post-SRC. Articles published in English (until June 2020) were retrieved by standard research engine and gray literature searches (N = 4932), using PRISMA guidelines. Eligible studies were non-interventional naturalistic original studies that conducted DTI within 6 months of SRC in current athletes from all levels of play, types of sports, and sex. A total of 29 articles were included in the review, and after quality appraisal by two raters, data from 10 studies were extracted after being identified as high quality. High-quality studies showed widespread moderate-to-large WM differences when SRC samples were compared to controls during the acute to early chronic stage (days to weeks) post-SRC, including both increased and decreased fractional anisotropy and axial diffusivity and decreased mean diffusivity and radial diffusivity. WM differences remained stable in the chronic stage (2-6 months post-SRC). DTI metrics were commonly associated with SRC symptom severity, although standardized SRC diagnostics would improve future research. This indicates that microstructural recovery is often incomplete at return to play and may lag behind clinically assessed recovery measures. Future work should explore interindividual trajectories to improve understanding of the heterogeneous and dynamic WM patterns post-SRC

Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std β=-0.73; p=0.007) and posterior cingulate (Std β=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin β7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products

µ-Calpain Conversion of Antiapoptotic Bfl-1 (BCL2A1) into a Prodeath Factor Reveals Two Distinct alpha-Helices Inducing Mitochondria-Mediated Apoptosis

Anti-apoptotic Bfl-1 and pro-apoptotic Bax, two members of the Bcl-2 family sharing a similar structural fold, are classically viewed as antagonist regulators of apoptosis. However, both proteins were reported to be death inducers following cleavage by the cysteine protease µ-calpain. Here we demonstrate that calpain-mediated cleavage of full-length Bfl-1 induces the release of C-terminal membrane active α-helices that are responsible for its conversion into a pro-apoptotic factor. A careful comparison of the different membrane-active regions present in the Bfl-1 truncated fragments with homologous domains of Bax show that helix α5, but not α6, of Bfl-1 induces cell death and cytochrome c release from purified mitochondria through a Bax/Bak-dependent mechanism. In contrast, both helices α5 and α6 of Bax permeabilize mitochondria regardless of the presence of Bax or Bak. Moreover, we provide evidence that the α9 helix of Bfl-1 promotes cytochrome c release and apoptosis through a unique membrane-destabilizing action whereas Bax-α9 does not display such activities. Hence, despite a common 3D-structure, C-terminal toxic domains present on Bfl-1 and Bax function in a dissimilar manner to permeabilize mitochondria and induce apoptosis. These findings provide insights for designing therapeutic approaches that could exploit the cleavage of endogenous Bcl-2 family proteins or the use of Bfl-1/Bax-derived peptides to promote tumor cell clearance

Synthesis of P-Stereogenic Phosphines Based on Chiral Aminoalcohols as Chiral Auxiliary.

Part XI, Chapter

Development of acute hydrocephalus does not change brain tissue mechanical properties in adult rats, but in juvenile rats

Introduction Regional changes in brain stiffness were previously demonstrated in an experimental obstructive hydrocephalus juvenile rat model. The open cranial sutures in the juvenile rats have influenced brain compression and mechanical properties during hydrocephalus development and the extent by which closed cranial sutures in adult hydrocephalic rat models affect brain stiffness in-vivo remains unclear. The aims of this study were to determine changes in brain tissue mechanical properties and brain structure size during hydrocephalus development in adult rat with fixed cranial volume and how these changes were related to brain tissue deformation. Methods Hydrocephalus was induced in 9 female ten weeks old Sprague-Dawley rats by injecting 60 μL of a kaolin suspension (25%) into the cisterna magna under anaesthesia. 6 sham-injected age-matched female SD rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before and then at 3 days post injection. T2-weighted anatomical MR images were collected to quantify ventricle and brain tissue cross-sectional areas. MR elastography (800 Hz) was used to measure the brain stiffness (G*, shear modulus). Results Brain tissue in the adult hydrocephalic rats was more compressed than the juvenile hydrocephalic rats because the skulls of the adult hydrocephalic rats were unable to expand like the juvenile rats. In the adult hydrocephalic rats, the cortical gray matter thickness and the caudate-putamen cross-sectional area decreased (Spearman, P < 0.001 for both) but there were no significant changes in cranial cross-sectional area (Spearman, P = 0.35), cortical gray matter stiffness (Spearman, P = 0.24) and caudate-putamen (Spearman, P = 0.11) stiffness. No significant changes in the size of brain structures were observed in the controls. Conclusions This study showed that although brain tissue in the adult hydrocephalic rats was severely compressed, their brain tissue stiffness did not change significantly. These results are in contrast with our previous findings in juvenile hydrocephalic rats which had significantly less brain compression (as the brain circumference was able to stretch with the cranium due to the open skull sutures) and had a significant increase in caudate putamen stiffness. These results suggest that change in brain mechanical properties in hydrocephalus is complex and is not solely dependent on brain tissue deformation. Further studies on the interactions between brain tissue stiffness, deformation, tissue oedema and neural damage are necessary before MRE can be used as a tool to track changes in brain biomechanics in hydrocephalus

Measurement of large strain properties in calf muscles in vivo using magnetic resonance elastography and spatial modulation of magnetization

It is important to measure the large deformation properties of skeletal muscle in vivo in order to understand and model movement and the force-producing capabilities of muscle. As muscle properties are non-linear, an understanding of how the deformation state affects the measured shear moduli is also useful for clinical applications of magnetic resonance elastography (MRE) to muscle disorders. MRE has so far only been used to measure the linear viscoelastic (small strain) properties of muscles. This study aims to measure the shear moduli of human calf muscles under varying degrees of strain using MRE. Nine healthy adults (four males; age range, 25–38 years) were recruited, and the storage modulus G′ was measured at three ankle angle positions: P0 (neutral), P15 (15° plantarflexed) and P30 (30° plantarflexed). Spatial modulation of magnetization (SPAMM) was used to measure the strain in the calf associated with the ankle rotations between P0 to P15 and P0 to P30. SPAMM results showed that, with plantarflexion, there was a shortening of the medial gastrocnemius and soleus muscles, which resulted in an expansion of both muscles in the transverse direction. Strains for each ankle rotation were in the range 3–9% (in compression). MRE results showed that this shortening during plantarflexion resulted in a mean decrease in G′ in the medial gastrocnemius (p = 0.013, linear mixed model), but not in the soleus (p = 0.47). This study showed that MRE is a viable technique for the measurement of large strain deformation properties in vivo in soft tissues by inducing physiological strain within the muscle during imaging