Long-term whole-body vibration induces degeneration of intervertebral disc and facet joint in a bipedal mouse model.

Background: Whole body vibration (WBV) has been used to treat various musculoskeletal diseases in recent years. However, there is limited knowledge about its effects on the lumbar segments in upright posture mice. This study was performed to investigate the effects of axial Whole body vibration on the intervertebral disc (IVD) and facet joint (FJ) in a novel bipedal mouse model. Methods: Six-week-old male mice were divided into control, bipedal, and bipedal + vibration groups. Taking advantage of the hydrophobia of mice, mice in the bipedal and bipedal + vibration groups were placed in a limited water container and were thus built standing posture for a long time. The standing posture was conducted twice a day for a total of 6 hours per day, 7 days per week. Whole body vibration was conducted during the first stage of bipedal building for 30 min per day (45 Hz with peak acceleration at 0.3 g). The mice of the control group were placed in a water-free container. At the 10th-week after experimentation, intervertebral disc and facet joint were examined by micro-computed tomography (micro-CT), histologic staining, and immunohistochemistry (IHC), and gene expression was quantified using real-time polymerase chain reaction. Further, a finite element (FE) model was built based on the micro-CT, and dynamic Whole body vibration was loaded on the spine model at 10, 20, and 45 Hz. Results: Following 10 weeks of model building, intervertebral disc showed histological markers of degeneration, such as disorders of annulus fibrosus and increased cell death. Catabolism genes' expression, such as Mmp13, and Adamts 4/5, were enhanced in the bipedal groups, and Whole body vibration promoted these catabolism genes' expression. Examination of the facet joint after 10 weeks of bipedal with/without Whole body vibration loading revealed rough surface and hypertrophic changes at the facet joint cartilage resembling osteoarthritis. Moreover, immunohistochemistry results demonstrated that the protein level of hypertrophic markers (Mmp13 and Collagen X) were increased by long-durationstanding posture, and Whole body vibration also accelerated the degenerative changes of facet joint induced by bipedal postures. No changes in the anabolism of intervertebral disc and facet joint were observed in the present study. Furthermore, finite element analysis revealed that a larger frequency of Whole body vibration loading conditions induced higher Von Mises stresses on intervertebral disc, contact force, and displacement on facet joint. Conclusion: The present study revealed significant damage effects of Whole body vibration on intervertebral disc and facet joint in a bipedal mouse model. These findings suggested the need for further studies of the effects of Whole body vibration on lumbar segments of humans.

Changes of adjacent segment biomechanics after anterior cervical interbody fusion with different profile design plate: single- versus double-level.

Low-profile angle-stable spacer Zero-P is claimed to reduce the morbidity associated with traditional plate and cage construct (PCC). Both Zero-P and PCC could achieve comparable mid- and long-term clinical and radiological outcomes in anterior cervical discectomy and fusion (ACDF). It is not clear whether Zero-P can reduce the incidence of adjacent segment degeneration (ASD), especially in multi-segmental fusion. This study aimed to test the effect of fusion level with Zero-P versus with PCC on adjacent-segment biomechanics in ACDF. A three-dimensional finite element (FE) model of an intact C2-T1 segment was built and validated. Six single- or double-level instrumented conditions were modeled from this intact FE model using Zero-P or the standard PCC. The biomechanical responses of adjacent segments at the cephalad and caudal levels of the operation level were assessed in terms of range of motion (ROM), stresses in the endplate and disc, loads in the facets. When comparing the increase of adjacent-segment motion in single-level PCC fusion versus Zero-P fusion, a significantly larger increase was found in double-level fusion condition. The fold changes of PCC versus Zero-P of intradiscal and endplate stress, and facet load at adjacent levels in the double-level fusion spine were significantly larger than that in the single-level fusion spine during the sagittal, the transverse, and the frontal plane motion. The increased value of biomechanical features was greater at above segment than that at below. The fold changes of PCC versus Zero-P at adjacent segment were most notable in flexion and extension movement. Low-profile device could decrease adjacent segment biomechanical burden compared to traditional PCC in ACDF, especially in double-level surgery. Zero-P could be a good alternative for traditional PCC in ACDF. Further clinical/in vivo studies will be necessary to explore the approaches selected for this study is warranted.

Estrogen receptor ß/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain.

Introduction: Discogenic low back pain (DLBP) is the most commonly described form of back pain. Our previous studies indicated that estrogen-dependent DLBP mechanism was mediated by estrogen receptors (ERs) in the intervertebral disc (IVD) tissue, and the IVD degeneration degree is accompanied by downregulation of ERs, particularly ERß. However, the neuropathological mechanisms underlying ERs modulation of DLBP are still not well understood. In this study, we investigated the antinociceptive effects of selective ERß agonists on DLBP-related behavior by regulating substance P in spinal cord and dorsal root ganglia. Methods: Two weeks after ovariectomies, 18-week-old female mice were randomly separated into four groups: control group; DLBP sham surgery plus vehicle group; DLBP plus vehicle group; DLBP plus ERß-specific agonist diarylpropionitrile (DPN) group. Behavioral data was collected including behavioral measures of axial back pain (grip force and tail suspension tests) and radiating hypersensitivity (mechanical sensitivity and cold sensitivity test). Dual label scanning confocal immunofluorescence microscopy was used to observe spatial colocalization of ERß and substance P in spinal cord. Substance P changes in spinal cord and dorsal root ganglia were measured by immunohistochemistry and real-time PCR. Results: ERß activation could improve both axial and radiating behavioral disorders of DLBP. DPN facilitated the decrease of the amount of time in immobility 1 week after agonist administration. At the time point of 3 weeks, DPN group spent significantly less time in immobility than the vehicle group. In the grip strength tests, starting from postoperative week 1-week 3, DPN injection DLBP mice showed more resistance to stretch than the vehicle injection DLBP mice. Significant differences of cold withdrawal latency time were observed between the DLBP plus DPN injection and DLBP vehicle injection groups at 2- and 3-week injection time point. DPN significantly reversed the paw withdrawal threshold of DLBP mice at the time point of 1, 2, and 3 weeks. Substance P colocalized with ERß in spinal dorsal horn, mainly in laminae I and II, a connection site of pain transmission. Substance P levels in dorsal horn and dorsal root ganglia of DLBP group were distinctly increased compared with that of control and DLBP sham group. DPN therapy could decrease substance P content in the dorsal horn and the dorsal root ganglia of DLBP mice compared with that of vehicle-treated DLBP mice. Discussion: Activation of ERß is antinociceptive in the DLBP model by controlling substance P in spinal cord and dorsal root ganglia, which might provide a therapeutic target to manage DLBP in the clinic.

Impact of adjacent pre-existing disc degeneration status on its biomechanics after single-level anterior cervical interbody fusion.

BACKGROUND AND OBJECTIVE: Mechanics and biology may be interconnected and amplify each other during disc degeneration. It remains unknown the influence of pre-existing disc degeneration and its impact on adjacent segment degeneration (ASD) after anterior cervical discectomy and fusion (ACDF). This study aimed to discuss the necessity of including degenerated adjacent segments in single-level ACDF surgery from a biomechanical view. METHODS: A poroelastic C2-T1 finite element model was created and validated. A C5-C6 ACDF model was developed based on this normal model. Moderate C4-C5 disc degeneration was created by appropriately modifying the morphology and tissue material properties in this fusion model. Degenerative morphology was modeled based on Thompson's grading system and Walraevens's scoring system for cervical spine, including disc height, whole disc area, nucleus pulposus (NP) area, endplate sclerosis and curvature. Stresses in disc and endplate and loads in facet joint were computed under moment loads in the fusion models with normal and pre-existing degenerative disc condition. RESULTS: As for the adjacent disc, the stress values in degenerative condition were 7.41%, 5% and 5.26% larger than that in normal situation during extension, axial rotation and lateral bending motion, respectively. The disc stress changes mainly stemmed from annulus fibrosus (AF) tissue, but not NP. In the endplate, stress values of degeneration status were 4.17, 4.35 and 6.06% larger than that of normal condition under axial rotation, lateral bending and extension. The facet load magnitudes of pre-existing degeneration were 11.28, 11.57, 11.78 and 11.42% greater than that of normal condition in flexion, extension, axial rotation and lateral bending motion. CONCLUSION: Pre-existing degenerated disc experience increased biomechanical changes in adjacent segment after single-level ACDF. It may pose a long-term cumulative problem related to biomechanics in cervical spine after fusion. Before surgery, surgeons should be careful about selecting the fusion level.

Substance P Mediates Estrogen Modulation Proinflammatory Cytokines Release in Intervertebral Disc.

Intervertebral disc degeneration (IDD) is a main contributor to low back pain. A close relationship exists between inflammation and pain. Estrogen can affect inflammation and may play a crucial role in IDD and pain. Substance P (SP) can also regulate the expression of pro-inflammatory cytokines in intervertebral disc (IVD). This study aimed to investigate the potential role of SP in estrogen regulation of IDD. Nine-week-old C57BL/6 female mice were divided into four groups as follows: sham surgery (sham), ovariectomy (OVX), ovariectomy plus estrogen replacement therapy (ERT) group (OVX+E2), and ovariectomy, ERT plus neurokinin 1 receptor (NK1R) agonist (OVX+E2+G). Serum E2, body, and uterus weight were recorded. Immunohistochemistry study and quantitative real-time PCR were used for SP, NK1R, IL-1ß, IL-6, and TNF-α examination and comparison in IVD at protein and gene levels. After OVX, the gene and protein expression of TNF-α, IL-1ß, IL-6, SP, and NK1R in NP cells significantly increased compared with the sham group. ERT can reverse these impacts. ERT plays anti-inflammatory and anti-hyperalgesic roles in IDD of OVX mice. The estrogen-induced changes of the pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, are significantly inhibited by NK1R agonists. SP may be a mediator of estrogen regulating pro-inflammatory factors in IDD. Estrogen may affect IVD inflammation through two ways: one is to directly affect the level of pro-inflammatory cytokines and the other is by means of modulation of SP.

Adjacent-level biomechanics after single-level anterior cervical interbody fusion with anchored zero-profile spacer versus cage-plate construct: a finite element study.

BACKGROUND: The development of adjacent segment degeneration (ASD) following ACDF is well established. There is no analytical study related to effects of plate profile on the biomechanics of the adjacent-level after ACDF. This study aimed to test the effects of plate profile on the adjacent-level biomechanics after single-level anterior cervical discectomy and fusion (ACDF). METHODS: A three-dimensional finite element model (FEM) of an intact C2-T1 segment was built and validated. From this intact model, two instrumentation models were constructed with the anchored zero-profile spacer or the standard plate-interbody spacer after a C5-C6 corpectomy and fusion. Motion patterns, the stresses in the disc, the endplate, and the facet joint at the levels cephalad and caudal to the fusion were assessed. RESULTS: Compared with the normal condition, the biomechanical responses in the adjacent levels were increased after fusion. Relative to the intact model, the average increase of range of motion (ROM) and stresses in the endplate, the disc, and the facet of the zero-profile spacer fusion model were slightly lower than that of the standard plate-interbody spacer fusion model. The kinematics ROM and stress variations above fusion segment were larger than that below. The biomechanical features of the adjacent segment after fusion were most affected during extension. CONCLUSIONS: The FE analysis indicated that plate profile may have an impact on the biomechanics of the adjacent-level after a single-level ACDF. The impact may be long-term and cumulative. The current findings may help explain the decreasing incidence of ASD complications in the patients using zero-profile spacer compared with the patients using cage and plate construct.

Efficacy of percutaneous transforaminal endoscopic decompression treatment for degenerative lumbar spondylolisthesis with spinal stenosis in elderly patients.

The efficacy of fusion combined with decompression for the treatment of spinal stenosis with degenerative lumbar spondylolisthesis (DLS) has been debated. Percutaneous transforaminal endoscopic decompression (PTED) under local anesthesia is an ultra-minimally invasive procedure. The present study aimed to evaluate whether PTED is an effective alternative therapy for spinal stenosis associated with DLS in elderly patients. PTED was performed in elderly patients exhibiting lumbar stenosis and low-grade (Meyerding grades I and II) DLS; these patients also exhibited leg-dominant symptoms and had tolerable or absent mechanical back pain. Administration of general anesthesia may be considerably hazardous in patients when combined with comorbid conditions that result from aging. Therefore, the present procedure was performed under local anesthesia. No obvious radiographic lumbar intervertebral instability was identified prior to surgery. Pre- and post-operative visual analogue scale (VAS) score, Oswestry Disability Index (ODI) and walking distance data were collected. The clinical global outcomes following surgery were evaluated using modified MacNab criteria. A total of 18 elderly patients underwent surgery using PTED techniques. The mean follow-up time was 27.7 months (range, 24-33 months) and the mean estimated blood loss was 18.33 ml (range, 10-35 ml). The mean pre-operative ODI, VAS score of the back and VAS score of the leg were 68.2±6.5, 2.8±1.4 and 6.6±1.2, respectively. All average scores improved post-operatively to 31.7±5.2, 1.5±0.6 and 1.7±0.8, respectively, at the latest follow-up. A statistically significant improvement was observed for all scores at 1 month and that the scores remained relatively stable after that. According to modified MacNab criteria, the good-to-excellent rate was 83.3%. Only 1 patient required micro-decompression surgery due to poor rating. The present study indicated that PTED may be an effective alternative therapeutic option for elderly patients with low-grade DLS associated with spinal stenosis. However, PTED techniques continue to evolve and further follow-up studies are required to determine the long-term outcomes of this treatment technique.

The role of estrogen in intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a main contributor to low back and radicular pain, which imposes heavy economic burdens on society. However, the etiology and mechanism of IVDD are complex and still not completely clear. In particular, the role of estrogen in IVDD has not received much attention in recent research, although estrogen plays a crucial role in the metabolic dysfunction of others musculoskeletal structures, such as bone, muscle, and tendon. In this review, we attempt to describe the role of estrogen in IVDD and to summarize the proposed mechanisms in vivo and in vitro, as well as, to outline several interesting questions in this field.

Endoscopic Ventral Decompression for Spinal Stenosis with Degenerative Spondylolisthesis by Partially Removing Posterosuperior Margin Underneath the Slipping Vertebral Body: Technical Note and Outcome Evaluation.

BACKGROUND: Decompression alone is a treatment option in patients with lumbar spinal stenosis (LSS) and degenerative lumbar spondylolisthesis (DLS). This study aims to describe the procedure of percutaneous transforaminal endoscopic ventral decompression technique and to demonstrate the clinical outcomes. METHODS: Two years of retrospective data were collected from 26 patients with predominant unilateral leg pain caused by LSS and low-grade DLS (Meyerding grades I and Ⅱ). All patients underwent endoscopic ventral decompression by removing the posterosuperior margin underneath the slipping vertebral body, combined with dorsal decompression without excessive resection of facet joints. The surgical outcomes were assessed using the visual analog scale (VAS), Oswestry Disability Index (ODI), modified MacNab criteria, and walking distance improvement evaluation. RESULTS: The mean age of the 18 women and 8 men was 69.2 years. The mean preoperative ODI and VAS of the leg and the back scores were 64.7 ± 8.1, 7.0 ± 1.4, and 3.0 ± 1.2, respectively. All mean scores improved postoperatively to 31.4 ± 5.6, 2.4 ± 1.1, and 1.7 ± 1.1 at the final follow-up. In 88.5% of cases, patients' estimated walking distance improved. The outcomes of the modified MacNab criteria showed that 81.3% of patients obtained good-to-excellent rate. There were no statistically significant differences between the percent slip of spondylolisthesis before surgery and at the end of follow-up. CONCLUSIONS: Based on the initial short-term follow-up results, transforaminal endoscopic ventral decompression by partially removing the posterosuperior margin underneath the slipping vertebral body, combined with dorsal decompression, might be an efficient alternative treatment for leg dominant symptoms in patients with LSS and low-grade DLS.

Effects of Low Bone Mineral Status on Biomechanical Characteristics in Idiopathic Scoliotic Spinal Deformity.

BACKGROUND: Low bone mass in patients with adolescent idiopathic scoliosis has been well reported. Poor bone quality was regarded as a new and unique prognostic factor in aggravating curve progression. However, the potential biomechanical correlation between them remains unclear. METHODS: Three-dimensional finite element models of idiopathic scoliotic spine with different bone mineral status were created for axial loading simulation. An axial load of 3 different body weights was applied on different bone mineral mass models. The mechanical responses of the vertebral cortical and cancellous bone, facet joints, end plate, and intervertebral disc were analyzed. RESULTS: Accompanied with the low bone mineral status, thoracic scoliosis produced asymmetric and higher stress in the cortical bone, lumbar facet joints, and end plate at the concave side of the thoracic structure curve. Stress increased in the disc at the apex of the scoliosis, whereas it mildly decreased in the L4-5 and L5-S1 disc. Body weight gain increased the stress in scoliotic spine structures in all bone mineral statues. CONCLUSIONS: Biomechanical simulations indicated that low bone mineral mass might aggravate curve progression and induce more serious lumbar compensatory scoliosis in patients with adolescent idiopathic scoliosis. Weight gain was also a risk factor for curve progression.

Estradiol Alleviates Intervertebral Disc Degeneration through Modulating the Antioxidant Enzymes and Inhibiting Autophagy in the Model of Menopause Rats.

OBJECTIVE: To investigate the effects of menopause on redox balance in the intervertebral disc and to examine whether oxidative stress and autophagy were associated with disc degeneration in menopause rats. METHODS: Thirty female Sprague-Dawley rats were randomly divided into three groups (sham, ovariectomized with vehicle, and ovariectomized with estrogen). At the end of the 3-month treatment, the rats were examined by 3.0 T MRI. Serum estradiol (E2) level was measured. Redox balance of nucleus pulposus was determined by measuring total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH), and oxidized glutathione (GSSG). Transmission electron microscopy (TEM), immunohistochemical staining, and Western blot were used to determine the nucleus pulposus autophagy level. At the same time, Spearman's correlation coefficient was used to describe the relationship between intervertebral disc grade, oxidative stress status, serum E2, and autophagy level. RESULTS: The level of serum E2 was significantly decreased by ovariectomy and can be corrected by the estrogen replacement therapy (ERT). In OVX rats, an increased oxidative stress and high level of autophagy were observed in nucleus pulposus tissue. ERT prevented the intervertebral disc degeneration (IVDD), restored the redox balance, and reduced autophagy level. CONCLUSION: Ovariectomy induced oxidative stress, autophagy, and intervertebral disc degeneration. Autophagy of the intervertebral disc was negatively correlated with oxidative stress, and the level of autophagy can be reduced by ERT through modulating the redox balance and downregulating the autophagy level. Regulating the redox balance of IVD may be a potential therapeutic option for degeneration of the disc in the postmenopausal women.

Estrogen receptors involvement in intervertebral discogenic pain of the elderly women: colocalization and correlation with the expression of Substance P in nucleus pulposus.

Estrogenic modulation of pain is an exceedingly complex phenomenon. However, whether estrogen is involved in discogenic low back pain still remains unclear. Here, immunoreactivity staining technique was used to examine the expression level of the estrogen receptors (ERα and ERß) and a pain related neuropeptide, Substance P in the lumbar intervertebral discs to analyze the relationship between the ERs and Substance P. Nucleus pulposus tissues of 23 elderly female patients were harvested during spinal surgeries and made to detect the immunoreactivity staining of ERα, ERß and Substance P. The colocalization and intensities of ERs and Substance P were explored and evaluated respectively. The correlations between changes of ERα, ERß and Substance P were also assessed.Our results revealed that Substance P colocalized with ERα and ERß both in cytoplasm and nucleus of the nucleus pulposus cells. HSCORE analysis indicated that Substance P negatively correlated with both ERα and ERß expression. Collectively, the crosstalk between ERs and Substance P might exist in the disc tissue. Estrogen-dependent pain mechanism might partly be mediated through ERs and Substance P in the nucleus pulposus of the elderly females. Estrogen and its receptors might be drug targets in discogenic low back pain diseases.

Anesthetic effects of propofol in the healthy human brain: functional imaging evidence.

Functional imaging methods, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have become important tools for studying how anesthetic drugs act in the human brain to induce the state of general anesthesia. Recent imaging studies using fMRI and PET techniques have demonstrated the regional effects of propofol on the brain. However, the pharmacological mechanism of the action of propofol in the intact human central nervous system is unclear. To explore the possible action targets of propofol in the human brain, a systematic review of the literature was performed. The literature search was performed with limiting factors of "propofol," "functional imaging," "positron emission tomography", and "functional magnetic resonance imaging" from 1966 to July 2013 (using Medline, EMBASE, CINAHL and hand searches of references). Studies meeting the inclusion criteria were reviewed and critiqued for the purpose of this literature research. Eighteen researches meeting the inclusion criteria were reviewed in terms of the appropriateness of valuation technique. In the unconscious state, propofol sharply reduces the regional glucose metabolism rate (rGMR) and regional cerebral blood flow (rCBF) in all brain regions, particularly in the thalamus. However, GMR, such as in the occipital, temporal, and frontal lobes, was obviously decreased at a sedative dosage of propofol, whereas, changes in the thalamus were not obvious. Using fMRI, several studies observed a decrease of connectivity of the thalamus versus an increase of connectivity within the pons of the brainstem during propofol-induced mild sedation. During deep sedation, propofol preserves cortical sensory reactivity, the specific thalamocortical network is moderately affected, whereas the nonspecific thalamocortical network is severely suppressed. In contrast, several recent fMRI studies are consistent on the systemic decreased effects of propofol in the frontoparietal network. Accumulating evidence suggest that propofol-induced unconsciousness is associated with a global metabolic and vascular depression in the human brain and especially with a significant reduction in the thalamocortical network and the frontoparietal network.

Estrogen receptor expression in lumbar intervertebral disc of the elderly: gender- and degeneration degree-related variations.

OBJECTIVES: Sexual dimorphism does occur in intervertebral disc (IVD) degeneration. The involvement of estrogen on IVD health has been well reported in recent years. The estrogen receptors (ER) are the main mediators of estrogen action. ER might play specific roles in the sexual variations of the IVD degeneration. METHODS: Thirty-six elderly patients with lumbar disc degeneration were selected and graded using Pfirrmann's system based on MRI images. Differences of ERα and ERß immunoreactivity staining in nucleus pulposus of each sex and degeneration degree were recorded and compared. RESULTS: Both cytoplasmic and nuclear staining of ERα and ERß immunoreactivity were observed in the nucleus pulposus cells. ERα and ERß expression significantly decreased along with the aggravation of IVD degeneration both in males and females. Expression of ERα and ERß protein in nucleus pulposus of males was significantly higher than that of females. CONCLUSIONS: Gender-specific expression of ER might play a part in sexual dimorphism of IVD degeneration. Gender and degeneration condition differences should be taken into account when the effects of estrogen on IVD metabolism are studied further.