Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity

<p>Abstract</p> <p>Background</p> <p>Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.</p> <p>We have used a clinically relevant model (pig) of BBBD to attempt brain delivery of TALL-104, a human leukemic T cell line. TALL-104 cells are potent tumor killers and have demonstrated potential for systemic tumor therapy. The pig model used is analogous to the clinical BBBD procedure. Cells were injected in the carotid artery after labeling with the MRI T1 contrast agent GdHPDO3A. Contrast CT scans were used to quantify BBBD and MRI was used to detect Gd⁺⁺-loaded cells in the brain. Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed.</p> <p>Results</p> <p>At the concentration used TALL-104 cells were tolerated. Incomplete BBBD did not allow cell entry into the brain. MRI scans at 24 and 48 hours post-injection allowed visualization of topographically segregated cells in the hemisphere that underwent successful BBBD. Perivascular location of TALL-104 was confirmed in the BBBD hemisphere by Cresyl violet and CD8 immunocytochemistry. No significant alteration in CBF or EEG activity was recorded during cell injections.</p> <p>Conclusions</p> <p>Our data show that targeted CNS cell therapy requires blood-brain barrier disruption. MRI-detectable cytotoxic anti-neoplastic cells can be forced to transverse the BBB and accumulate in the perivascular space. The virtual absence of toxicity, the high anti-tumor activity of TALL-104, and the clinical feasibility of human osmotic BBBD suggest that this approach may be adopted to treat brain or spinal cord tumors. In addition, BBBD may favor CNS entry of other cells that normally lack CNS tropism.</p

Value of prominent flow voids without cord edema in the detection of spinal arteriovenous fistulae

Purpose: To determine the prevalence of spinal dural arteriovenous fistulae (SDAVF) in patients presenting with prominent vascular flow voids on imaging without other imaging findings suggestive of SDAVF. Methods: We retrospectively identified patients from January 1, 2005 to March 1, 2012 who underwent spinal angiography for suspected SDAVF with prominent vascular flow voids on prior imaging. We excluded patients with other major spinal pathology or other imaging findings of SDAVF including cord hyperintensity, enhancement, or expansion. We calculated the proportion of patients with positive findings for SDAVF on angiography and evaluated the prevalence of SDAVF for this finding alone and in correlation with clinical findings. Results: 18 patients underwent spinal angiography for prominent flow voids on imaging without other spinal pathology or imaging findings of SDAVF. Three had a SDAVF detected on angiography. The prevalence of SDAVF in this population was low, only 17% (95% CI 6-39%). All of the patients with positive angiography findings had myelopathy, increasing the prevalence to 100% if the additional clinical finding of myelopathy was present. Conclusions: Prominent flow voids without other imaging findings suggestive of SDAVF is poorly predictive of the presence of a SDAVF, unless myelopathy is present clinically. © 2014 Alhilali et al

Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

Objectives.: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods.: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results.: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion.: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes

Stable population structure in Europe since the Iron Age, despite high mobility

Ancient DNA research in the past decade has revealed that European population structure changed dramatically in the prehistoric period (14,000–3000 years before present, YBP), reflecting the widespread introduction of Neolithic farmer and Bronze Age Steppe ancestries. However, little is known about how population structure changed from the historical period onward (3000 YBP - present). To address this, we collected whole genomes from 204 individuals from Europe and the Mediterranean, many of which are the first historical period genomes from their region (e.g. Armenia and France). We found that most regions show remarkable inter-individual heterogeneity. At least 7% of historical individuals carry ancestry uncommon in the region where they were sampled, some indicating cross-Mediterranean contacts. Despite this high level of mobility, overall population structure across western Eurasia is relatively stable through the historical period up to the present, mirroring geography. We show that, under standard population genetics models with local panmixia, the observed level of dispersal would lead to a collapse of population structure. Persistent population structure thus suggests a lower effective migration rate than indicated by the observed dispersal. We hypothesize that this phenomenon can be explained by extensive transient dispersal arising from drastically improved transportation networks and the Roman Empire’s mobilization of people for trade, labor, and military. This work highlights the utility of ancient DNA in elucidating finer scale human population dynamics in recent history