Little is known about which components of the axonal cytoskeleton might break during rapid mechanical deformation, such as occurs in traumatic brain injury. Here, we micropatterned neuronal cell cultures on silicone membranes to induce dynamic stretch exclusively of axon fascicles. After stretch, undulating distortions formed along the axons that gradually relaxed back to a straight orientation, demonstrating a delayed elastic response. Subsequently, swellings developed, leading to degeneration of almost all axons by 24 h. Stabilizing the microtubules with taxol maintained the undulating geometry after injury but greatly reduced axon degeneration. Conversely, destabilizing microtubules with nocodazole prevented undulations but greatly increased the rate of axon loss. Ultrastructural analyses of axons postinjury revealed immediate breakage and buckling of microtubules in axon undulations and progressive loss of microtubules. Collectively, these data suggest that dynamic stretch of axons induces direct mechanical failure at specific points along microtubules. This microtubule disorganization impedes normal relaxation of the axons, resulting in undulations. However, this physical damage also triggers progressive disassembly of the microtubules around the breakage points. While the disintegration of microtubules allows delayed recovery of the "normal" straight axon morphology, it comes at a great cost by interrupting axonal transport, leading to axonal swelling and degeneration.

Outpatients with HFrecEF have a different clinical course than patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and fewer composite end points. These patients may need to be investigated separately in outcomes studies and clinical trials.

As a common feature of many neurological diseases and injury, the loss of axon pathways can have devastating effects on function. Here, we demonstrate a new strategy to restore damaged axon pathways using transplantable miniature constructs consisting of living neurons and axonal tracts internalized within hydrogel tubes. These hydrogel microconduits were developed through an iterative process to support neuronal survival and directed axon growth. The design included hollow agarose tubes providing a relatively stiff outer casing to direct constrained unidirectional outgrowth of axons through a central soft collagen matrix, with overall dimensions of 250 μm inner diameter ×500 μm outer diameter and extending up to several centimeters. The outer casing was also designed to provide structural support of neuronal/axonal cultures during transplantation of the construct. Using neuron culture conditions optimized for the microconduits, dissociated dorsal root ganglia neurons were seeded in the collagen at one end of the conduits. Over the following week, high-resolution confocal microscopy demonstrated that the neurons survived and the somata remained in a tight cluster at the original seeding site. In addition, robust outgrowth of axons from the neurons was found, with axon fascicles constrained in a longitudinal projection along the internal collagen canal and extending over 5 mm in length. Notably, this general geometry recapitulates the anatomy of axon tracts. As such, these constructs may be useful to repair damaged axon projections by providing a transplantable bridge of living axons. Moreover, the small size of the construct permits follow-on studies of minimally invasive transplantation into potentially sensitive regions of the nervous system.

Microwave ablation is an effective and safe treatment technique for painful spinal metastases. Further studies may be helpful in determining the role of microwave ablation in locoregional control of metastases.

Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-β42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-β42 formation by direct inhibition of the γ-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptorγ (PPARγ) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. Ibuprofen activates PPARγ in neuron-like PC12 and B104 cells. Activation of PPARγ with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARγ blocks RhoA suppression of PPARγ agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARγ inhibition. These findings support that PPARγ plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer’s disease.

Neural-electrical interface platforms are being developed to extracellularly monitor neuronal population activity. Polyaniline-based electrically conducting polymer fibers are attractive substrates for sustained functional interfaces with neurons due to their flexibility, tailored geometry and controlled electro-conductive properties. In this study, we addressed the neurobiological considerations of utilizing small diameter (<400 microm) fibers consisting of a blend of electrically conductive polyaniline and polypropylene (PA-PP) as the backbone of encapsulated tissue-engineered neural-electrical relays. We devised new approaches to promote survival, adhesion and neurite outgrowth of primary dorsal root ganglion neurons on PA-PP fibers. We attained a greater than ten-fold increase in the density of viable neurons on fiber surfaces to approximately 700 neurons mm(-2) by manipulating surrounding surface charges to bias settling neuronal suspensions toward fibers coated with cell-adhesive ligands. This stark increase in neuronal density resulted in robust neuritic extension and network formation directly along the fibers. Additionally, we encapsulated these neuronal networks on PA-PP fibers using agarose to form a protective barrier while potentially facilitating network stability. Following encapsulation, the neuronal networks maintained integrity, high viability (>85%) and intimate adhesion to PA-PP fibers. These efforts accomplished key prerequisites for the establishment of functional electrical interfaces with neuronal populations using small diameter PA-PP fibers-specifically, improved neurocompatibility, high-density neuronal adhesion and neuritic network development directly on fiber surfaces.

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Non-Hispanic blacks undergoing bariatric surgery demonstrate higher in-hospital mortality than their racial counterparts. It is unclear if this disparity is due to susceptibility to obesity-related mortality or suboptimal delivery of healthcare in the perioperative setting.