Postoperative screw pullout of severe spondylolisthesis in osteogenesis imperfecta: a case report with 3-year follow-up.

Introduction and importance: Osteogenesis imperfecta (OI) is a rare skeletal disorder characterized by bone fragility and deformities in both paediatric and adult populations. The occurrence of severe spondylolisthesis in OI patients is even more infrequent. However, there is no consensus regarding the optimal treatment approach for OI patients afflicted with severe spondylolisthesis. The selection of surgical procedures and the effective management of postoperative complications present significant challenges in this context. Case presentation: A 30-year-old male patient diagnosed with OI type IV (Sillence classification) underwent the lumbar laminectomy and postero-lateral fusion due to severe spondylolisthesis (grade Ⅲ). Following the surgery, the patient experienced postoperative screw pullout while on bedrest. However, aside from experiencing back pain, there were no neurological symptoms present. To address this issue, the patient received salvage treatment in the form of cast immobilization combined with bisphosphonates. At the 3-year follow-up, the patient exhibited absence of sciatic nerve pain and reported mild numbness in the lower extremities. Moreover, the patient demonstrated the ability to ambulate a distance exceeding 1500 m. Nevertheless, the persistence of sexual dysfunction was observed. Clinical discussion: This study presented the initial instance of surgical complications observed in patients with severe spondylolisthesis and OI. This highlights the importance to exercise meticulous caution and thoroughness when assessing surgical interventions. Conclusion: In cases where the fixation fails to offer adequate biomechanical stability, the administration of bisphosphonates and robust immobilization remains crucial, even in the presence of complications.

0.2-4.0 THz broadband terahertz detector based on antenna-coupled AlGaN/GaN HEMTs arrayed in a bow-tie pattern.

To satisfy the demand for broadband and high-sensitivity terahertz detectors, we designed and verified a broadband terahertz detector built with antenna-coupled AlGaN/GaN high-electron-mobility transistors (HEMTs). Eighteen pairs of dipole antennas with different center frequency from 0.24 to 7.4 THz are arrayed into a bow-tie pattern. The corresponding eighteen transistors have common a source and a drain but different gated channels coupled by the corresponding antennas. The photocurrents generated by each gated channel are combined in the drain as the output port. With incoherent terahertz radiation from a hot blackbody in a Fourier-transform spectrometer (FTS), the detector exhibits a continuous response spectrum from 0.2 to 2.0 THz at 298 K and from 0.2 to 4.0 THz at 77 K, respectively. The results agree well with simulations taking into account the silicon lens, antenna and blackbody radiation law. The sensitivity is characterized under coherent terahertz irradiation, the average noise-equivalent power (NEP) is about 188 p W/H z at 298 K and 19 p W/H z at 77 K from 0.2 to 1.1 THz, respectively. A maximum optical responsivity of 0.56 A/W and a minimum NEP of 7.0 p W/H z at 0.74 THz are achieved at 77 K. The blackbody response spectrum is divided by the blackbody radiation intensity to obtain a performance spectrum, which is calibrated by measuring coherence performance from 0.2 to 1.1 THz to evaluate detector performance at frequencies above 1.1 THz. At 298 K, the NEP is about 1.7 n W/H z at 2.0 THz. At 77 K, the NEP is about 3 n W/H z at 4.0 THz. For further improvements in sensitivity and bandwidth, high-bandwidth coupling components, smaller series resistance, smaller gate lengths and high-mobility materials need to be considered.

Terahertz direct polarization detector based on integrated antenna-coupled AlGaN/GaN high-electron-mobility transistors.

The foundation for polarization-based terahertz applications is the acquisition of polarization information. To develop an all-electronic terahertz straightforward polarization detection system, in this paper, a terahertz polarization detector based on three antenna-coupled AlGaN/GaN high-electron-mobility transistors (HEMTs) on a single chip is designed and fabricated. The function of the direct polarization detector is proven by measuring the polarization angle of linearly polarized continuous-wave terahertz radiation at 216 GHz. The average deviation and maximum deviation of the measured polarization angle are 3.7 degrees and 10 degrees, respectively. The error comes mainly from the disturbance of the local terahertz field by the interference effect. Simulations locate the sources of interference and guide the further device design and packaging of such kind of direct polarization detectors.

Passive terahertz imaging detectors based on antenna-coupled high-electron-mobility transistors.

Aiming at the requirement of passive terahertz imaging, we report a high-sensitivity terahertz detector based on an antenna-coupled AlGaN/GaN high-electron-mobility transistor (HEMT) at 77 K without using low-noise terahertz amplifier. The measured optical noise-equivalent power and the noise-equivalent temperature difference of the detector were about 0.3p W/H z and 370 mK in a 200 ms integration time over a bandwidth of 0.7 - 0.9 THz, respectively. By using this detector, we demonstrated passive terahertz imaging of room-temperature objects with signal-to-noise ratio up to 13 dB. Further improvement in the sensitivity may allow passive terahertz imaging using AlGaN/GaN-HEMT at room temperature.

Human peripheral blood-derived mesenchymal stem cells with NTRK1 over-expression enhance repairing capability in a rat model of Parkinson's disease.

The potency of mesenchymal stem cells (MSCs) for tissue repair and regeneration is mainly based on their ability to secret beneficial molecules. Administration of MSCs has been proposed as an innovative approach and is proved by a number of clinical trials to a certain degree for the therapy of many diseases including Parkinson's disease (PD). However, the efficacy of MSCs alone is not significant. We investigated the effect of neurotrophic tyrosine receptor kinase 1 (NTRK1) overexpressed peripheral blood MSCs (PB-MSCs) on PD rat model. NTRK1 was overexpressed in PB-MSCs, which were then injected into PD rat model, Dopaminergic (DA) neuron regeneration and rotational performance was assessed. We found that DA neuron repair was increased in lesion site, rotational performance was also improved in MSC transplanted PD rat, with most potent effect in NTRK1 overexpressed PB-MSC transplanted PD rat. Our results indicate that overexpression of NTRK1 in MSCs could be an optimized therapeutic way via MSCs for PD treatment.

Cyclooxygenase-2 deficiency causes delayed ossification of lumbar vertebral endplates.

Based on previous findings that cyclooxygenase-2 (COX-2) is a critical molecule in chondrocyte differentiation and skeletal repair, we hypothesized that COX-2 deficiency or inhibition affects the ossification of vertebral endplates (VEP) and degeneration of intervertebral discs (IVD) and thus is involved in the pathogenesis of low back pain (LBP). We aimed to delineate the COX-2 working mechanism and its interacting molecules, and to explore the effect of NSAIDs and selective COX-2 inhibitor on degenerative spinal diseases. Here, lumbar spinal samples harvested from Cox-2 mutant (Cox-2-/-) and wild type (WT) mice were used for histological examinations. Nucleus pulposus (NP) cells isolated from rat were treated with PGE-2. Mouse endplate chondrocytes (mEC) isolated from mice were treated with a recombinant sonic hedgehog (Shh) protein. A mouse IVD organ culture system was established and treated COX-2 inhibitor Celecoxib. Human lumbar endplate chondrocytes were cultured and treated with Celecoxib. Immunohistochemical (IHC) studies were done in the human and mouse VEP samples. Radiographic and histological examinations revealed delayed VEP ossification in Cox-2-/- mice compared to WT ones. Decreased PGE-2 expression was found to promote Shh expression in rat NP cells, while Shh increased noggin expression in mEC. IHC showed that noggin expression was increased while pSmad1 expression decreased in the VEP of Cox-2-/- mice. Human VEP samples from patients with severe IVD degeneration showed decreased expression of Shh and noggin and increased expression of COX-2 and pSmad1 compared with milder cases. In cultured mouse IVDs and human endplate chondrocytes, Celecoxib enhanced expression of Shh and noggin and decreased Smad1 phosphorylation. In conclusion, COX-2/PGE-2 axis plays an important role in VEP ossification and IVD degeneration through crosstalk with Shh and BMP signaling pathways. These findings may facilitate clinical use of COX-2 inhibitor to prevent LBP progression.

Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor­mediated angiogenesis.

Intermittent low­dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X­ray and micro­computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC­derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated­serine/threonine protein kinase (pAKT), hypoxia­inducible factor­1α (HIF1α) and VEGF were significantly decreased in BMSC­derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1α, VEGF, runt­related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC­derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1α/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing.

ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo.

mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo, CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo. CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition.

Interleukin-13 Inhibits Expression of cyp27b1 in Peripheral CD14+ Cells That Is Correlated With Vertebral Bone Mineral Density of Patients With Ulcerative Colitis.

Osteoporosis is a common problem in aged people and those with related diseases, such as inflammatory bowel diseases. Deregulation of vitamin D metabolism plays a role in the pathogenesis of osteoporosis. Micro RNA (miR) can regulate cytokine expression in cells. This study test a hypothesis that inflammatory cytokine interleukin (IL)-13 increases miR-19a to compromise cyp27b1 (a vitamin D hydroxylase) in peripheral CD14+ cells. Bone mineral density of L2-L4 was measured in 20 patients with ulcerative colitis (UC) and 20 healthy subjects. Peripheral CD14+ cells were isolated from healthy people and patients with UC. Expression of cyp27b1 by CD14+ cells was analyzed in the presence or absence of IL-13 in the culture. We observed that bone mineral density (BMD) in UC patients was significantly lower than healthy subjects. The BMD is negatively correlated with miR-19a in peripheral CD14+ cells. MiR-19a in peripheral CD14+ cell was correlated with serum IL-13 in UC patients. Expression of cyp27b1 in peripheral CD14+ cells was correlated with miR-19a and serum IL-13 in UC patients. IL-13 suppressed cyp27b1 expression in CD14+ cells. IL-13 increased expression of miR-19a in CD14+ cells. IL-13 suppresses cyp27b1 expression in peripheral CD14+ cells via up regulating miR-19a expression. J. Cell. Biochem. 118: 376-381, 2017. © 2016 Wiley Periodicals, Inc.

Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function.

Lupus nephritis (LN) is the major clinical manifestation of systemic lupus erythematosus. LN is promoted by T helper 17 (Th17) cells, which are the major pro-inflammatory T cell subset contributing to autoimmunity regulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is critical for suppressing reactive oxygen species (ROS) and relieving oxidant stress by regulating antioxidant gene expression. Previous studies have demonstrated that Nrf2 deficiency promotes drug-induced or spontaneous LN. However, whether NRF2 regulates Th17 function during LN development is still unclear. In this study, we introduced Nrf2 deficiency into a well-known LN model, the B6/lpr mouse strain, and found that it promoted early-stage LN with altered Th17 activation. Th17 cells and their relevant cytokines were dramatically increased in these double-mutant mice. We also demonstrated that naïve T cells from the double-mutant mice showed significantly increased differentiation into Th17 cells in vitro, with decreased expression of the Th17 differentiation suppressor Socs3 and increased phosphorylation of STAT3. Our results demonstrated that Nrf2 deficiency promoted Th17 differentiation and function during LN development. Moreover, our results suggested that the regulation of Th17 differentiation via NRF2 could be a therapeutic target for the treatment of subclinical LN patients.

Identification of Tetraazacyclic Compounds as Novel Potent Inhibitors Antagonizing RORγt Activity and Suppressing Th17 Cell Differentiation.

CD4+ T-helper cells that produce interleukin-17 (Th17 cells) are characterized as pathological T-helper cells in autoimmune diseases. Differentiation of human and mouse Th17 cells requires a key transcription regulator, retinoic acid receptor-related orphan receptor γt (RORγt), which is a potential therapeutic target for autoimmune diseases. To develop a therapeutic agent for Th17-mediated autoimmune diseases, we have established a high-throughput screening (HTS) assay for candidate screening, in which the luciferase activity in RORγt-LBD positive and negative Jurkat cells were analyzed to evaluate induction of RORγt activity by compounds. This technique was applied to screen a commercially-available drug-like chemical compound library (Enamine) which contains 20155 compounds. The screening identified 17 compounds that can inhibit RORγt function in the HTS screen system. Of these, three tetraazacyclic compounds can potently inhibit RORγt activity, and suppress Th17 differentiation and IL-17 production. These three candidate compounds could significantly attenuate the expression of the Il17a by 65%- 90%, and inhibit IL-17A secretion by 47%, 63%, and 74%, respectively. These compounds also exhibited a potent anti-RORγt activity, with EC50 values of 0.25 µM, 0.67 µM and 2.6 µM, respectively. Our data demonstrated the feasibility of targeting the RORγt to inhibit Th17 cell differentiation and function with these tetraazacyclic compounds, and the potential to improve the structure of these compounds for autoimmune diseases therapeutics.

Inhibition of RORγt activity and Th17 differentiation by a set of novel compounds.

BACKGROUND: Retinoic acid receptor-related orphan receptor gamma t (RORγt) is the master regulator of Th17 cell differentiation, which plays a critical role in the pathology of several autoimmune diseases. By directing Th17 cells function, RORγt could be a potential target for drug development for Th17 related autoimmune disease. METHODS: A Jurkat cell-based reporter assay system was used for screening RORγt inhibitors from a drug-like chemical library, following with mouse Th17 cells differentiation study to identify the effect of targeted compounds in primary T cells. 293T cell-based reporter assay was conducted to determine the cell specificity, and MTT assay was performed to determine the cell toxicity of those compounds. RESULTS: In this study, we identified four lead compounds that suppressed RORγt activity, Th17 differentiation and IL-17A secretion. These candidates displayed inhibition ability on RORγt activity in T cell derived Jurkat cell, but not in 293 T cell, which indicated the restricted effects of these compounds to other cells or tissues. Futhermore, our results demonstrated that these candidates exhibited more robust inhibitory on IL-17 F transcription expression than IL-17A, which is different from one reported compound, SR1001, that mainly suppressed IL-17A, rather than IL-17 F production. CONCLUSIONS: Our study discovered four novel compounds that inhibited RORγt activity and Th17 function, which indicates their potential in therapeutic application of Th17 related autoimmune disorders.

Relationship Between Signal Changes on T2-weighted Magnetic Resonance Images and Cervical Dynamics in Cervical Spondylotic Myelopathy.

STUDY DESIGN: Technical note. OBJECTIVE: To determine the correlation between the high-intensity lesions observed on T2-weighted magnetic resonance images (T2W MRI) and the cervical dynamic characteristics of patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Intramedullary high signal intensity is frequently observed on T2W MRI of CSM patients and represents pathologic changes in the spinal cord. However, few studies have attempted to identify the effects on cervical dynamics associated with such changes in MRI signals. METHODS: This study included 71 CSM patients who were admitted to our hospital between May, 2009 and May, 2012 (44 men, 27 women; average age, 52.5±11.7 y). They were divided into 3 groups depending on T2W MRI data: group 1, no hyperintensity; group 2, slight hyperintensity; and group 3, bright hyperintensity. The Cobb angle on cervical flexion-extension radiographs was measured as a parameter of cervical spine dynamics. RESULTS: Total hyperflexion, hyperextension curvature, range of movement (ROM), and segmental hyperflexion curvature did not differ among the groups (P>0.05). Segmental hyperextension curvature and ROM were greater in groups 2 and 3 than in group 1 (P<0.05) but did not differ significantly between groups 2 and 3 (P>0.05). CONCLUSIONS: Increased segmental hyperextension curvature (≥10 degrees) and ROM are risk factors for high-intensity lesions on T2W MRI in CSM patients.

Risk factors for new osteoporotic vertebral compression fractures after vertebroplasty: a systematic review and meta-analysis.

STUDY DESIGN: Literature review and meta-analysis. OBJECTIVE: To perform a systematic review and meta-analysis of risk factors for new osteoporotic vertebral compression fracture (VCF) after vertebroplasty. SUMMARY OF BACKGROUND DATA: New osteoporotic VCF is one of the serious complications of vertebroplasty, and it is important to investigate the risk factors for such VCFs. The risk factors for new VCFs reported so far remain controversial because of limited data and lack of uniform measurements and evaluation. METHODS: We searched the electronic database of PubMed for case-control studies about the risk of new osteoporotic VCFs after vertebroplasty. RESULTS: A total of 116 studies were identified, of which 16 studies including 559 cases and 1736 controls met the inclusion criteria. The significant risk factors for new VCFs were low bone mineral density [BMD; standardized mean difference (SMD), -0.73; 95% confidence interval (CI), -1.26 to -0.20], low body mass index (BMI; SMD, -0.30; 95% CI, -0.51 to -0.10), and intradiscal cement leakage [odds ratio (OR), 2.13; 95% CI, 1.40-2.36]. The significant risk factors for new VCFs adjacent to the treated VCF were low BMD (SMD, -0.43; 95% CI, -0.76 to -0.09), low BMI (SMD, -0.52; 95% CI, -0.81 to -0.22), and intradiscal cement leakage (OR, 2.61; 95% CI, 1.63-4.17). Low BMD, low BMI, intradiscal cement leakage, cement volume, surgical approach, age, sex, and thoracolumbar junction fracture were all not significant risk factors for new VCFs away from the original VCF. Only one study reported dynamic characteristics as risk factors for new VCFs. CONCLUSIONS: The results of this meta-analysis strongly suggested that patients with low BMD, low BMI, and intradiscal cement leakage were at high risk for new VCFs after vertebroplasty, and risk-reduction options should be considered for such patients.