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.

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.

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)

Long noncoding RNA RMRP ameliorates doxorubicin-induced apoptosis by interacting with PFN1 in a P53-Dependent manner.

Doxorubicin (DOX) often causes acute or chronic cardiotoxicity during its application. LncRNA RMRP has been reported to be associated with several biological processes, such as cartilage-hair hypoplasia, but the relationship between RMRP and DOX-induced cardiotoxicity and chronic heart failure remains obscure. To test this hypothesis, GSE124401 and GSE149870 were processed for bioinformatics, and differentially expressed RMRP was then verified in the peripheral blood of 21 patients with heart failure compared with 7 controls. For in vitro validation, we used AC16 and HEK-293T cells. qPCR was used to detect the mRNA expression levels. The degree of apoptosis was detected by Western blot and TUNEL staining. Furthermore, the interaction between RMRP and PFN1 mRNA was verified by dual-luciferase reporter assays. In bioinformatics, RMRP showed significant downregulation, which was verified in clinical samples (p < 0.001) and DOX-treated AC16 models (p < 0.0001). Next, overexpression of RMRP could significantly alleviate DOX-induced apoptosis, and a potential downstream molecule of RMRP, PFN1, was also negatively associated with this change. RESCUE experiments further confirmed that PFN1 could be regulated by RMRP at both the RNA and protein levels, serving as a downstream mediator of RMRP's cardioprotective effects. This interaction was then confirmed to be a direct combination (p < 0.0001). Finally, we found that overexpression of RMRP could inhibit the expression of p53 and its phosphorylation level by suppressing PFN1. In summary, RMRP could exert cardioprotective effects via the PFN1/p53 axis, holding great promise for serving as a therapeutic target and potential biomarker.

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.

A study on the differential of solid lung adenocarcinoma and tuberculous granuloma nodules in CT images by Radiomics machine learning.

To study the classification efficiency of using texture feature machine learning method in distinguishing solid lung adenocarcinoma (SADC) and tuberculous granulomatous nodules (TGN) that appear as solid nodules (SN) in non-enhanced CT images. 200 patients with SADC and TGN who underwent thoracic non-enhanced CT examination from January 2012 to October 2019 were included in the study, 490 texture eigenvalues of 6 categories were extracted from the lesions in the non-enhanced CT images of these patients for machine learning, the classification prediction model is established by using relatively the best classifier selected according to the fitting degree of learning curve in the process of machine learning, and the effectiveness of the model was tested and verified. The logistic regression model of clinical data (including demographic data and CT parameters and CT signs of solitary nodules) was used for comparison. The prediction model of clinical data was established by logistic regression, and the classifier was established by machine learning of radiologic texture features. The area under the curve was 0.82 and 0.65 for the prediction model based on clinical CT and only CT parameters and CT signs, and 0.870 based on Radiomics characteristics. The machine learning prediction model developed by us can improve the differentiation efficiency of SADC and TGN with SN, and provide appropriate support for treatment decisions.

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.

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.

Identification of Sex-Specific Plasma Biomarkers Using Metabolomics for Major Depressive Disorder in Children and Adolescents.

Background: Children and adolescents are at a high risk of major depressive disorder (MDD) with known sex differences in epidemiology. However, there are currently no objective laboratory-based sex-specific biomarkers available to support the diagnoses of male and female patients with MDD. Methods: Here, a male set of 42 cases and 27 healthy controls (HCs) and a female set of 42 cases and 22 HCs were recruited. This study investigated the sex differences of plasma metabolite biomarkers in young patients with MDD by the application of ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry. Results: The metabolic profiles showed clear separations in both male and female sets. In total, this study identified 57 male-related and 53 female-related differential metabolites. Compared with HCs, both male and female subjects with MDD displayed four significantly altered pathways. Notably, biliverdin was selected as an independent diagnostic male-specific biomarker with an area under the receiver operating characteristic curve of 0.966, and phosphatidylcholine (10:0/14:1) was selected as a female-specific biomarker, achieving an area under the curve (AUC) of 0.957. Conclusion: This metabolomics study may aid in the development of a plasma-based test for the diagnosis of male and female children and adolescents with MDD, as well as give new insight into the pathophysiology of sex differences in children and 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.

Neglected Foreign Body Aspiration Mimicking Lung Cancer Recurrence.

Foreign body aspiration (FBA) occurs less frequently in adults than in children. Case reports of FBAs occurring in adults after lung surgery are not found in the literature, and this particular condition is often misdiagnosed. We report a case in which the patient was diagnosed after various events. A 56-year-old female patient had undergone robotic-assisted resection of the right upper lobe. The patient recovered well after the operation, with a slight irritant dry cough. Chest computed tomography (CT) examination of the patient showed no obvious abnormality early postoperatively. However, she developed intermittent cough and hemoptysis at six months. Repeat chest CT showed a soft tissue shadow near the bronchus in the lower lobe of the right lung. Cancer recurrence, surgery-related foreign body residue, lymphoid reactive hyperplasia, or other reasons was considered. Further examination revealed a piece of watermelon seed shell blocking the bronchial opening of the lower lung. This case highlights the importance of medical history, careful physical examination and fiberoptic bronchoscopic examination after lung cancer surgery due to lung cancer recurrence risk or FBA.

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.

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.

Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: a systematic review and network meta-analysis.

BACKGROUND: Available evidence on the comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder (PTSD) in children and adolescents remains uncertain. OBJECTIVE: We aimed to compare and rank the different types and formats of psychotherapies for PTSD in children and adolescents. METHODS: We searched eight databases and other international registers up to 31 December 2020. The pairwise meta-analyses and frequentist network meta-analyses estimated pooled standardised mean differences (SMDs) and ORs with random-effects model. Efficacy at post-treatment and follow-up, acceptability, depressive and anxiety symptoms were measured. FINDINGS: We included 56 randomised controlled trials with 5327 patients comparing 14 different types of psychotherapies and 3 control conditions. For efficacy, cognitive processing therapy (CPT), behavioural therapy (BT), individual trauma-focused cognitive-behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing, and group TF-CBT were significantly superior to all control conditions at post-treatment and follow-up (SMDs between -2.42 and -0.25). Moreover, CPT, BT and individual TF-CBT were more effective than supportive therapy (SMDs between -1.92 and -0.49). Results for depressive and anxiety symptoms were similar to the findings for the primary outcome. Most of the results were rated as 'moderate' to 'very low' in terms of confidence of evidence. CONCLUSIONS: CPT, BT and individual TF-CBT appear to be the best choices of psychotherapy for PTSD in young patients. Other types and different ways of delivering psychological treatment can be alternative options. Clinicians should consider the importance of each outcome and the patients' preferences in real clinical practice.

The diagnostic value of dynamic volume computed tomography angiography in children with anomalous origin of the left coronary artery from the pulmonary artery.

There have been almost no reports on the technique of dynamic volume computed tomography angiography (DVCTA) in children with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). Twelve children with ALCAPA, aged 5 months to 15 years, were enrolled in this retrospective study to explore the clinical value of DVCTA in the diagnosis of ALCAPA in children. All patients underwent low-dose prospective ECG-gated 320-slice DVCTA and transthoracic echocardiography. Two radiologists evaluated the image quality of the DVCTA and recorded the radiation dose at the same time. The accuracy of DVCTA in the diagnosis of ALCAPA was 100%, with the left coronary artery (LCA) opening in the left wall of the pulmonary artery in 4 cases (33.3%), the right wall in 2 cases (16.7%), and the posterior wall in 6 cases (50.0%). All children completed 320-slice DVCTA at a single timepoint; all of the images were diagnosable, and the subjective score was 3.3±0.6, with good consistency between the evaluations performed by the two radiologists (k=0.79). From the echocardiographs of these cases, 4 cases (33.3%) of ALCAPA were diagnosed correctly, 4 cases (33.3%) were misdiagnosed as LCA-pulmonary artery fistula, and 4 cases (33.3%) were missed, including a small LCA that was not displayed in 2 cases. The average CT radiation dose was 0.83±0.57 mSv. Low-dose DVCTA clearly showed the origin, course, and collateral vessels of ALCAPA and could be used reliably for noninvasive diagnosis of ALCAPA in children.

Proteomic and metabolomic characterization of amygdala in chronic social defeat stress rats.

BACKGROUND: Depression is a leading cause of disability worldwide. There is increasing evidence showing that depression is associated with the pathophysiology in amygdala; however, the underlying mechanism remains poorly understood. METHOD: We established a rat model of chronic social defeat stress (CSDS) and conducted a series of behavior tests to observe behavioral changes. Then liquid chromatography mass spectrometry (LC-MS)-based metabolomics and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics were employed to detect metabolomes and proteomes in the amygdala, respectively. Ingenuity pathway analysis (IPA) and other bioinformatic analyses were used to analyze differentially expressed metabolites and proteins. RESULTS: The significantly lower sucrose preference index in the sucrose preference test and longer immobile time in the forced swim test were observed in the CSDS rats compared with control rats. In the multi-omics analysis, thirty-seven significantly differentially expressed metabolites and 123 significant proteins were identified. Integrated analysis of differentially expressed metabolites and proteins by IPA revealed molecular changes mainly associated with synaptic plasticity, phospholipase c signaling, and glutamine degradation I. We compared the metabolites in the amygdala with those in the hippocampus and prefrontal cortex from our previous studies and found two common metabolites: arachidonic acid and N-acetyl-l-aspartic acid among these three brain regions. CONCLUSION: Our study revealed the presence of depressive-like behaviors and molecular changes of amygdala in the CSDS rat model, which may provide further insights into the pathogenesis of depression, and help to identify potential targets for antidepressants.