Safety and risk factors of TINAVI robot-assisted percutaneous pedicle screw placement in spinal surgery.

OBJECTIVE: To determine the rates and risk factors of pedicle screw placement accuracy and the proximal facet joint violation (FJV) using TINAVI robot-assisted technique. METHODS: Patients with thoracolumbar fractures or degenerative diseases were retrospectively recruited from June 2018 and June 2020. The pedicle penetration and proximal FJV were compared in different instrumental levels to identify the safe and risk segments during insertion. Moreover, the factors were also assessed using univariate and multivariate analyses. RESULTS: A total of 72 patients with 332 pedicle screws were included in the current study. The optimal and clinically acceptable screw positions were 85.8% and 93.4%. Of the 332 screws concerning the intra-pedicular accuracy, 285 screws (85.8%) were evaluated as Grade A according to the Gertzbein and Robbins scale, with the remaining 25 (7.6%), 10 (3.0%), 6 (1.8%), and 6 screws (1.8%) as Grades B, C, D, and E. Moreover, in terms of the proximal FJV, 255 screws (76.8%) screws were assessed as Grade 0 according to the Babu scale, with the remaining 34 (10.3%), 22 (6.6%), and 21 screws (6.3%) as Grades 1, 2, and 3. Furthermore, the univariate analysis showed significantly higher rate of penetration for patients with age < 61 years old, sex of female, thoracolumbar insertion, shorter distance from skin to insertion point, and smaller facet angle. Meanwhile, the patients with the sex of female, BMI < 25.9, grade I spondylolisthesis, lumbosacral insertion, longer distance from skin to insertion point, and larger facet angle had a significantly higher rate of proximal FJV. The outcomes of multivariate analyses showed that sex of male (adjusted OR 0.320, 95% CI 0.140-0.732; p = 0.007), facet angle ≥ 45° (adjusted OR 0.266, 95% CI 0.090-0.786; p = 0.017), distance from skin to insertion point ≥ 4.5 cm (adjusted OR 0.342, 95% CI 0.134-0.868; p = 0.024), and lumbosacral instrumentation (adjusted OR 0.227, 95% CI 0.091-0.566; p = 0.001) were independently associated with intra-pedicular accuracy; the L5 insertion (adjusted OR 2.020, 95% CI 1.084-3.766; p = 0.027) and facet angle ≥ 45° (adjusted OR 1.839, 95% CI 1.026-3.298; p = 0.041) were independently associated with the proximal FJV. CONCLUSION: TINAVI robot-assisted technique was associated with a high rate of pedicle screw placement and a low rate of proximal FJV. This new technique showed a safe and precise performance for pedicle screw placement in spinal surgery. Facet angle ≥ 45° is independently associated with both the intra-pedicular accuracy and proximal FJV.

An innovative adjustable prone positioning frame for treatment of severe kyphosis secondary to ankylosing spondylitis with two-level osteotomy.

PURPOSE: This study aims to introduce an innovative adjustable prone positioning frame (APPF) and explore its feasibility and safety for treatment of severe kyphosis secondary to ankylosing spondylitis (AS) with two-level osteotomy. METHODS: A retrospective, non-controlled study was conducted to illustrate the process where 13 patients diagnosed with severe kyphosis secondary to AS received operations on the APPF. Parameters of chin brow vertical angle (CBVA), global kyphosis (GK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL) and sagittal vertical axis (SVA) were measured. Positioning time, operation time, intraoperative blood loss ahd complications were also determined. The Scoliosis Research Society outcomes instrument (SRS-22) was applied for clinical assessment. RESULTS: All patients were placed on the APPF successfully with the positioning time of 2.92 ± 0.76 min, received operation with 457.00 ± 88.04 min and had blood loss of 2330.77 ± 1423.25 ml. Four cases experienced pain due to tensional skin of the abdomen and one case suffered cerebrospinal fluid leakage postoperatively, but these patients were all cured conservatively. No neurological complications were observed, although sagittal translation occurred in four patients. Significant improvements were detected in CBVA, GK, TLK, LL and SVA postoperatively (P < 0.05), but no significant difference was observed between postoperation and the final follow-up (P > 0.05). The SRS-22 scores at 2 years after operation were significantly higher than those before operation (P < 0.05). CONCLUSION: The innovative APPF provided great convenience to place patients with severe kyphosis secondary to AS in a prone position. Performing two-level osteotomy with the aid of APPF is safe, feasible and effective.

The Rates and Risk Factors of Intra-Pedicular Accuracy and Proximal Facet Joint Violation for Single-Level Degenerative Lumbar Diseases: Cortical Bone Trajectory Versus Traditional Trajectory Pedicle Screw.

STUDY DESIGN: A retrospective study. OBJECTIVE: To compare the accuracy of pedicle screw placement and proximal facet joint violation (FJV) in single-level degenerative lumbar diseases using cortical bone trajectory (CBT) and traditional trajectory (TT) techniques, and analyze their possible risk factors. SUMMARY OF BACKGROUND DATA: CBT screws have been utilized increasingly to improve cortical bone contact to prevent screw pullout and reduce approach-related morbidity. However, the studies on intra-pedicular accuracy and proximal FJV between the two methods are rare. METHODS: A total of 40 patients who required single-level instruments were included in the retrospective study treated with the CBT-TLIF and the TT-TLIF at a 1:1 ratio from March 2019 to August 2020. The radiographic outcomes were the intra-pedicular accuracy and proximal FJV. Moreover, the possible risk factors were assessed using bivariate and multivariate analyses. RESULTS: As for the intra-pedicular accuracy, 73 screws (91.3%) were classified as grade A, 7 screws (8.7%) classified as grade B in the CBT group. A total of 71 screws (88.8%) were graded A with remaining 8 screws (10.0%) graded B and 1 screw (1.2%) graded C in the TT group. The proportion of optimal and clinically acceptable screw positions in the two groups were not significantly different (P > 0.05). In addition, the rate of proximal FJV in CBT approach (8.3%) was significantly lower than that in the TT approach (35.0%) (P < 0.001). Multivariate analysis showed the TT insertion approach and facet angle ≥45° were the independent risk factors for proximal FJV, but no factors above affected intra-pedicular accuracy. CONCLUSION: Compared with the TT approach in TLIF, the CBT approach showed similar intra-pedicular accuracy and remarkable superiority in proximal facet joint protection. Facet angle ≥45° is the independent risk factors for proximal FJV.Level of Evidence: 2.

Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases.

Reactive oxygen species (ROS) are essential in regulating various physiological functions. However, overproduction of ROS is implicated in the pathogenesis of various inflammatory diseases. Antioxidant therapy has thus represented an effective strategy for the treatment of oxidative stress relevant inflammatory diseases. Conventional anti-oxidative agents showed limited in vivo effects owing to their non-specific distribution and low retention in disease sites. Over the past decades, significant achievements have been made in the development of antioxidant nanotherapies that exhibit multiple advantages such as excellent pharmacokinetics, stable anti-oxidative activity, and intrinsic ROS-scavenging properties. This review provides a comprehensive overview on recent advances in antioxidant nanotherapies, including ROS-scavenging inorganic nanoparticles, organic nanoparticles with intrinsic antioxidant activity, and drug-loaded anti-oxidant nanoparticles. We highlight the biomedical applications of antioxidant nanotherapies in the treatment of different inflammatory diseases, with an emphasis on inflammatory bowel disease, cardiovascular disease, and brain diseases. Current challenges and future perspectives to promote clinical translation of antioxidant nanotherapies are also briefly discussed.

Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of ß-amyloid peptide.

BACKGROUND: Brain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes ß-amyloid (Aß) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aß to reduce the amount of cytotoxic Aß oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aß content and the number of amyloid plaques. METHOD: In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of ß-amyloid (Aß). We further verified the binding of ZGM1 to Aß42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aß under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aß. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. RESULTS: ZGM1 can bind with Aß directly and mediate a new Aß assembly process to form reticular aggregates and reduce the amount of Aß oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aß plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. CONCLUSION: Our research suggests that promoting Aß aggregation is a promising treatment method for AD and deserves further investigation.

New vertebral fractures after osteoporotic vertebral compression fracture between balloon kyphoplasty and nonsurgical treatment PRISMA.

BACKGROUND: Because of aging of population, osteoporotic vertebral compression fracture (OVCF) appears an increasing incidence rate. Conservative therapy (CT) and balloon kyphoplasty (BKP) have been used to treat OVCFs. However, an increase in new vertebral compression fractures at nontreated levels following BKP is of concern. It is still not clear whether new fractures were a result of BKP and the purpose of this meta-analysis was to evaluate the new fractures risk after BKP compared with CT. METHODS: An exhaustive literature search of PubMed, EMBASE, and the Cochrane Library was conducted to identify randomized controlled trials and prospective nonrandomized controlled study that compared BKP with CT for patients suffering OVCF. A random-effect model was used. Results were reported as standardized mean difference or risk ratio with 95% confidence interval. RESULTS: Twelve studies were included and there was no significant difference in total new fractures (P = .33) and adjacent fractures (P = .83) between 2 treatments. Subgroup analyses did not demonstrate significant differences in follow-up period, mean age, anti-osteoporosis therapy, and the proportion of women. CONCLUSION: Our systematic review revealed that an increased risk of fracture of vertebral bodies was not associated with BKP compared with CT.

Biomechanical Fixation Properties of the Cortical Bone Trajectory in the Osteoporotic Lumbar Spine.

OBJECTIVE: Selecting optimal strategies for improving fixation in osteoporotic lumbar spine is an important issue in clinical research. Cortical bone trajectory (CBT) screws have been proven to enhance screw pullout strength, but biomechanical efficacy of these screws remains understudied. The aim of this study was to evaluate biomechanical efficacy of CBT screws in osteoporotic lumbar spine. METHODS: Thirty-one vertebrae from 14 cadaveric lumbar spines were obtained. All specimens were measured by computed tomography; the diameter of pedicles, excluding those of vertebral bodies with very small pedicle developments, was calculated. After measuring bone mineral density, the CBT screw was randomly inserted into 1 side, and the traditional trajectory (TT) screw was inserted into the contralateral side. Maximum insertional torque was recorded after screw insertion. Of vertebrae, 21 were subjected to pullout testing at a rate of 5 mm/minute, and 10 were subjected to cyclic fatigue testing. Each construct was loaded until exceeding 5 mm. RESULTS: Average bone mineral density was 0.567 ± 0.101 g/cm2. CBT screws had higher maximum insertional torque (degrees of freedom = 30, t = 5.78, P < 0.001, 0.333 N-m vs. 0.188 N-m) and higher axial pullout strength (degrees of freedom = 20, t = 7.41, P < 0.001, 394 N vs. 241 N) than TT screws. Increased bone mineral density was not significantly associated with higher pullout load. Compared with TT screws, CBT screws showed better resistance to fatigue testing and required more cycles to exceed 5 mm (degrees of freedom = 9, t = 5.62, P < 0.001, 6161 cycles vs. 3639 cycles). Failure load for displacing screws was also significantly greater for CBT screws than for TT screws (degrees of freedom = 9, t = 5.75, P < 0.001, 443 N vs. 317 N). CONCLUSIONS: CBT screws had better biomechanical fixation in osteoporotic lumbar spine compared with standard pedicle screws.

Posterior osteosynthesis with monoaxial lateral mass screw-rod system for unstable C1 burst fractures.

BACKGROUND CONTEXT: Surgical treatment for unstable atlas fractures has evolved in recent decades from C1-C2 or C0-C2 fusion to motion-preservation techniques of open reduction and internal fixation (ORIF). However, regardless of a transoral or a posterior approach, the reduction is still not satisfactory. PURPOSE: The article describes and evaluates a new technique for treating unstable atlas fractures by using a monoaxial screw-rod system. STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: The sample includes adult patients with unstable C1 fractures treated with a posterior monoaxial screw-rod system. OUTCOME MEASURES: The outcome measures included a visual analog pain scale, radiographic reduction (lateral mass displacement [LMD]), maintenance of reduction, C1-C2 instability (anterior atlantodens interval), and complications. MATERIALS AND METHODS: From August 2013 to May 2016, nine consecutive patients with unstable atlas fractures were retrospectively reviewed. All patients were treated with posterior ORIF by using a monoaxial screw-rod system. The medical records and the preoperative and postoperative radiographs were reviewed. Preoperative and postoperative computed tomography scans were used to specify the fracture types and to assess the reduction. RESULTS: All nine patients with a mean age of 50.3 years successfully underwent surgery with this technique, and a follow-up of 17.4±9.3 months was performed. Transverse atlantal ligament (TAL) injury was found in eight of the nine patients: one of type I and seven of type II. The preoperative LMD averaged 7.0±2.2 mm and was restored completely after surgery; all the fractures achieved bony healing without loss of reduction or implant failure. None of the patients had complications of neurologic deficit, vertebral artery injury, or wound infection associated with the surgical procedure. Two patients complained of greater occipital nerve neuralgia after the operation, which gradually disappeared in 1 month. All patients had a well-preserved range of motion of the upper cervical spine at the final follow-up. CONCLUSIONS: Posterior osteosynthesis with a monoaxial screw-rod system is capable of an almost anatomical reduction for the unstable atlas fractures. The TAL incompetence may not be a contraindication to ORIF for C1 fractures, but the long-term effect of C1-C2 instability remains to be further investigated.

Activation of Toll-like receptors by intestinal microflora reduces radiation-induced DNA damage in mice.

Activation of Toll-like receptors (TLRs) signaling by intestinal microflora-derived bacterial products plays a key role in injury defence for the host. We investigated the role of TLRs activated by intestinal microflora in radiation-induced DNA damage in mice. We analyzed DNA damage induced by 2Gy γ-ray radiation in an intestinal commensal bacteria-depleted mouse model (CD group), in which TLRs (TLR2/6, TLR4 and TLR5) ligand levels in serum were reduced. Chromosomal aberrations were measured in bone marrow cells and peripheral blood leukocyte comet assays were performed. DNA damage was increased in the CD group compared with the control group. Treatment of mice with TLR agonists (CBLB502, LPS and lipopeptide) 1h before radiation resulted in a significant decrease in DNA damage. Genes induced by TLR5 activation were analyzed; activation of TLRs regulated the expression of Gadd45b, Sod2, and Rad21, which are involved in DNA damage repair. In summary, our data indicate that TLRs activation by intestinal microflora reduces DNA damage induced by radiation and regulates expression of several DNA repair genes.

Surgical management of the fractures of axis body: indications and surgical strategy.

PURPOSE: The axis body fractures are relatively uncommon and have a variety of presentations. Surgical management to them has been only reported as case reports or included as a minor part of clinical management. The objective of this study is to summarize the indications for surgery and report the clinical outcome of surgical treatment based on different fracture patterns. METHODS: A retrospective analysis of 28 consecutive patients presenting with the axis body fractures was undertaken. The indications for surgical treatment were defined as: (1) fractures associated with instability of adjacent joints; (2) irreducible displaced superior articular facet fracture; (3) fractures resulting in spinal cord compression. The fractures were classified as sagittal, coronal, transverse and lateral mass fracture. One of the following surgical procedures was applied according to the fracture pattern: posterior C1-C2 pedicle screws fixation and fusion (I); posterior C1-C3 screws fixation and fusion (II); posterior osteosynthesis with C2 transpedicular half-thread lag screws (III). RESULTS: 13 patients were successfully managed operatively. Two transverse and two unilateral lateral mass fractures were treated with surgical procedure I, five sagittal fractures with II, four coronal fractures with III. Complications of malposition of screws and neurologic deficit did not occur during operation. Satisfactory reduction and bony union were demonstrated on postoperative radiographics. CONCLUSIONS: Conservative treatment is still advocated as primary management for most axis body fractures. But for patients with obvious adjacent joints instability or irreducible displaced superior articular facet fracture, surgical intervention based on the different fracture pattern is necessary.

A de novo 1.38 Mb duplication of 1q31.1 in a boy with hemifacial microsomia, anophthalmia, anotia, macrostomia, and cleft lip and palate.

We reported a 2-year-old boy with developmental delay, mild mental retardation, and severe craniofacial malformation, including facial asymmetry with hypoplasia of the left zygoma, maxilla, and mandible, and left anophthalmia and anotia. A genome-wide screen revealed a 1.38 Mb duplication on chromosome 1q31.1, which was absent in his parents and 27 healthy controls. The duplication region contains two Refseq genes, PLA2G4A and C1orf99, which have not been reported to be implicated in craniofacial malformation. Functional studies of these genes and additional clinical analysis are necessary to elucidate the pathogenesis of craniofacial malformation.

Overexpression of the human ubiquitin E3 ligase CUL4A alleviates hypoxia-reoxygenation injury in pheochromocytoma (PC12) cells.

The ubiquitin E3 ligase CUL4A plays important roles in diverse cellular processes including carcinogenesis and proliferation. It has been reported that the expression of CUL4A can be induced by hypoxic-ischemic injury. However, the effect of elevated expression of CUL4A on hypoxia-reoxygenation injury is currently unclear. In this study, human CUL4A (hCUL4A) was expressed in rat pheochromocytoma (PC12) cells using adenoviral vector-mediated gene transfer, and the effects of hCUL4A expression on hypoxia-reoxygenation injury were investigated. In PC12 cells subjected to hypoxia and reoxygenation, we found that hCUL4A suppresses apoptosis and DNA damage by regulating apoptosis-related proteins and cell cycle regulators (Bcl-2, caspase-3, p53 and p27); consequently, hCUL4A promotes cell survival. Taken together, our results reveal the beneficial effects of hCUL4A in PC12 cells upon hypoxia-reoxygenation injury.

Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.

Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum.

Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.

[The application of C1-2 pedicle screw fixation in treating atlantoaxial instability].

OBJECTIVE: To explore the feasibility of C1-2 pedicle screw fixation and fusion technique in treating atlantoaxial instability. METHODS: From January 2006 to January 2009,18 patients with atlantoaxial instability were treated with C1-2 pedicle screws and plates fixation under general anesthesia. There were 11 males and 7 females, the age for 17-62 years with the mean of 37.7 years. The course of disease was from 3 days to 30 months with an average of 10.6 months. The patients had different degrees neck pain and disturbance of sensation or (and) dyskinesia, had atlantoaxial instability from images before operation. The JOA scoring before operation were from 8 to 15 with an average of 11.4. Bone fusion of patients was observed with X-rays, CT and MR image at the same time after operation and the JOA scoring was compared with preoperative. RESULTS: A total of 72 screws were successfully placed in 18 cases, among them, 15 cases were followed up from 6 to 24 months with an average of 11.5 months. Fifteen cases obtained bone fusion with time for 3-6 months without the complications of internal fixation failure or redislocation of atlas. The spinal compression had differently improved, postoperative JOA scoring was from 12 to 17 scores with an average of 14.5 scores. CONCLUSION: Pedicle screw fixation and fusion in atlas has advantages of firm fixation and high fusion rate, it is a better choices for atlantoaxial instability. It is not suitable for variations of sulcus of vertebral artery of atlas and posterior arch of atlas.

Two neighboring microdeletions of 5q13.2 in a child with oculo-auriculo-vertebral spectrum.

We describe a patient with multiple congenital anomalies, including hemifacial microsomia, asymmetric macrostomia, dysplastic mandible, multiple preauricular tags, atresia of the external auricular canal, and vertebral anomalies, which coincide with oculo-auriculo-vertebral spectrum. G-banding ( approximately 850 band level) showed a normal 46, XY karyotype. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphism (SNP) arrays revealed a 1Mb and a 167 kb deletion both on chromosome 5q13.2, which were absent in the parents and in 27 controls. Sixteen genes were located in the deleted region, including BIR1C and OCLN, which are involved in apoptosis. Haploinsufficiency of these genes may be contributing to the phenotype in this patient. To our knowledge, there are no previous reports of this 5q13.2 deletion in a patient with oculo-auriculo-vertebral spectrum.

Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity.

Recently, we showed that carnosine protects against NMDA-induced excitotoxicity in differentiated PC12 cells through a histaminergic pathway. However, whether the protective effect of the carnosine metabolic pathway also occurs in ischemic brain is unknown. Utilizing the model of permanent middle cerebral artery occlusion (pMCAO) in mice, we found that carnosine significantly improved neurological function and decreased infarct size in both histidine decarboxylase knockout and the corresponding wild-type mice to the same extent. Carnosine decreased the glutamate levels and preserved the expression of glutamate transporter-1 (GLT-1) but not the glutamate/aspartate transporter in astrocytes exposed to ischemia in vivo and in vitro. It suppressed the dissipation of Delta Psi(m) and generation of mitochondrial reactive oxygen species (ROS) induced by oxygen-glucose deprivation in astrocytes. Furthermore, carnosine also decreased the mitochondrial ROS and reversed the decrease in GLT-1 induced by rotenone. These findings are the first to demonstrate that the mechanism of carnosine action in pMCAO may not be mediated by the histaminergic pathway, but by reducing glutamate excitotoxicity through the effective regulation of the expression of GLT-1 in astrocytes due to improved mitochondrial function. Thus, our study reveals a novel antiexcitotoxic agent in ischemic injury.

[Recent advances in treatment of glial scar-induced inhibition of nerve regeneration].

Glial scar formed by central nervous system (CNS) injury is the main inhibitory barrier of nerve regeneration. How to promote axonal regeneration after injury,how to accelerate neural network reconstruction and how to improve brain function recovery have become a hot problem to be solved in the field of neuroscience. This article focuses on the recent advances of therapeutic strategies for axonal regeneration.

Physicochemical characterization, in vitro, and in vivo evaluation of indomethacin-loaded nanocarriers self-assembled by amphiphilic polyphosphazene.

Copolymeric nanocarriers assembled by amphiphilic polyphosphazene bearing poly(N-isopropylacrylamide) (PNIPAAm) and ethyl glycinate (EtGly) as substitutes, were investigated as drug vehicles for indomethacin (IND). The physicochemical characteristics of the novel nanocontainers were studied, including lower critical solution temperature (LCST), critical micelle concentration (CMC) and drug loading capacity. LCST measurements revealed that copolymer is more sensitive to the introduction of salts into aqueous solution compared with homopolymer. A significant decrease in CMC was observed when the temperature increased above LCST. As evidenced by transmission electron microscopy (TEM) measurement, morphological transformation from multicompartment into spherical nanoparticles was observed when nanocarriers with higher IND content were concerned. In vitro release tests suggested that IND-loaded nanocontainers exhibited pH dependent release profiles. In vivo pharmacokinetic study after subcutaneous administration provided a relatively sustained release behavior. Additionally, compared with free drug solution at the same dose, IND concentration in rat plasma showed a prolonged retention in experimental group treated with IND-loaded micelles. In vivo pharmacodynamic study based on both carrageenan-induced acute and complete Freund's adjuvant (CFA) induced adjuvant-arthritis models indicated that sustained therapeutic efficacy could be achieved through intraarticular injection of IND-loaded micelles. Most importantly, local delivery of IND can avoid the severe gastrointestinal stimulation, which is frequently associated with oral administration.

Local delivery of indomethacin to arthritis-bearing rats through polymeric micelles based on amphiphilic polyphosphazenes.

PURPOSE: Preparation, in vitro and in vivo evaluation of indomethacin-loaded polymeric micelles based on amphiphilic polyphosphazene. METHODS: Amphiphilic polyphosphazenes (PNIPAAm/EAB-PPPs) with poly (N-isopropylacrylamide) (PNIPAAm) and ethyl 4-aminobenzoate (EAB) as side groups were synthesized through thermal ring-opening polymerization and subsequent substitution reactions. Indomethacin (IND) loaded polymeric micelles based on PNIPAAm/EAB-PPPs were prepared by dialysis procedure. In vitro IND release kinetics was investigated in 0.1 M PBS (pH 7.4), while in vivo pharmacokinetics was performed in Sprague-Dawley rats. In vivo pharmacodynamic study was carried out based on two animal models, i.e. carrageenan-induced acute paw edema and complete Freund's adjuvant (CFA) induced ankle arthritis model. RESULTS: Drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in PBS suggested that there was no significant difference in release rate between micelles based on copolymers with various EAB content. Compared with the rats administered with free IND aqueous solution, IND concentration in rats' plasma showed a prolonged maintenance in experimental group treated with IND-loaded polymeric micelles. In vivo pharmacodynamic study indicated that sustained therapeutic efficacy could be achieved through topical injection of the aqueous solution of IND-loaded micelles. Local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration as evidenced by ulceration evaluation. CONCLUSIONS: The promising results of current preliminary study suggest that this type of amphiphilic copolymers could be used as injectable drug carriers for hydrophobic drugs.