Zhourui Wu

The Strain at Bone-Implant Interface Determines the Effect of Spinopelvic Reconstruction following Total Sacrectomy: A Strain Gauge Analysis in Various Spinopelvic Constructs

Purpose There is still some controversy regarding the optimal biomechanical concept for spinopelvic stabilization following total sacrectomy for malignancy. Strains at specific anatomical sites at pelvis/sacrum and implants interfaces have been poorly investigated. Herein, we compared and analyzed the strains applied at key points at the bone-implant interface in four different spinopelvic constructs following total sacrectomy; consequently, we defined a balanced architecture for spinopelvic fusion in that situation. Methods Six human cadaveric specimens, from second lumbar vertebra to proximal femur, were used to compare the partial strains at specific sites in a total sacrectomy model. Test constructs included: (1) intact pelvis (control), (2) sacral-rod reconstruction (SRR), (3) bilateral fibular flap reconstruction (BFFR), (4) four-rods reconstruction (FRR), and (5) improved compound reconstruction (ICR). Strains were measured by bonded strain gauges onto the surface of three specific sites (pubic rami, arcuate lines, and posterior spinal rods) under a 500 N axial load. Results ICR caused lower strains at specific sites and, moreover, on stress distribution and symmetry, compared to the other three constructs. Strains at pubic rami and arcuate lines following BFFR were lower than those following SRR, but higher at the posterior spinal rod construct. The different modes of strain distribution reflected different patient’s parameter-related conditions. FRR model showed the highest strains at all sites because of the lack of an anterior bracing frame. Conclusions The findings of this investigation suggest that both anterior bracing frame and the four-rods load dispersion provide significant load sharing. Additionally, these two constructs decrease the peak strains at bone-implant interface, thus determining the theoretical surgical technique to achieve optimal stress dispersion and balance for spinopelvic reconstruction in early postoperative period following total sacrectomy.

Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury

AbstractThe mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

TBI-ACTIVATED AEP IS A NOVEL PROTEASE THAT CONTRIBUTES TO AD ONSET THROUGH C/EBPβ ACTIVATION

contributes to neurodegenerative progression. Specifically, hyperactivation of calpain-1 (CAPN1), a modulary cysteine protease, has been implicated in the early pathogenesis of Alzheimer’s Disease (AD), traumatic brain injury (TBI), and ischemic stroke. Prolonged CAPN1 over-activation indirectly permeabilizes lysosomes, leading to release of cathepsin B (CTSB), a lysosomal cysteine-protease implicated in neurodegeneration. Several reports propose CAPN1 and CTSB as therapeutic targets in AD and TBI, but do not unambiguously provide evidence for a desired strategy, and selectivity for inhibition of CAPN1 over CTSB has been the goal of the most developed program in pharma. We hypothesize that dual CAPN1/CTSB inhibition will afford superior efficacy in AD and TBI over selective inhibition. Methods: Inhibition profiles (potency, selectivity, reversibility) of small molecules were characterized through enzyme kinetic assays. Subsequently, neuroprotection was characterized in neuronal cells using Oxygen Glucose Deprivation (OGD), an in vitro model simulating ischemia-reperfusion injury in stroke. Additional in vitro models using chemical insults were utilized to monitor CAPN1/CTSB substrates with roles in neuroplasticity/neurodegeneration via immunoblots. Finally, selective and dual inhibitors were tested in a mild TBI (mTBI) mouse model. Results: We have identified selective and dual inhibitors and established enzyme inhibition and neuroprotective profiles. All inhibitors were differentially neuroprotective against OGDinduced cell death, depending on the treatment paradigm (pretreatment, ischemia, and reperfusion). Monitoring spectrin breakdown products (CAPN1-specific) identified different pathways of neuronal death with varying neuro-insults. After establishing the selectivity of inhibitors for CAPN1 and CTSB, monitoring of peptide substrate proteolysis confirmed inhibitory effects in neuronal cultures, and allowed selection of inhibitors for further study in vivo. Conclusions: Neuroprotective profiles of selective versus dual CAPN1/CTSB inhibitors in vitro varied, depending on timing of treatment and neuronal insult. In a mouse model of mTBI manifesting cognitive deficit and cytokine surge, benefit was seen in behavioral and biochemical analysis. Further drug development for selective and dual inhibitor strategies will need to overcome limitations in brain bioavailability.