Time from injury to acute surgery for patients with traumatic cervical spinal cord injury in South-East Norway.

Background: The recommended treatment for cervical spinal cord injury (cSCI) is surgical decompression and stabilization within 24 h after injury. The aims of the study were to estimate our institutional compliance with this recommendation and identify potential factors associated with surgical delay. Methods: Population-based retrospective database study of patients operated for cSCI in 2015-2022 within the South-East Norway Health Region (3.1 million inhabitants). Data extracted were demographics, injury description, management timeline, place of primary triage [local hospital (LH) or neurotrauma center (NTC)]. Main outcome variables were: (1) time from injury to surgery at NTC, (2) time from injury to admission NTC, and (3) time from admission NTC to surgery. Results: We found 243 cSCI patients having acute neck surgery. Their median age was 63 years (IQR 47-74 years), 77% were male, 48% were ≥65 years old. Primary triage at an LH occurred in 150/243 (62%). The median time from injury to acute surgery was 27.8 h (IQR 15.4-61.9 h), and 47% had surgery within 24 h. The median time from injury to NTC admission was 5.6 h (IQR 1.9-19.4 h), and 67% of the patients were admitted to the NTC within 12 h. Significant factors associated with increased time from injury to NTC admission were transfer via LH, severe preinjury comorbidities, less severe cSCI, time of injury other than night, absence of multiple injuries. The median time from NTC admission to surgery was 16.7 h (IQR 9.5-31.0 h), and 70% had surgery within 24 h. Significant factors associated with increased time from NTC admission to surgery were increasing age and non-translational injury morphology. Conclusion: Less than half of the patients with cSCI were operated on within the recommended 24 h time frame after injury. To increase the fraction of early surgery, we suggest the following: (1) patients with clinical suspicion of cSCI should be transported directly to the NTC from the scene of the accident, (2) MRI should be performed only at the NTC, (3) at the NTC, surgery should commence on the same calendar day as arrival or as the first operation the following day.

Odontoid fractures: impact of age and comorbidities on surgical decision making.

BACKGROUND: Surgical fixation is recommended for type II and III odontoid fractures (OFx) with major translation of the odontoid fragment, regardless of the patient's age, and for all type II OFx in patients aged ≥50 years. The level of compliance with this recommendation is unknown, and our hypothesis is that open surgical fixation is less frequently performed than recommended. We suspect that this discrepancy might be due to the older age and comorbidities among patients with OFx. METHODS: We present a prospective observational cohort study of all patients in the southeastern Norwegian population (3.0 million) diagnosed with a traumatic OFx in the period from 2015 to 2018. RESULTS: Three hundred thirty-six patients with an OFx were diagnosed, resulting in an overall incidence of 2.8/100000 persons/year. The median age of the patients was 80 years, and 45% were females. According to the Anderson and D'Alonzo classification, the OFx were type II in 199 patients (59%) and type III in 137 patients (41%). The primary fracture treatment was rigid collar alone in 79% of patients and open surgical fixation in 21%. In the multivariate analysis, the following parameters were significantly associated with surgery as the primary treatment: independent living, less serious comorbidities prior to the injury, type II OFx and major sagittal translation of the odontoid fragment. Conversion from external immobilization alone to subsequent open surgical fixation was performed in 10% of patients. Significant differences the in conversion rate were not observed between patients with type II and III fractures. The level of compliance with the treatment recommendations for OFx was low. The main deviation was the underuse of primary surgical fixation for type II OFx. The most common reasons listed for choosing primary external immobilization instead of primary surgical fixation were an older age and comorbidities. CONCLUSION: Major comorbidities and an older age appear to be significant factors contributing to physicians' decision to refrain from the surgical fixation of OFx. Hence, comorbidities and age should be considered for inclusion in the decision tree for the choice of treatment for OFx in future guidelines.

Predifferentiated brain-derived adult human progenitor cells migrate toward ischemia after transplantation to the adult rat brain.

BACKGROUND: The adult human brain contains neural stem/progenitor cells (AHNPCs) that can survive transplantation into the adult rat brain, migrate toward a lesion, and display limited neuronal differentiation in vivo. OBJECTIVE: To investigate the effect of manipulating AHNPCs before grafting by predifferentiation, ie, initiating neuronal differentiation before transplantation, and to determine whether this cell priming would affect their ability to migrate in vivo. METHODS: AHNPCs were prepared from temporal lobe resections for epilepsy. Seven days after global brain ischemia, predifferentiated AHNPCs (exposed to basic fibroblast growth factor, heparin, and laminin) were transplanted to the left hippocampus. Four and 10 weeks after transplantation, brain sections were analyzed by immunohistochemistry. RESULTS: Transplanted primed cells expressed committed neuronal markers at a much earlier stage compared with nonprimed AHNPCs and were found colabeled with human markers within the damaged CA1 region 4 weeks after grafting. Furthermore, predifferentiated AHNPCs migrated preferentially into an ischemic lesion, similar to their undifferentiated counterparts. The chemoattractant effect from the expression of stromal cell-derived factor-1α (SDF-1α) in ischemic CA1 on AHNPCs expressing CXC chemokine receptor 4 (CXCR4) may explain this preference in migration in vivo. CONCLUSION: The plasticity of neural progenitors derived from the adult human brain may be greater than previously assumed in that manipulation before grafting may influence the phenotypes seen in vivo. The SDF-1α-CXCR4 axis is involved in the targeted migration toward an ischemic lesion in the adult rat brain, similar to previous reports on endogenous progenitors in rats and grafted fetal human neural progenitors.

Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions.

Traditional in vitro culturing of tumor cells has been shown to induce changes so that cultures no longer represent the tumor of origin. Serum-free culturing conditions are used in a variety of cancers to propagate stem-like cells in vitro. Limited reports, however, exist on the effects of such propagation. We have compared cells from brain tumor biopsies cultivated under serum-free conditions at passages 2 and 10 to describe the effects of in vitro culturing. We were able to establish cell lines from 7 of 10 biopsies from patients with glioblastoma. The cell lines adapted to conditions and had 2.2 times increased population doubling rate at later passages. Karyotyping and comparative genomic hybridization analysis revealed that all examined cell lines had cytogenetic aberrations commonly found in glioblastomas, and there were only minor differences between tumor and early and late passages in the same culture. Whole-transcriptome analysis shows that tumors had interindividual differences. Changes in the overall expression patterns through passaging were modest, with a significant change in only 14 genes; the variation among cultures was, however, reduced through passages. The ability to differentiate differed among tumors but was maintained throughout passaging. The cells initiated tumors upon transplantation to immunodeficient mice with differing phenotypes, but a given cell culture maintained tumor phenotype after serial cultivation. The cultures established maintained individual characteristics specific to culture identity. Thus, each cell culture reflects an image of the tumor--or a personalized model--from which it was derived and remains representative after moderate expansion.

A comparison of epithelial and neural properties in progenitor cells derived from the adult human ciliary body and brain.

Cells isolated from the ciliary body (CB) of the adult human eye possess properties of retinal stem/progenitor cells and can be propagated as spheres in culture. As these cells are isolated from a non-neural epithelium which has neuroepithelial origin, they may have both epithelial and neural lineages. Since it is the properties of neural progenitor cells that are sought after in a future scenario of autotransplantation, we wanted to directly compare human CB spheres with neurospheres derived from the human subventricular zone (SVZ), which is the best characterized neural stem cell niche in the CNS of adults. The CB epithelium was dissected from donor eyes (n = 8). Biopsies from the ventricular wall were harvested during neurosurgery due to epilepsy (n = 7). CB and SVZ tissue were also isolated from Brown Norwegian rats. Dissociated single cells were cultivated in a sphere-promoting medium and passaged every 10-30 days. Fixed spheres were studied by immunohistochemistry, quantitative RT-PCR and scanning/transmission electron microscopy. We found that both CB and SVZ spheres contained a mixed population of cells embedded in extracellular matrix. CB spheres, in contrast to SVZ neurospheres, contained pigmented cells with epithelial morphology that stained for cytokeratins (3/12 + 19), were connected through desmosomes and tight-junctions and produced PEDF. Markers of neural progenitors (nestin, Sox-2, GFAP) were significantly lower expressed in human CB compared to SVZ spheres, and nestin positive cells in the CB spheres also contained pigment. There was higher expression of EGF and TGF-beta receptors in human CB spheres, and a comparative greater activation of the canonical Wnt pathway. These results indicate that adult human CB spheres contain progenitor cells with epithelial properties and limited expression of neural progenitor markers compared to CNS neurospheres. Further studies mapping the regulation between epithelial and neural properties in the adult human CB spheres are vital to fully utilize them as a clinical source of retinal progenitor cells in the future.

Isolation of human multipotent neural progenitors from adult filum terminale.

Stem cells have been isolated from several CNS regions, including the spinal cord. However, the terminal end of the spinal cord, filum terminale, has been referred to as a fibrovascular tag without neurogenic potential and of no clinical significance. Recently, we were fortunate to acquire some samples of this tissue. We show for the first time that progenitor cells exhibiting the hallmarks of stem cells can be isolated from adult human filum terminale (FTNPs). More specifically, FTNPs self-renew and proliferate to form neurospheres, and exhibit tripotent differentiation into neurons, astrocytes, and oligodendrocytes. Equally important, FTNPs develop the electrophysiological profile of neurons and glia. Whole-cell patch-clamp recordings show beta-III-tubulin(+) neurons exhibiting overshooting action potentials, displaying both the fast inactivating TTX-sensitive sodium current as well as 4-AP and TEA sensitive potassium currents. To assess potency in vivo, FTNPs were transplanted into the posterior periventricular region of control or ischemic rat brains. Despite a vigorous immune response against the xenograft, FTNPs survived and were found not only in the graft area but had also migrated to the lesioned CA1 region. Notwithstanding the immune response, FTNPs differentiated into astrocytes, but no neuronal differentiation was observed in the transplant milieu tested. However, neuronal differentiation in vivo cannot be ruled out and assessment of the conditions necessary to promote neurogenesis in vivo requires more research. Significantly, no tumor formation or aberrant cell morphology was seen in or adjacent to the graft area. Thus, filum terminale provides a novel source of adult human neural progenitor cells that develop into functional neurons with possible clinical applications.

A comparison between stem cells from the adult human brain and from brain tumors.

OBJECTIVE: To directly compare stem cells from the normal adult human brain (adult human neural stem cells [AHNSC]), Grade II astrocytomas (AC II), and glioblastoma multiforme (GBM), with respect to proliferative and tumor-forming capacity and differentiation potential. METHODS: Cells were isolated from tissue obtained during epilepsy surgery (AHNSCs) or tumor surgery (glioma stem cells [GSC]). They were cultured and investigated in vitro or after transplantation in immunodeficient mice. RESULTS: Under identical experimental conditions, the following were found: 1) GBM stem cells formed tumors after orthotopic transplantation; AHNSCs showed no sign of tumor formation; 2) GSCs showed a significantly higher growth rate and self-renewal capacity; 3) both the growth rate and telomerase expression were high in GSCs and correlated with malignancy grade (GBM higher than AC II); AHNSCs had low telomerase expression; 4) GSCs invaded normal neurospheres, not vice versa; 5) both AHNSCs and stem cells from AC II and GBM responded to differentiation cues with a dramatic decrease in the proliferation index (Ki-67); 6) GSCs differentiated faster than AHNSCs; 7) upon differentiation, AHNSCs produced normal glia and neurons; GSCs produced morphologically aberrant cells often expressing both glial and neuronal antigens; and 8) differentiation of AHNSCs resulted in 2 typical functional phenotypes: neurons (high electrical membrane resistance, ability to generate action potentials) and glial cells (low membrane resistance, no action potentials). In contrast, GSCs resulted in only 1 functional phenotype: cells with high electrical resistance and active membrane properties capable of generating action potentials. CONCLUSION: AHNSCs and stem cells from AC II and GBM differ with respect to proliferation, tumor-forming capacity, and rate and pattern of differentiation.

Transplantation of stem cells from the adult human brain to the adult rat brain.

OBJECTIVE: To investigate the migration, proliferation, and differentiation of stem cells and neural progenitor cells (NPCs) from the adult human brain after transplantation into adult rodent brains. METHODS: Adult human NPCs were obtained from temporal lobe specimens removed because of medical intractable epilepsy. The cells were transplanted into the posterior periventricular region above the hippocampus in the brains of either healthy adult rats (control) or rats with selective injury of the hippocampal CA1 region (global ischemia). RESULTS: In the control animals, grafted cells were mainly distributed from the site of transplantation toward the midline along white matter tracts. The density of transplanted cells elsewhere, including the hippocampus, was low and apparently random. In animals with CA1 damage, NPCs showed targeted migration into the injured area. Cell survival at 10 weeks was 4.7 +/- 0.3% (control, n = 3) and 3.7 +/- 1.1% (ischemia, n = 3); at 16 weeks, cell survival was 3.4 +/- 0.6% (control, n = 2) and 7.2 +/- 1.5% (ischemia, n = 2), i.e., comparable to what has been observed earlier when transplanting embryonic tissue into the human brain or progenitor cells between inbred rats. The number of dividing cells decreased with time. Sixteen weeks after transplantation, 4 +/- 1% (n = 4) of the cells showed proliferative activity. We did not observe signs of tumor formation or aberrant cell morphology. Neuronal differentiation was much slower than what has been observed earlier in vitro or after transplantation to the developing nervous system, and 16 weeks after transplantation many surviving cells were still in maturation. CONCLUSION: The present study shows that adult human NPCs survive, show targeted migration, proliferate, and differentiate after grafting into the adult rat brain.