Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study.

RATIONALE: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. OBJECTIVES: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. METHODS: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel. RESULTS: In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD. CONCLUSIONS: Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD.

An analysis of neutrophil-to-lymphocyte ratios and monocyte-to-lymphocyte ratios with six-month prognosis after cerebral contusions.

Background and purpose: Neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) have been identified as potential prognostic markers in various conditions, including cancer, cardiovascular disease, and stroke. This study aims to investigate the dynamic changes of NLR and MLR following cerebral contusion and their associations with six-month outcomes. Methods: Retrospective data were collected from January 2016 to April 2020, including patients diagnosed with cerebral contusion and discharged from two teaching-oriented tertiary hospitals in Southern China. Patient demographics, clinical manifestations, laboratory test results (neutrophil, monocyte, and lymphocyte counts) obtained at admission, 24 hours, and one week after cerebral contusion, as well as outcomes, were analyzed. An unfavorable outcome was defined as a Glasgow Outcome Score (GOS) of 0-3 at six months. Logistic regression analysis was performed to identify independent predictors of prognosis, while receiver characteristic curve analysis was used to determine the optimal cutoff values for NLR and MLR. Results: A total of 552 patients (mean age 47.40, SD 17.09) were included, with 73.19% being male. Higher NLR at one-week post-cerebral contusion (adjusted OR = 4.19, 95%CI, 1.16 - 15.16, P = 0.029) and higher MLR at admission and at 24 h (5.80, 1.40 - 24.02, P = 0.015; 9.06, 1.45 - 56.54, P = 0.018, respectively) were significantly associated with a 6-month unfavorable prognosis after adjustment for other risk factors by multiple logistic regression. The NLR at admission and 24 hours, as well as the MLR at one week, were not significant predictors for a 6-month unfavorable prognosis. Based on receiver operating characteristic curve analysis, the optimal thresholds of NLR at 1 week and MLR at admission after cerebral contusion that best discriminated a unfavorable outcome at 6-month were 6.39 (81.60% sensitivity and 70.73% specificity) and 0.76 (55.47% sensitivity and 78.26% specificity), respectively. Conclusion: NLR measured one week after cerebral contusion and MLR measured at admission may serve as predictive markers for a 6-month unfavorable prognosis. These ratios hold potential as parameters for risk stratification in patients with cerebral contusion, complementing established biomarkers in diagnosis and treatment. However, further prospective studies with larger cohorts are needed to validate these findings.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Adolescent male rats show altered gut microbiota composition associated with depressive-like behavior after chronic unpredictable mild stress: Differences from adult rats.

Accumulating evidence reveals the metabolism and neurotransmitter systems are different in major depressive disorder (MDD) between adolescent and adult patients; however, much is still unknown from the gut microbiome perspective. To minimize confounding factors such as geographical location, ethnicity, diet, and drugs, we investigated the gut microbial differences between adolescent and adult male Sprague-Dawley rats. We exposed the adolescent rats to chronic unpredictable mild stress (CUMS) for 3 weeks and assessed their behavior using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). We collected and sequenced fecal samples after the behavioral tests and compared them with our previous data on adult rats. Both adolescent and adult CUMS rats exhibited reduced sucrose preference in SPT, reduced total distance in OFT, and increased immobility time in FST. Moreover, compared to their respective controls, the adolescent CUMS rats had distinct amplicon sequence variants (ASVs) mainly in the Muribaculaceae family, Bacteroidetes phylum, while the adult CUMS rats had those in the Lachnospiraceae family, Firmicutes phylum. In the adolescent group, the Muribaculaceae negatively correlated with FST and positively correlated with SPT and OFT. In the adult group, the different genera in the Lachnospiraceae showed opposite correlations with FST. Furthermore, the adolescent CUMS rats showed disrupted microbial functions, such as "Xenobiotics biodegradation and metabolism" and "Immune system", while the adult CUMS rats did not. These results confirmed the gut microbiota differences between adolescent and adult rats after CUMS modeling and provided new insight into the age-related influence on depression models.

Comparative analysis of the nucleus accumbens transcriptional features in multiple depressive animal models.

Chronic stress is deemed a significant clinical contributor to depression. The use of animal models of chronic stress can fully reveal the complex pathological mechanisms and their changing trends in the pathogenesis of depression, which is crucial for both disease prevention and therapy. It is also unknown how various forms of stress differ in their impact on animal physiology and behavior. The nucleus accumbens (NAc), an essential brain area for the pathophysiology of depression, and its underlying neural mechanisms remain unclear. Here, we systematically compared transcriptional signatures in the NAc of four chronic stress models in rats: chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), learned helplessness (LH), chronic restraint stress (CRS). The majority of differentially expressed genes (DEGs) were unique to a single depression model, while the rank-rank hypergeometric overlap analysis showed that the CSDS and CRS models had the greatest overlap, and the CRS and CUMS models had the least. Then, we performed pathway analysis of the differential genes and found that the neuroactive ligand-receptor interaction pathway was significantly enriched not only in the LH, CRS and CSDS stress models, but also significantly enriched in stress genes that were also altered in at least two stress models. Finally, we found three hub genes (Dcx, Tnc and Wdfy4) by constructing co-expression networks for stress genes. In summary, our research has the potential to offer fresh insights into the molecular mechanisms underlying depression induced by different types of stress, highlighting both their similarities and differences. It may provide valuable clues for understanding the pathogenesis of depression.

AgrA directly binds to the promoter of vraSR and downregulates its expression in Staphylococcus aureus.

Staphylococcus aureus is an important human pathogen and vancomycin is widely used for the treatment of S. aureus infections. The global regulator agr is known as a well-described virulence regulator. Previous studies have found that agr-dysfunction strains are more likely to develop into vancomycin-resistant strains, but the mechanism for this phenomenon remains unknown. VraSR is a two-component regulatory system related to vancomycin resistance. In this study, we found that the expression levels of vraR were higher in agr-dysfunction clinical strains than in the agr-functional strains. We knocked out agr in a clinical strain, and quantitative reverse transcription PCR and ß-galactosidase activity assays revealed that agr repressed transcription of vraR. After vancomycin exposures, population analysis revealed larger subpopulations displaying reduced susceptibility in agr knockout strain compared with wild-type strain, and this pattern was also observed in agr-dysfunction clinical strains compared with the agr-functional strains. Electrophoretic mobility experiment demonstrated binding of purified AgrA to the promoter region of vraR. In conclusion, our results indicated that the loss of agr function in S. aureus may contribute to the evolution of reduced vancomycin susceptibility through the downregulation of vraSR.

Assessment of early scientific research skills training for medical undergraduates in China.

The medical field is facing a physician-scientist shortage, threatening future medical research and development. Medical institutions can contribute to developing physician-scientists by stimulating students' involvement in research. In this study, a medical undergraduate teaching module to develop research skills and encourage interest in research was held in Chongqing, China. Undergraduate medical students at Chongqing Medical University completed research skills training. Before and after the training, an online, anonymous, self-reported questionnaire was administered. The self-reported questionnaire investigated students' demographic characteristics, students' perception of attitudes toward conducting research, research skills (e.g., identifying and utilizing information, critical appraisal of literature, paper writing, and understanding of research), and feedback on scientific research training. The module was implemented with 25 students from July 2019 to October 2019, and 96.0% (N = 24) of participants responded to the questionnaire both prior to and after the training. In the evaluation of research skills, results showed that use of appropriate tools for research (Z = -3.340, p < 0.01), students' ability to undertake a focused literature search (Z = -3.40, p < 0.01), identifying and utilizing information (Z = -3.34, p < 0.01), and paper-writing skills (Z = -3.49, p < 0.01) were significantly improved after the undergraduates participated in the scientific research training. A qualitative analysis of the feedback showed that students found that the training helped to enhance their knowledge, improve their study scores, and motivate them to conduct research in the future. Early scientific research ability training strengthened the research skills of medical undergraduates and motivated them to pursue research.

Childhood trauma is linked to abnormal static-dynamic brain topology in adolescents with major depressive disorder

Childhood trauma is a leading risk factor for adolescents developing major depressive disorder (MDD); however, the underlying neuroimaging mechanisms remain unclear. This study aimed to investigate the association among childhood trauma, MDD and brain dysfunctions by combining static and dynamic brain network models. We recruited 46 first-episode drug-naïve adolescent MDD patients with childhood trauma (MDD-CT), 53 MDD patients without childhood trauma (MDD-nCT), and 90 healthy controls (HCs) for resting-state functional magnetic resonance imaging (fMRI) scans; all participants were aged 13–18 years. Compared to the HCs and MDD-nCT groups, the MDD-CT group exhibited significantly higher global and local efficiency in static brain networks and significantly higher temporal correlation coefficients in dynamic brain network models at the whole-brain level, and altered the local efficiency of default mode network (DMN) and temporal correlation coefficients of DMN, salience (SAN), and attention (ATN) networks at the local perspective. Correlation analysis indicated that altered brain network features and clinical symptoms, childhood trauma, and particularly emotional neglect were highly correlated in adolescents with MDD. This study may provide new evidence for the dysconnectivity hypothesis regarding the associations between childhood trauma and MDD in adolescents from the perspectives of both static and dynamic brain topology. (AU)

Childhood trauma is linked to abnormal static-dynamic brain topology in adolescents with major depressive disorder.

Childhood trauma is a leading risk factor for adolescents developing major depressive disorder (MDD); however, the underlying neuroimaging mechanisms remain unclear. This study aimed to investigate the association among childhood trauma, MDD and brain dysfunctions by combining static and dynamic brain network models. We recruited 46 first-episode drug-naïve adolescent MDD patients with childhood trauma (MDD-CT), 53 MDD patients without childhood trauma (MDD-nCT), and 90 healthy controls (HCs) for resting-state functional magnetic resonance imaging (fMRI) scans; all participants were aged 13-18 years. Compared to the HCs and MDD-nCT groups, the MDD-CT group exhibited significantly higher global and local efficiency in static brain networks and significantly higher temporal correlation coefficients in dynamic brain network models at the whole-brain level, and altered the local efficiency of default mode network (DMN) and temporal correlation coefficients of DMN, salience (SAN), and attention (ATN) networks at the local perspective. Correlation analysis indicated that altered brain network features and clinical symptoms, childhood trauma, and particularly emotional neglect were highly correlated in adolescents with MDD. This study may provide new evidence for the dysconnectivity hypothesis regarding the associations between childhood trauma and MDD in adolescents from the perspectives of both static and dynamic brain topology.

AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models.

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.

Disturbances of purine and lipid metabolism in the microbiota-gut-brain axis in male adolescent nonhuman primates with depressive-like behaviors.

INTRODUCTION: Major depressive disorder (MDD) in adolescents is a widespread and growing global public health concern with unique characteristics and pathophysiological mechanisms that are distinct from MDD in adults. OBJECTIVE: The purpose of our work was to address this knowledge gap about the unique characteristics and pathophysiological mechanisms of adolescent depression from a microbiota-gut-brain (MGB) axis perspective. METHOD: Ten healthy male cynomolgus macaques (Macaca fascicularis) were paired into five pairs based on age and body weight, and two cynomolgus macaques from each pair were randomly allocated to chronic unpredictable mild stress group, or unstressed control group. At endpoint, microbe composition from cecum, ascending colon, transverse colon, and descending colon were analyzed by metagenome sequencing, and the metabolite profiles of MGB axis including central (prefrontal cortex, hippocampus and amygdala) and peripheral (plasma, gut and feces of cecum, ascending colon, transverse colon and descending colon) samples were analyzed by metabolomic profiling. Then, we compare the gut microbiome and metabolic signatures in MGB axis between adolescent and adult depressed macaques. RESULTS: The microbial composition and gut-brain metabolic signatures were widely divergent between adolescent and adult depressed macaques, though the phylum Firmicutes and lipid metabolism pathways were persistently altered in both populations. Purine and arginine biosynthesis metabolism were a specific hallmark of adolescent depressed macaques, while fatty acyl metabolism was specially altered in adult. These differential metabolic pathways in adolescent and adult depressed macaques were mainly mapped into the prefrontal cortex and hippocampus, respectively. Notably, the genus Clostridium and Haemophilus, characteristically disturbed in adolescent depressed macaques but not in adult, were also significantly associated with the majority of purine metabolites in MGB axis. CONCLUSION: These findings provide a new framework describing divergent pathophysiological mechanisms between adolescent and adult depression, and may open new windows for more effective treatment strategies of adolescent depression.

Lidocaine inhibits influenza a virus replication by up-regulating IFNα4 via TBK1-IRF7 and JNK-AP1 signaling pathways.

Influenza A viruses (IAV), significant respiratory pathogenic agents, cause seasonal epidemics and global pandemics in intra- and interannual cycles. Despite effective therapies targeting viral proteins, the continuous generation of drug-resistant IAV strains is challenging. Therefore, exploring novel host-specific antiviral treatment strategies is urgently needed. Here, we found that lidocaine, widely used for local anesthesia and sedation, significantly inhibited H1N1(PR8) replication in macrophages. Interestingly, its antiviral effect did not depend on the inhibition of voltage-gated sodium channels (VGSC), the main target of lidocaine for anesthesia. Lidocaine significantly upregulated early IFN-I, interferon α4 (IFNα4) mRNA, and protein levels, but not those of early IFNß in mouse RAW 264.7 cell line and human THP-1 derived macrophages. Knocking out IFNα4 by CRISPR-Cas9 partly reversed lidocaine's inhibition of PR8 replication in macrophages. Mechanistically, lidocaine upregulated IFNα4 by activating TANK-binding kinase 1 (TBK1)-IRF7 and JNK-AP1 signaling pathways. These findings indicate that lidocaine has an incredible antiviral potential by enhancing IFN-I signaling in macrophages. In conclusion, our results indicate the potential auxiliary role of lidocaine for anti-influenza A virus therapy and even for anti-SARS-CoV-2 virus therapy, especially in the absence of a specific medicine.

Biomarkers of intestinal permeability and blood-brain barrier permeability in adolescents with major depressive disorder.

BACKGROUND: The etiology in major depressive disorder (MDD) has not been fully understood. Accumulating evidence suggests an association between altered intestinal and blood-brain barrier (BBB) permeability and psychiatric disorders, while its changes in adolescent MDD populations have been received less attention. In this study, our aim was to explore the differences in plasma levels of intestinal and blood-brain barrier permeability markers in adolescents with MDD compared with healthy controls (HCs). METHODS: We enrolled MDD (n = 50), and HCs (n = 40) with the age of 13-18 years old. The plasma level of zonulin, I-FABP, LPS, and claudin-5 were quantified. The Hamilton Depression Scale 17 items (HAMD-17) and Hamilton Anxiety Scale 14 items (HAMA-14) were used for symptom assessments. RESULTS: The plasma levels of zonulin, I-FABP, LPS, and claudin-5 in the MDD group were significantly higher than those in the HCs. Plasma I-FABP levels in MDD with moderate to severe anxiety were significantly higher than those in MDD without moderate to severe anxiety and HCs. In addition, these four biomarkers (alone or combined) can be used as diagnostic markers for MDD in adolescents. LIMITATIONS: The key limitation of this study is the blood measurements at a single time point with a relatively small sample size. CONCLUSIONS: These findings advance our understanding of the pathophysiology of intestinal barrier injury, bacterial translocation, and blood-brain barrier injury involved in adolescents with MDD.

Comparative analysis of gut microbiota and fecal metabolome features among multiple depressive animal models.

BACKGROUNDS: Emerging studies reported that gut microbiota and fecal metabolites take part in major depressive disorder (MDD) pathogenesis. However, the conclusions based on a single depressive animal model seem inconsistent or even controversial. METHODS: Multiple depression rat models, including chronic unpredictable mild stress, chronic restraint stress, social defeat, and learned helplessness, were used. Then, the 16S ribosomal RNA gene sequencing and liquid chromatography-mass spectrometry analysis determined the alteration of gut microbiota and fecal metabolites. RESULTS: The results of sucrose preference test and forced swimming test suggested that each model successfully established depression-like behavior. A total of 179 discriminative amplicon sequence variants (ASVs) were identified among four models. The overall discriminative ASVs mainly belonged to the family Lachnospiraceae, Muribaculaceae, and Oscillospiraceae. Moreover, the fecal metabolomic analysis identified 468 differential expressed metabolites. Among all the differential metabolites, 11 specific pathways significantly altered, which were mainly belonged to lipid and amino acid metabolism. Finally, co-occurrence network analysis suggested that target differential metabolites were associated with discriminative ASVs mainly assigned to family taxon Lachnospiraceae, Muribaculaceae, and Oscillospiraceae. LIMITATIONS: The heterogeneity of MDD in humans cannot be totally imitated by animal models. CONCLUSIONS: In multiple depression models, the alterations of family Lachnospiraceae, Muribaculaceae, and Oscillospiraceae with the dysbiosis of lipid and amino acid metabolism were gut microbiota and fecal metabolome features. The findings of our research may help us to have a comprehensive understanding of gut microbiota and fecal metabolome in depression.

TGF-ß1 Protects Trauma-injured Murine Cortical Neurons by Upregulating L-type Calcium Channel Cav1.2 via the p38 Pathway.

Traumatic brain injury (TBI) is a leading cause of disability and death in adolescents, and there is a lack of effective methods of treatment. The neuroprotective effects exerted by TGF-ß1 can ameliorate a range of neuronal lesions in multiple central nervous system diseases. In this study, we used an in-vitro TBI model of mechanical injury on murine primary cortical neurons and the neuro-2a cell line to investigate the neuroprotective role played by TGF-ß1 in cortical neurons in TBI. Our results showed that TGF-ß1 significantly increased neuronal viability and inhibited apoptosis for 24 h after trauma. The expression of Cav1.2, an L-type calcium channel (LTCC) isoform, decreased significantly after trauma injury, and this change was reversed by TGF-ß1. Nimodipine, a classic LTCC blocker, abolished the protective effect of TGF-ß1 on trauma-induced neuronal apoptosis. The knockdown of Cav1.2 in differentiated neuro-2a cells significantly inhibited the anti-apoptosis effect of TGF-ß1 exerted on injured neuro-2a cells. Moreover, TGF-ß1 rescued and enhanced the trauma-suppressed neuro-2a intracellular Ca2+ concentration, while the effect of TGF-ß1 was partially inhibited by nimodipine. TGF-ß1 significantly upregulated the expression of Cav1.2 by activating the p38 MAPK pathway and by inhibiting trauma-induced neuronal apoptosis. In conclusion, TGF-ß1 increased trauma-injured murine cortical neuronal activity and inhibited apoptosis by upregulating Cav1.2 channels via activating the p38 MAPK pathway. Therefore, the TGF-ß1/p38 MAPK/Cav 1.2 pathway has the potential to be used as a novel therapeutic target for TBI.

A diathesis-stress rat model induced suicide-implicated endophenotypes and prefrontal cortex abnormalities in the PKA and GABA receptor signaling pathways.

Suicide is one of the leading causes of death and represents a significant public health problem worldwide; however, the underlying mechanism of suicide remains unclear, and there is no animal model with suicide-implicated endophenotypes for investigating the etiology, course and potential treatment targets of suicide. Thus, we generated a diathesis-stress rat model to simulate suicide-implicated endophenotypes. First, two hundred rats were screened in two rounds of learned helplessness (LH) tests and selected as learned helplessness-sensitive (LHS) rats (n = 37) and learned helplessness-resistant (LHR) rats (n = 39). Then, all LHS rats and half of the rats (randomly selected) in the LHR group were exposed to four weeks of social defeat stress (SDS) (LHS + SDS group, n = 37 and LHR + SDS group, n = 20, respectively). The remainder of the LHR rats were handled as controls (LHR + CON group, n = 19). The LHS + SDS group showed significantly more suicide-implicated endophenotypes than the LHR + CON group, including longer immobile times in the forced swim test (hopelessness), higher scores in the irritability test (irritability), shorter latencies to attack (impulsivity), longer total attack times in the resident-intruder test (aggression), and lower sucrose preference indices (anhedonia). Proteomic analyses revealed that the canonical pathways that were the most common between the LHS + SDS and LHR + CON groups were the PKA and GABA receptor pathways in the prefrontal cortex. A diathesis-stress paradigm would be a useful way to establish a rat model with suicide-implicated endophenotypes, providing novel perspectives for revealing the potential mechanism of suicide.

Comparative short-term efficacy and acceptability of a combination of pharmacotherapy and psychotherapy for depressive disorder in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Although the clinical efficacy and safety of combination of pharmacotherapy and psychotherapy in the treatment of depressive disorders in children and adolescents have been studied, the results remain controversial. This meta-analysis aimed to study the short-term efficacy and acceptability of combined therapy for children and adolescents with depressive disorders. METHODS: We conducted a systematic search in multiple databases for randomised controlled trials (RCTs), up to 31 December 2020, that assessed the combination of pharmacotherapy and psychotherapy against other active treatment options (pharmacotherapy, psychotherapy and placebo combined psychotherapy) in children and adolescents ( ≤ 18 years old) with depressive disorder. This study was registered with PROSPERO (CRD42020196701). RESULTS: A total of 14 RCTs involving 1,325 patients were included. For the primary and secondary outcomes, there were no statistically significant differences between the compared interventions in terms of remission (odds ratios [OR] = 1.37; 95% confidence interval [CI]: 0.93 to 2.04), acceptability (OR = 0.99; 95% CI: 0.72 to 1.38), efficacy (standardised mean differences = -0.07; 95% CI: -0.32 to 0.19), and suicidality (OR = 1.17; 95% CI: 0.67 to 2.06). Limited evidence showed that the combination of fluoxetine (OR = 1.90, 95% CI: 1.10 to 3.29) or non-selective serotonin reuptake inhibitors (non-SSRI) (OR = 2.46, 95% CI: 1.06 to 5.72) with cognitive-behavioural therapy (CBT) was superior to other active treatment options. Most included trials were rated as 'some concerns' in terms of risk of bias assessment. CONCLUSION: There is no evidence from the limited available data that all combined therapies are superior to other active treatment options for the acute treatment of depressive disorder in children and adolescents. However, it showed that fluoxetine or non-SSRI pharmacotherapies combined with CBT might be superior to other therapies in short-term. Mixed characteristics (e.g. age) and small sample size of non-SSRI combined therapy may influence the generalisability of the results.

Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior.

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.

A Clinical Predictive Nomogram for Traumatic Brain Parenchyma Hematoma Progression.

INTRODUCTION: Acute traumatic intraparenchymal hematoma (tICH) expansion is a major cause of clinical deterioration after brain contusion. Here, an accurate prediction tool for acute tICH expansion is proposed. METHODS: A multicenter hospital-based study for multivariable prediction model was conducted among patients (889 patients in a development dataset and 264 individuals in an external validation dataset) with initial and follow-up computed tomography (CT) imaging for tICH volume evaluation. Semi-automated software was employed to assess tICH expansion. Two multivariate predictive models for acute tICH expansion were developed and externally validated. RESULTS: A total of 198 (22.27%) individuals had remarkable acute tICH expansion. The novel Traumatic Parenchymatous Hematoma Expansion Aid (TPHEA) model retained several variables, including age, coagulopathy, baseline tICH volume, time to baseline CT time, subdural hemorrhage, a novel imaging marker of multihematoma fuzzy sign, and an inflammatory index of monocyte-to-lymphocyte ratio. Compared with multihematoma fuzzy sign, monocyte-to-lymphocyte ratio, and the basic model, the TPHEA model exhibited optimal discrimination, calibration, and clinical net benefits for patients with acute tICH expansion. A TPHEA nomogram was subsequently introduced from this model to facilitate clinical application. In an external dataset, this device showed good predicting performance for acute tICH expansion. CONCLUSIONS: The main predictive factors in the TPHEA nomogram are the monocyte-to-lymphocyte ratio, baseline tICH volume, and multihematoma fuzzy sign. This user-friendly tool can estimate acute tICH expansion and optimize personalized treatments for individuals with brain contusion.

Impact of Inosine on Chronic Unpredictable Mild Stress-Induced Depressive and Anxiety-Like Behaviors With the Alteration of Gut Microbiota.

Current antidepressants do not confer a clear advantage in children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on adult MDD, and gut microbiomes are significantly associated with MDD via the microbiota-gut-brain axis. However, few studies have investigated possible associations between inosine and gut microbiota in adolescents with MDD. The current study investigated the potential antidepressant effects of inosine in adolescent male C57BL/6 mice. After 4 weeks of chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by body weight, the sucrose preference test (SPT), open field test, and the elevated plus maze (EPM). The microbiota compositions of feces were determined by 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors in adolescent mice including SPT and EPM results. Fecal microbial composition differed in the CON+saline, CUMS+saline, and CUMS+inosine groups, which were characterized by 126 discriminative amplicon sequence variants belonging to Bacteroidetes and Firmicute at the phylum level and Muribaculaceae and Lachnospiraceae at the family level. Muribaculaceae was positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine might affect gut microbiota through carbohydrate metabolism and lipid metabolism pathways. The results of the study indicated that inosine improved depressive and anxiety-like behaviors in adolescent mice, in conjunction with the alteration of fecal microbial composition. Our findings may provide a novel perspective on the antidepressant effects of inosine in children and adolescents.