Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.
IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients.OBJECTIVE To characterize the transcriptomics of peripheral monocytes in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction. MAIN OUTCOMES AND MEASURESThe differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling. RESULTSThe demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.
Advances in imaging and computer technology have led to the development of different simulation models to complement traditional surgical training. Sophisticated virtual reality (VR) simulators with haptic feedback and impressive imaging technology have provided novel options for training in neurosurgery. Breakthrough training simulation using 3D printing technology holds promise for future simulation practice, proving high-fidelity patient-specific models to complement residency surgical learning.
Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of a constitutively active form of GSK3β enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9+/microtubule-associated protein 2 (MAP2)+ motor neurons in vitro. More importantly, blocking PI3K not only enhances motor neuron differentiation from hNSCs grafted into the ventral horn of adult rat spinal cords, but also permits ectopic generation of motor neurons in the dorsal horn by overriding environmental influences. Our data suggest that FGF2 and EGF affect the motor neuron fate decision in hNSCs differently through a fine tuning of the PI3K/AKT/GSK3β pathway, and that manipulation of this pathway can enhance motor neuron generation.
Variability exists in the incidence of PSIs and HACs in patients with brain tumors based on insurance status. Controlling for both patient and hospital factors can explain these differences. The cause of these disparities should be studied prospectively to begin the process of improving quality metrics in vulnerable patient populations.
This mixed reality simulator provides a real-life experience, and will be an instrumental tool in training the next generation of neurosurgeons. We have now implemented a standard where incoming residents must prove efficiency and skill on the simulator before their first interaction with a patient.
Helmet use in two-wheeled vehicle accidents is widely reported to decrease the rates of death and traumatic brain injury. Previous reports suggest that there exists a trade off with helmet use consisting of an increased risk of cervical spine injuries. Recently, a review of a national trauma database demonstrated the opposite, with reduction in cervical spinal cord injuries in motorcycle crashes (MCC). In 2000, the State of Florida repealed its mandatory helmet law to make helmet use optional for individuals older than 21 with $10,000 of health insurance coverage. To better ascertain the risks of cervical spine injury with non-helmet use in all two-wheeled vehicles, we analyzed the University of Florida level one trauma center experience. We reviewed the Traumatic injury database over a five-year period (January 1, 2005, to July 1, 2010) for all patients involved in two-wheeled vehicle accidents. Patients were stratified according to vehicle type (motorcycle, scooter, and bicycle), helmet use, and the presence or absence of a cervical spine injury. Outcomes were compared for injury severity, cervical spine injury, cervical spinal cord injury, and presence of cervical spine injuries requiring surgery. Population means were compared using paired t-test. A total of 1331 patients were identified: 995 involved in motorcycle accidents, 87 involved in low-powered scooter accidents, and 249 involved in bicycle accidents. Helmet use was variable between each group. One hundred thirty-five total cervical spine injuries were identified. No evidence was found to suggest an increased risk of cervical spine injury or increased severity of cervical spine injury with helmet use. This fact, in combination with our previous findings, suggest that the law's age and insurance exemption should be revoked and a universal helmet law be reinstated in the state of Florida.
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