Pathophysiological mechanisms of chronic compressive spinal cord injury due to vascular events.

Cervical spondylotic myelopathy is the main cause of non-traumatic spinal cord injury, with chronic static and/or dynamic compressive spinal cord injury as the unique pathogenesis. In the progression of this condition, the microvascular network is compressed and destroyed, resulting in ischemia and hypoxia. The main pathological changes are inflammation, damage to the blood spinal cord barriers, and cell apoptosis at the site of compression. Studies have confirmed that vascular regeneration and remodeling contribute to neural repair by promoting blood flow and the reconstruction of effective circulation to meet the nutrient and oxygen requirements for nerve repair. Surgical decompression is the most effective clinical treatment for this condition; however, in some patients, residual neurological dysfunction remains after decompression. Facilitating revascularization during compression and after decompression is therefore complementary to surgical treatment. In this review, we summarize the progress in research on chronic compressive spinal cord injury, covering both physiological and pathological changes after compression and decompression, and the regulatory mechanisms of vascular injury and repair.

Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain.

BACKGROUND: Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer's disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. METHODS: Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. RESULTS: Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. CONCLUSIONS: Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

NLRP3-dependent microglial training impaired the clearance of amyloid-beta and aggravated the cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia, is marked by progressive cognitive decline, deposition of misfolded amyloid-ß (Aß) peptide and formation of neurofibrillary tangles. Recently, microglial training has emerged as an important contributor to neurological diseases, which augments the subsequent inflammation. However, how it affects the pathology of AD remains unknown. Here, using a mouse model of sporadic Alzheimer's disease (SAD) induced by streptozotocin injection, we demonstrated that microglial training exacerbated Aß accumulation, neuronal loss, and cognitive impairment. In addition, we injected MCC950 to inhibit NLRP3 activation and used an inducible Cre recombinase to delete the NLRP3 gene in microglia. Inhibition or depletion of microglial NLRP3 could protect against the pathologies of SAD and abolish the effects of microglial training. Our results identified microglial training as an important modifier of neuropathology in SAD and demonstrated that activation of NLRP3 inflammasome contributed to the pathologies and microglial training in SAD. Therefore, NLRP3 could be a potential therapeutic target for SAD treatment.

Ideal T1 laminar screw fixation based on computed tomography morphometry.

BACKGROUND: The application of laminar screws is an alternative fixation for the first thoracic vertebra (T1). This paper is to determine the anatomical characteristics for adequate laminar screw fixation, and present a modified method of sagittal reconstruction of T1 to provide more accurate measurements. METHODS: Computed tomography (CT) images of 62 patients (32 males, 30 females) were used for the analysis. The following parameters of the T-1 lamina were measured using Mimics software: lamina length, axis angle, minimal outer cortical width, cancellous width, minimal outer cortical height, cancellous height, and spinous process height. Right or left modified sagittal reconstructions (parallel to right or left screws) were innovatively used for measurement. RESULTS: There were no significant differences between the left and right sides for each measurement performed (P > 0.05), but significant differences were detected between males and females (P < 0.05). The mean length of the T1 lamina was 32.8 mm of the T1 minimal outer cortical width was 7.4 mm, and 3.8% of males had a minimal outer cortical width < 5 mm, while 8.6% of females had a minimal outer cortical width < 5 mm. The mean minimal outer cortical height was 10.8 mm, and 1.9% of males had a minimal outer cortical height < 9 mm, while 7.7% of females had a minimal outer cortical height < 9 mm. CONCLUSION: This study suggests there are no anatomical limitations for T1 laminar screw placement in most people. The modified sagittal reconstruction method described allows for easy and precise measurement to aid in the insertion of laminar screws in T1, and gives good visualization of laminar screw insertion direction.

Comparison of unilateral versus bilateral percutaneous kyphoplasty for the treatment of patients with osteoporosis vertebral compression fracture (OVCF): a systematic review and meta-analysis.

PURPOSE: To compare the short- and long-term clinical outcomes, operation times, restoration rate, dosage of polymethylmeth-acrylate (PMMA) injected, complications and X-rays exposure frequency between unilateral and bilateral kyphoplasty approaches for the treatment of OVCF. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Randomized or non-randomized controlled trials published up to April 2015 that compared the unilateral and bilateral PKP for the treatment of OVCF were acquired by a comprehensive search in the Cochrane Controlled Trial Register, PubMed, MEDLINE, EMBASE, Web of Science, OVID. Exclusion criteria were patients with neoplastic etiology (metastasis or myeloma), infection, neural compression syndrome, invasive and degenerative disease, traumatic fracture, re-operation, neurological deficits, significant scoliosis and spinal stenosis. The main end points included: operation times, the short- and long-term postoperative Visual Analogue Scale (VAS) scores, the short-term postoperative Oswestry Disability Index (ODI), restoration rate, dosage of PMMA injected, cement leakage, X-ray exposure frequency and postoperative adjacent-level fractures. RESULTS: A total of 8 studies involving 428 patients were included in the meta-analysis. The mean operative time was shorter in the unilateral groups compared with the bilateral groups [P < 0.05, weighted mean difference (WMD) -19.74 (-30.56, -8.92)]. There was no significant difference in the short-term postoperative VAS scores [P > 0.05, WMD 0.03 (-0.34, 0.40)], the long-term postoperative VAS scores between them [P > 0.05, WMD 0.01 (-0.42, 0.45)] and the short-term postoperative ODI [P > 0.05, WMD -0.33 (-2.36, 1.69)] between the two groups. The unilateral approaches required significantly less dosage of PMMA than the bipedicular approaches did [P < 0.05, WMD -1.56 (-1.59, -1.16)]. The restoration rate in the bilateral groups was higher than the unilateral groups [P < 0.05, WMD -7.82 (-12.23, -3.41)]. There was no significant difference in the risk ratio of cement leakage [P > 0.05, RR 0.86 (0.36, 2.06)] and postoperative adjacent-level fractures [P > 0.05, RR 0.91 (0.25, 3.26)] between the two methods. The mean X-ray exposure frequency in the unilateral groups was greater than the bilateral groups [P < 0.05, WMD -5.69 (-10.67, -0.70)]. CONCLUSIONS: A definitive verdict could not be reached regarding which approach is better for the treatment of OVCF. Although unilateral PKP was associated with shorter operative time, less X- ray exposure frequency and dosage of PMMA than bilateral PKP. There was no apparent difference in the short- and long-term clinical outcomes and complications between them. However, bilateral PKP approaches were higher than unilateral PKP in term of the restoration rate. But on account of lack of some high-quality evidence, we hold that amounts of high-quality randomized controlled trials should be required and more complications should be analysed to resolve which surgical approach is better for the treatment of OVCF in the future.

Role of hypoxia-induced VEGF in blood-spinal cord barrier disruption in chronic spinal cord injury.

Chronic spinal cord lesions (CSCL) which result in irreversible neurologic deficits remain one of the most devastating clinical problems. Its pathophysiological mechanism has not been fully clarified. As a crucial factor in the outcomes following traumatic spinal cord injury (SCI), the blood-spinal cord barrier (BSCB) disruption is considered as an important pathogenic factor contributing to the neurologic impairment in SCI. Vascular endothelial growth factor (VEGF) is a multirole element in the spinal cord vascular event. On one hand, VEGF administrations can result in rise of BSCB permeability in acute or sub-acute periods and even last for chronic process. On the other hand, VEGF is regarded to be correlated with angiogenesis, neurogenesis and improvement of locomotor ability. Hypoxia inducible factor-1 (HIF-1) is a primary regulator of VEGF during hypoxic conditions. Therefore, hypoxia-mediated up-regulation of VEGF may play multiple roles in the BSCB disruption and react on functional restoration of CSCL. The purpose of this article is to further explore the relationship among HIF-1, hypoxia-mediated VEGF and BSCB dysfunction, and investigate the roles of these elements on CSCL.

A dosimetry study precisely outlining the heart substructure of left breast cancer patients using intensity-modulated radiation therapy.

The purpose of this study was to evaluate the feasibility of delineating the substructure of the heart by using 64-slice spiral CT coronary angiography (CTA) in breast cancer patients who underwent left breast-conserving surgery, and to compare the dosimetric differences between the targets and organs at risk in the prone and supine positions in intensity-modulated radiation therapy (IMRT) planning. From January to December 2011, ten patients who underwent left breast-conserving surgery were enrolled in this study. CTA was performed in both the supine and prone positions during the simulation, and conventional scanning without CTA was performed at the same time. Image registration was performed for paired image series using a commercially available planning system. In a conventional image series, the clinical target volume (CTV) of the whole breast, planning target volume (PTV), bilateral lungs (L-Lung, R-Lung), spinal cord, contralateral breast (R-Breast), and heart were delineated. In the CTA image series, the left ventricular (LV) and left anterior descending coronary arteries (LAD) and the planning risk volume (LAD-PRV) of the LAD (LAD with a 1 cm margin) were outlined. For each patient, two separate IMRT plans were developed for the supine and prone positions. A total of 20 plans were generated. The following indicators were compared: Dmean and D95 for the PTV; Dmean, V5, and V20 for the left lung; Dmean, V10, V20, V25, V30, and V40 for the heart and its substructures (LAD-PRV, LV); Dmean and V5 for the right lung; and Dmax and Dmean for the right breast. Using CTA to delineate the substructures of the heart is simple and straightforward. Plans for both the prone and supine positions reached the prescribed dose for the PTV without significant differences. Dose distributions were acceptable for both the prone and supine positions. However, the LAD-PRV, LV, heart, and L-Lung received smaller doses in the prone position plans than in the supine position plans. The Dmean values reduced by 445.83 cGy (p = 0.043), 575.00 cGy (p = 0.003), 402.00 cGy (p = 0.039), and 553.33 cGy (p = 0.004) in the LAD-PRV, LV, heart, and L-Lung. In addition, the V25 lessened 12.54% (p = 0.042) and 8.70% (p = 0.019) in the LV and heart, while the V20 was decreased 8.57% (p = 0.042), 15.21% (p = 0.026), 12.59% (p = 0.011), and 10.62% (p = 0.006) in the LAD-PRV, LV, heart, and L-Lung, respectively. Similarly, the V10 and V30 were reduced by 28.31% (p = 0.029) and 5.54% (p = 0.034) in the heart, while the V5 was cut back 27.86% (p = 0.031) in the L-Lung. For most Asian women with average-sized breasts after breast conserving treatment (BCT), prone positioning during IMRT radiation will reduce the dose to the ipsilateral lung, heart, and substructures of the heart, which may reduce the incidence of cardiovascular events after radiotherapy more than radiation therapy performed in a supine position. Using CTA to delineate the substructures of the heart is easy and intuitive. It is cost-effective and highly recommended for breast cancer IMRT. However, the dose-volume limits of the heart substructures remain to be determined.

Value of micro-CT for monitoring spinal microvascular changes after chronic spinal cord compression.

Neurological degeneration can occur after compression of the spinal cord. It is widely accepted that spinal cord compression leads to ischemic lesions and ultimately neurological dysfunction due to a narrowed spinal canal. Therefore, an in-depth understanding of the pathogenesis of spinal cord compression injury is required to help develop effective clinical interventions. In the present study, we propose a new method of quantitative 3D micro-CT to observe microvascular events in a chronic spinal cord compression rat model. A total of 36 rats were divided into two groups: sham control group (n = 12) and compressive spinal cord injury group (n = 24). Rats were scarified at four weeks after surgery. In each group, CD34 micro-vessel immunohistochemical staining was performed in half of the animals, while micro-CT scanning was performed in the other half. Microvessel density (MVD) was measured after immunohistochemical staining, while the vascular index (VI) was measured in 3D micro-CT. In comparison with sham control, abnormal somatosensory evoked potentials (SEP) can be seen in all 24 cases of the compression group, and VI shows the amount of microvessels reduced consistently and significantly (p < 0.01). A significant correlation is also found between MVD and VI (r = 0.95, p < 0.01). These data suggest that quantitative 3D micro-CT is a sensitive and promising tool for investigating microvascular changes during chronic compressive spinal cord injury.

Enhanced tumor radiosensitivity by a survivin dominant-negative mutant.

Radiosensitivity of tumors is due to a complex interaction of various factors, it has been reported that survivin also acts as a constitutive and inducible radioresistance factor in a panel of tumor cells and approaches designed to inhibit survivin expression or function may lead to tumor sensitisation to chemical and physical agents. Previously, we found that the plasmid encoding the phosphorylation-defective mouse survivin threonine 34-->alanine mutant complexed to DOTAP-chol liposome (Lip-mS) can suppress murine primary breast carcinoma. However, little is known regarding the biological effect of Lip-mS combined with radiation. The present study was designed to determine whether Lip-mS could enhance the anti-tumor activity of radiation. The Lewis Lung Carcinoma (LLC) cells treated with a combination of Lip-mS and radiation displayed apparently increased apoptosis compared with those treated with Lip-mS or radiation alone. Mice bearing LLC tumors were treated with intravenous injections of Lip-mS and radiation, the combined treatment significantly reduced mean tumor volume compared with either treatment alone. Moreover, the anti-tumor effect of Lip-mS combined with radiation was greater than their additive effect when compared with the expected effect of the combined treatment. These data suggest that inhibition of survivin using a dominant-negative mutant, survivin T34A, could sensitize LLC cells to radiation efficiently and the synergistic anti-tumor activity may in part result from increasing the apoptosis of tumor cells, inhibiting tumor angiogenesis and inducing a tumor-protective immune response in the combined treatment.