Local axonal protection by WldS as revealed by conditional regulation of protein stability
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2015; 112 (33): 10093-10100
The expression of the mutant Wallerian degeneration slow (WldS) protein significantly delays axonal degeneration from various nerve injuries and in multiple species; however, the mechanism for its axonal protective property remains unclear. Although WldS is localized predominantly in the nucleus, it also is present in a smaller axonal pool, leading to conflicting models to account for the WldS fraction necessary for axonal protection. To identify where WldS activity is required to delay axonal degeneration, we adopted a method to alter the temporal expression of WldS protein in neurons by chemically regulating its protein stability. We demonstrate that continuous WldS activity in the axonal compartment is both necessary and sufficient to delay axonal degeneration. Furthermore, by specifically increasing axonal WldS expression postaxotomy, we reveal a critical period of 4-5 h postinjury during which the course of Wallerian axonal degeneration can be halted. Finally, we show that NAD(+), the metabolite of WldS/nicotinamide mononucleotide adenylyltransferase enzymatic activity, is sufficient and specific to confer WldS-like axon protection and is a likely molecular mediator of WldS axon protection. The results delineate a therapeutic window in which the course of Wallerian degeneration can be delayed even after injures have occurred and help narrow the molecular targets of WldS activity to events within the axonal compartment.
View details for DOI 10.1073/pnas.1508337112
View details for Web of Science ID 000359738300028
View details for PubMedCentralID PMC4547231
The role of automatic computer-aided surgical trajectory planning in improving the expected safety of stereotactic neurosurgery
INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY
2015; 10 (7): 1127-1140
Minimal invasion computer-assisted neurosurgical procedures with various tool insertions into the brain may carry hemorrhagic risks and neurological deficits. The goal of this study is to investigate the role of computer-based surgical trajectory planning tools in improving the potential safety of image-based stereotactic neurosurgery.Multi-sequence MRI studies of eight patients who underwent image-guided neurosurgery were retrospectively processed to extract anatomical structures-head surface, ventricles, blood vessels, white matter fibers tractography, and fMRI data of motor, sensory, speech, and visual areas. An experienced neurosurgeon selected one target for each patient. Five neurosurgeons planned a surgical trajectory for each patient using three planning methods: (1) conventional; (2) visualization, in which scans are augmented with overlays of anatomical structures and functional areas; and (3) automatic, in which three surgical trajectories with the lowest expected risk score are automatically computed. For each surgeon, target, and method, we recorded the entry point and its surgical trajectory and computed its expected risk score and its minimum distance from the key structures.A total of 120 surgical trajectories were collected (5 surgeons, 8 targets, 3 methods). The surgical trajectories expected risk scores improved by 76 % ([Formula: see text], two-sample student's t test); the average distance of a trajectory from nearby blood vessels increased by 1.6 mm ([Formula: see text]) from 0.6 to 2.2 mm (243 %). The initial surgical trajectories were changed in 85 % of the cases based on the expected risk score and the trajectory distance from blood vessels.Computer-based patient-specific preoperative planning of surgical trajectories that minimize the expected risk of vascular and neurological damage due to incorrect tool placement is a promising technique that yields consistent improvements.
View details for DOI 10.1007/s11548-014-1126-5
View details for Web of Science ID 000357278000012
View details for PubMedID 25408305
Molecular and Genetic Predictors of Breast-to-Brain Metastasis: Review and Case Presentation.
2015; 7 (1)
Brain metastases are the most common intracranial malignancy, and breast cancer is the second most common cancer to metastasize to the brain. Intracranial disease is a late manifestation of breast cancer with few effective treatment options, affecting 15-50% of breast cancer patients, depending upon molecular subtype. In this review article, we describe the genetic, molecular, and metabolic changes in breast cancer cells that facilitate breast to brain metastasis. We believe that advances in the understanding of breast to brain metastasis pathogenesis will lead to targeted molecular therapies and to improvements in the ability to prospectively identify patients at increased risk for developing intracranial disease.
View details for DOI 10.7759/cureus.246
View details for PubMedID 26180670
View details for PubMedCentralID PMC4494590
Cervical Fracture Stabilization within 72 Hours of Injury is Associated with Decreased Hospitalization Costs with Comparable Perioperative Outcomes in a Propensity Score-Matched Cohort.
2015; 7 (1)
Prior studies have indicated that early decompression of traumatic cervical fractures can be performed safely and is associated with improved outcomes, though the economic impact of the timing of surgery in the American population has not been studied. After adjusting for patient, hospital, and injury confounders, we performed propensity score modeling (PSM) on a large clinical administrative database to determine associated costs depending upon timing of surgery for acute cervical fracture.A total of 3,348 patients with surgically treated, traumatic, cervical fractures were identified. Patients were sorted into early (within 72 hours of admission) and late (beyond 72 hours) surgery groups. PSM was able to match 2,132 early and late surgery patients on age, comorbidity, expected payer, trauma severity, hospital type, urgent admission, and surgical approach. Perioperative complications, mortality, and resource utilization were assessed.Late surgery was more frequently associated with increased age, more comorbidities, higher ICISS score, and non-private insurance. Following PSM matching, there were no significant, preoperative differences between early and late surgery groups. Surgery performed after 72 hours was associated with an increase in in-hospital complications (OR=1.3). The early surgery group was associated with decreased length of stay (11 days vs. 16 days, p <0.0001) and hospital charges ($237,786 v. $282,727, p <0.0001).After controlling for potential confounding differences through PSM matching and multivariate analyses, we found late surgery independently associated with increased in-hospital complications, length of stay, and hospital resource utilization. These data suggest surgery within 72 hours may decrease resource utilization without a corresponding increase in postoperative morbidity.
View details for DOI 10.7759/cureus.244
View details for PubMedID 26180668
View details for PubMedCentralID PMC4494543
Axon degeneration: Molecular mechanisms of a self-destruction pathway
JOURNAL OF CELL BIOLOGY
2012; 196 (1): 7-18
Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.
View details for DOI 10.1083/jcb.201108111
View details for Web of Science ID 000299269000003
View details for PubMedID 22232700
View details for PubMedCentralID PMC3255986