Glial cell line-derived neurotrophic factor influences proliferation of osteoblastic cells

Little is known about the role of neurotrophic growth factors in bone metabolism. This study investigated the short-term effects of glial cell line-derived neurotrophic factor (GDNF) on calvarial-derived MC3T3-E1 osteoblasts. MC3T3-E1 expressed GDNF as well as its canonical receptors, GFRα1 and RET. Addition of recombinant GDNF to cultures in serum-containing medium modestly inhibited cell growth at high concentrations; however, under serum-free culture conditions GDNF dose-dependently increased cell proliferation. GDNF effects on cell growth were inversely correlated with its effect on alkaline phosphatase (ALP) activity showing a significant dose-dependent inhibition of relative ALP activity with increasing concentrations of GDNF in serum-free culture medium. Live/dead and lactate dehydrogenase assays demonstrated GDNF did not significantly affect cell death or survival under serum-containing and serum-free conditions. The effect of GDNF on cell growth was abolished in the presence of inhibitors to GFR α 1 and RET indicating that GDNF stimulated calvarial osteoblasts via its canonical receptors. Finally, this study found that GDNF synergistically increased tumor necrosis factor-α (TNF-α)-stimulated MC3T3-E1 cell growth suggesting that GDNF interacted with TNF-α-induced signaling in osteoblastic cells. In conclusion, this study provides evidence for a direct, receptor-mediated effect of GDNF on osteoblasts highlighting a novel role for GDNF in bone physiology. \ud \u

Development and external validation of a clinical prediction model for functional impairment after intracranial tumor surgery

OBJECTIVE Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized num-bers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impair-ment. METHODS The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of >= 10 points. Two prospective registries in Swit- zerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS In the development (2437 patients, 48.2% male; mean age +/- SD: 55 +/- 15 years) and external validation (2427 patients, 42.4% male; mean age +/- SD: 58 +/- 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, al- though machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

The Age of Striatum Determines the Pattern and Extent of Dopaminergic Innervation: a Nigrostriatal Double Graft Study

In animal models of Parkinson's disease, transplanted fetal mesencephalic dopaminergic neurons can innervate the dopamine-depleted host brain, but it is unclear why large portions of the host striatum are left uninnervated. During normal development, the dopaminergic innervation first occurs in the form of a dense patchy pattern in the striatum, followed by a widespread nerve fiber network. Using intraocular double grafts we have investigated dopaminergic growth patterns initiated when ventral mesencephalic grafts innervate striatal targets. The fetal lateral ganglionic eminence was implanted into the anterior eye chamber. After maturation in oculo, fetal ventral mesencephalon was implanted and placed in contact with the first graft. In other animals the two pieces of tissue were implanted simultaneously. Tyrosine hydroxylase (TH) immunohistochemistry revealed a pattern of dense TH-positive patches throughout the total volume of the striatal grafts in simultaneously transplanted cografts, while a widespread, less dense, pattern was found when mature striatal transplants were innervated by fetal dopaminergic grafts. To investigate which type or types of growth patterns that developed after grafting to striatum in situ of an adult host, fetal ventral mesencephalic tissue was implanted into the lateral ventricle adjacent to the dopamine-lesioned striatum. After maturation of the mesencephalic graft, the fetal lateral ganglionic eminence was implanted into the reinnervated part of the host striatum. TH immunohistochemistry revealed a few nerve fibers within the striatal graft and the growth pattern was of the widespread type. In conclusion, grafted dopaminergic neurons preferably innervate mature striatum with a widespread sparse nerve fiber network, while the innervation of the immature striatum occurs in the form of dense patches. Furthermore, when the patchy pattern is formed, the total volume of the striatal target is innervated while growth of the widespread type terminates prior to reaching distal striatal parts. Thus, the growth pattern seems essential to the final volume that is innervated. Once the widespread growth pattern is initiated, the presence of immature striatum does not change the dopaminergic growth pattern. </jats:p