Variability in the prevalence of depression among adults with chronic pain: UK Biobank analysis through clinical prediction models.

BACKGROUND: The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence of depression among people with chronic pain and generate clinical prediction models to estimate the probability of depression among individuals with chronic pain. METHODS: Participants were from the UK Biobank. The primary outcome was a "lifetime" history of depression. The model's performance was evaluated using discrimination (optimism-corrected C statistic) and calibration (calibration plot). RESULTS: Analyses included 24,405 patients with chronic pain (mean age 64.1 years). Among participants with chronic widespread pain, the prevalence of having a "lifetime" history of depression was 45.7% and varied (25.0-66.7%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.66; good calibration on the calibration plot) included age, BMI, smoking status, physical activity, socioeconomic status, gender, history of asthma, history of heart failure, and history of peripheral artery disease. Among participants with chronic regional pain, the prevalence of having a "lifetime" history of depression was 30.2% and varied (21.4-70.6%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.65; good calibration on the calibration plot) included age, gender, nature of pain, smoking status, regular opioid use, history of asthma, pain location that bothers you most, and BMI. CONCLUSIONS: There was substantial variability in the prevalence of depression among patients with chronic pain. Clinically relevant factors were selected to develop prediction models. Clinicians can use these models to assess patients' treatment needs. These predictors are convenient to collect during daily practice, making it easy for busy clinicians to use them.

Epidemiological age-based differences in traumatic spinal cord injury patients: A multicenter study based on 13,334 inpatients.

CONTEXT: Compared with younger traumatic spinal cord injury (TSCI) patients, the elderly had longer delays in admission to surgery, higher proportion of incomplete injury, and longer hospital stays. However, in China, the country with the largest number of TSCI patients, there have been no large-scale reports on their age differences. OBJECTIVES: To explore the age-based differences among TSCI inpatients, focusing on the demographic and clinical characteristics, treatment status, and economic burden. METHODS: We collected the medical records of 13,334 inpatients with TSCI in the 30 hospitals of China, from January 1, 2013 to December 31, 2018. Trends are expressed as annual percentage changes (APCs) and 95% confidence intervals (CIs). RESULTS: A total of 13,334 inpatients were included. Both the number and proportion of the elderly showed an increasing trend. The APC of the number and proportion in patients ≥85 years were 39.5% (95% CI, 14.3 to 70.3; P < 0.01) and 30.5% (95% CI, 8.6 to 56.9; P < 0.01), respectively. Younger patients were more likely to undergo decompression surgery, and older patients were more likely to receive high-dose methylprednisolone sodium succinate/methylprednisolone (MPSS/MP). Of the patients ≥85 years, none underwent decompression surgery within 8 h, and only 1.4% received a high dose of MPSS/MP within 8 h after injury. Elderly patients had lower hospitalization costs than younger. The total and daily medical costs during hospitalization of patients ≥85 years were 8.06 ± 18.80 (IQR: 5.79) and 0.61 ± 0.73 (IQR: 0.55) thousands dollars, respectively. CONCLUSIONS: As the first study to focus on age differences of TSCI patients in China, this study found many differences, in demographic and clinical characteristics, treatment status, and economic costs, between older and younger TSCI patients. The number and proportion of elderly patients increased, and the rate of early surgery for elderly patients is low.

Low back pain-driven inpatient stays in the United States: a nationwide repeated cross-sectional analysis.

BACKGROUND: Low back pain (LBP)-driven inpatient stays are resource-intensive and costly, yet data on contemporary national trends are limited. MATERIALS AND METHODS: This study used repeated cross-sectional analyses through a nationally representative sample (US National Inpatient Sample, 2016-2019). Outcomes included the rate of LBP-driven inpatient stays; the resource utilization (the proportion of receiving surgical treatments and hospital costs) and prognosis (hospital length of stay and the proportion of nonroutine discharge) among LBP-driven inpatient stays. LBP was classified as overall, nonspecific, and specific (i.e. cancer, cauda equina syndrome, vertebral infection, vertebral compression fracture, axial spondyloarthritis, radicular pain, and spinal canal stenosis). Analyses were further stratified by age, sex, and race/ethnicity. RESULTS: 292 987 LBP-driven inpatient stays (weighted number: 1 464 690) were included, with 269 080 (91.8%) of these for specific LBP and 23 907 (8.2%) for nonspecific LBP. The rate of LBP-driven inpatient stays varied a lot across demographic groups and LBP subtypes (e.g. for overall LBP, highest for non-Hispanic White 180.4 vs. lowest for non-Hispanic Asian/Pacific Islander 42.0 per 100 000 population). Between 2016 and 2019, the rate of nonspecific LBP-driven inpatient stays significantly decreased (relative change: 46.9%); however, substantial variations were found within subcategories of specific LBP-significant increases were found for vertebral infection (relative change: 17.2%), vertebral compression fracture (relative change: 13.4%), and spinal canal stenosis (relative change: 19.9%), while a significant decrease was found for radicular pain (relative change: 12.6%). The proportion of receiving surgical treatments also varied a lot (e.g. for overall LBP, highest for non-Hispanic White 74.4% vs. lowest for non-Hispanic Asian/Pacific Islander 62.8%), and significantly decreased between 2016 and 2019 (e.g. for nonspecific LBP, relative change: 28.6%). Variations were also observed for other outcomes. CONCLUSIONS: In the US, the burden of LBP-driven inpatient stays (i.e. rates of LBP-driven inpatient stays, resource utilization, and prognosis among LBP-driven inpatient stays) is enormous. More research is needed to understand why the burden varies considerably according to the LBP subtype (i.e. nonspecific and specific LBP as well as subcategories of specific LBP) and the subpopulation concerned (i.e. stratified by age, sex, and race/ethnicity).

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Global, regional and national burden of traumatic brain injury and spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.

OBJECTIVES: To evaluate the most up-to-date burden of traumatic brain injury (TBI) and spinal cord injury (SCI) and analyse their leading causes in different countries/territories. DESIGN: An analysis of Global Burden of Disease (GBD) data. SETTING: The epidemiological data were gathered from GBD Results Tool (1 January, 1990─31 December 2019) covering 21 GBD regions and 204 countries/ territories. PARTICIPANTS: Patients with TBI/SCI. MAIN OUTCOMES AND MEASURES: Absolute numbers and age-standardised rates/estimates of incidence, prevalence and years lived with disability (YLDs) of TBI/SCI by location in 2019, with their percentage changes from 1990 to 2019. The leading causes (eg, falls) of TBI/SCI in 204 countries/territories. RESULTS: Globally, in 2019, TBI had 27.16 million new cases, 48.99 million prevalent cases and 7.08 million YLDs. SCI had 0.91 million new cases, 20.64 million prevalent cases and 6.20 million YLDs. Global age-standardised incidence rates of TBI decreased significantly by -5.5% (95% uncertainty interval -8.9% to -3.0%) from 1990 to 2019, whereas SCI had no significant change (-6.1% (-17.3% to 1.5%)). Regionally, in 2019, Eastern Europe and High-income North America had the highest burden of TBI and SCI, respectively. Nationally, in 2019, Slovenia and Afghanistan had the highest age-standardised incidence rates of TBI and SCI, respectively. For TBI, falls were the leading cause in 74% (150/204) of countries/territories, followed by pedestrian road injuries (14%, 29/204), motor vehicle road injuries (5%, 11/204), and conflict and terrorism (2%, 4/204). For SCI, falls were the leading cause in 97% (198/204) of countries/territories, followed by conflict and terrorism (3%, 6/204). CONCLUSIONS: Global age-standardised incidence rates of TBI have decreased significantly since 1990, whereas SCI had no significant change. The leading causes of TBI/SCI globally were falls, but variations did exist between countries/territories. Policy-makers should continue to prioritise interventions to reduce falls, but priorities may vary between countries/territories.

Traumatic spinal injury-related hospitalizations in the United States, 2016-2019: a retrospective study.

BACKGROUND: Traumatic spinal injury (TSI) is associated with significant fatality and social burden; however, the epidemiology and treatment of patients with TSI in the US remain unclear. MATERIALS AND METHODS: An adult population was selected from the National Inpatient Sample database from 2016 to 2019. TSI incidence was calculated and TSI-related hospitalizations were divided into operative and nonoperative groups according to the treatments received. TSIs were classified as fracture, dislocation, internal organ injury, nerve root injury, or sprain injuries based on their nature. The annual percentage change (APC) was calculated to identify trends. In-hospital deaths were utilized to evaluate the prognosis of different TSIs. RESULTS: Overall, 95 047 adult patients were hospitalized with TSI in the US from 2016 to 2019, with an incidence rate of 48.4 per 100 000 persons in 2019 (95% CI: 46.2-50.6). The total incidence increased with an APC of 1.5% (95% CI: 0.1-3%) from 2016 to 2019. Operative TSI treatment was more common than nonoperative (32.8 vs. 3.8; 95% CI: 32.3-33.2 vs. 3.6-4%). The number of operations increased from 37 555 (95% CI: 34 674-40 436) to 40 460 (95% CI: 37 372-43 548); however, the operative rate only increased for internal organ injury (i.e. spinal cord injury [SCI])-related hospitalizations (APC, 3.6%; 95% CI: 2.8-4.4%). In-hospital mortality was highest among SCI-related hospitalizations, recorded at 3.9% (95% CI: 2.9-5%) and 28% (95% CI: 17.9-38.2%) in the operative and nonoperative groups, respectively. CONCLUSIONS: The estimated incidence of TSI in US adults increased from 2016 to 2019. The number of operations increased; however, the proportion of operations performed on TSI-related hospitalizations did not significantly change. In 2019, SCI was the highest associated mortality TSI, regardless of operative or nonoperative treatment.

A critical appraisal of clinical practice guidelines on surgical treatments for spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury (SCI) is a global health problem with a heavy economic burden. Surgery is considered as the cornerstone of SCI treatment. Although various organizations have formulated different guidelines on surgical treatment for SCI, the methodological quality of these guidelines has still not been critically appraised. PURPOSE: We aim to systematically review and appraise the current guidelines on surgical treatments of SCI and summarize the related recommendations with the quality evaluation of supporting evidence. STUDY DESIGN: Systematic review. METHODS: Medline, Cochrane library, Web of Science, Embase, Google Scholar, and online guideline databases were searched from January 2000 to January 2022. The most updated and recent guidelines containing evidence-based or consensus-based recommendations and established by authoritative associations were included. The Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument containing 6 domains (eg, applicability) was used to appraise the included guidelines. An evidence-grading scale (ie, level of evidence, LOE) was utilized to evaluate the quality of supporting evidence. The supporting evidence was categorized as A (the best quality), B, C, and D (the worst quality). RESULTS: Ten guidelines from 2008 to 2020 were included, however, all of them acquired the lowest scores in the domain of applicability among all the six domains. Fourteen recommendations (eight evidence-based recommendations and six consensus-based recommendations) were totally involved. The SCI types of the population and timing of surgery were studied. Regarding the SCI types of the population, eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and three guidelines (3/10, 30%) recommended surgical treatment for patients with SCI without further clarification of characteristics, incomplete SCI, and traumatic central cord syndrome (TCCS), respectively. Besides, one guideline (1/10, 10%) recommended against surgery for patients with SCI without radiographic abnormality. Regarding the timing of surgery, there were eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and two guidelines (2/10, 20%) with recommendations for patients with SCI without further clarification of characteristics, incomplete SCI, and TCCS, respectively. For patients with SCI without further clarification of characteristics, all eight guidelines (8/8, 100%) recommended for early surgery and five guidelines (5/8, 62.5%) recommended for the specific timing, which ranged from within 8 hours to within 48 hours. For patients with incomplete SCI, two guidelines (2/2, 100%) recommended for early surgery, without specific time thresholds. For patients with TCCS, one guideline (1/2, 50%) recommended for surgery within 24 hours, and another guideline (1/2, 50%) simply recommended for early surgery. The LOE was B in eight recommendations, C in three recommendations, and D in three recommendations. CONCLUSIONS: We remind the reader that even the highest quality guidelines often have significant flaws (eg, poor applicability), and some of the conclusions are based on consensus recommendations which is certainly less than ideal. With these caveats, we found most included guidelines (8/10, 80%) recommended early surgical treatment for patients after SCI, which was consistent between evidence-based recommendations and consensus-based recommendations. Regarding the specific timing of surgery, the recommended time threshold did vary, but it was usually within 8 to 48 hours, where the LOE was B to D.

Sex-related Differences in Epidemiology, Treatment, and Economic Burden of Traumatic Spinal Cord Injury in China (2013-2018).

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVE: To describe differences based on biological sex in the epidemiology and treatment of the economic burden of traumatic spinal cord injury (TSCI) in China (2013-2018). SUMMARY OF BACKGROUND DATA: Although there have been many regional single-center studies on TSCI in China, there are few reports involving multicenter data, especially those that report on discrepancies related to biological sex. MATERIALS AND METHODS: This study is a nationally representative hospital-based retrospective study. The treatment data of TSCI patients in 30 hospitals in 11 provinces/cities from January 2013 to December 2018 were analyzed. Sociodemographic characteristics, accident and related injury characteristics, treatment methods, and hospital costs were obtained. Regression models were used to evaluate differences in the outcomes of interest based on biological sex and other factors. RESULTS: There were 13,465 individuals with TSCI, with a mean age of 50.0 years, and females (52.2) older than males (49.3). Overall, the average ratio of males to females was 3.1:1, ranging from 3.0:1 in 2013 to 2.8:1 in 2018. The overall proportion of patients with TSCI increased from 2013 to 2018 [annual percentage change (APC)=6.8%, 95% CI, 3.3-10.4] ( P < 0.05). The percent increase in females (APC=8.2%, 95% CI, 5.6-10.8) was greater than that of males (APC=6.3%, 95% CI, 2.1-10.6). Overall, high-level falls mainly affected males (30.8%), and low-level falls mainly occurred in females (36.6%). Females demonstrated a higher frequency of thoracolumbar trauma and less severe neurological impairment. CONCLUSIONS: This study suggests that although the main population of TSCI is male, the average ratio of males to females is decreasing. The frequency of TSCI may be increasing faster in females than in males. Therefore, it is necessary to develop sex-specific public prevention measures. In addition, more medical resources should be devoted to improving the ability of hospitals to perform early surgery.

A critical appraisal of clinical practice guidelines for management of four common complications after spinal cord injury.

BACKGROUND CONTEXT: Complications such as pressure sores, pulmonary infection, urinary tract infection (UTI), and venous thromboembolism (VTE) are common after spinal cord injury (SCI). These have serious consequences for patients' physical, social, and vocational well-being. Several authoritative organizations have developed guidelines for managing these complications after SCI. PURPOSE: We aim to systematically review and appraise guidelines on the management of four common complications (pressure sores, pulmonary infection, UTI, and VTE) after SCI as well as to summarize relevant recommendations and assess the quality of their supporting evidence. DESIGN: Systematic review. METHODS: We searched Medline, Embase, Cochrane, and Web of Science, as well as guideline-specific databases (eg, National Guideline Clearinghouse) and Google Scholar, from January 2000 to January 2022. We included the most updated guidelines developed by specific authoritative organizations. We evaluated the included guidelines using the Appraisal of Guidelines for Research and Evaluation 2nd edition instrument, which measures six domains (eg, applicability). Recommendations extracted from guidelines were categorized as for, against, or neither for nor against. An evidence assessment was adopted to classify the quality of supporting evidence as poor, fair, or good. RESULTS: Eleven guidelines from 2005 to 2020 were included, all of which, among the six domains, scored lowest in the domain of applicability. For pressure sores, guidelines recommended for skin inspection, repositioning, and the use of pressure reduction equipment as preventive measures and dressings, debridement, and surgery as treatment measures. For pulmonary infection, guidelines recommended for physical (eg, the use of an insufflation-exsufflation device) and pharmacological measures (eg, the use of bronchodilators). For UTI, guidelines recommended for antibiotics as a treatment measure but recommended against cranberries, methenamine salts, and acidification or alkalinization agents as preventive measures. For VTE prophylaxis, five guidelines recommended for low molecular weight heparin (LMWH). Three guidelines recommended against unfractionated heparin, whereas one guideline recommended for it. Most of the supporting evidence was of poor quality (130/139), and the rest was of fair quality (9/139). CONCLUSIONS: For pressure sores, pulmonary infection, and UTI, evidence of poor to fair quality indicated consistent recommendations for prevention and treatment measures. For VTE, LMWH was consistently recommended, whereas recommendations on the use of unfractionated heparin were controversial.

Comparison of the efficacy of expandable interbody fusion cage (EXP-IFC) and non-expandable interbody fusion cage (NE-IFC) in MIS-TLIF for lumbar degenerative diseases: A systematic retrospective study on 62 patients.

Objectives: To investigate the clinical and radiographic outcomes of EXP-IFC in single-level MIS-TLIF. Methods: This study included patients aged ≥18 years who received a single-level MIS-TLIF procedure with at least 1 year of follow-up. Outcome measures: clinical features, preoperative and neurological complications. Imaging analysis included disc height (DH) restoration, surgical and contralateral side foraminal height (FH), lumbar lordosis angle (LL), segmental lordosis (SL). Visual analog scale (VAS) score for low back pain (VAS-LBP) and leg pain (VAS-LP), Oswestry Disability Index (ODI) and Japanese Orthopaedic Association (JOA) score were used to evaluate clinical outcomes. Statistical analysis was performed using independent sample t-test and sample t-test. The significance was set to p < 0.05 in univariate analysis. Results: A total of 62 patients undergoing single level MIS-TLIFs between January 2017 and January 2019 were included, with 32 NE-IFC 46.9% female, mean age 54.86 ± 11.65, mean body mass index (BMI) 24.59 ± 3.63) and 30 EXP (40% female, mean age 58.32 ± 12.99, mean BMI 24.45 ± 2.76) with no significant differences in demographics. There were no significant differences between two groups in Operative time (OT), Estimated blood loss (EBL) and Length of stay (LOS). No significant differences were found in VAS-LBP, VAS-LP, JOA and ODI in post-operation and the last follow-up between the two groups. The imaging outcome demonstrated that the mean increase in DH was significantly greater for the patients with EXP-IFC than those with NE-IFC group at 1 year follow-up (8.92 ± 0.51 mm EXP-IFC vs. 7.96 ± 0.96 mm NE-IFC, p < 0.001). The mean change in FH of operative and contralateral sides were observed to be significantly higher for the patients with EXP-IFC at 1 year follow-up (operative side:17.67 ± 2.29 mm EXP-IFC vs. 16.01 ± 2.73 mm NE-IFC, p = 0.042; contralateral side:17.32 ± 2.26 mm EXP-IFC vs. 16.10 ± 2.32 mm NE-IFC, p < 0.001), but changes in LL and SL were not significantly different. At the last follow-up, we did not find any significant difference in the fusion rate between the two groups. Conclusion: Our results indicated that there may be no significant difference in short-term clinical outcomes between EXP-IFC and NE-IFC, but the use of EXP-IFC in MIS-TLIF can provide a significant restoration of disc height, and neural foraminal height compared to NE-IFC.

Identification and characterization of aging/senescence-induced genes in osteosarcoma and predicting clinical prognosis.

Background: Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction. Methods: Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM. Results: Three molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score. Conclusion: Aging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.

Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.

The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for ß-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-ß-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

The potential role and trend of HIF­1α in intervertebral disc degeneration: Friend or foe? (Review).

Lower back pain (LBP) is one of the most common reasons for seeking medical advice in orthopedic clinics. Increasingly, research has shown that symptomatic intervertebral disc degeneration (IDD) is mostly related to LBP. This review first outlines the research and findings of studies into IDD, from the physiological structure of the intervertebral disc (IVD) to various pathological cascades. The vicious cycles of IDD are re­described in relation to the analysis of the relationship among the pathological mechanisms involved in IDD. Interestingly, a 'chief molecule' was found, hypoxia­inducible factor­1α (HIF­1α), that may regulate all other mechanisms involved in IDD. When the vicious cycle is established, the low oxygen tension activates the expression of HIF­1α, which subsequently enters into the hypoxia­induced HIF pathways. The HIF pathways are dichotomized as friend and foe pathways according to the oxygen tension of the IVD microenvironment. Combined with clinical outcomes and previous research, the trend of IDD development has been predicted in this paper. Lastly, an early precautionary diagnosis and treatment method is proposed whereby nucleus pulposus tissue for biopsy can be obtained through IVD puncture guided by B­ultrasound when the patient is showing symptoms but MRI imaging shows negative results. The assessment criteria for biopsy and the feasibility, superiority and challenges of this approach have been discussed. Overall, it is clear that HIF­1α is an indispensable reference indicator for the accurate diagnosis and treatment of IDD.

Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines.

BACKGROUND/OBJECTIVE: Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI. METHOD: NTP was intraperitoneally administered to adult female Wistar rats subjected to contusion-induced SCI. Functional recovery was evaluated with behavioural scores and electrophysiological examinations. Tissue recovery was assessed with magnetic resonance imaging as well as histological staining with haematoxylin and eosin and Luxol Fast Blue. Neuronal survival and gliosis were observed after NeuN and glial fibrillary acidic protein immunofluorescence. Levels of apoptosis were demonstrated with TdT-mediated dUTP nick-end labeling (TUNEL) staining, Caspase-3 and B-cell lymphoma-2 (Bcl-2) Western blot, and Annexin V/propidium iodide flow cytometry. A protein antibody chip analysis was performed to evaluate the expression levels of 67 rat cytokines. RESULTS: NTP treatment improved the hindlimb locomotor recovery of the injured animals as well as their electrophysiological outcomes after SCI. A dosage of 50 NTP units/kg was found to optimize the efficacy of NTP. Magnetic resonance imaging revealed that lesion sizes decreased after NTP treatment. The haematoxylin and eosin and Luxol Fast Blue staining showed significant increases in the amount of spared tissue. The NeuN and glial fibrillary acidic protein immunofluorescence revealed that NTP treatment increased neuronal survival and reduced gliosis in tissue samples obtained from the lesion's epicentre. That NTP inhibited apoptosis was confirmed by the decreased number of TUNEL-positive cells, level of Caspase-3 expression, and number of Annexin V/propidium iodide-positive cells, as well as the increased level of Bcl-2 expression. The protein array analysis identified 28 differentially expressed proteins in the NTP group, and the gene ontology (GO) analysis showed that the enriched differentially expressed proteins implicate janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathways. The expression levels of proinflammatory cytokines such as interleukin 6, thymus chemokine-1(TCK-1), and lipopolysaccharide-induced CXC chemokine (LIX) decreased after NTP treatment, whereas the levels of prorepair cytokine hepatocyte growth factor and adiponectin increased. CONCLUSION: Our research provides evidence that NTP can improve functional outcomes and alleviate secondary injury after SCI by inhibiting apoptosis and modulating cytokines. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The multicomponent NTP might have broad target spectra in SCI pathophysiology and halt the secondary injury cascade. As a safe drug that features sixty years of clinical use as an analgesic, translating this demonstrated efficacy of NTP to addressing SCI in human patients may potentially be accelerated.

PTEN modulates neurites outgrowth and neuron apoptosis involving the PI3K/Akt/mTOR signaling pathway.

The present study aimed to explore the role of the PTEN/Akt/mTOR signaling pathway in the neurite outgrowth and apoptosis of cortical neurons. Cortical neurons were seeded on or adjacent to chondroitin sulfate proteoglycans. The length, number and crossing behavior of the neurites were calculated. Immunohistochemical staining and TUNEL data were analyzed. Neurites treated with PTEN inhibitor exhibited significant enhancements in elongation, initiation and crossing abilities when they encountered chondroitin sulfate proteoglycans in vitro. These effects disappeared when the PTEN/Akt/mTOR signaling pathway was blocked. Neurons exhibited significant enhancements in survival ability following PTEN inhibition. The present study demonstrated that PTEN inhibition can promote axonal elongation and initiation in cerebral cortical neurons, as well as the ability to cross the chondroitin sulfate proteoglycan border. In addition, PTEN inhibition is useful for protecting the neuron from apoptosis. The PTEN/Akt/mTOR signaling pathway is an important signaling pathway.

proBDNF inhibits the proliferation and migration of OLN­93 oligodendrocytes.

In contrast with mature brain­derived neurotrophic factor (mBDNF), proBDNF induces cell apoptosis. However, the function of proBDNF in oligodendrocytes remains unclear. In the present study, the OLN­93 oligodendroglia cell line was utilized as an in vitro model to analyse the functions of proBDNF in oligodendroglia. p75NTR, sortilin and proBDNF were expressed in cultured OLN­93 cells. It was indicated that proBDNF inhibited OLN­93 cell proliferation in a dose­dependent manner as determined using the MTT assay and BrdU staining. Furthermore, proBDNF suppressed the migration of OLN­93 cells as demonstrated using the scratch assay. proBDNF also decreased cell viability and promoted apoptosis as indicated by activated cysteine­aspartic acid protease­3 (caspase­3) immunocytochemistry. Notably, anti­proBDNF treatment neutralized the effect of proBDNF and resulted in increased cell proliferation and migration and decreased apoptosis. However, these effects were not observed in the presence of recombinant p75NTR extracellular domain­human FC fusion protein and p75NTR antibody, indicating that proBDNF imparts its inhibitory effects on oligodendrocytes through the p75NTR signal pathway.

Microenvironment Imbalance of Spinal Cord Injury.

Spinal cord injury (SCI), for which there currently is no cure, is a heavy burden on patient physiology and psychology. The microenvironment of the injured spinal cord is complicated. According to our previous work and the advancements in SCI research, 'microenvironment imbalance' is the main cause of the poor regeneration and recovery of SCI. Microenvironment imbalance is defined as an increase in inhibitory factors and decrease in promoting factors for tissues, cells and molecules at different times and spaces. There are imbalance of hemorrhage and ischemia, glial scar formation, demyelination and re-myelination at the tissue's level. The cellular level imbalance involves an imbalance in the differentiation of endogenous stem cells and the transformation phenotypes of microglia and macrophages. The molecular level includes an imbalance of neurotrophic factors and their pro-peptides, cytokines, and chemokines. The imbalanced microenvironment of the spinal cord impairs regeneration and functional recovery. This review will aid in the understanding of the pathological processes involved in and the development of comprehensive treatments for SCI.

Identification and Verification of Candidate Genes Regulating Neural Stem Cells Behavior Under Hypoxia.

BACKGROUND/AIMS: Neural stem cells (NSCs) reside in a hypoxic environment, and hypoxia plays an important role in their development and differentiation. This study aimed to explore the underlying mechanisms by which hypoxia affects NSC behavior. METHODS: In the current study, we downloaded the gene expression dataset GSE68572 and identified the differentially expressed genes (DEGs) by analyzing high-throughput gene expression in hypoxic and normoxic NSCs. Subsequently, we analyzed these data using a combined bioinformatics approach and predicted the microRNAs (miRNAs) targeting the key gene using miRNA databases. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of the top five DEGs. RESULTS: In total, 1347 genes were identified as DEGs. We identified the predominant gene ontology categories and Kyoto Encyclopedia of Genes and Genomes pathways that were significantly over-represented in the hypoxic NSCs. A protein-protein interaction network he identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer the top 10 core genes. Vascular endothelial growth factor A (VEGFA) had the highest degree and may be the key gene concerning NSC behavior under hypoxia. Further validation of the top five DEGs by qRT-PCR demonstrated that four DEGs were significantly higher and one DEG was significantly lower in the hypoxic group than in the control group. Seven miRNAs were predicted and proved to target VEGFA. CONCLUSION: This preliminary study can prompt the understanding of the molecular mechanisms by which hypoxia has an impact on NSC behavior and can help to optimize stem cell therapies for central nervous system injuries and diseases.

MicroRNA-29a regulates neural stem cell neuronal differentiation by targeting PTEN.

Neural stem cells (NSCs) are self-renewing, pluripotent, and undifferentiated cells which have benefits as candidates for central nervous system (CNS) injury. However, the transplanted NSCs usually maintain their undifferentiated characteristics, or differentiated potentially along the glial lineage after transplantation. MicroRNAs (miRNAs) are small, non-coding RNAs that play key roles in cell differentiation. However, it is unknown whether miR-29a could play a role in the process of NSC's differentiation. Primary NSCs were derived from rat embryonic cortex. Lentiviral vector-mediated miR-29a (LV-miR-29a) and negative control (LV-null) were infected into NSCs. Quantitative real-time PCR was used to detect expression of miR-29a and PTEN. Immunocytochemistry was used to stain neurons, astrocytes, and oligodendrocytes. Dual luciferase assay to study the interaction between miR-29a and PTEN. The current study showed that the expression of miR-29a was upregulated during NSC differentiation, while the expression of PTEN was downregulated during NSC differentiation. After infection with LV-miR-29a, MAP-2-positive neurons significantly increased, and GFAP-positive astrocytes significantly decreased. Furthermore, we demonstrated that PTEN is a molecular target of miR-29a. miR-29a promote the neuronal differentiation and decrease the astrocytes differentiation of NSCs via targeting PTEN. This may give insight into a novel mechanism of NSC differentiation and provide a promising therapeutic target.