Major depressive disorder: hypothesis, mechanism, prevention and treatment.

Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

An intelligent quantification system for fetal heart rhythm assessment: A multicenter prospective study.

BACKGROUND: The motion relationship and time intervals of the pulsed-wave Doppler (PWD) spectrum are essential for diagnosing fetal arrhythmia. However, few technologies currently are available to automatically calculate fetal cardiac time intervals (CTIs). OBJECTIVE: The purpose of this study was to develop a fetal heart rhythm intelligent quantification system (HR-IQS) for the automatic extraction of CTIs and establish the normal reference range for fetal CTIs. METHODS: A total of 6498 PWD spectrums of 2630 fetuses over the junction between the left ventricular inflow and outflow tracts were recorded across 14 centers. E, A, and V waves were manually labeled by 3 experienced fetal cardiologists, with 17 CTIs extracted. Five-fold cross-validation was performed for training and testing of the deep learning model. Agreement between the manual and HR-IQS-based values was evaluated using the intraclass correlation coefficient and Spearman's rank correlation coefficient. The Jarque-Bera test was applied to evaluate the normality of CTIs' distributions, and the normal reference range of 17 CTIs was established with quantile regression. Arrhythmia subset was compared with the non-arrhythmia subset using the Mann-Whitney U test. RESULTS: Significant positive correlation (P <.001) and moderate-to-excellent consistency (P <.001) between the manual and HR-IQS automated measurements of CTIs was found. The distribution of CTIs was non-normal (P <.001). The normal range (2.5th to 97.5th percentiles) was successfully established for the 17 CTIs. CONCLUSIONS: Using our HR-IQS is feasible for the automated calculation of CTIs in practice and thus could provide a promising tool for the assessment of fetal rhythm and function.

A novel murine model of mania.

Neuropathological mechanisms of manic syndrome or manic episodes in bipolar disorder remain poorly characterised, as the research progress is severely limited by the paucity of appropriate animal models. Here we developed a novel mania mice model by combining a series of chronic unpredictable rhythm disturbances (CURD), which include disruption of circadian rhythm, sleep deprivation, exposure to cone light, with subsequent interference of followed spotlight, stroboscopic illumination, high-temperature stress, noise disturbance and foot shock. Multiple behavioural and cell biology tests comparing the CURD-model with healthy controls and depressed mice were deployed to validate the model. The manic mice were also tested for the pharmacological effects of various medicinal agents used for treating mania. Finally, we compared plasma indicators of the CURD-model mice and the patients with the manic syndrome. The CURD protocol produced a phenotype replicating manic syndrome. Mice exposed to CURD presented manic behaviours similar to that observed in the amphetamine manic model. These behaviours were distinct from depressive-like behaviours recorded in mice treated with a depression-inducing protocol of chronic unpredictable mild restraint (CUMR). Functional and molecular indicators in the CURD mania model showed multiple similarities with patients with manic syndrome. Treatment with LiCl and valproic acid resulted in behavioural improvements and recovery of molecular indicators. A novel manic mice model induced by environmental stressors and free from genetic or pharmacological interventions is a valuable tool for research into pathological mechanisms of mania.

Novel pathogenesis of post-traumatic stress disorder studied in transgenic mice.

Posttraumatic stress disorder (PTSD) is very common after exposure to trauma, mental stress or violence. Because objective biological markers for PTSD are lacking, exactly diagnosing PTSD is a challenge for clinical psychologists. In-depth research on the pathogenesis of PTSD is a key for solving this problem. In this work, we used male Thy1-YFP transgenic mice, in which neurons are fluorescently labeled, to research the effects of PTSD on neurons in vivo. We initially discovered that pathological stress associated with PTSD increased the activation of glycogen synthesis kinase-beta (GSK-3ß) in neurons and induced the translocation of the transcription factor forkhead box-class O3a (FoxO3a) from the cytoplasm to the nucleus, which decreased the expression of uncoupling protein 2 (UCP2) and increased mitochondrial production of reactive oxygen species (ROS) to trigger neuronal apoptosis in the prefrontal cortex (PFC). Furthermore, the PTSD model mice showed increased freezing and anxiety-like behaviors and more severe decrease of memory and exploratory behavior. Additionally, leptin attenuated neuronal apoptosis by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which further elevated the expression of UCP2 and inhibited the mitochondrial production of ROS induced by PTSD, thus reducing neuronal apoptosis and ameliorating PTSD-related behaviors. Our study is expected to promote the exploration of PTSD-related pathogenesis in neural cells and the clinical effectiveness of leptin for PTSD.

Leptin Attenuates Fear Memory by Inhibiting Astrocytic NLRP3 Inflammasome in Post-traumatic Stress Disorder Model.

Accumulating evidence suggests that the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Astrocytes, the homeostatic cells of the central nervous system are intimately involved into pathophysiology of various mental disorders including PTSD. We demonstrated previously that leptin exerts neuroprotection and ameliorates chronic sleep deprivation-induced depressive-like behaviours. Here, we extended the study of therapeutic effects of leptin to PTSD model mice. We discovered that PTSD is associated with significant activation of NLRP3 inflammasome in astrocytes sorted from GFAP-GFP transgenic mice, while administration of leptin markedly suppressed the activation of astrocytic NLRP3 inflammasome. Leptin effectively improved PTSD-associated behavioural alterations including fear memory, cognitive impairments, and depressive-like behaviours. Therapeutic effects of leptin were mediated by the signal transducer and activator of transcription 3 (STAT3) in astrocytes. In addition, the PTSD-related activation of NLRP3 inflammasome impairs astrocytic mitochondria suppressing ATP synthesis and leading to an increased ROS production. Leptin reversed mitochondrial inhibition by stimulating STAT3 in astrocytes. We propose leptin as a novel candidate for the pharmacological treatment of PTSD.

Fetal umbilical artery thrombosis: prenatal diagnosis, treatment and follow-up.

BACKGROUND: To analyze the ultrasound imaging and clinical characteristics of fetuses with umbilical artery thrombosis (UAT), explore the potential causes of UAT and construct a prognostic prediction model to guide clinical practice. METHODS: This was a retrospective cohort study of fetal UAT cases examined at two academic tertiary referral care centers from 2014 to 2020. The basic information of the participants was obtained by interview during follow-up, and data on clinical treatment, delivery conditions, diagnosis and confirmation were obtained through medical records. Probable causes of thrombosis were explored by comparative analysis of the UAT group to the control group and by further regression analysis. Multivariable logistic regression models were used to evaluate risk factors for adverse pregnancy outcomes. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic value of the prognostic prediction model. RESULTS: Thirty fetuses with UAT were included in this study. UAT occurred mostly in the third trimester of pregnancy, and there was an obvious predominance of right UAT. An abnormal pregnancy history (53.3%) was the most common comorbidity, followed by gestational diabetes mellitus (GDM) (20.0%). GDM and umbilical cord (UC) abnormalities were found to be independent risk factors for the development of UAT. After comprehensive decision-making, over two-thirds of the patients with UAT received urgent treatment, and less than one-third received expectant management. Surprisingly, there were no significant differences in fetal outcomes between the urgent treatment and expectant management groups. Multivariate logistic regression analysis showed that gestational age (GA) at clinical diagnosis and UC abnormalities were independent risk factors for adverse pregnancy outcomes (OR 0.781, p = 0.042; OR 16.779, p = 0.023, respectively). Based on this, we constructed a comprehensive prognostic prediction model. The area under the ROC curve (AUC) was 0.877 (95% CI 0.698-0.970; p < 0.001), which suggested that the combination of GA and UC abnormalities was a better predictor for fetal outcomes in our setting. CONCLUSION: In summary, maternal GDM and fetal UC abnormalities are independent risk factors for UAT. UAT is more frequently observed on the right side. Moreover, poor clinical outcomes for fetuses with UAT are ascribed mainly to GA and UC abnormalities, which should be comprehensively evaluated to choose the appropriate treatment.

Prediction of small-for-gestational-age neonates at 33-39 weeks' gestation in China: logistic regression modeling of the contributions of second- and third-trimester ultrasound data and maternal factors.

OBJECTIVES: A screening model for prediction of small-for-gestational-age (SGA) neonates (SGAp) was established by logistic regression using ultrasound data and maternal factors (MF). We aimed to evaluate the ability of SGAp as well as abdominal circumference (AC) and estimated fetal weight (EFW) measurements to predict SGA neonates at 33-39 weeks' gestation. METHODS: This retrospective study evaluated 5298 singleton pregnancies that had involved three ultrasound examinations at 21+0-27+6, 28+0-32+6, and 33+0-39+6 weeks. All ultrasound data were transformed to MoM values (multiple of the median). Multivariate logistic regression was used to analyze the correlation between SGA status and various variables (ultrasound data and MF) during pregnancy to build the SGAp model. EFW was calculated according to the Hadlock formula at 33-39 weeks of gestation. The predictive performance of SGAp, AC MoM value at 33+0-39+6 weeks (AC-M), EFW MoM value (EFW-M), EFW-M plus MF, AC value at 33+0-39+6 weeks (AC), AC growth velocity, EFW, and EFW plus MF was evaluated using ROC curves. The detection rate (DR) of SGA neonate with SGAp, AC-M, EFW-M, and EFW-M plus MF at false positive rate (FPR) of 5% and 10%, and the FPR at DR of 85%, 90%, and 95% were observed. RESULTS: The AUCs of SGAp, AC-M, EFW-M, EFW-M plus MF, AC, AC growth velocity, EFW, and EFW plus MF for SGA neonates screening were 0.933 (95%CI: 0.916-0.950), 0.906 (95%CI: 0.887-0.925), 0.920 (95%CI: 0.903-0.936), 0.925 (95%CI: 0.909-0.941), 0.818 (95%CI: 0.791-0.845), 0.786 (95%CI: 0.752-0.821), 0.810 (95%CI: 0.782-0.838), and 0.834 (95%CI: 0.807-0.860), respectively. The screening efficiency of SGAp, AC-M, EFW-M, and EFW-M plus MF are significantly higher than AC, AC growth velocity, EFW, and EFW plus MF. The DR of SGAp, AC-M, EFW-M, and EFW-M plus MF for SGA neonates were 80.4%, 69.6%, 73.8% and 74.3% at 10% FPR. The AUCs of SGAp, AC-M, EFW-M, and EFW-M plus MF 0.950 (95%CI: 0.932-0.967), 0.929 (95%CI: 0.909-0.948), 0.938 (95%CI: 0.921-0.956) and 0.941 (95%CI: 0.924-0.957), respectively for screening SGA neonates delivered within 2 weeks after the assessment. The DR for these births increased to 85.8%, 75.8%, 80.0%, and 82.5%, respectively. CONCLUSION: The rational use of ultrasound data can significantly improve the prediction of SGA statuses.

Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment.

Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.

The neuroprotective mechanism of lithium after ischaemic stroke.

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3ß/ß-catenin and AKT/FoxO3a/ß-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.

Hollow Magnetic Nanocatalysts Drive Starvation-Chemodynamic-Hyperthermia Synergistic Therapy for Tumor.

Magnetic hyperthermia therapy (MHT) has been considered as an excellent alternative for treatment of deep tumor tissue; however, up-regulation of heat shock proteins (HSPs) impairs its hyperthermal therapeutic effect. Reactive oxygen species (ROS) and competitive consumption of ATP are important targets that can block excessive HSP generation. We developed a magnetic nanocatalytic system comprised of glucose oxidase (GOD)-loaded hollow iron oxide nanocatalysts (HIONCs) to drive starvation-chemodynamic-hyperthermia synergistic therapy for tumor treatment. The Fe2+ present in HIONCs contributed to ROS generation via the Fenton reaction, relieving thermo-resistance and inducing cell apoptosis by chemodynamic action. The Fenton effect was enhanced through the conditions created by increased MHT-related temperature, GOD-mediated H2O2 accumulation, and elevated tumor microenvironment acidity. The HIONCs catalase-like activity facilitated conversion of H2O2 to oxygen, thereby replenishing the oxygen levels. We further demonstrated that locally injected HIONCs-GOD effectively inhibited tumor growth in PC3 tumor-bearing mice. This study presents a multifunctional nanocarrier system driving starvation-chemodynamic-magnetic-thermal synergistic therapy via ROS and oxygen modulation for prostate tumor treatment.