Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:To analyze the revision strategies for failed atlantoaxial dislocation (AAD) surgery.Methods:A retrospective analysis was conducted on 145 patients who underwent revision surgery for AAD at the General Hospital of Southern Theatre Command of PLA between September 2009 and December 2023. The cohort included 74 males and 71 females, with a mean age of 43±16 years (range, 6-72 years). The initial surgical approaches were: anterior 31 cases, posterior 114 cases. Based on imaging assessments of immediate postoperative reduction and fusion status prior to revision, the cases of failure were classified into reduction-nonfusion type (22 cases), nonreduction-fusion type (31 cases), and nonreduction-nonfusion type (92 cases). Among the nonreduction-nonfusion cases, 39 had initial surgery with internal fixation for reduction, while 53 had initial surgery with simple decompression (posterior arch resection, foramen magnum decompression) without reduction. In the nonreduction-fusion cases, 8 cases had spot fusion and 23 had extensive fusion. Japanese Orthopaedic Association (JOA) scores were compared before and after revision, and complication rates were observed.Results:All patients successfully underwent surgery. The revision approaches included: anterior (anterior fixation and fusion 52 cases, anterior implant removal combined anterior fixation and fusion 4 cases, transoral odontoidectomies 16 cases, anterior implant removal combined transoral odontoidectomy 2 cases), posterior (posterior fixation and fusion 2 cases, posterior implant removal combined posterior fixation and fusion 22 cases), and combined anterior-posterior (posterior implant removal combined anterior fixation and fusion 18 cases, anterior implant removal combined posterior fixation and fusion 25 cases, posterior implant removal combined transoral odontoidectomy 5 cases). Operative time was 254.20±107.63 min (range, 90-660 min), and blood loss was 218.83±172.17 ml (range, 20-800 ml). Except for 3 patients who died due to postoperative complications, all patients were followed up for a duration of 12±11 months (range, 3-60 months). Six patients who failed to achieve bony fusion after the initial revision surgery underwent a second revision due to poor reduction (1 case), infection (1 case), suboptimal implant position (3 cases), and graft nonunion (1 case). All three patients with bony fusion after the initial revision surgery underwent a second revision due to poor reduction. Following the second revision surgery, none of the 9 patients exhibited graft nonunion or spinal cord compression. The 136 successful initial revision cases had a final follow-up JOA score of 14.75±2.00, significantly higher than the preoperative score of 11.93±2.92 ( t=-18.869, P<0.001). Conclusions:Revision surgery for AAD should take into account the immediate postoperative reduction status and fusion status prior to revision. An appropriate revision strategy should be selected to achieve satisfactory reduction and bony fusion.

BACKGROUND:At present,the surgical treatment of atlantoaxial dislocation mainly adopts the posterior atlantoaxial screw-rod internal fixation system for lifting and reduction.During the operation,the curvature of the connecting rod is often increased to increase the drop between the atlantoaxial vertebrae to improve the reduction effect,but it increases the difficulty and risk of surgery.The axis pivot screw directly increases the reduction drop between the atlantoaxial vertebrae,but the extent to which it increases the reduction capacity is unclear.OBJECTIVE:To test the reduction ability of axis pivot screw and compare it with ordinary screw.METHODS:Six fresh human craniocervical specimens were used in study.The joint capsules of two lateral mass joints and atlanto-odontoid joint and transverse ligament were removed to make an atlantoaxial instability model.Three kinds of internal fixation were performed successively on both sides of the axis of each specimen:uniaxial axis pivot screws(group A),multi-axial axis pivot screws(group B)and ordinary screws(group C).Flexible ultra-thin film pressure sensors were placed in the anterior atlanto-odontoid space.Two connecting rods with the same curvature were placed to simulate the lifting and reduction,and the pressure of the anterior atlanto-odontoid space was obtained.Comparative analysis was conducted among the three groups.RESULTS AND CONCLUSION:(1)The anterior atlanto-odontoid space pressure of groups A-C was(97.59±8.58),(60.43±5.09),and(22.74±0.81)N,respectively.There were significant differences among the three groups(F=251.603,P=0.000).The pairwise comparison among the three groups showed significant differences(P=0.000).(2)The axis pivot screw applied to the posterior atlantoaxial screw-rod internal fixation system can improve the reduction capacity compared with the common cervical posterior screw,and the uniaxial axis pivot screw has more reduction capacity than the multi-axis uniaxial axis pivot screw to improve the posterior atlantoaxial screw-rod internal fixation system.

Objective:To analyze the revision strategies for failed atlantoaxial dislocation (AAD) surgery.Methods:A retrospective analysis was conducted on 145 patients who underwent revision surgery for AAD at the General Hospital of Southern Theatre Command of PLA between September 2009 and December 2023. The cohort included 74 males and 71 females, with a mean age of 43±16 years (range, 6-72 years). The initial surgical approaches were: anterior 31 cases, posterior 114 cases. Based on imaging assessments of immediate postoperative reduction and fusion status prior to revision, the cases of failure were classified into reduction-nonfusion type (22 cases), nonreduction-fusion type (31 cases), and nonreduction-nonfusion type (92 cases). Among the nonreduction-nonfusion cases, 39 had initial surgery with internal fixation for reduction, while 53 had initial surgery with simple decompression (posterior arch resection, foramen magnum decompression) without reduction. In the nonreduction-fusion cases, 8 cases had spot fusion and 23 had extensive fusion. Japanese Orthopaedic Association (JOA) scores were compared before and after revision, and complication rates were observed.Results:All patients successfully underwent surgery. The revision approaches included: anterior (anterior fixation and fusion 52 cases, anterior implant removal combined anterior fixation and fusion 4 cases, transoral odontoidectomies 16 cases, anterior implant removal combined transoral odontoidectomy 2 cases), posterior (posterior fixation and fusion 2 cases, posterior implant removal combined posterior fixation and fusion 22 cases), and combined anterior-posterior (posterior implant removal combined anterior fixation and fusion 18 cases, anterior implant removal combined posterior fixation and fusion 25 cases, posterior implant removal combined transoral odontoidectomy 5 cases). Operative time was 254.20±107.63 min (range, 90-660 min), and blood loss was 218.83±172.17 ml (range, 20-800 ml). Except for 3 patients who died due to postoperative complications, all patients were followed up for a duration of 12±11 months (range, 3-60 months). Six patients who failed to achieve bony fusion after the initial revision surgery underwent a second revision due to poor reduction (1 case), infection (1 case), suboptimal implant position (3 cases), and graft nonunion (1 case). All three patients with bony fusion after the initial revision surgery underwent a second revision due to poor reduction. Following the second revision surgery, none of the 9 patients exhibited graft nonunion or spinal cord compression. The 136 successful initial revision cases had a final follow-up JOA score of 14.75±2.00, significantly higher than the preoperative score of 11.93±2.92 ( t=-18.869, P<0.001). Conclusions:Revision surgery for AAD should take into account the immediate postoperative reduction status and fusion status prior to revision. An appropriate revision strategy should be selected to achieve satisfactory reduction and bony fusion.

BACKGROUND:At present,the surgical treatment of atlantoaxial dislocation mainly adopts the posterior atlantoaxial screw-rod internal fixation system for lifting and reduction.During the operation,the curvature of the connecting rod is often increased to increase the drop between the atlantoaxial vertebrae to improve the reduction effect,but it increases the difficulty and risk of surgery.The axis pivot screw directly increases the reduction drop between the atlantoaxial vertebrae,but the extent to which it increases the reduction capacity is unclear.OBJECTIVE:To test the reduction ability of axis pivot screw and compare it with ordinary screw.METHODS:Six fresh human craniocervical specimens were used in study.The joint capsules of two lateral mass joints and atlanto-odontoid joint and transverse ligament were removed to make an atlantoaxial instability model.Three kinds of internal fixation were performed successively on both sides of the axis of each specimen:uniaxial axis pivot screws(group A),multi-axial axis pivot screws(group B)and ordinary screws(group C).Flexible ultra-thin film pressure sensors were placed in the anterior atlanto-odontoid space.Two connecting rods with the same curvature were placed to simulate the lifting and reduction,and the pressure of the anterior atlanto-odontoid space was obtained.Comparative analysis was conducted among the three groups.RESULTS AND CONCLUSION:(1)The anterior atlanto-odontoid space pressure of groups A-C was(97.59±8.58),(60.43±5.09),and(22.74±0.81)N,respectively.There were significant differences among the three groups(F=251.603,P=0.000).The pairwise comparison among the three groups showed significant differences(P=0.000).(2)The axis pivot screw applied to the posterior atlantoaxial screw-rod internal fixation system can improve the reduction capacity compared with the common cervical posterior screw,and the uniaxial axis pivot screw has more reduction capacity than the multi-axis uniaxial axis pivot screw to improve the posterior atlantoaxial screw-rod internal fixation system.

Objective: To compare the clinical outcomes of transoral anterior Jefferson-fracture reduction plate (JeRP) and posterior screw rod (PSR) surgery for unstable atlas fractures via C1-ring osteosynthesis. Methods: From June 2009 to June 2022, 49 consecutive patients with unstable atlas fractures were treated by transoral anterior JeRP fixation (JeRP group) or PSR fixation (PSR group) and followed up at General Hospital of Southern Theatre Command of PLA; 30 males and 19 females were included. The visual analogue scale (VAS) score, Neck Disability Index (NDI), distance to anterior arch fracture (DAAF), distance to posterior arch fracture (DPAF), lateral mass displacement (LMD), Redlund-Johnell value, postoperative complications, and fracture healing rate were retrospectively collected and statistically analyzed. Results: Compared with that in the PSR group, the bleeding volume in the JeRP group was lower, and the length of hospital stay was longer. The VAS scores and NDIs of both groups were significantly improved after surgery. The postoperative DAAF and DPAF were significantly smaller after surgery in both groups. Compared with the significantly shorter DPAF in the PSR group, the JeRP group had a smaller DAAF, shorter LMDs and larger Redlund-Johnell value postoperatively and at the final follow-up. The fracture healing rate at 3 months after surgery was significantly greater in the JeRP group (p < 0.05). Conclusion Both C1-ring osteosynthesis procedures for treating unstable atlas fractures yield satisfactory clinical outcomes. Transoral anterior JeRP fixation is more effective than PSR fixation for holistic fracture reduction and short-term fracture healing, but the hospital stay is longer.

BACKGROUND:The addition of traditional rod-rod fixation for atlantoaxial joint disease to C1-C2 pedicle screw-rod fixation(C1-C2 PSR)can provide stronger anti-rotation stability for screw/rod fixation,but there is a risk of installation difficulties,impact on bone graft bed,and spinal cord injury.The new horizontal screw-screw crosslink(hS-S CL)designed by the authors can effectively overcome the above shortcomings,but its biomechanical properties are unclear. OBJECTIVE:To analyze biomechanical properties of new horizontal screw-screw crosslink in C1-C2 PSR by three-dimensional finite element analysis. METHODS:CT thin layer scanning data were collected from the occipital base to the axis(C0-2)of one adult healthy male volunteer.The atlantoaxial finite element models were established respectively:the normal group,the unstable group,the non-crosslink group(unstable+C1-C2 PSR),and the crosslink group(C1-C2 PSR+hS-S CL).Range of motion and Von Miss Stresses in flexion and extension,lateral flexion and rotation of the four groups were calculated by applying 1.5 Nm torque to each finite element model,and the stress cloud was extracted. RESULTS AND CONCLUSION:(1)Range of motion of the unstable group was increased by 43.8%-78.7%compared with the normal group,and the range of motion of the internal fixation groups was 90.2%-98.7%lower than that of the unstable group under six conditions.The range of motion of the crosslink group and the non-crosslink group was basically the same in flexion and extension states,but in lateral flexion and rotation states,the range of motion of the crosslink group decreased 34.3%-43.8%and 78.6%-79.1%,respectively,compared with the non-crosslink group,and range of motion decreased most obviously in rotation state.(2)The stress peak of the internal plant model:The maximum stress of the crosslink group was generally smaller than that of the non-crosslink group,and the stress peak value of all the internal fixation groups was the lowest when the extension was carried out.(3)The stress cloud of internal plants showed that there was no obvious stress concentration phenomenon in the internal fixation,and the main stress distribution areas were the screw root and bone joint,and the crosslink ends were the screw tail groove or the joint rod joint.(4)The new horizontal screw-screw crosslink can obviously improve the anti-rotation stability of internal fixation and it can share part of the pressure in the three-dimensional motion direction of the internal fixation system and reduce the maximum stress of the internal plants.However,the stress distribution is obvious at both ends of the crosslink,and this part may be prone to fracture of the crosslink.

BACKGROUND:Posterior atlantoaxial pedicle screw rod internal fixation is the main method for treating atlantoaxial dislocation,and the horizontal crosslink plays an important role in the antirotation ability of the internal fixation system.The new horizontal screw-screw crosslink can effectively overcome the disadvantages of traditional horizontal crosslink,such as inconvenient installation,impact on bone grafting bed,and potential spinal cord injury.However,the biomechanical properties of the new horizontal screw-screw crosslink with different installation modes are still unclear. OBJECTIVE:To investigate the biomechanical characteristics of new different installation modes of horizontal screw-screw crosslink in the C1-C2 pedicle screw-rod fixation and to provide a theoretical basis for optimal installation mode. METHODS:Six fresh human occipitocervical specimens were divided into the intact state group(group A),and the atlantoaxial instability model of type Ⅱ odontoid fracture was established based on the intact state group as the instability group(group B).The C1-C2 pedicle screw-rod fixation was performed on each specimen based on the instability group(group C).In group C,different installation modes of horizontal screw-screw crosslink were successively installed in each specimen,including upper transverse connection(two atlas screw tails)as group D,lower transverse connection(two axis screw tails)as group E,diagonal transverse connection(upper left and lower right for group F,lower left and upper right for group G),and cross transverse connection as group H.The specimen models were tested in order of flexion,extension,lateral flexion and lateral rotation on a three-dimensional motion machine,and the atlantoaxial range of motion of each group of specimens was obtained.Repeated measure analysis of variance was used to evaluate the biomechanical properties of each group. RESULTS AND CONCLUSION:(1)Under six states,the range of motion of groups A,C,D,E,F,G and H was smaller than that of group B,and there were statistically significant differences(P＜0.05).(2)In the flexion and extension states,there was no significant difference among the five types of horizontal screw-screw crosslink groups(P＞0.05).(3)In the left and right rotation directions,there were significant differences in D and E groups compared with F,G and H groups(P＜0.05);there were no significant differences between D and E groups,and F and G groups(P＞0.05),and there were no significant differences in F and G groups compared with H group(P＞0.05).(4)In conclusion,under flexion-extension states,the biomechanical stability of five types of horizontal screw-screw crosslink groups was similar,but under the rotation state,the stability of diagonal horizontal screw-screw crosslink group and cross horizontal screw-screw crosslink group was obviously better than that of transverse horizontal screw-screw crosslink group;however,the stability of diagonal horizontal screw-screw crosslink group is similar to the cross horizontal screw-screw crosslink group,so the former is more worthy of clinical recommendation.

Objective: To compare the clinical outcomes of transoral anterior Jefferson-fracture reduction plate (JeRP) and posterior screw rod (PSR) surgery for unstable atlas fractures via C1-ring osteosynthesis. Methods: From June 2009 to June 2022, 49 consecutive patients with unstable atlas fractures were treated by transoral anterior JeRP fixation (JeRP group) or PSR fixation (PSR group) and followed up at General Hospital of Southern Theatre Command of PLA; 30 males and 19 females were included. The visual analogue scale (VAS) score, Neck Disability Index (NDI), distance to anterior arch fracture (DAAF), distance to posterior arch fracture (DPAF), lateral mass displacement (LMD), Redlund-Johnell value, postoperative complications, and fracture healing rate were retrospectively collected and statistically analyzed. Results: Compared with that in the PSR group, the bleeding volume in the JeRP group was lower, and the length of hospital stay was longer. The VAS scores and NDIs of both groups were significantly improved after surgery. The postoperative DAAF and DPAF were significantly smaller after surgery in both groups. Compared with the significantly shorter DPAF in the PSR group, the JeRP group had a smaller DAAF, shorter LMDs and larger Redlund-Johnell value postoperatively and at the final follow-up. The fracture healing rate at 3 months after surgery was significantly greater in the JeRP group (p < 0.05). Conclusion Both C1-ring osteosynthesis procedures for treating unstable atlas fractures yield satisfactory clinical outcomes. Transoral anterior JeRP fixation is more effective than PSR fixation for holistic fracture reduction and short-term fracture healing, but the hospital stay is longer.

Objective: To compare the clinical outcomes of transoral anterior Jefferson-fracture reduction plate (JeRP) and posterior screw rod (PSR) surgery for unstable atlas fractures via C1-ring osteosynthesis. Methods: From June 2009 to June 2022, 49 consecutive patients with unstable atlas fractures were treated by transoral anterior JeRP fixation (JeRP group) or PSR fixation (PSR group) and followed up at General Hospital of Southern Theatre Command of PLA; 30 males and 19 females were included. The visual analogue scale (VAS) score, Neck Disability Index (NDI), distance to anterior arch fracture (DAAF), distance to posterior arch fracture (DPAF), lateral mass displacement (LMD), Redlund-Johnell value, postoperative complications, and fracture healing rate were retrospectively collected and statistically analyzed. Results: Compared with that in the PSR group, the bleeding volume in the JeRP group was lower, and the length of hospital stay was longer. The VAS scores and NDIs of both groups were significantly improved after surgery. The postoperative DAAF and DPAF were significantly smaller after surgery in both groups. Compared with the significantly shorter DPAF in the PSR group, the JeRP group had a smaller DAAF, shorter LMDs and larger Redlund-Johnell value postoperatively and at the final follow-up. The fracture healing rate at 3 months after surgery was significantly greater in the JeRP group (p < 0.05). Conclusion Both C1-ring osteosynthesis procedures for treating unstable atlas fractures yield satisfactory clinical outcomes. Transoral anterior JeRP fixation is more effective than PSR fixation for holistic fracture reduction and short-term fracture healing, but the hospital stay is longer.