Factors influencing discharge against medical advice (DAMA) in traumatic brain injury patients requiring decompressive surgery: a comprehensive analysis.

raumatic brain injury (TBI) is a significant global health concern, particularly affecting young individuals, and is a leading cause of mortality and morbidity worldwide. Despite improvements in treatment infrastructure, many TBI patients choose discharge against medical advice (DAMA), often declining necessary surgical interventions. We aimed to investigate the factors that can be associated with DAMA in TBI patients that were recommended to have surgical treatment. This study was conducted at single tertiary university center (2008-2018), by retrospectively reviewing 1510 TBI patients whom visited the emergency room. We analyzed 219 TBI surgical candidates, including 50 declining surgery (refused group) and the others whom agreed and underwent decompressive surgery. Retrospective analysis covered demographic characteristics, medical history, insurance types, laboratory results, CT scan findings, and GCS scores. Statistical analyses identified factors influencing DAMA. Among surgical candidates, 169 underwent surgery, while 50 declined. Age (60.8 ± 17.5 vs. 70.5 ± 13.8 years; p < 0.001), use of anticoagulating medication (p = 0.015), and initial GCS scores (9.0 ± 4.3 vs. 5.3 ± 3.2; p < 0.001) appeared to be associated with refusal of decompressive surgery. Based on our analysis, factors influencing DAMA for decompressive surgery included age, anticoagulant use, and initial GCS scores. Contrary to general expectations and some previous studies, our analysis revealed that the patients' medical conditions had a larger impact than socioeconomic status under the Korean insurance system, which fully covers treatment for TBI. This finding provides new insights into the factors affecting DAMA and could be valuable for future administrative plans involving national insurance.

Fibronectin Type III Domain Containing 3B as a Potential Prognostic and Therapeutic Biomarker for Glioblastoma.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.

Comparison of the efficacy in improving trigeminal neuralgia in petroclival meningioma between microsurgery and radiosurgery: a meta-analysis.

The purpose of this study was to systematically review studies in the literature to assess the superiority between microsurgery and radiosurgery regarding the efficacy in improving petroclival meningioma (PCM)-related trigeminal neuralgia (TN). PubMed, Embase, Web of Science, and Cochrane clinical trial databases were systematically searched from the inception until December 08, 2022. The overall proportion of patients with improved TN after treatment in all six included studies was 56% (95% confidence interval [CI], 35-76.9%). Higgins I2 statistics showed significant heterogeneity (I2 = 90%). Subgroup analysis showed that the proportion of improved TN was higher in the microsurgery group than that in the radiosurgery group (89%; 95% CI, 81-96.5% vs. 37%, 95% CI, 22-52.7%, respectively, p < 0.01). Subgroup analysis (for studies that documented the number of posttreatment Barrow Neurological Institute scores 1 and 2) revealed that the proportion of pain-free without medication after treatment was higher in the microsurgery group than that in the radiosurgery group (90.7%; 95% CI, 81-99.7% vs. 34.5%, 95% CI, 21.3-47.7.7%, respectively, p < 0.01). Based on the results of this meta-analysis, we concluded that microsurgery is superior to radiosurgery in controlling PCM-related TN.

Antibiotics Prophylaxis for Endoscopic Endonasal Approach for Skull Base Tumor Surgery: A Meta-Analysis.

BACKGROUND: The regimen of prophylactic antibiotic for endoscopic endonasal skull base surgery (EE-SBS) varies considerably depending on surgeons and their institutes. The purpose of the present meta-analysis is to assess the effect of antibiotic regimens on EE-SBS surgery for anterior skull base tumor. METHODS: The PubMed, Embase, Web of Science, and Cochrane clinical trial databases were systematically searched through October 15, 2022. RESULTS: The 20 included studies were all retrospective. The studies included a total of 10,735 patients who underwent EE-SBS for skull base tumor. The proportion of patients with postoperative intracranial infection across all 20 studies was 0.9% (95% confidence interval [CI] 0.5%-1.3%). The proportion of postoperative intracranial infection in the multiple antibiotics group did not show statistically significant difference to that of the single antibiotic agent group (proportion: 0.6%, 95% CI 0%-1.4% vs. proportion: 1%, 95% CI 0.6%-1.5%, respectively, P = 0.39). The ultra-short duration maintenance group showed lower incidence of postoperative intracranial infection, although it did not reach statistical significance (ultra-short group: 0.7%, 95% CI 0.5%-0.9%; short duration: 1.8%, 95% CI 0.5%-3%; and long duration: 1%, 95% CI 0.2%-1.9%, P = 0.22) The combination of the multiple antibiotics group did not show meaningful low incidence of postoperative intracranial infection (antibiotics combination group: 0.6%, 95% CI 0%-1.4%; cefazolin single group: 0.8%, 95% CI 0%-1.6%; and single antibiotics other than cefazolin: 1.2%, 95% CI 0.7%-1.7%, P = 0.22). CONCLUSIONS: Multiple antibiotics did not show superiority compared with single antibiotic agent. Also, long maintenance duration of antibiotics did not reduce the incidence of postoperative intracranial infection.

Clinical features and treatment strategies for vertex epidural hematoma: a systematic review and meta-analysis from individual participant data.

Vertex epidural hematoma (VEDH) is a rare extradural hematoma and often misdiagnosed because of its variety of clinical symptoms and characteristic location. Determining optimal timing and technique for VEDH surgery is difficult because of its midline location and atypical clinical course. This study aims to understand the clinical manifestations and current treatment strategies for VEDH. We searched the published literature regarding VEDH through PubMed and Google Scholar, and individual patient data (IPD) were obtained from the eligible articles. A systematic review and IPD meta-analysis were conducted. In total, 70 patients' individual participant data were gathered. Most patients were male (87%), and traffic-related accidents were the most common injury mechanism (49%). Approximately half the patients (47%) were neurologically intact with nonspecific symptoms such as headache, dizziness, and vomiting at admission. Motor weakness alone (17%) and symptoms related to cranial nerve dysfunction such as anosmia, blurred vision, or diplopia (10%) were also noted. A surgical approach was initially chosen for 20 patients (28%), but eventually chosen for 20 more (total 40, 57%) during the observation period (average delay to surgery, 5 days). Patients who received surgery showed significantly poorer neurological status and larger hematoma size. Totally, two patients (3%) died, but most patients (94%) had a favorable outcome scoring 5 on the Glasgow Outcome Scale. Although VEDH generally showed favorable outcomes, clinicians must be aware of a high rate of delayed neurological deterioration during the observation period, which can be fatal due to central downward herniation.

Efficacy and Safety of Timely Urgent Superficial Temporal Artery-to-Middle Cerebral Artery Bypass Surgery in Patients with Acute Ischemic Stroke: A Single-Institutional Prospective Study and a Pooled Analysis.

BACKGROUND: Clinical outcome in patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) is not satisfactory if reperfusion treatment fails or is not tried. AIMS: We aimed to assess the efficacy and safety of urgent superficial temporal-to-middle cerebral artery (STA-MCA) bypass surgery in selected patients. METHODS: Patients who were diagnosed with LVO-induced AIS in the anterior circulation but had a failed intra-arterial thrombectomy (IAT) or were not tried due to IAT contraindications were prospectively enrolled. Timely urgent STA-MCA bypass surgery was performed if they showed perfusion-diffusion mismatch or symptom-diffusion mismatch in the acute phase of disease. Clinical and radiological data of these patients were assessed to demonstrate the safety and efficacy of urgent bypass procedures. A pooled analysis of published data on urgent bypass surgery in acute stroke patients was conducted and analyzed. RESULTS: In 18 patients who underwent timely bypass, the National Institutes of Health Stroke Scale (NIHSS) score improved from 12.11 ± 4.84 to 9.89 ± 6.52, 1 week after surgery. Three-month and long-term (9.72 ± 5.00 months) favorable outcomes (modified Rankin Scale [mRS] scores 0-2) were achieved in 50 and 75% of the patients, respectively. The pooled analysis (117 patients from 10 articles, including ours) identified favorable mRS scores in 71.79% patients at 3 months. A significant NIHSS score improvement from 11.51 ± 4.89 to 7.59 ± 5.50 was observed after surgery with significance. Major complications occurred in 3 patients (2.6%, 3/117) without mortality. CONCLUSIONS: Urgent STA-MCA bypass surgery can be regarded as a safe optional treatment to prevent cerebral infarct expansion and to improve clinical and radiological outcomes in highly selected patients.

Extra-domain B of fibronectin as an alternative target for drug delivery and a cancer diagnostic and prognostic biomarker for malignant glioma.

Extra-domain B of fibronectin (EDB-FN) is an alternatively spliced form of fibronectin with high expression in the extracellular matrix of neovascularized tissues and malignant cancer cells. In this study, we evaluated the practicality of using EDB-FN as a biomarker and therapeutic target for malignant gliomas (MGs), representative intractable diseases involving brain tumors. Methods: The microarray- and sequence-based patient transcriptomic database 'Oncopression' and tissue microarray of MG patient tissue samples were analyzed. EDB-FN data were extracted and evaluated from 23,344 patient samples of 17 types of cancer to assess its effectiveness and selectivity as a molecular target. To strengthen the results of the patient data analysis, the utility of EDB-FN as a molecular marker and target for MG was verified using active EDB-FN-targeting ultrasmall lipidic micellar nanoparticles (~12 nm), which had a high drug-loading capacity and were efficiently internalized by MG cells in vitro and in vivo. Results: Brain tumors had a 1.42-fold cancer-to-normal ratio (p < 0.0001), the second highest among 17 cancers after head and neck cancer. Patient tissue microarray analysis showed that the EDB-FN high-expression group had a 5.5-fold higher risk of progression than the EDB-FN low-expression group (p < 0.03). By labeling docetaxel-containing ultrasmall micelles with a bipodal aptide targeting EDB-FN (termed APTEDB-DSPE-DTX), we generated micelles that could specifically bind to MG cells, leading to superior antitumor efficacy of EDB-FN-targeting nanoparticles compared to nontargeting controls. Conclusions: Taken together, these results show that EDB-FN can be an effective drug delivery target and biomarker for MG.

Hemodynamic Features of Microsurgically Identified, Thin-Walled Regions of Unruptured Middle Cerebral Artery Aneurysms Characterized Using Computational Fluid Dynamics.

BACKGROUND: Thin-walled regions (TWRs) of aneurysm surfaces observed in microscopic surgery are thought to be vulnerable areas for growth and rupture of unruptured intracranial aneurysms (UIAs). OBJECTIVE: To identify hemodynamic features of TWRs of aneurysms by using computational fluid dynamics (CFD) analyses of unruptured middle cerebral artery bifurcation (MCAB) aneurysms. METHODS: Nine patients with 11 MCAB aneurysms were enrolled, and their TWRs were identified. CFD analysis was performed using 3 parameters: pressure, wall shear stress (WSS), and WSS divergence (WSSD). Each parameter was evaluated for its correspondence with TWR. RESULTS: Among 11 aneurysms, 15 TWRs were identified. Corresponding matches with CFD parameters (pressure, WSS, and WSSD) were 73.33, 46.67, and 86.67%, respectively. CONCLUSION: WSSD, a hemodynamic parameter that accounts for both magnitude and directionality of WSS, showed the highest correspondence. High WSSD might correspond with TWR of intracranial aneurysms, which are likely high-risk areas for rupture.

Delivery of therapeutic miRNA using polymer-based formulation.

MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in many cellular processes such as development, proliferation, differentiation, and apoptosis. For this reason, miRNAs have been proposed and investigated as biomarkers and therapeutics for various diseases such as cancer, diabetes, and cardiovascular disease. However, delivery of miRNAs and their antagomirs to target sites remains challenging because of poor cellular uptake and degradation by nucleases. Various delivery systems have been investigated for enhanced delivery of miRNAs to cells, organs, and tissues of interest, thereby enabling evaluation of their biological functions and clinical trials. In particular, non-viral, polymer-based carriers have shown advantages such as versatility of structural modifications and protection of unstable miRNA. Herein, we review properties and applications of poly (lactic-co-glycolic acid), chitosan, polyethyleneimine, and polyamidoamine dendrimers as carriers for effective delivery systems of miRNA mimic or anti-miRNAs that directly target essential miRNAs and/or their target genes. A number of miRNAs in clinical trials appear to use chemically modified miRNAs without any particular delivery system except one study with liposomal miRNA. With more accumulation of positive research results on polymeric delivery of miRNA in vitro and in vivo, we expect that polymeric delivery system will accelerate advancement of miRNA therapeutics to clinical study in the near future.

Unexpected Daily Changes in Tumor Volume during Fractionated Gamma Knife Radiosurgery for Solitary Intraventricular Metastatic Renal Cell Carcinoma: A Case Report.

For most fractionated stereotactic radiosurgery treatment plans, daily imaging is not routinely performed, because there is little expectation that lesions will change significantly in the short term. However, here, we present the case of an abrupt increase and decrease in tumor volume during fractionated gamma knife radiosurgery (GKRS) for metastatic brain cancer. A 65-year-old man with a history of nephrectomy due to renal cell carcinoma was admitted to our hospital because of mild cognitive disorder and gait disturbance. An initial MRI of the brain demonstrated a 5 × 3 × 4.5 cm-sized, heterogeneously well-enhanced tumor with a large cystic component compressing the left thalamus and corpus callosum near the lateral ventricle. Owing to its large size and proximity to critical structures, we decided to perform 3 fractionated GKRSs over 3 consecutive days. After the first fraction of 9 Gy with 50% isodose, follow-up MRI the next day revealed an unexpected increase in tumor volume up to 30%. Therefore, the radiosurgical plan was adjusted, and GKRS was performed again using the same dose for the second fraction. The image taken on the third day showed rapid shrinkage of the tumor volume. This case shows that a tumor may change its shape and volume unexpectedly even during the short period of a fractionated GKRS session. Hence, for optimal fractionated GKRS treatment of tumors with the likelihood of an abrupt change in the short term, interval imaging should be considered.

Analysis of Complications After Cranioplasty with a Customized Three-Dimensional Titanium Mesh Plate.

OBJECTIVE: To report outcomes of cranioplasty (CP) with a customized three-dimensional (3D) titanium mesh plate and identify the relationship between various clinical variables and complications after CP. METHODS: Twenty patients who underwent surgery with customized 3D titanium mesh plates and had follow-up for >6 months from January 2015 to December 2017 were enrolled. Complications related to CP were retrospectively reviewed. Patients were divided into 2 groups (no complication group and complication group), and clinical variables related to complications were compared between the 2 groups. Correlation analysis was performed to identify the clinical variable significantly correlated with complications after CP with a customized 3D titanium mesh plate. RESULTS: Of 20 patients, 11 developed complications, including extrusion, intracranial infection, severe operative site pain, and wound dehiscence. Among the clinical variables, only the presence of a ventriculoperitoneal shunt was significantly correlated with the overall complication rate (odds ratio = 18.66; 95% confidence interval, 1.56-222.92; P = 0.021). CONCLUSIONS: A customized 3D titanium mesh plate is associated with a lower risk of intracranial infection, but the rate of postoperative complications, mainly cosmetic problems, such as forehead mesh extrusion and dehiscence, was high at 55%. A ventriculoperitoneal shunt was significantly correlated with the overall complication rate after CP with a customized 3D titanium mesh plate.

Defining "early" cranioplasty to achieve lower complication rates of bone flap failure: resorption and infection.

BACKGROUND: Although cranioplasty (CP) is a frequently performed and simple procedure, complications are common, particularly bone flap resorption and infection. The timing of surgery is as an important contributory factor, but the optimal timing has not been clearly determined. OBJECTIVE: We retrospectively investigated bone flap resorption and surgical site infection after CP to determine the optimal timing of surgery for reduction of complications. METHODS: The study enrolled 126 patients who underwent decompressive craniectomy (DC) and subsequent CP. Patients with bone flap resorption or surgical site infection were analyzed as the "complication" group. Receiver operating characteristic curve analysis was performed and the Youden index was used to dichotomize "early CP" and "late CP" groups. Univariate and multivariate survival analyses were performed. RESULTS: The complication group included 42 patients. The Youden index was used to identify a cutoff value for the DC-CP interval of > 44 days, and this was used to define early (< 45 days) and late (≥ 45 days) CP. Late CP was a significant risk factor in univariate and multivariate Cox regression analyses. CONCLUSION: This study showed that early CP before 45 days after DC is associated with a lower rate of bone flap resorption and surgical site infection than late CP.

Efficacy of superficial temporal artery-middle cerebral artery bypass in cerebrovascular steno-occlusive diseases: Hemodynamics assessed by perfusion computed tomography.

OBJECTIVES: Our purpose of this study was to assess the cerebral hemodynamic improvement with perfusion computed tomography (CT), before and after superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery in patients with cerebrovascular steno-occlusive diseases including both moyamoya disease and nonmoyamoya steno-occlusions. MATERIALS AND METHODS: Twenty-four STA-MCA bypasses were performed to 22 patients with symptomatic cerebrovascular steno-occlusive diseases, including both moyamoya disease and nonmoyamoya steno-occlusive diseases. Brain perfusion CT images were obtained before and after the bypass surgery. The relative parameters such as cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) derived from the perfusion CT were collected and analyzed to assess the efficacy of STA-MCA bypass. RESULTS: The CBF increased, and MTT decreased after the bypass surgery in both moyamoya group and nonmoyamoya group. The increase of CBF in nonmoyamoya group and the decrease of MTT delay in moyamoya group, overall group were statistically significant (P < 0.05). No significant postoperative change in CBV was noted. During the postoperative follow-up period, none of the 22 patients experienced any repeated ischemic/hemorrhagic attacks nor any newly developed neurologic deficits. CONCLUSION: The STA-MCA bypass is an effective surgical management for patients with cerebrovascular steno-occlusive diseases, such as moyamoya disease and internal carotid artery/MCA steno-occlusion. And perfusion CT can be used as an effective quantitative modality to assess the cerebral perfusion before and after the STA-MCA bypass surgery.

The Role of Hypoxia in Angiogenesis and Extracellular Matrix Regulation of Intervertebral Disc Cells During Inflammatory Reactions.

BACKGROUND: The intervertebral disc (IVD) is an avascular structure, and is therefore stable under hypoxic conditions. Previous studies have demonstrated that hypoxia might be related to symptomatic degenerative disc diseases (DDDs); however, the pathomechanism is still poorly understood. OBJECTIVE: To identify the effect of hypoxia on the production of inflammatory mediators, angiogenic factors, and extracellular matrix-regulating enzymes of IVD cells during inflammatory reactions. METHODS: Human nucleus pulposus (NP) and annulus fibrosus (AF) cells harvested during surgery for DDDs were cultured in macrophage conditioned media or interleukin (IL)-1ß-stimulated media under hypoxic (2%) and normoxic (21%) conditions. Hypoxia-inducible factor-1α transcription factor activation was analyzed by western blotting. IL-6, IL-8, vascular endothelial growth factor (VEGF), vascular cell adhesion molecule (VCAM), matrix metalloproteinase (MMP)-1, MMP-3, tissue inhibitor of metalloprotease (TIMP)-1, and TIMP-2 in conditioned media were measured by an enzyme-linked immunosorbent assay. RESULTS: NP cells expressed higher hypoxia-inducible factor-1α in the IL-1ß-stimulated group under hypoxic condition. MMP-1 was significantly increased in the AF cells under hypoxic condition; TIMP-1 and TIMP-2 were significantly decreased in both naïve NP and AF cells during hypoxia. Both cells in macrophage conditioned media significantly diminished the production of IL-6 and VCAM, while VEGF significantly increased during hypoxia. After 1 ng/mL IL-1ß stimulation, IL-8, VEGF, MMP-1, and MMP-3 were significantly increased in both cell types during hypoxia, while VCAM, TIMP-1, and TIMP-2 were decreased. CONCLUSION: We found that hypoxia can enhance the angiogenic ability of IVD during inflammatory reactions, and cause progress in development of DDD via extracellular matrix regulation in this in vitro study.

Primary Glioblastoma of the Cerebellopontine Angle: Case Report and Review of the Literature.

Glioblastoma multiforme (GBM) is located most frequently in the cerebral hemispheres. Glioblastoma presenting as an extraaxial mass of cerebellopontine angle (CPA) is very rare in adults. We report a rare case of GBM arising in the CPA. The patient was a 71-year-old female, who complained of progressive gait disturbance and poor memory. Initial magnetic resonance imaging (MRI) revealed a 1.4×1.3 cm mass in the left CPA, with broad base to the petrous bone, showing homogenous enhancement. Follow-up MRI showed a rapid increase in size of mass (2.7×2.2 cm) with a necrotic portion. A stereotactic biopsy was done under the guidance of navigation system, and the histopathologic diagnosis was GBM, World Heath Organization grade IV. Further surgical resection was not performed considering her general condition, and the patient underwent concurrent chemotherapy with radiation therapy. Although rare, the possibility of glioblastoma should be included in the differential diagnosis of atypical CPA tumor.

Microelectrode recording (MER) findings during sleep-awake anesthesia using dexmedetomidine in deep brain stimulation surgery for Parkinson's disease.

OBJECTIVE: The preferred choice of anesthesia for deep brain stimulation (DBS) has been local anesthesia due to the need of patients' cooperation during the procedure, and concern on the interference of sedatives on microelectrode recording (MER) results. However, local anesthesia during the whole procedure may be impossible in some patients due to uncontrolled anxiety, fear, delirium or exhaustion. Therefore, sedative drugs have been used for DBS, but findings of MER during the procedures have not been reported in detail, especially in the globus pallidus internus (GPi). We introduce our experience using 'asleep-awake' technique by dexmedetomidine (DEX) anesthesia with MER findings during DBS in idiopathic Parkinson's disease (IPD) patients. PATIENTS AND METHODS: Data from 14 different subcortical nuclei from 8 consecutive IPD patients whom had DBS at the GPi (6 patients) and subthalamic nucleus (STN) (2 patients) were retrospectively reviewed. We used continuous DEX and intermittent small boluses of propofol during the painful procedure ('asleep phase'), accompanied with continuous intraoperative monitorings of bispectral index (BIS) and modified observer's assessment of sedation (MOAA/S). Then sedatives were discontinued during MER recording ('awake phase'). Characteristic findings and firing rates of neurons were analyzed and compared to those from other 6 patients who underwent surgery under local anesthesia. RESULTS: All patients were satisfactorily sedated using this technique without any respiratory or hemodynamic complications. Characteristics of spike activities of each nucleus were inspected and analyzed quantitatively. We could inspect changes of spike activities according to level of patients' consciousness in some cases, but the localizing value was good to decide the target in all cases. Firing rates of group whom sedatives were given during asleep phase ('sedatives') were significantly lower than those of group under local anesthesia ('no sedative'). Intraoperative length of target nuclei, postoperative imaging and postoperative changes of UPDRS III score indicated satisfactory outcome. CONCLUSION: We concluded that though MER findings may change during DEX-based monitored 'sleep-awake' anesthesia, it did not affect the results of target localization for the clinical purpose. However, it should be considered that use of sedatives before MER could result in changes of firing rate and pattern depending on the patient's state of consciousness.

Induction of proinflammatory cytokine production in intervertebral disc cells by macrophage-like THP-1 cells requires mitogen-activated protein kinase activity.

OBJECTIVE: To determine the role played by mitogen-activated protein kinase (MAPK) signaling in the interactions between macrophages and intervertebral disc (IVD) cells, it was hypothesized that MAPK inhibition would modulate the production of the proinflammatory cytokines associated with inflammatory reaction in IVD cells. METHODS: Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were cocultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells, with and without SB202190 (a p38-α and -ß inhibitor), SP600125 (a c-Jun N-terminal kinase [JNK] inhibitor), and PD98059 (an extracellular signal-regulated kinase [ERK] 1/2 inhibitor). The cytokines in conditioned media from cocultured and macrophage-exposed (nemotic) cells were assayed using enzyme-linked immunosorbent assays (ELISAs). RESULTS: Interleukin (IL)-6 and IL-8 were secreted in greater quantities by the cocultured cells compared with naive IVD cells and macrophages (MΦ) cultured alone. The tumor necrosis factor (TNF)- α and IL-6 levels produced by the NP cells cocultured with MΦs (NP-MΦ) were significantly lower than those produced by AF cells cocultured with MΦs (AF-MΦ). SB202190 dose-dependently suppressed IL-6 secretion by AF-MΦ and NP-MΦ cocultures, and 10 µM SB202190 significantly decreased IL-6 and IL-8 production in nemotic AF and NP pellets. SP600125 at 10 µM significantly suppressed the production of TNF α IL-6. and IL-8 in AF-MΦ and NP-MΦ cocultures and significantly suppressed IL-1ß production in the NP-MΦ coculture. Administration of 10 µM PD98059 significantly decreased IL-6 levels in the AF-MΦ coculture, and decreased the levels of TNF α and IL-8 in both the AF-MΦ and NP-MΦ cocultures. CONCLUSIONS: The present study shows that inhibitors of p38 MAPK effectively controlled IL-6 production during inflammatory reactions and that JNK and ERK1/2 inhibitors successfully suppressed the production of major proinflammatory cytokines during interactions between macrophages and IVD cells. Therefore, selective blockade of these signals may serve as a therapeutic approach to symptomatic IVD degeneration.

Expression of matrix metalloproteinase-2 and -9 in human ligamentum flavum cells treated with tumor necrosis factor-α and interleukin-1ß.

OBJECT: An in vitro study was performed to understand the potential roles of matrix metalloproteinase (MMP)-2 and MMP-9 in the elastin degradation of human ligamentum flavum (LF) cells via treatment with tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß). Previous studies have identified a decreased elastin to collagen ratio in hypertrophic LF. Among the extracellular matrix remodeling endopeptidases, MMP-2 and MMP-9 are known to have elastolytic activity. The hypothesis that activated LF cells exposed to inflammation would secrete MMP-2 and MMP-9, thereby resulting in elastin degradation, was examined. METHODS: To examine MMP-2 and MMP-9 expression in human LF, cells were isolated and cultured from LF tissues that were obtained during lumbar disc surgery. Isolated LF cells were equally divided into 3 flasks and subcultured. Upon cellular confluency, the LF cells were treated with TNFα, IL-1ß, or none (as a control) and incubated for 48 hours. The conditioned media were collected and assayed for MMP-2 and MMP-9 using gelatin zymography and Western blot analysis. The electrophoresis bands were compared on densitometric scans using ImageJ software. RESULTS: The conditioned media from the isolated human LF cells naturally expressed 72-kD and 92-kD gelatinolytic activities on gelatin zymography. The IL-1ß-treated LF cells presented sustained increases in the proenzyme/zymogen forms of MMP-2 and -9 (proMMP-2 and proMMP-9), and activeMMP-9 expression (p = 0.001, 0.022, and 0.036, respectively); the TNFα-treated LF cells showed the most elevated proMMP9 secretion (p = 0.006), as determined by Western blot analyses. ActiveMMP-2 expression was not observed on zymography or the Western blot analysis. CONCLUSIONS: TNFα and IL-1ß promote proMMP-2 and proMMP-9 secretion. IL-1ß appears to activate proMMP-9 in human LF cells. Based on these findings, selective MMP-9 blockers or antiinflammatory drugs could be potential treatment options for LF hypertrophy.

Intracranial Undifferentiated Sarcoma Arising from a Low-Grade Glioma: A Case Report and Literature Review.

Undifferentiated sarcomas are rarely identified in the intracranial region. A 23-year-old man was admitted with a chief complaint of headache. Initial magnetic resonance images showed signs of low-grade glioma in the frontal lobe. Stereotactic biopsy was performed, and a diagnosis of diffuse astrocytoma was confirmed. Three months later, the patient presented with a high-grade tumor as seen on imaging studies. He underwent total resection of the tumor and histopathological tests identified an undifferentiated sarcoma. The patient died eight months later due to massive tumor bleeding. To the best of our knowledge, this is the first report of undifferentiated sarcoma arising from low-grade glioma without any chemotherapy or radiotherapy.

The Mechanism of Ligamentum Flavum Hypertrophy: Introducing Angiogenesis as a Critical Link That Couples Mechanical Stress and Hypertrophy.

BACKGROUND: Biochemical alterations associated with mechanical stress have been explored as an initiating step in the pathological progression of ligamentum flavum hypertrophy (LFH); however, this mechanism remains poorly understood. Recently, the inflammation induced after mechanical stress and the subsequent response of ligamentum flavum (LF) cells have been implicated in LFH pathology. OBJECTIVE: To investigate the hypothesis that angiogenesis may be a critical link between hypertrophy and a series of stimulating events, including mechanical stress. METHODS: LF from 20 lumbar spinal canal stenosis (LSCS) patients and 16 non-LSCS patients (control group) were collected during surgery. Patient demographic and radiographic data were obtained. The levels of angiogenic factors (vascular endothelial growth factor [VEGF], angiopoietin-1, vascular cell adhesion molecule, and basic fibroblast growth factor) in the LF were investigated by using an enzyme-linked immunosorbent assay. Angiogenesis was also quantified by immunohistochemical detection of CD34-positive capillaries. The correlations among clinical factors, including radiographic factors, angiogenic factors, and angiogenesis, were statistically analyzed. RESULTS: The LSCS group was older and exhibited a longer symptom duration, wider segmental motion, and thicker LF than the control group. The LSCS group showed significantly higher tissue concentrations of VEGF (P < .001) that positively correlated with LF thickness (r = 0.557, P < .001) and segmental motion (r = 0.586, P < .001). The LSCS group showed significantly more CD34-positive capillaries than the control group (P = .004). CONCLUSION: The LSCS group showed greater segmental motion, higher VEGF concentrations, and more CD34-positive capillaries than the control group. These data indicate that VEGF-mediated angiogenesis following mechanical stress may be a critical step within the series of pathological events in LFH.