Application of a count data model to evaluate the anti-metastatic efficacy of QAP14 in 4T1 breast cancer allografts.

Dopamine D1 receptor (D1DR) is proved to be a promising target to prevent tumor metastasis, and our previous studies showed that QAP14, a potent anti-cancer agent, exerted inhibitory effect on lung metastasis via D1DR activation. Therefore, the purpose of the study was to establish count data models to quantitatively characterize the disease progression of lung metastasis and assess the anti-metastatic effect of QAP14. Data of metastatic progression were collected in 4T1 tumor-bearing mice. Generalized Poisson distribution best described the variability of metastasis counts among the individuals. An empirical PK/PD model was developed to establish mathematical relationships between steady plasma concentrations of QAP14 and metastasis growth dynamics. The latency period of metastasis was estimated to be 12 days after tumor implantation. Our model structure also fitted well to other D1DR agonists (fenoldopam and l-stepholidine) which had inhibitory impact on breast cancer lung metastasis likewise. QAP14 40 mg/kg showed the best inhibitory efficacy, for it provided the longest prolongation of metastasis-free periods compared with fenoldopam or l-stepholidine. This study provides a quantitative method to describe the lung metastasis progression of 4T1 allografts, as well as an alternative PD model structure to evaluate anti-metastatic efficacy.

An integrated PK/PD model investigating the impact of tumor size and systemic safety on animal survival in SW1990 pancreatic cancer xenograft.

Survival is one of the most important endpoints in cancer therapy, and parametric survival analysis could comprehensively reveal the overall result of disease progression, drug efficacy, toxicity as well as their interactions. In this study we investigated the efficacy and toxicity of dexamethasone (DEX) combined with gemcitabine (GEM) in pancreatic cancer xenograft. Nude mice bearing SW1990 pancreatic cancer cells derived tumor were treated with DEX (4 mg/kg, i.g.) and GEM (15 mg/kg, i.v.) alone or in combination repeatedly (QD, Q3D, Q7D) until the death of animal or the end of study. Tumor volumes and net body weight (NBW) were assessed every other day. Taking NBW as a systemic safety indicator, an integrated pharmacokinetic/pharmacodynamic (PK/PD) model was developed to quantitatively describe the impact of tumor size and systemic safety on animal survival. The PK/PD models with time course data for tumor size and NBW were established, respectively, in a sequential manner; a parametric time-to-event (TTE) model was also developed based on the longitudinal PK/PD models to describe the survival results of the SW1990 tumor-bearing mice. These models were evaluated and externally validated. Only the mice with good tumor growth inhibition and relatively stable NBW had an improved survival result after DEX and GEM combination therapy, and the simulations based on the parametric TTE model showed that NBW played more important role in animals' survival compared with tumor size. The established model in this study demonstrates that tumor size was not always the most important reason for cancer-related death, and parametric survival analysis together with safety issues was also important in the evaluation of oncology therapies in preclinical studies.

The effect of local intraoperative corticosteroid application on postoperative dysphagia following anterior cervical spine surgery.

Dysphagia is a common complication following anterior cervical spine surgery (ACSS). Although several literatures have reported the potential benefit of local corticosteroid application on dysphagia, its safety and efficacy are still unclear. A systematic review was performed aiming to evaluate the evidence of local corticosteroid application in prevention or treatment of postoperative dysphagia following ACSS. A systematic search was performed in September 2018 in PubMed and Embase database. The following information was extracted: study investigator, year of publication, number of patients, study design, inclusion/exclusion criteria, administration protocol of steroid, type of surgical procedure, number of levels performed, assessment methodology of dysphagia, radiologic assessment of prevertebral soft tissue swelling (PSTS), follow-up time points, outcome of dysphagia, and corticosteroid-related complications. Qualitative synthesis was performed. Finally, 5 studies met the inclusion/exclusion criteria. Four studies found that local corticosteroid application could decrease the incidence and magnitude of postoperative dysphagia while 1 study showed no effect on dysphagia significantly at 6 weeks and 3 months follow-up time. A total of 2325 patients received local corticosteroid intraoperatively; no early corticosteroid-related complication was reported. Totally, 4 adverse events occurred in long-term follow-up time, including 2 bone nonunion at 1.5 and 2.5 years postoperatively, 2 esophageal perforation at 2 months and 11 months of follow-up, respectively. Local corticosteroid application can reduce the incidence and severity of dysphagia following ACSS without increasing early corticosteroid-related complications. But further high-quality study is necessary to analyze potential delayed complications.

A novel classification and its clinical significance in Chiari I malformation with syringomyelia based on high-resolution MRI.

BACKGROUND: The existing classification in Chiari I malformation (CM-I) has limited significance for the selection of surgical methods. OBJECTIVE: The purpose of this study was to investigate the surgery of CM-I with syringomyelia based on the high-resolution MR imaging (HRMRI) findings. METHODS: Data from 115 patients were collected and retrospectively analyzed. For those with syringomyelia up to the level of C1, HRMRI was performed and according to the communication status between the fourth ventricle and the syringomyelia, patients can be divided into four types, namely Type A: classic communicating; Type B: partial communicating; Type C: non-communicating; Type D: atrophic. All operations were performed with Foramen magnum and Magendie dredging (FMMD), and all intradural factors that may have induced the obstruction of CSF circulation were recorded. The efficiency of operation on syringomyelia was evaluated by mJOA, imaging findings, and complications in the follow-up periods. RESULTS: The postoperative follow-up period was from 12 to 24 months, with an average of 14.3 months. At 1 year, the mJOA of 115 patients was significantly higher than that before the operations (before surgery 12.1 ± 2.3 vs. after surgery 14. 2 ± 1.4, P < 0.05). In addition, postoperative re-examination showed that the size of the syringomyelia was reduced or completely resolved in patients of Type A, 100% (2/2); Type B, 81% (9/11); Type C, 84% (81/97); and Type D, 20% (1/5). CONCLUSIONS: According to our new classification based on HRMRI, FMMD is the key to surgical treatment, especially for Type A and Type B patients.

Wireless Epidural Electrical Stimulation in Combination With Serotonin Agonists Improves Intraspinal Metabolism in Spinal Cord Injury Rats.

OBJECTIVES: The combination of epidural electrical stimulation (EES) and serotonin agonists (5-HTA) effectively restores rhythmic lower-limb movements and improves intraspinal hemodynamics after spinal cord injury (SCI). Nonetheless, whether EES + 5-HTA improves intraspinal metabolism remains unclear. The present study aimed to evaluate the effects of EES + 5-HTA on intraspinal metabolism in SCI rats. MATERIALS AND METHODS: Wireless EES (WEES) implantation with complete T8 transection was performed in SCI rats. Electrodes were placed at the T12 and L2 vertebral levels. After rest for a week, the SCI rats received 11 weeks of WEES + 5-HTA treatment and treadmill training. WEES was switched off after each daily training. Locomotor function was evaluated by motion capture at week 12. Positron emission tomography-computed tomography was conducted to evaluate basal metabolism when WEES was switched off and assess task metabolism when WEES was switched on. RESULTS: With locomotor recovery after training for 11 weeks, WEES + 5-HTA conjointly improved basal metabolism (vs. each intervention alone; p < 0.05) and linearly modulated task metabolism in a frequency-dependent manner (R2 = 0.8901). Furthermore, 60 Hz of WEES was identified as the threshold for the extensive activation of the spinal cord's task metabolism below the transection plane (p < 0.05). CONCLUSIONS: WEES + 5-HTA could conjointly restore basal metabolism to a healthy level and modulate task metabolism by adjusting the stimulation frequency.

Dexamethasone inhibits pancreatic tumor growth in preclinical models: Involvement of activating glucocorticoid receptor.

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

Predictors of mortality in patients with primary spinal cord glioblastoma.

PURPOSE: Primary spinal cord glioblastoma (GBM) is a rare and devastating disease. Little attention was ever paid to this rare disease. As a result, the standard treatment protocol and prognostic factors of primary spinal cord GBM were not well established. The aim of this study was to determine the predictors associated with survival in patients with primary spinal cord GBM. METHODS: A total of 122 patients with primary spinal cord GBM from Surveillance, Epidemiology, and End Results database and our institution were included in this retrospective analysis. Information about age, sex, race, tumor invasion, extent of resection, radiation, chemotherapy and year of diagnosis was collected. Univariate and multivariate accelerated failure time (AFT) regression model was performed to identify prognostic factors. RESULTS: Of the 122 patients, 102 (83.6%) expired at the time of data collection. Overall survival at 1 year, 2 years, 3 years and 5 years was 48.4%, 22.8%, 17.1% and 8.4%, respectively, and median survival time was 12 months. Only radiation was found to be associated with survival in the AFT regression model (time ratio 1.94, 95% CI 1.01-3.72, p < 0.05). Radiotherapy could improve survival slightly; patients who received RT survived approximately two times as long as patients who did not receive RT, but the advantage was short term. CONCLUSION: The survival of primary spinal cord GBM is poor in the current treatment strategy. Radiotherapy was associated with better survival, but the advantage was short term.

N-arylpiperazine-containing compound (C2): An enhancer of sunitinib in the treatment of pancreatic cancer, involving D1DR activation.

Previous studies showed that dopamine (DA) significantly reduces the frequency of cancer stem-like cells (CSC) and enhances the efficacy of sunitinib (SUN) in the treatment of breast cancer and non-small cell lung cancer (NSCLC). To overcome the shortcomings of DA in clinical practice, the purpose of this study was to investigate the efficacy as well as the underlying mechanism of an orally available, N-arylpiperazine-containing compound C2, in the treatment of pancreatic cancer when used alone or in combination with SUN. Our results showed that C2 and SUN exerted synergistic effects on inhibiting the growth of SW1990 and PANC-1 pancreatic cancer cells. C2 significantly inhibited colony formation and migration of both cells. SW1990 xenograft and patient-derived xenograft (PDX) models were utilized for pharmacodynamic investigation in vivo. C2 alone showed little inhibition effect on tumor growth but increased the anti-tumor efficacy of SUN in both xenografts. Moreover, C2 down-regulated CSC markers (CD133 and ALDH) of both cancer cells and up-regulated the expression of dopamine receptor D1 (D1DR) in tumor. Besides, the SW1990 tumor growth was dose-dependently inhibited when the cells were pretreated with C2 before implantation. C2 increased intratumoral cAMP level, and the combination with D1DR specific antagonist SCH23390 reversed the above-mentioned effects of C2 both in vitro and in vivo, indicating the activation of D1DR may be involved in the underlying mechanism of C2 action. In summary, C2 could reduce the CSC frequency and enhance the anti-cancer effect of SUN in the treatment of pancreatic cancer, demonstrating its potential in cancer therapy.

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer.

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg-1·d-1) or SUL (25, 50 mg·kg-1·d-1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill's function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.

Effectiveness of posterior reduction and fixation in atlantoaxial dislocation: a retrospective cohort study of 135 patients with a treatment algorithm proposal.

PURPOSE: Surgical procedures on atlantoaxial dislocation remain controversial. The aim of this observational retrospective study was to investigate the treatment algorithm of surgical procedures. METHODS: According to CT and intraoperative evaluation during direct posterior reduction, 135 AAD cases were categorized into three groups: Group I: reducible dislocation; Group II: irreducible dislocation (Group IIa: effective decompression achieved after posterior reduction; Group IIb: no effective decompression after posterior reduction); and Group III: fixed dislocation. Group III presented with extensive bony fusions. Group I and Group IIa were treated with direct posterior reduction and fixation. Group IIb underwent posterior fixation and transoral odontoidectomy. Group III underwent transoral odontoidectomy alone. Japanese Orthopedic Association scores (JOA) were assessed to evaluate clinical status before and 6, 12 months after surgery. RESULTS: Our study included 118 Group I cases, 16 Group II cases (Group IIa: 11 cases; Group IIb: 5 cases), and one Group III case. Follow-up ranged from 12 to 36 months. PRIMARY OUTCOME: Anatomic atlantoaxial reduction was achieved in 118 of 135 patients (87.4%). Clinical improvements were seen in 96.3% (130/135) all the patients. Solid atlantoaxial fusion was shown in 134 patients. Secondary outcome: The overall complication rate was 3.7% (5/135). For Group I, the mean postoperative 6-month JOA was 14.5 versus 12.2 in preoperative patients (paired Student's t test, P < 0.01). CONCLUSIONS: This article proposes a clinical procedure that assists with therapeutic decision making and indicates the severity and difficulty of reduction of the atlantoaxial joint. These slides can be retrieved under Electronic Supplementary Material.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

Is anterior release and cervical traction necessary for the treatment of irreducible atlantoaxial dislocation? A systematic review and meta-analysis.

PURPOSE: To compare the clinical and radiographic outcomes of irreducible atlantoaxial dislocation (IAAD) treated with posterior fusion after anterior release and direct posterior reduction of the dislocation. METHODS: Online databases were searched for articles describing IAAD published from 1999 to 2015. Five studies (105 patients) described treatment with posterior fusion after periodontoid tissue release, and five studies (113 patients) described treatment with direct posterior reduction of the dislocation. The primary outcomes in this study were the complete reduction rate, Japanese Orthopedic Association score, perioperative morbidity, perioperative mortality, complications, vascular injury, and infection. Standard meta-analysis techniques were used to compare the outcomes. RESULTS: Of 319 citations examined, 10 articles involving 218 participants were eligible. Overall, there were no significant differences between the anterior release and posterior fixation (ARPF) group and direct posterior reduction and fixation (DPRF) group in the complete reduction rate, neurologic recovery rate, perioperative morbidity, perioperative mortality, vascular injury, or infection. However, the complication rate in the DPRF group was much lower than that in the ARPF group. CONCLUSIONS: Compared with posterior fusion after anterior release, direct posterior reduction of the dislocation showed no significant differences in terms of the complete reduction rate, neurologic recovery rate, or fusion rate; however, it was a simpler process associated with less surgical trauma and a shorter operation time. Because of the limitations of the small sample in this study, whether direct posterior reduction of the dislocation is more effective and safer than posterior fusion after anterior release remains unclear. LEVEL OF EVIDENCE: III. These slides can be retrieved under Electronic Supplementary Material.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Biomimetic Peripheral Nerve Stimulation Promotes the Rat Hindlimb Motion Modulation in Stepping: An Experimental Analysis.

Peripheral nerve stimulation is an effective neuromodulation method in patients with lower extremity movement disorders caused by stroke, spinal cord injury, or other diseases. However, most current studies on rehabilitation using sciatic nerve stimulation focus solely on ankle motor regulation through stimulation of common peroneal and tibial nerves. Using the electrical nerve stimulation method, we here achieved muscle control via different sciatic nerve branches to facilitate the regulation of lower limb movements during stepping and standing. A map of relationships between muscles and nerve segments was established to artificially activate specific nerve fibers with the biomimetic stimulation waveform. Then, characteristic curves depicting the relationship between neural electrical stimulation intensity and joint control were established. Finally, by testing the selected stimulation parameters in anesthetized rats, we confirmed that single-cathode extraneural electrical stimulation could activate combined movements to promote lower limb movements. Thus, this method is effective and reliable for use in treatment for improving and rehabilitating lower limb motor dysfunction.

Association between plasma Netrin-1 levels and motor and nonmotor symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and diverse motor and nonmotor symptoms. Early diagnosis and intervention are crucial but challenging due to reliance on clinical presentation. Recent research suggests potential biomarkers for early detection, including plasma netrin-1 (NTN-1), a protein implicated in neuronal survival. METHODS: This cross-sectional study recruited 105 PD patients and 65 healthy controls, assessing plasma NTN-1 levels and correlating them with clinical characteristics. Statistical analyses explored associations between NTN-1 levels and PD symptoms, considering demographic factors. RESULTS: PD patients exhibited significantly lower plasma NTN-1 levels compared to controls. NTN-1 demonstrated moderate potential as a PD biomarker. Positive correlations were found between NTN-1 levels and motor, depression, and cognitive symptoms. Multiple regression analysis revealed disease duration and NTN-1 levels as key factors influencing symptom severity. Gender also impacted symptom scores. CONCLUSION: Reduced plasma NTN-1 levels correlate with PD severity, suggesting its potential as a biomarker. However, further research is needed to elucidate the roles of NTN-1 in PD pathophysiology and validate its diagnostic and therapeutic implications. Understanding the involvement of NTN-1 may lead to personalized management strategies for PD.

The Ex vivo Preparation of Spinal Cord Slice for the Whole-Cell Patch-Clamp Recording in Motor Neurons During Spinal Cord Stimulation.

Spinal cord stimulation (SCS) can effectively restore locomotor function after spinal cord injury (SCI). Because the motor neurons are the final unit to execute sensorimotor behaviors, directly studying the electrical responses of motor neurons with SCS can help us understand the underlying logic of spinal motor modulation. To simultaneously record diverse stimulus characteristics and cellular responses, a patch-clamp is a good method to study the electrophysiological characteristics at a single-cell scale. However, there are still some complex difficulties in achieving this goal, including maintaining cell viability, quickly separating the spinal cord from the bony structure, and using the SCS to successfully induce action potentials. Here, we present a detailed protocol using patch-clamp to study the electrical responses of motor neurons to SCS with high spatiotemporal resolution, which can help researcher improve their skills in separating the spinal cord and maintaining the cell viability at the same time to smoothly study the electrical mechanism of SCS on motor neuron and avoid unnecessary trial and mistake.

Comparison of 3D-printed Navigation Template-assisted Pedicle Screws versus Freehand Screws for Scoliosis in Children and Adolescents: A Systematic Review and Meta-analysis.

BACKGROUND: There is a lack of attention to screw placement techniques for surgical treatment of scoliosis in children and adolescents. This meta-analysis aims to compare the accuracy and safety of pedicle screw placement between the 3D-printed navigation template technique and the freehand technique during corrective surgery for scoliosis in children and adolescents. METHODS: A comprehensive search was conducted for relevant articles up to December 2021 in databases including PubMed, Embase, MEDLINE, Cochrane, and Web of Science. The systematic meta-analysis compared the efficacy of pedicle screw placement between the two techniques, including accuracy of pedicle screw placement, complication rate, operation time, blood loss, mean placement time per screw, and mean times for fluoroscopy. RESULTS: The seven articles analyzed in this study involved 229 patients altogether. A total of 2,805 pedicle screws were placed by the two methods. Our results revealed that the 3D-printed guide template technique was more accurate than the freehand technique in pedicle screw placement (odds ratio [OR] =2.96; 95% confidence interval [CI]: 2.24-3.91; p < 0.000) with a lower complication rate (OR = 0.21; 95% CI: 0.06-0.78; p = 0.02). The operation time (mean difference [MD] = -34.37; 95% CI: -67.47 to -1.28; p = 0.04) and mean placement time per screw (MD = -3.11; 95% CI: -6.13 to -0.09; p = 0.04) and mean times for fluoroscopy (MD = -6.60; 95% CI: -8.66 to -4.55; p < 0.000) significantly decreased among patients in the 3D-printed navigation template group compared with those in the freehand technique group. In addition, the two techniques had no significant statistical difference in blood loss. CONCLUSIONS: Compared with the traditional freehand technique, the 3D-printed guide template is a promising technique with higher accuracy and safety in screw placement for surgical treatment of scoliosis in children and adolescents, and is worth popularizing and validating through more prospective clinical studies.

An imbalance of netrin-1 and DCC during nigral degeneration in experimental models and patients with Parkinson's disease.

AIMS: Multiple guidance cues, such as netrin-1 (NTN-1)/deleted in colorectal carcinoma (DCC), control the guidance of axons and help establish functional neural circuits during development. However, the function of these guidance molecules during the neurodegenerative process is unclear. METHODS: To access the alterations of NTN-1 and DCC during the onset and progression of PD, we first established two subacute and one chronic PD model. Then, we investigated the relationship between the NTN-1/DCC pathway and cell death in SH-SY5Y cells. Finally, we conducted correlation studies between plasma NTN-1 and parkinsonian symptoms in patients to understand how this pathway contributes to PD. RESULTS: We found that the imbalance of NTN-1 and DCC was a common feature of nigral DA neuron injury in PD mouse models. We investigated that MPP+ inhibited NTN-1 expression and increased DCC expression in a concentration- and time-dependent manner. We further discovered a significant decrease in plasma NTN-1 levels and a positive correlation with UPDRS scores in PD patients. CONCLUSION: Our findings confirmed the imbalance of NTN-1/DCC signaling during nigral degeneration in experimental PD models and found for the first time a correlation of plasma NTN-1 with PD symptoms in patients.