Adult Spinal Cord Radial Glia Display a Unique Progenitor Phenotype

Radial glia (RG) are primarily embryonic neuroglial progenitors that express Brain Lipid Binding Protein (Blbp a.k.a. Fabp7) and Glial Fibrillary Acidic Protein (Gfap). We used these transcripts to demarcate the distribution of spinal cord radial glia (SCRG) and screen for SCRG gene expression in the Allen Spinal Cord Atlas (ASCA). We reveal that neonatal and adult SCRG are anchored in a non-ventricular niche at the spinal cord (SC) pial boundary, and express a “signature” subset of 122 genes, many of which are shared with “classic” neural stem cells (NSCs) of the subventricular zone (SVZ) and SC central canal (CC). A core expressed gene set shared between SCRG and progenitors of the SVZ and CC is particularly enriched in genes associated with human disease. Visualizing SCRG in a Fabp7-EGFP reporter mouse reveals an extensive population of SCRG that extend processes around the SC boundary and inwardly (through) the SC white matter (WM), whose abundance increases in a gradient from cervical to lumbar SC. Confocal analysis of multiple NSC-enriched proteins reveals that postnatal SCRG are a discrete and heterogeneous potential progenitor population that become activated by multiple SC lesions, and that CC progenitors are also more heterogeneous than previously appreciated. Gene ontology analysis highlights potentially unique regulatory pathways that may be further manipulated in SCRG to enhance repair in the context of injury and SC disease

Neural Stem/Progenitor Cells from the Adult Human Spinal Cord Are Multipotent and Self-Renewing and Differentiate after Transplantation

Neural stem/progenitor cell (NSPC) transplantation is a promising therapy for spinal cord injury (SCI). However, little is known about NSPC from the adult human spinal cord as a donor source. We demonstrate for the first time that multipotent and self-renewing NSPC can be cultured, passaged and transplanted from the adult human spinal cord of organ transplant donors. Adult human spinal cord NSPC require an adherent substrate for selection and expansion in EGF (epidermal growth factor) and FGF2 (fibroblast growth factor) enriched medium. NSPC as an adherent monolayer can be passaged for at least 9 months and form neurospheres when plated in suspension culture. In EGF/FGF2 culture, NSPC proliferate and primarily express nestin and Sox2, and low levels of markers for differentiating cells. Leukemia inhibitory factor (LIF) promotes NSPC proliferation and significantly enhances GFAP expression in hypoxia. In differentiating conditions in the presence of serum, these NSPC show multipotentiality, expressing markers of neurons, astrocytes, and oligodendrocytes. Dibutyryl cyclic AMP (dbcAMP) significantly enhances neuronal differentiation. We transplanted the multipotent NSPC into SCI rats and show that the xenografts survive, are post-mitotic, and retain the capacity to differentiate into neurons and glia

Missense mutation of Brain Derived Neurotrophic Factor (BDNF) alters neurocognitive performance in patients with mild traumatic brain injury: a longitudinal study

The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen’s d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers

The necrosis-avid small molecule HQ4-DTPA as a multimodal imaging agent for monitoring radiation therapy-induced tumor cell death

textabstractPurpose: Most effective antitumor therapies induce tumor cell death. Non-invasive, rapid and accurate quantitative imaging of cell death is essential for monitoring early response to antitumor therapies. To facilitate this, we previously developed a biocompatible necrosis-avid near-infrared fluorescence (NIRF) imaging probe, HQ4, which was radiolabeled with 111Indium-chloride (111In-Cl3) via the chelate diethylene triamine pentaacetic acid (DTPA), to enable clinical translation. The aim of the present study was to evaluate the application of HQ4-DTPA for monitoring tumor cell death induced by radiation therapy. Apart from its NIRF and radioactive properties, HQ4-DTPA was also tested as a photoacoustic imaging probe to evaluate its performance as a multimodal contrast agent for superficial and deep tissue imaging. Materials and methods: Radiation-induced tumor cell death was examined in a xenograft mouse model of human breast cancer (MCF-7). Tumors were irradiated with three fractions of 9 Gy each. HQ4-DTPA was injected intravenously after the last irradiation, NIRF and photoacoustic imaging of the tumors were performed at 12, 20, and 40 h after injection. Changes in probe accumulation in the tumors were measured in vivo, and ex vivo histological analysis of excised tumors was performed at experimental endpoints. In addition, biodistribution of radiolabeled [111In]DTPA-HQ4 was assessed using hybrid single-photon emission computed tomography-computed tomography (SPECT-CT) at the same time points. Results: In vivo NIRF imagin

CONSORT Flow diagram for Part 1 of clinical study.

<p>Flow diagram of the progress through the phases of enrollment, allocation, follow-up, and data analysis for Part 1 of the clinical study.</p

Autofluorescence detection of clinically-significant bacterial load in wound periphery and off-site areas.

<p><i>A</i>. White light image of a type II diabetic foot ulcer in a 78 y old female. <i>B</i>. Corresponding AF image showing heavy growth of S. aureus in the wound periphery missed by white light imaging. <i>C</i>. White light shows unremarkable areas between toes, while in <i>D</i>. the corresponding AF imaging detected bacterial biofilm, confirmed by microbiology. <i>E</i>. Schematic illustrates different wound locations where fluorescence imaging detected clinically significant bacterial load. <i>F</i>. Comparison of accuracy for correctly detecting clinically-significant bioburden between standard WL and AF imaging in wound bed, wound periphery and off-site areas. <i>Scale bars</i>: <i>A</i>,<i>B</i>. <i>1 cm; C</i>. <i>2 cm</i>, <i>D</i>. <i>1 cm</i>.</p

Photographs of the handheld prototype PRODIGI imaging device and its use for real-time autofluorescence imaging of bacterial load invisible by white light examination.

<p><i>A</i>. Front view of PRODIGI showing wound fluorescence image displayed in real-time on the LCD screen in high definition. <i>B</i>. Back view of PRODIGI showing white light and 405 nm LED arrays providing illumination of the wound, while the fluorescence mission filter is placed in front of the CCD sensor. Inset shows side profile of the device. <i>C-E</i>. Photograph of PRODIGI device used to examine a diabetic foot ulcer with room lights on, in a hard shell carrying case in a typical wound clinic setting, and placed on typical wound care cart, respectively. Room lights are turned off for fluorescence imaging. <i>F</i>. PRODIGI white light image of type II diabetic foot ulcer in a 52 y old male patient. <i>G</i>. Corresponding AF image taken in < 1 sec showing bright red fluorescence of pathogenic bacteria in the wound periphery (yellow arrow) and in ‘off site’ areas (white arrow) away from the primary wound (confirmed by swab microbiology as mainly heavy growth S. aureus). Bacterial fluorescence appears red against a background of green fluorescence from connective tissues of the healthy skin, which provides anatomical context for localizing the bacteria within and around the wound. The bacterial regions were not seen under white-light visualization. <i>H</i>. A magnified view of <i>G</i>. showing S. aureus growing within the fissures of the wound periphery. Bright fluorescent ‘hot spots’ (yellow arrow) illustrate heterogeneity in the distribution of bioburden in the wound periphery. Fluorescence imaging allowed targeted swabbing of bacterial areas not possible by white light visualization. The heavy growth S. aureus growing in the off-site area was invisible by traditional clinical examination. <i>Scale bars</i>: <i>A</i>. <i>2 cm</i>, <i>B</i>. <i>2 cm</i>, <i>C</i>. <i>1 cm</i>.</p