Hyper-inflammation of astrocytes in patients of major depressive disorder: Evidence from serum astrocyte-derived extracellular vesicles.

Astrocyte-derived extracellular vesicles (ADEs) allow the in vivo probing of the inflammatory status of astrocytes practical. Serum sample and ADEs were used to test the inflammatory hypothesis in 70 patients with major depressive disorder (MDD) and 70 matched healthy controls (HCs). In serum, tumor necrosis factor α (TNF-α) and interleukin (IL)-17A were significantly increased, where as IL-12p70 was significantly reduced in the MDD patients compared with HCs. In ADEs, all inflammatory markers (Interferon-γ, IL-12p70, IL-1ß, IL-2, IL-4, IL-6, TNF-α, and IL-17A) except IL-10 were significantly increased in the MDD patients, the Hedge's g values of elevated inflammatory markers varied from 0.48 to 1.07. However, there were no differences of all inflammatory markers whether in serum or ADEs between MDD-drug free and medicated subgroups. The association of inflammatory biomarkers between ADEs and serum did not reach statistically significance after multi-comparison correction neither in the HCs nor MDD patients. The spearman coefficients between inflammatory factors and clinical characteristics in the MDD patients, such as onset age, disease course, current episode duration, and severity of depression, were nonsignificant after multi-comparison correction. In the receiver operating characteristic curves analysis, the corrected partial area under the curve (pAUC) of each inflammatory markers in ADEs ranged from 0.522 to 0.696, and the combination of these inflammatory factors achieved a high pAUC (>0.9). Our findings support the inflammatory glial hypothesis of depression, and suggests that in human ADEs could be a useful tool to probe the in vivo astrocyte status.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy.

AIM: The current study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma. METHODS: A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls were recruited at baseline, and 34 patients with TRD completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein [GFAP] and S100ß), an extracellular vesicle marker cluster of differentiation 81 (CD81), and nine inflammatory markers in ADEVs were measured as main analyses. In addition, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis. RESULTS: At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100ß, as well as CD81 compared with the healthy controls. Inflammatory markers interferon γ (IFN-γ), interleukin (IL) 1ß, IL-4, IL-6, tumor necrosis factor α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECT, there was a significant reduction in the levels of GFAP, S100ß, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100ß, CD81, and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function. CONCLUSION: This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert an anti-inflammatory effect through inhibition of such activation of astrocytes.

Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in major depressive disorder patients.

BACKGROUND: The microbiota-gut-brain axis, especially the microbial tryptophan (Trp) biosynthesis and metabolism pathway (MiTBamp), may play a critical role in the pathogenesis of major depressive disorder (MDD). However, studies on the MiTBamp in MDD are lacking. The aim of the present study was to analyze the gut microbiota composition and the MiTBamp in MDD patients. METHODS: We performed shotgun metagenomic sequencing of stool samples from 26 MDD patients and 29 healthy controls (HCs). In addition to the microbiota community and the MiTBamp analyses, we also built a classification based on the Random Forests (RF) and Boruta algorithm to identify the gut microbiota as biomarkers for MDD. RESULTS: The Bacteroidetes abundance was strongly reduced whereas that of Actinobacteria was significantly increased in the MDD patients compared with the abundance in the HCs. Most noteworthy, the MDD patients had increased levels of Bifidobacterium, which is commonly used as a probiotic. Four Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologies (KOs) (K01817, K11358, K01626, K01667) abundances in the MiTBamp were significantly lower in the MDD group. Furthermore, we found a negative correlation between the K01626 abundance and the HAMD scores in the MDD group. Finally, RF classification at the genus level can achieve an area under the receiver operating characteristic curve of 0.890. CONCLUSIONS: The present findings enabled a better understanding of the changes in gut microbiota and the related Trp pathway in MDD. Alterations of the gut microbiota may have the potential as biomarkers for distinguishing MDD patients form HCs.

Short-term effects of air pollution on cause-specific mental disorders in three subtropical Chinese cities.

BACKGROUND: The effects of ambient air pollution on specific mental disorders are rarely studied, and the reported results are inconsistent. OBJECTIVE: To assess the short-term effect of ambient air pollution on the morbidity of mental disorders in three subtropical Chinese cities. METHODS: Daily concentrations of air pollution were averaged from 19 fixed monitoring stations across each city, and data on patients were collected from three psychiatric specialty hospitals. A time-series study combined with a generalized additive Poisson model was conducted to investigate the association between air pollution and mental disorders. The exposure-response relationships were explored and stratified analyses by age and sex were conducted. RESULTS: A total of 1,133,220 outpatient visits were recorded in three subtropical cities (Huizhou, Shenzhen, and Zhaoqing). The number of daily outpatient visits for mental disorders increased with higher air pollutant (PM2.5, PM10, SO2 and NO2) concentrations, and the effect of NO2 appeared to be consistently significant across the three cities, with excess risk (ER) of 4.45% (95% CI: 2.90%, 6.04%) in Huizhou, 7.94% (95% CI: 6.28%, 9.62%) in Shenzhen, and 2.19% (95% CI: 0.51%, 3.89%) in Zhaoqing, respectively, at lag03. We also observed significant effect of PM2.5 at lag0 (ER = 1.20%, 95% CI: 0.28%, 2.13%), PM10 at lag0 (ER = 0.99%, 95% CI: 0.36%, 1.62%), and SO2 at lag0 (ER = 10.74%, 95% CI: 3.20%, 18.84%) in Shenzhen. For specific mental disorders, significant associations were found in all the air pollutants except between SO2 and affective disorder and between PM2.5 and schizophrenia. In addition, we found that air pollution exhibited stronger effects for males and adults (≥18 years). CONCLUSION: Acute exposure to air pollution, especially NO2, might be an important trigger of mental disorders.

Study protocol for a parallel-group, double-blinded, randomized, controlled, noninferiority trial: the effect and safety of hybrid electroconvulsive therapy (Hybrid-ECT) compared with routine electroconvulsive therapy in patients with depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the most rapid and effective treatment for patients with depression, ECT can achieve remarkable antidepressant effects in the initial 3-4 sessions, but significant side effects limit its use. However, recent low-charge electrotherapy (LCE) studies have demonstrated antidepressant or antipsychotic effects with significantly fewer side effects. The aim of this study is to propose a novel two-step charge set strategy for ECT treatment, referred to as Hybrid-ECT, to decrease side effects by using a low charge while preserving treatment efficacy. METHODS/DESIGN: A randomized, double-blinded, standard-controlled, parallel-group design will be carried out. We plan to enroll 112 inpatients diagnosed with depression (unipolar or bipolar) and randomly assign them to conventional ECT (control group) or to Hybrid-ECT (treatment group, 3 ECT sessions followed by LCE sessions (approximately 2.8 joules per session)). We will evaluate participants across a wide variety of domains including clinical symptoms, cognitive, psychological and functional metrics. We will also perform magnetic resonance imaging (MRI) and event-related potential (ERPs) assessments during treatment to explore brain function differences between ECT and LCE. DISCUSSION: This research proposes a simple but completely novel ECT strategy that aims to rapidly relieve depressive symptoms and minimize side effects. The mechanism of ECT and LCE will be further discussed. TRIAL REGISTRATION: Chinese Clinical Trial Registry, Number: ChiCTR1900022905 (Registration date: April 30, 2019).

Survival analysis of patients with spinal chordomas.

This study was aimed to analyze the survival of patients with spinal chordomas. Patients' data in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved and analyzed statistically. There were 765 patients with spinal chordomas between 1974 and 2013. The overall survival did not improve significantly over decades for patients receiving surgery and radiotherapy (SR) (P = 0.221). There were significant differences in overall survival among subgroups of patients receiving surgery (S), radiotherapy (R), and neither S nor R (NSR) (P = 0.031, 0.037, and 0.031, respectively). Cancer-specific survival did not change significantly among subgroups of patients receiving R (P = 0.411), while it increased steadily among subgroups of patients receiving S, SR, and NSR (P < 0.001, 0.001, and 0.049, respectively). In the multivariate Cox regression model, younger onset age (hazard ratio [HR] 1.052, P < 0.001), surgery (HR 0.291, P = 0.001), and tumor location of the sacrum (HR 0.401, P = 0.002) were associated with a better overall survival. Similarly, younger onset age (HR 1.036, P = 0.029), surgery (HR 0.221, P = 0.009), and tumor location of the sacrum (HR 0.287, P = 0.002) were also associated with a higher cancer-specific survival. The changes in overall and cancer-specific survival over time differ among different treatment groups. Younger onset age, surgical strategy, and tumor location of the sacrum may be correlated with a higher overall and cancer-specific survival.

A cohort study comparing the serum levels of pro- or anti-inflammatory cytokines in patients with lumbar radicular pain and healthy subjects.

PURPOSE: The factors influencing the presence or absence of pain in sciatica secondary to disc herniation remain incompletely understood. We hypothesized that the imbalance in inflammatory cytokines is implicated in the generation of pain. In our study, serum levels of pro-inflammatory and anti-inflammatory cytokines were investigated among patients with severe sciatica; the serum levels were compared with those of patients with mild sciatica and healthy subjects. METHODS: In this prospective study, blood protein levels of the pro-inflammatory cytokines, namely, interleukin-6 (IL-6), interleukin-8 (IL-8),and tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokines, namely, interleukin-4 (IL-4) and interleukin-10 (IL-10), of 58 patients with severe sciatica, 50 patients with mild sciatica, and 30 healthy control subjects were analyzed through ELISA. Physical and mental health symptoms were determined using the Oswestry Disability Index (ODI) and short form-36 (SF-36) questionnaire. Spearman rank correlation coefficient was also determined to calculate the correlation between the scores obtained from the questionnaires and the serum levels of cytokines. RESULTS: IL-6 protein was detected in the three groups and median levels were about 1.5 times higher in patients with severe sciatica than the mild sciatica group (p = 0.02) and the controls (p = 0.03). Median levels of IL-8 in sciatica patients were higher than those of the healthy controls (p = 0.001 for severe sciatica, p = 0.02 for mild sciatica). The TNF-α protein values were approximately twofold higher in the severe sciatica group than in the mild sciatica group (p < 0.01) and in the healthy control group (p < 0.01). Median levels of IL-4 were about 2.5-fold higher in mild sciatica (p < 0.01) and about twofold higher in patients with severe sciatica (p = 0.012) when compared with controls. Median protein levels of IL-10 showed a trend to be higher in patients with mild sciatica compared with severe sciatica (p < 0.01) and with healthy controls (p < 0.01). ODI was significantly correlated with IL-6 (r = 0.394, p = 0.013), TNF-α (r = 0.629, p < 0.001), and IL-10 (r = -0.415, p = 0.009). ODI was not significantly correlated with IL-4 (r = -0.174, p = 0.29) and IL-8 (r = -0.133, p = 0.418). CONCLUSIONS: These findings support our hypothesis that sciatica pain is accompanied by the imbalance in inflammatory cytokines.

Evaluation of transforaminal endoscopic lumbar discectomy in the treatment of lumbar disc herniation.

PURPOSE: The purpose of this study was to evaluate the efficacy of transforaminal endoscopic lumbar discectomy (TELD) in the treatment of lumbar disc herniation (LDH) and to identify the relationship between TELD efficacy and age. METHODS: A total of 207 consecutive LDH patients who had undergone TELD with the THESSYS system from January 2013 to September 2014 were divided into two groups on the basis of their age, with 108 cases in the ≤ 45-year-old age group and 99 cases in the >45-year-old group. The Oswestry Disability Index (ODI) was used to quantify the pain relief. The degree of pain and disability were measured on the basis of the visual analog scale (VAS) and the modified MacNab criteria. Complications, duration of hospital stay, surgical costs, and operation time were recorded and compared between the two groups. Spearman's coefficient of rank correlation was used to assess the learning curves for TELD. RESULTS: The mean pre-operative and postoperative VAS and ODI scores significantly improved in both age ≤ 45 group and age >45 group, with no significant differences between them. In age ≤45 group, 56 % had excellent outcomes, 28 % good, 14 % fair, and 3 % poor. In the age >45 group, 51 % had excellent outcomes, 20 % good, 25 % fair, and 4 % poor. The average lengths of hospital stay for the age ≤ 45 group and age >45 group were 6.8 and 8.4 days, respectively. The mean time to return to work or normal activities was ten days for the age ≤ 45 group and 15 days for the age >45 group. The mean operative time for the age ≤ 45 group was 94 minutes and that for age >45 group was 97 minutes. The surgical cost of age ≤ 45 group was 15,480 RMB, which was lower than the 16,381 RMB of age >45 group. A total of 14 patients in the age ≤ 45 group and 13 patients in age >45 group used analgesic medications. Three and five recurrences were reported in the age ≤ 45 group and age >45, respectively. The steep learning curves of operative time plotted against the number of surgeries conducted suggest that the TELD technique can be mastered quickly in terms of reducing the duration of operation. CONCLUSIONS: The efficacy of TELD is relatively good for the selected young and elderly patients in this study. Therefore, age is not a predictor of TELD surgery-related outcomes.

Evaluation of intervertebral disc regeneration with implantation of bone marrow mesenchymal stem cells (BMSCs) using quantitative T2 mapping: a study in rabbits.

PURPOSE: The aim of the study was to investigate the curative effects of transplantation of bone marrow mesenchymal stem cells (BMSCs) on intervertebral disc regeneration and to investigate the feasibility of the quantitative T2 mapping method for evaluating repair of the nucleus pulposus after implantation of BMSCs. METHODS: Forty-eight New Zealand white rabbits were used to establish the lumber disc degenerative model by stabbing the annulus fibrosus and then randomly divided into four groups, i.e. two weeks afterwards, BMSCs or phosphate-buffered saline (PBS) were transplanted into degenerative discs (BMSCs group and PBS group), while the operated rabbits without implantation of BMSCs or PBS served as the sham group and the rabbits without operation were used as the control group. At weeks two, six and ten after operation, the T2 values and disc height indices (DHI) were calculated by magnetic resonance imaging (MRI 3.0 T), and the gene expressions of type II collagen (COL2) and aggrecan (ACAN) in degenerative discs were evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR). T2 values for the nucleus pulposus were correlated with ACAN or COL2 expression by regression analysis. RESULTS: Cell clusters, disorganised fibres, interlamellar glycosaminoglycan (GAG) matrix and vascularisation were observed in lumber degenerative discs. BMSCs could be found to survive in intervertebral discs and differentiate into nucleus pulposus-like cells expressing COL2 and ACAN. The gene expression of COL2 and ACAN increased during ten weeks after transplantation as well as the T2 signal intensity and T2 value. The DHI in the BMSCs group decreased more slowly than that in PBS and sham groups. The T2 value correlated significantly with the gene expression of ACAN and COL2 in the nucleus pulposus. CONCLUSIONS: Transplantation of BMSCs was able to promote the regeneration of degenerative discs. Quantitative and non-invasive T2 mapping could be used to evaluate the regeneration of the nucleus pulposus with good sensitivity.

In vivo evidence of increased vascular endothelial growth factor in patients with major depressive disorder.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a candidate mediator of blood-brain barrier (BBB) disruption in depression. However, previous studies have mainly focused on peripheral blood VEGF levels, and the results are heterogeneous. Here we use astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma to explore the in vivo changes of VEGF levels in patients with major depressive disorder (MDD). METHODS: Thirty-five unmedicated patients with MDD and 35 healthy controls (HCs) were enrolled, and plasma ADEVs were isolated from each participant. VEGF levels in ADEVs and glial fibrillary acidic protein (GFAP) in plasma were measured. Additionally, Alix and CD81, two established extracellular vesicle markers, were quantified in ADEVs. RESULTS: At baseline, MDD patients exhibited significantly increased levels of VEGF in ADEVs and GFAP in plasma. Following four weeks of selective serotonin reuptake inhibitor treatment, these target protein levels did not significantly change. ROC curve analysis revealed an AUC of 0.711 for VEGF in ADEVs. In exploratory analysis, VEGF levels in ADEVs were positively correlated with Alix and CD81. LIMITATIONS: Multiple factors regulate BBB permeability. This study focused solely on VEGF and the sample size for longitudinal analysis was relatively small. CONCLUSION: Our study is the first to confirm increased ADEV-derived VEGF levels in patients with MDD, thereby providing preliminary evidence supporting the hypothesis that the BBB is disrupted in depression.

Investigating Neuroplasticity Changes Reflected by BDNF Levels in Astrocyte-Derived Extracellular Vesicles in Patients with Depression.

Purpose: To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels. Patients and Methods: Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. Results: After false discovery rate correction, patients with MDD exhibited higher CD81 levels (P FDR = 0.040) and lower BDNF levels (P FDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (P FDR = 0.002) and Alix (P FDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (P FDR = 0.046), while BDNF levels normalized to CD81 increased (P FDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334). Conclusion: This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.

Effects of autotaxin and lysophosphatidic acid deficiencies on depression-like behaviors in mice exposed to chronic unpredictable mild stress.

The involvement of lipids in the mechanism of depression has triggered extensive discussions. Earlier studies have identified diminished levels of lysophosphatidic acid (LPA) and autotaxin (ATX) in individuals experiencing depression. However, the exact significance of this phenomenon in relation to depression remains inconclusive. This study seeks to explore the deeper implications of these observations. We assessed alterations in ATX and LPA in both the control group and the chronic unpredictable mild stress (CUMS) model group. Additionally, the impact of ATX adeno-associated virus (AAV-ATX) injection into the hippocampus was validated through behavioral tests in CUMS-exposed mice. Furthermore, we probed the effects of LPA on synapse-associated proteins both in HT22 cells and within the mouse hippocampus. The mechanisms underpinning the LPA-triggered shifts in protein expression were further scrutinized. Hippocampal tissues were augmented with ATX to assess its potential to alleviate depression-like behavior by modulating synaptic-related proteins. Our findings suggest that the decrement in ATX and LPA levels alters the expression of proteins associated with synaptic plasticity in vitro and in vivo, such as synapsin-I (SYN), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Moreover, we discerned a role for the ERK/CREB signaling pathway in mediating the effects of ATX and LPA. Importantly, strategic supplementation of ATX effectively mitigated depression-like behaviors. This study indicates that the ATX-LPA pathway may influence depression-like behaviors by modulating synaptic plasticity in the brains of CUMS-exposed mice. These insights augment our understanding of depression's potential pathogenic mechanism in the context of lipid metabolism and propose promising therapeutic strategies for ameliorating the disease.

The Neuroprotective Effects of BMSC-Derived Exosomes against Glutamate-Induced HT22 Cell Cytotoxicity.

Many central nervous system diseases are closely related to nerve damage caused by dysregulation of the endogenous neurotransmitter glutamate. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) play an important role in improving injury and regeneration functions. However, its mechanism remains unknown. Therefore, the aim of this study is to investigate whether and how BMSC-Exos improve neurotoxicity caused by glutamate and to fill the gap in the literature. In this study, glutamate-treated HT22 cells were first exposed to mouse-derived BMSC-Exos at different concentrations to observe their effects on HT22 apoptosis. Next, we treated glutamate-treated HT22 cells with mouse-derived BMSC-Exos. We then inhibited the PI3K/Akt/mTOR signaling pathways using the PI3K/Akt inhibitor and the mTOR inhibitor, respectively, and observed the protective effect of mouse-derived BMSC-Exos on HT22 cells treated with glutamate. Our results show that BMSC-Exos reduced apoptosis triggered by glutamate stimulation, increased cell vitality, and decreased the levels of proapoptotic proteins while increasing the levels of anti-apoptotic proteins. The protective effect of BMSC-Exos was weakened when PI3K/Akt inhibitor and mTOR inhibitor were added. To sum up, we draw the following conclusions: BMSC-Exos can reduce neuronal apoptosis and apoptosis-related protein expression after glutamate stimulation by regulating the PI3K/Akt/mTOR signaling pathway.

Altered in vivo early neurogenesis traits in patients with depression: Evidence from neuron-derived extracellular vesicles and electroconvulsive therapy.

BACKGROUND: The neurogenesis hypothesis is a promising candidate etiologic hypothesis for depression, and it is associated with electroconvulsive therapy (ECT). However, human in vivo molecular-level evidence is lacking. OBJECTIVE: We used neuron-derived extracellular vesicles (NDEVs) as a "window to the neurons" to explore the in vivo neurogenesis status associated with ECT in patients with treatment-resistant depression (TRD). METHODS: In this study, we enrolled 40 patients with TRD and 35 healthy controls (HCs). We isolated NDEVs from the plasma of each participant to test the levels of doublecortin (DCX), a marker of neurogenesis, and cluster of differentiation (CD) 81, a marker of EVs. We also assessed the plasma levels of brain-derived neurotrophic factor (BDNF), a protein that is known to be associated with ECT and neuroplastic processes. RESULTS: Our findings indicated that both the levels of DCX in NDEVs and BDNF in plasma were significantly lower in TRD patients compared to HCs at baseline, but increased following ECTs. Conversely, levels of CD81 in NDEVs were found higher in TRD patients at baseline, but did not change after the ECT treatments. Exploratory analyses revealed that lower levels of BDNF in plasma and DCX in NDEVs, along with higher CD81 levels in NDEVs, were associated with more severe depressive symptoms and reduced cognitive function at baseline. Furthermore, higher baseline CD81 concentrations in NDEVs were correlated with greater decreases in depression symptoms. CONCLUSIONS: We first present human in vivo evidence of early neurogenesis using DCX through NDEVs: decreased in TRD patients, increased after ECTs.

Efficacy and Side Effects of Mixed-Strategy Electroconvulsive Therapy: A Proof-of-Concept Randomized Clinical Trial on Late Life Depression.

OBJECTIVE: Patients with late life depression sometimes refuse to receive electroconvulsive therapy (ECT) owing to its adverse reactions. To alleviate patient's resistance, a novel ECT stimulation strategy named mixed-strategy ECT (msECT) was designed in which patients are administered conventional ECT during the first three sessions, followed by low energy stimulation during the subsequent sessions. However, whether low energy electrical stimulation in the subsequent stage of therapy affect its efficacy and reduce adverse reactions in patients with late life depression remains unknown. To explore differences between msECT and regular ECT(RECT) with respect to clinical efficacy and side effects. METHODS: This randomized, controlled trial was conducted from 2019 to 2021 on 60 patients with late life depression who were randomly assigned to two groups: RECT or msECT. A generalized estimating equation (GEE) was used to compare the two stimulation strategies regarding their efficacy and side effects on cognition. Chi-squared test was used to compare side effects in the two strategies. RESULTS: In the intent-to-treat group, the GEE model suggested no differences between-group difference in Hamilton Depression Rating Scale-17 score over time (Wald χ2=7.275, p=0.064), whereas the comparison of side effects in the two strategies favored msECT (Wald χ2=8.463, p=0.015) as fewer patients had adverse events during the second phase of treatment with msECT (χ2 =13.467, p=0.004). CONCLUSION: msECT presents its similar efficacy to RECT. msECT may have milder side effects on cognition.

Oligodendrocyte-derived exosomes-containing SIRT2 ameliorates depressive-like behaviors and restores hippocampal neurogenesis and synaptic plasticity via the AKT/GSK-3ß pathway in depressed mice.

AIMS: To investigate the antidepressant role of oligodendrocyte-derived exosomes (ODEXs)-containing sirtuin 2 (SIRT2) and the underlying mechanism both in vivo and in vitro. METHODS: Oligodendrocyte-derived exosomes isolated from mouse serum were administered to mice with chronic unpredictable mild stress (CUMS)-induced depression via the tail vein. The antidepressant effects of ODEXs were assessed through behavioral tests and quantification of alterations in hippocampal neuroplasticity. The role of SIRT2 was confirmed using the selective inhibitor AK-7. Neural stem/progenitor cells (NSPCs) were used to further validate the impact of overexpressed SIRT2 and ODEXs on neurogenesis and synapse formation in vitro. RESULTS: Oligodendrocyte-derived exosome treatment alleviated depressive-like behaviors and restored neurogenesis and synaptic plasticity in CUMS mice. SIRT2 was enriched in ODEXs, and blocking SIRT2 with AK-7 reversed the antidepressant effects of ODEXs. SIRT2 overexpression was sufficient to enhance neurogenesis and synaptic protein expression. Mechanistically, ODEXs mediated transcellular delivery of SIRT2, targeting AKT deacetylation and AKT/GSK-3ß signaling to regulate neuroplasticity. CONCLUSION: This study establishes how ODEXs improve depressive-like behaviors and hippocampal neuroplasticity and might provide a promising therapeutic approach for depression.

Elevated triglycerides and low triiodothyronine: Key risk factors for coronary artery calcification in patients with schizophrenia.

OBJECTIVE: Coronary artery calcification (CAC) is a well-established independent predictor of coronary heart disease, and patients with schizophrenia have significantly higher rates compared to the general population. We performed this study to examine the population-specific risk factors associated with CAC in patients with schizophrenia. METHODS: In this cross-sectional study, patients with schizophrenia who underwent low-dose chest CT scans between January 2020 and December 2021 were analyzed. Ordinary CAC scores and results of routine blood tests were obtained. Logistic regression was used to calculate the odds ratio (OR) for potential risk factors in patients with and without CAC, while the negative binomial additive model was used to explore the dose-response relationship between risk factors and CAC score. RESULTS: Of the 916 patients, 233 (25.4 %) had CAC, while 683 (74.6 %) did not. After adjusting for confounding factors, higher triglyceride levels (OR = 1.20, 95 % confidence interval (CI): 1.04 to 1.38, p = 0.013) and low triiodothyronine levels (OR = 0.50, 95 % CI: 0.29 to 0.84; p = 0.010) were identified as risk factors for CAC. Both triglycerides (p = 0.021) and triiodothyronine (p = 0.010) were also found to have significant dose-response relationships with CAC scores according to the negative binomial additive model in the exploratory analysis. CONCLUSIONS: This study highlights elevated serum triglycerides and decreased triiodothyronine levels as population-specific risk factors for CAC in patients with schizophrenia, suggest the need for close monitoring of CAC in patients with schizophrenia and further prospective trials to provide additional evidence on this topic.

Promotion of bone repair by implantation of cryopreserved bone marrow-derived mononuclear cells in a rabbit model of steroid-associated osteonecrosis.

OBJECTIVE: Cytotherapy is an insufficient method for promoting bone repair in steroid-associated osteonecrosis (SAON), and this has been attributed to impairment of the bioactivity of bone marrow-derived stem cells (BMSCs) after pulsed administration of steroids. Cryopreserved autologous bone marrow-derived mononuclear cells (BMMNCs), which contain BMSCs, might maintain their bioactivity in vitro. This study sought to investigate the effects of cryopreserved BMMNCs, before steroid administration, on the enhancement of bone repair in an established rabbit model of SAON. METHODS: For in vitro study, bone marrow was harvested 4 weeks before SAON induction from the iliac crests of rabbits (n = 10) to isolate fresh BMMNCs, and the BMMNCs were then cryopreserved for 8 weeks. Both the fresh and the cryopreserved BMMNCs were evaluated for their bioactivity and osteogenic differentiation capacity. In addition, BMMNCs were isolated 2 weeks after SAON induction and subjected to the same evaluations. For in vivo study, cryopreserved BMMNCs were implanted into the bone tunnel during core decompression of the femur (n = 12 rabbits) after the induction of SAON, and tissue regeneration was evaluated by micro-computed tomography and histologic analyses at 12 weeks postoperation. RESULTS: In vitro, there were no significant differences in the bioactivity or ability to undergo osteogenic differentiation between fresh BMMNCs and cryopreserved BMMNCs, but after SAON induction, both features were decreased significantly. In vivo, the bone mineral density, ratio of bone volume to total volume of bone, and volume and diameter of neovascularization within the bone tunnel were significantly higher in the BMMNC-treated group compared to the nontreated control group at 12 weeks postoperation. CONCLUSION: Cryopreserved BMMNCs maintained their bioactivity and promoted bone regeneration and neovascularization within the bone tunnel after core decompression in this rabbit model of SAON.

The needle in the haystack: Identifying and validating common genes of depression, insomnia, and inflammation.

BACKGROUND: Insomnia, inflammation, and depression are often co-occurring conditions. The mechanisms underlying these conditions remain unclear. MATERIALS AND METHODS: We collected microarray datasets of depression and insomnia from GEO and analyzed them for differentially expressed genes (DEGs). We then overlapped the DEGs with a list of inflammatory response-related genes to identify genes associated with all three conditions. We next performed analyses of enrichment analyses, KEGG mapping, and protein-protein interaction to identify hub genes. Furthermore, we established a depression rat model with inflammation and insomnia to validate the potential genes. At last, a two-sample Mendelian randomization (MR) study was conducted to confirm the association of identified target genes with depression outcomes. RESULTS: We obtained 32 common DEGs associated with the depression, insomnia and inflammatory, and found that the PI3K-AKT signaling pathway might be involved in the inflammatory response in insomnia and depression. CREB1, CYBB, FYN, and CCR5 were identified as targets for the next validation. In model rats, the CCR5 and PI3K-AKT pathways were significantly up-regulated, while the model group exhibited significantly lower hippocampal p-CREB protein expression. The MR study suggested a potential causal relationship between CREB1 and the risk of depression (OR = 1.11, p = 0.013). LIMITATIONS: The identified potential genes and pathways require further laboratory and clinical evidence verification. CONCLUSION: We identified four potential inflammatory related-genes (CREB1, CYBB, FYN, and CCR5). CREB1 may be a potential inflammatory response-related biomarker and drug target for depression and insomnia, as validated by the followed rat model and MR study.