Spatial and temporal changes in promoter activity of the astrocyte glutamate transporter GLT1 following traumatic spinal cord injury.

After traumatic spinal cord injury (SCI), there is an opportunity for preserving function by attenuating secondary cell loss. Astrocytes play crucial roles in the adult CNS and are responsible for the vast majority of glutamate buffering, potentially preventing excitotoxic loss of neurons and oligodendrocytes. We examined spatial and temporal changes in gene expression of the major astrocyte glutamate transporter GLT1 following moderate thoracic contusion SCI using transgenic BAC-GLT1-eGFP promoter reporter mice. In dorsal column white matter, total intensity of GLT1-eGFP expression per region was significantly reduced following SCI at both lesion epicenter and at rostral and caudal areas where no tissue loss occurred. This regional decrease in GLT1 expression was due to significant loss of GLT1-eGFP(+) cells, partially accounted for by apoptosis of eGFP(+) /GFAP(+) astrocytes in both white and gray matter. There were also decreased numbers of GLT1-eGFP-expressing cells in multiple gray matter regions following injury; nevertheless, there was sustained or even increased regional GLT1-eGFP expression in gray matter as a result of up-regulation in astrocytes that continued to express GLT1-eGFP. Although there were increased numbers of GFAP(+) cells both at the lesion site and in surrounding intact spinal cord following SCI, the majority of proliferating Ki67(+) /GFAP(+) astrocytes did not express GLT1-eGFP. These findings demonstrate that spatial and temporal alterations in GLT1 expression observed after SCI result from both astrocyte death and gene expression changes in surviving astrocytes. Results also suggest that following SCI a significant portion of astrocytes lacks GLT1 expression, possibly compromising the important role of astrocytes in glutamate homeostasis.

A Novel, Web-Based Quality Improvement Platform to Address ACGME CLER Requirements.

BACKGROUND: In 2014, the Accreditation Council for Graduate Medical Education (ACGME) formally mandated trainee (resident and fellow) participation in health care quality improvement (QI) projects as one of the Clinical Learning Environment Review (CLER) Pathways to Excellence. Subsequent national reviews showed large variations in how QI education is conducted, as well as a significant mismatch between educational and organizational goals. OBJECTIVE: We developed a web-based platform to engage trainees in QI that better aligned with best practice methodology and matched identified institutional priorities. METHODS: A needs assessment survey was distributed to trainees to understand the obstacles to compliance with ACGME QI requirements. Based on the results, a web-based clearinghouse, called the QI Platform, was developed and launched in July 2016, and utilization was analyzed in February 2019. RESULTS: A total of 196 of 440 needs assessment surveys (45%) were completed. Themes extracted from surveys to identify barriers in QI participation included difficulties designing projects, lack of mentorship or expert support, and difficulty engaging an interprofessional team. Over 2.5 years, 151 projects were registered on the platform. Of these, 17 (11%) were collaborative entries. At the time of analysis, 166 of 437 trainees (38%) were listed as participants in active QI projects. A total of 22 projects were archived as complete, and 68 incomplete projects were reassigned to the "Ideas" section as works in progress after lead trainee graduation. CONCLUSIONS: An institutional QI Platform clearinghouse for GME QI projects was feasible to develop and maintain, and it appeared acceptable to most GME programs and trainees for recording and tracking QI projects, and linking these to hospital QI priorities.

Integrating Adverse Event Reporting Into a Free-Text Mobile Application Used in Daily Workflow Increases Adverse Event Reporting by Physicians.

Adverse event (AE) reporting is a key component of patient safety and physicians are known to underreport. The authors hypothesized that integrating AE reporting into a mobile application used in daily physician workflow would increase physician reporting of AEs. After integrating AE reporting into a free-text mobile application used for daily workflow, the change in AE reporting by physicians was analyzed using Mann-Whitney U tests. AE reporting by physicians increased more than 37-fold (21 to 806; U = 7.5, P < .0001). AE reporting by physicians as a proportion of all AE reports received increased 120-fold (from 0.1% to 12% of all reports, U = 10, P < .0001). Integrating AE reporting into a free-text mobile application used in daily physician workflow markedly increased their reporting of AEs. This approach shifted time burden from physicians to quality officers. Implementation should be coupled with physician education about identifying AEs and content to include in reports.

Stem cell delivery by lumbar puncture as a therapeutic alternative to direct injection into injured spinal cord.

OBJECT: Using cellular transplants to treat spinal cord injury is a promising therapeutic strategy, but transplants grafted directly into the injury site can further damage the already compromised cord. To avoid additional trauma and to simplify translation to the clinic, it is advantageous to use less invasive delivery methods. METHODS: The authors compared the efficacy of intrathecal cell delivery at the lumbar region (lumbar puncture [LP]) to direct injection into a thoracic contusion injury using a mixed population of lineage-restricted neural precursor cells. RESULTS: Direct injection resulted in a higher volume of neural precursor cells located throughout the injury site, whereas fewer LP-delivered cells accumulated at the dorsal aspect of the injured cord. Both grafting methods were neuroprotective, resulting in reduction of injury size and greater tissue sparing compared with controls. Functional recovery was evaluated by assessing motor and bladder function. Animals that received cells via direct injection performed significantly better in the open-field locomotor test than did operated controls, while LP-treated animals showed intermediate recovery of function that did not differ statistically from that of either operated controls or directly injected animals. Bladder function, however, was significantly improved in both directly injected and LP-treated animals. CONCLUSION: Grafting of stem cells via LP resulted in localized accumulation of cells at the injury site, neuroprotection, and modest recovery of function. Further optimization of the LP procedure by increasing the number of cells that are delivered and determining the optimal delivery schedule may further improve recovery to levels comparable to direct injection.

Transplantation of human marrow stromal cells and mono-nuclear bone marrow cells into the injured spinal cord: a comparative study.

STUDY DESIGN: Two groups of 6 rats received dorsolateral funiculotomies followed by direct injection of bone marrow stromal cells (MSC) or mono-nuclear fraction of bone marrow (mnBM). Animals were killed at 4 or 21 days. OBJECTIVE: Cellular transplantation is a promising treatment strategy for spinal cord injury (SCI); however, most cells need to be cultured before transplantation introducing burdensome steps for clinical application. Cells immediately available for transplantation, like mnBM, would be preferable. SUMMARY OF BACKGROUND DATA: Previous studies have shown that MSC transplants promote protection and repair after SCI. MSC are attractive for transplantation because of easy isolation and availability of autologous sources. MSC are derived from whole bone marrow, purified and expanded in culture for a period of at least 2 weeks. Alternatively, mnBM could be used for transplantation. mnBM derived from bone marrow from through simple centrifugation can be reimplantated within hours; however, the presence of immune cells may be problematic. METHODS: Cultured MSC or mnBM from human donors were acutely transplanted into SCI. After sacrifice, spinal cord sections were histologically analyzed for presence of graft-derived immune cells, host immune response, tissue sparing, glial scar formation, and grafting efficacy. RESULTS: mnBM did not give rise to mature immune cells after transplantation into SCI, or evoke an increased host immune response or tissue loss compared to MSC-transplanted animals. In contrast, host macrophage/microglia response was increased early after MSC transplantation, perhaps due to exposure of cells to serum-containing media. The glial scar was less prominent after mnBM transplantation at day 4. At 21 days, differences had subsided and MSC and mnBM macrophage responses and effects on glial scarring were comparable. MSC and mnBM engraftment efficiencies were also similar. CONCLUSION: The use of mnBM is a viable alternative to MSC for transplantation into SCI and may dramatically ease clinical translation.

Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods.

STUDY DESIGN: Three groups of 6 rats received subtotal cervical spinal cord hemisections followed with marrow stromal cell (MSC) transplants by lumbar puncture (LP), intravenous delivery (IV), or direct injection into the injury (control). Animals survived for 4 or 21 days. OBJECTIVE: Cell therapy is a promising strategy for the treatment of spinal cord injury (SCI). The mode of cell delivery is crucial for the translation to the clinic. Injections directly into the parenchyma may further damage already compromised tissue; therefore, less invasive methods like LP or IV delivery are preferable. SUMMARY OF BACKGROUND DATA: Human MSC are multipotent mesenchymal adult stem cells that have a potential for autologous transplantation, obviating the need for immune suppression. Although previous studies have established that MSC can be delivered to the injured spinal cord by both LP and IV, the efficacy of cell delivery has not been directly compared with respect to efficacy of delivery and effects on the host. METHODS: Purified MSC from a human donor were transplanted into the CSF at the lumbar region (LP), into the femoral vein (IV), or directly into the injury (control). After sacrifice, spinal cord sections were analyzed for MSC graft size, tissue sparing, host immune response, and glial scar formation, using specific antibodies and Nissl-myelin staining. RESULTS: LP delivery of MSC to the injured spinal cord is superior to IV delivery. Cell engraftment and tissue sparing were significantly better after LP delivery, and host immune response after LP delivery was reduced compared with IV delivery. CONCLUSION: LP is an ideal minimally invasive technique to deliver cellular transplants to the injured spinal cord. It is superior to IV delivery and, together with the potential for autologous transplantation, lends itself for clinical application.