BDE-47 disturbs the immune response of lymphocytes to LPS by downregulating NF-κB pathway.

The health risks associated with 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47) have become an increasing concern due to its widespread presence in the environment and biological samples. To date, the potential toxicity of BDE-47 to immune system remains unclear. In this study, we aimed to study the immunotoxicity of BDE-47 using spleen-derived lymphocytes in vitro and BALB/c mice in vivo. In vitro results showed that lymphocytes exposed to 12.5-100 µM BDE-47 exhibited unchanged cell viability but decreased release of IL-6 and TNF-α when responding to lipopolysaccharide (LPS). The expression levels of p-p65, p-IκBα, TrkA and p-Akt involved in NF-κB pathway were obviously decreased, and NF-κB activator PMA could recover the BDE-47-induced inhibitory effect on IL-6 and TNF-α release by lymphocytes in response to LPS. In vivo data showed that BDE-47 orally administered to mice (1 mg/kg, 10 mg/kg, 100 mg/kg per day, 30 days) did not significantly affect body weight, organ index and histomorphology of spleen. However, ELISA assay showed that serum IL-6 and TNF-α levels from BDE-47-treated mice after intraperitoneal injection of LPS were significantly reduced, and high-throughput mouse cytokines screening found 13 more cytokines down-regulated in the serum. Transcriptomic sequencing of spleens identified 488 differential expressed genes (DEGs). GO enrichment analysis of these DEGs suggested that the GO term of response to LPS (GO: 0032,496) was significantly involved. KEGG enrichment analysis showed that the down-regulated DEGs significantly enriched in multiple immune-related signaling pathways including the NF-κB signaling pathway (mmu04064). Overall, these data suggested that BDE-47 could negatively regulate NF-κB signaling pathways to inhibit the immune response of lymphocytes to LPS, suggesting that exposures to BDE-47 may disturb the immune balance and increase the body's susceptibility to infectious diseases.

Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery.

Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.

BDE-47 induced PC-12 cell differentiation via TrkA downstream pathways and caused the loss of hippocampal neurons in BALB/c mice.

As the most abundant congener of polybrominated diphenyl ethers (PBDEs) detected in environment and human biotic samples, 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) has been found to accumulate in brain and induce neurotoxicity, however, the detailed mechanism has not been clearly elucidated. To investigate the neurotoxicity of BDE-47, undifferentiated PC-12 cells were exposed to different doses of BDE-47, and BDE-47 dissolved in corn oil was orally administered to mice for 8 consecutive weeks. Our data showed that BDE-47 obviously changed cell morphology, altered cell viability, promoted cell apoptosis, and induced reactive oxygen species (ROS) production. BDE-47 promoted the differentiation of PC-12 cells by enhancing the expression of TrkA receptor and the phosphorylation levels of ERK and Akt. Moreover, BDE-47-induced differentiation of PC-12 cells was suppressed by inhibitors of corresponding pathways (MAPK/ERK and PI3K/Akt). H&E staining of brain showed neurons in DG and CA1 areas of hippocampus decreased after BDE-47 exposure. Transcriptome sequencing of brain tissue suggested that multiple signaling pathways related to neuron death and nerve function were significantly regulated. In conclusion, these results provided new evidence for revealing the neurotoxicity of BDE-47, and offered important experimental basis for environmental controlling and post-exposure health risk assessment of BDE-47.

Cytotoxicity and transcriptome changes triggered by CuInS2/ZnS quantum dots in human glial cells.

As a newly developed cadmium-free quantum dot (QD), CuInS2/ZnS has great application potential in many fields, but its biological safety has not been fully understood. In this study, the in vitro toxicity of CuInS2/ZnS QDs on U87 human glioma cell line was explored. The cells were treated with different concentrations of QDs (12.5, 25, 50 and 100 µg/mL), and the uptake of QDs by the U87 cells was detected by fluorescence imaging and flow cytometry. The cell viability was observed by MTT assay, and the gene expression profile was analyzed by transcriptome sequencing. These results showed that QDs could enter the cells and mainly located in the cytoplasm. The uptake rate was over 90 % when the concentration of QDs reached 25 µg/mL. The cell viability (50 and 100 µg/mL) increased at 24 h (P < 0.05), but no significant difference after 48 h and 72 h treatment. The results of differential transcription showed that coding RNA accounted for the largest proportion (62.15 %), followed by long non-coding RNA (18.65 %). Total 220 genes were up-regulated and 1515 genes were down-regulated, and significantly altered gene functions included nucleosome, chromosome-DNA binding, and chromosome assembly. In conclusion, CuInS2/ZnS QDs could enter U87 cells, did not reduce the cell viability, but would obviously alter the gene expression profile. These findings provide valuable information for a proper understanding of the toxicity risk of CuInS2/ZnS QD and promote the rational utilization of QDs in the future.

Surgical treatment of atlantoaxial subluxation by intraoperative skull traction and C1-C2 fixation.

BACKGROUND: Atlantoaxial subluxation (AAS) is a not rare abnormality between the atlas (C1) and axis (C2). For AAS patients with persistent neck pain and neurologic symptoms, surgical intervention is a good choice. Nevertheless, there were still few reports about the use of intraoperative skull traction and different fixation methods in treatment of AAS. METHODS: From January 2012 to December 2018, a total of 86 cases were admitted to our hospital and diagnosed as AAS. All the patients received atlantoaxial reduction with the help of intraoperative skull traction and C1-C2 fixation. Clinical and radiological parameters were collected through chart review. RESULTS: There were 86 cases included in this study. The mean operative time was 153.9 ± 73.9 min, and the mean amount of intraoperative blood loss was 219.1 ± 195.6 ml. 81 patients underwent posterior reduction, internal fixation and fusion. 5 patients underwent anterior release, followed by posterior internal fixation and fusion. 82 patients got satisfactory postoperative outcomes while complications occurred in 4 patients. Significant neurologic improvement was observed in these patients. Bone fusion was achieved on the midline sagittal reconstructed CT images at the latest follow-up in all these patients except 1 case. All the patients were followed up for 34.84 ± 15.86 months at average (range 12-60 months). The mean ADI value was 7.55 ± 1.67 mm at average preoperatively, and improved to 4.03 ± 1.21 mm postoperatively, and to 4.21 ± 0.99 mm at the latest follow-up. The mean A-A angle was 15.48 ± 9.82 degrees at average preoperatively, and improved to 21.61 ± 10.43 degrees postoperatively, and to 19.73 ± 8.13 degrees at the latest follow-up. The mean A-A height was 35.61 ± 7.66 mm at average preoperatively, and improved to 40.08 ± 8.5 mm postoperatively, and to 38.83 ± 6.97 mm at the latest follow-up. There were complications in 4 patients, including pedicle misplacement, pedicle screw fracture, infection and one death. CONCLUSION: Intraoperative skull traction can effectively facilitate the surgical procedures for ASS caused by different etiologies. Further research will be needed to investigate the safety and effectiveness of this method in the future.

Selective anterior thoracolumbar/lumbar fusion and instrumentation in adolescent idiopathic scoliosis patients.

BACKGROUND: Selective anterior thoracolumbar/lumbar (TL/L) fusion and instrumentation in adolescent idiopathic scoliosis (AIS) patients with a structural major TL/L curve and a nonstructural minor thoracic curve is rarely reported. We investigate the correction results of these patients. METHODS: By reviewing the medical records and roentgenograms of AIS patients undergone selective anterior TL/L fusion and instrumentation, Cobb angle, correction rate of the major and minor curves, coronal balance, lowest instrumented vertebra (LIV) tilt, coronal disc angle immediately below the LIV (LIVDA) and radiographic shoulder height (RSH) were measured and analyzed. RESULTS: Forty patients were included. For the major TL/L curve, the mean coronal Cobb angle before and after operation were 43.9° and 8.7°, respectively, with an average correction rate of 80.2% (P = 0.000). While for the minor thoracic curve, the mean coronal Cobb angle before and after operation were 27.2° and 14.3°, respectively, with an average spontaneous correction rate of 47.4% (P = 0.000). At final follow-up, the coronal Cobb angles of the major and minor curves were 13.7° and 17.1°, respectively, with a mean correction loss of 5.0° and 2.9°, respectively. The coronal balance before and after operations was 13.2 mm and 11.5 mm, respectively. At the final follow-up, it turned to 5.6 mm, which was much better than that after operation (P = 0.001). The mean LIV tilt was 23.5° before operation, and was significantly improved after operation (8.3°, P = 0.000). At final follow-up, it was well maintained (10.6°). The LIVDA averaged 3.5° before operation, and aggravated to 5.5° after operation (P = 0.100) and 7.4° at final follow-up (P = 0.012), respectively. The RSH was 7.3 mm before operation, 5.6 mm after operation, and 2.2 mm at the final follow-up. The RSH at the final follow-up was significantly improved compared with that after operation (P = 0.002). CONCLUSIONS: Selective anterior TL/L fusion and instrumentation can get good correction results of both curves, with good results of the coronal balance and RSH in AIS patients, while a larger LIVDA.

[Selective anterior thoracolumbar or lumbar fusion for adolescent idiopathic scoliosis].

OBJECTIVE: To evaluate the outcomes of selective anterior thoracolumbar or lumbar (TL/L) fusion for adolescent idiopathic scoliosis (AIS) with PUMCIId1 curves (Lenke type 5). METHODS: Thirty-five consecutive AIS patients (PUMC type IId1, Lenke type 5) with selective anterior TL/L fusion with single solid rod instrumentation were reviewed. The average follow-up was 36 months (range, 18 - 42 months). Standing anteroposterior and lateral radiographs were measured and analyzed. RESULTS: The average preoperative Cobb angle of the TL/L curves was 45.6 degrees and corrected to 9.7 degrees postoperatively, with 79.7% curve correction. The thoracic curves decreased from 29.7 degrees preoperatively to 17.6 degrees postoperatively, with a spontaneous correction of 41.5%. There was an average 4.7 degrees and 2.5 degrees correction loss of the TL/L and the thoracic curves at the final follow-up respectively. Trunk shift deteriorated slightly from 14.0 mm preoperatively to 14.8 mm postoperatively, and improved significantly to 5.1 mm at the final follow-up. The lowest instrumented vertebra (LIV) tilt was significantly improved after surgery (from -21.8 degrees preoperatively to -1.5 degrees postoperatively) and well maintained at the final follow-up (-2.1 degrees). The coronal disc angle immediately above the upper instrumented vertebra (UIVDA) and below the LIV (LIVDA) averaged 0.5 degrees and 0.6 degrees respectively, and aggravated after surgery (0.9 degrees and 4.9 degrees, respectively). Both the UIVDA and LIVDA were significantly aggravated at the final follow-up (3.0 degrees and 7.8 degrees, respectively). The sagittal contours of T(5-12) and T(10)-L(2) were well maintained after surgery and at the final follow-up. The lumbar lordosis of L(1)-S(1) and the sagittal Cobb angle of the instrumented segments were reduced postoperatively and at the final follow-up. No pseudarthrosis or other complications were observed. CONCLUSION: Selective anterior TL/L fusion with single solid rod instrumentation is effective and safe for AIS with PUMCIId1 (Lenke type 5) curves, above and below the fusion and larger residual thoracic curve in some cases need further evaluated.

[Clinical diagnosis and surgical treatment of congenital contractural arachnodactyly: analysis of 6 cases].

OBJECTIVE: To discuss the clinical diagnosis and surgical treatment of congenital contractural arachnodactyly (CCA). METHODS: The clinical data of 6 CCA patients, 1 male and 5 female, aged 7.5 (5-14) were analyzed. All cases had kyphoscoliosis, 2 in the thoracic segments and 4 in the thoracolumbar segments. The average scoliosis Cobb angle was 88.6 degrees (85 degrees-117 degrees). The average kyphosis Cobb angle was 93.6 degrees (75 degrees-123 degrees). All of the cases underwent internal fixation with pedicle screw and lamina hooks instrumentation, in which 4 cases underwent posterior Smith-Petersen osteotomy. The diagnosis was based on a constellation of clinical findings. The clinical manifestations included marfanoid habitus, flexion contractures of multiple joints (elbow, knee, hip, and finger), kyphoscoliosis, muscular hypoplasia, and abnormal pinnae ("crumpled" outer helices). Molecular genetic testing showed mutation in the fibrillin-2 (FBN2) gene encoding the extracellular matrix microfibril. Four cases were followed up for 6-9 months. RESULTS: After operation the average Cobb angle of the scoliosis and kyphosis were 37.6 degrees (35 degrees-52 degrees) and 38.6 degrees (28 degrees-54 degrees) immediately, with 62.3% and 68.7% curve correction respectively. Three cases got excellent synostosis of posterior lamina, 1 case underwent revision with lamina hook because the distal screw was loose and hurt the nerve root, and the other 2 cases lost follow-up. The patients' body appearance and pulmonary function were obviously improved. CONCLUSION: The characteristic clinical manifestation include severe and stiff kyphoscoliosis, difficult to correct , and enhanced Cobb angle, and pedicle dysplasia of vertebral pedicle leading to difficulty in installing screws. Smith-Petersen osteotomy is often necessary. CCA should be differentiated with Marfan syndrome (MFS), Stickler syndrome, Homocystinuria, and distal arthrogryposis, especially MFS.