Hyperhomocysteinemia is associated with the risk of venous thromboembolism in patients with mental illness: a case-control study.

Objective: The risk of venous thromboembolism in patients with mental illness has been insufficiently addressed. This study aimed to assess the correlation between hyperhomocysteinemia and venous thromboembolism prevalence among this population. Methods: Patients with a diagnosis of mental illness and concurrent venous thromboembolism, admitted to Sir Run Run Shaw Hospital at Zhejiang University School of Medicine between January 2014 and December 2021, were included in the venous thromboembolism group. The control group, approximately twice the size, comprised individuals with mental illness but without venous thromboembolism. Basic clinical data were gathered for both cohorts. Results: In psychiatric patients, elevated D-dimer levels(OR=5.60,95% CI 3.28-10.00), hyperhomocysteinemia (OR=2.37,95% CI 1.10-5.14), and hyperprolactinemia(OR= 2.68,95% CI 1.12-6.42)were significant risk factors for venous thromboembolism. According to further subgroup analyses, hyperhomocysteinemia is a significant risk factor associated with pulmonary embolism, with an OR of 5.08 (95% CI 1.20-21.48). An interaction effect between gender and homocysteine level was found, with a p-interaction of 0.022. A subsequent analysis confirmed the association between hyperhomocysteinemia and venous thromboembolism in female psychiatric patients, with an OR of 3.34 (95% CI 1.68-6.65), indicating that hyperhomocysteinemia is a significant risk factor for venous thromboembolism in women. Conclusion: Patients with psychiatric disorders were found to have an elevated risk of venous thromboembolism, which was associated with increased levels of D-dimer, hyperprolactinemia, and hyperhomocysteinemia. A strong correlation between hyperhomocysteinemia and pulmonary embolism was identified in patients with mental illnesses. Furthermore, the study revealed that female psychiatric patients with hyperhomocysteinemia constituted a high-risk group for venous thromboembolism. This finding holds significant clinical implications, suggesting that early preventative measures could be implemented for this high-risk population to reduce the incidence of thromboembolic events during hospitalization for psychiatric patients.

Factors influencing the association between depressive symptoms and cardiovascular disease in US population.

Cardiovascular disease (CVD) and depression are common diseases that lead to adverse health outcomes. Depressive Symptoms may be a risk factor for CVD. But few studies focused on the impact of socioeconomic factors, common medical history and dietary intake about this association. This study analyzed National Health and Nutrition Examination Survey (NHANES) 2007-2016. Complex sampling-weighted logistic regression models were used to compare the odds ratios (ORs) of CVD in participants with different depressive symptoms. 11,516 NHANES participants aged ≥ 40 years were included in the final analysis, of whom 1842 had CVD. Compared with participants with no/minimal depression, participants with mild, moderate, and moderately severe/severe depression had OR values of 1.25 (95%  CI 1.01-1.54), 1.98 (95% CI 1.32-2.96), and 2.41 (95% CI 1.63-3.57). The association of depressive symptoms with CVD follow a dose-dependent pattern. The interactions of depressive symptoms with gender (Interaction P = 0.009), diabetes (Interaction P = 0.010), household income level (Interaction P = 0.002), dietary cholesterol intake (Interaction P = 0.017) on CVD were observed. More severe depressive symptoms are associated with increased risk of CVD in US population. The association may be more pronounced in the female population, population with diabetes, low family income level, or high dietary cholesterol intake.

Tumor markers and depression scores are predictive of non-suicidal self-injury behaviors among adolescents with depressive disorder: A retrospective study.

Background: Non-suicidal self-injury (NSSI) is an important risk factor for suicide in adolescents with depressive disorders; therefore, it is important to predict NSSI occurrence as early as possible. Disturbances in biological rhythms are characteristic manifestations of depressive disorders and can lead to immune dysfunction, leading to changes in tumor markers. This study aimed to produce an index that utilizes tumor markers to predict NSSI behaviors among adolescents with depressive disorders. Methods: A total of 120 hospitalized adolescent patients with depressive disorders aged 14-24 years were included in this study. Participants were divided into NSSI and non-NSSI groups based on self-reports using the Ottawa Self-Injury Inventory. Demographics, tumor marker concentrations, other peripheral blood indices, Hamilton Depression Rating Scale (HDRS) scores, and Hamilton Anxiety Rating Scale (HAMA) scores were compared between the two groups. Logistic regression analysis was conducted to develop a joint index, and a receiver operating characteristic (ROC) curve was created to predict NSSI behaviors among adolescents with depressive disorders. Results: Compared with the non-NSSI group, the NSSI group had significantly higher insight, retardation, insomnia, hopelessness, psychiatric anxiety, total HDRS and HAMA scores, and significantly higher levels of cancer antigen 125 (CA-125), cancer antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). In addition, a joint index was developed by combining CA-125, CA19-9, CEA, HDRS total score, HAMA total score and age using multiple logistic regression to predict NSSI behaviors. The area under the curve was 0.831, with a sensitivity and specificity of 0.734 and 0.891, respectively. Conclusion: A combination of depression score, tumor marker levels, and age can identify NSSI behaviors among adolescents with depressive disorders.

Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

Alterations of the electrophysiological properties from cortical layer 5 pyramidal neurons in temporary rapamycin-treated rodent brain slices.

The mammalian target of rapamycin (mTOR) signaling pathway is involved in neuro-developmental/degenerative and neuropsychiatric abnormalities. Rapamycin, a specific and potent inhibitor of mTOR signaling, could regulate synaptic plasticity and synaptic transmission of glutamatergic neurons following prolonged treatment. Its immediate effects on electrophysiological properties of cortical layer 5 (L5) pyramidal neurons where the information undergoes a sophisticated processing remain unknown. Here, we found that acute (within 2min) bath-application of rapamycin (0.5µgml(-1)) was able to depolarize the current-clamp baseline potentials significantly at postnatal day (P) 4, P10 in rats and P90 in mice (P<0.05), and altered the membrane current/voltage (I/V) curves in an age-dependent manner. Rapamycin not only increased the standard deviation or the peak amplitude of baseline membrane potential, but also increased the frequencies of spontaneous action potentials in more mature neurons (P10 and P90). In addition, rapamycin decreased the burst-firing frequencies of cortical L5 burst-spiking neurons from mature brains, and further switched their firing modes to regular-spiking ones. These findings suggest that acute inhibition of mTOR signaling by rapamycin induces an immediate impact on L5 pyramidal neurons' electrophysiological properties, indicating that its effects might involve mechanisms of ion channel's regulation.

Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke.

Notch signaling is critically involved in various biological events. Notch undergoes cleavage by the γ-secretase enzyme to release Notch intracellular domain that will translocate into nucleus to result in expression of target gene. γ-Secretase inhibitors have been developed as potential treatments for neurological degenerative diseases, but its effects against ischemic injury remain relatively uncertain. In the present study, we demonstrated that N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor not only rescued the cerebral hypoperfusion or ischemia neonatal rats from death, reduced apoptosis in penumbra, but also reduced brain infarct size. Furthermore, DAPT elicited some morphologic hallmarks such as neurogenesis and angiogenesis that related to the brain repair and functional recovery after stroke: increased accumulations of newborn cells in the peri-infarct region with a higher fraction of them adopting immature neuronal and glial markers instead of microglial markers on 5 days, enhanced vascular densities in penumbra at 14 days, and evident regulations of the gene profiles associated with neurogenesis in penumbral tissues. The current results suggest that DAPT is a potential neuroprotectants against ischemic injury in immature brain, and future treatment strategies such as clinical trials using γ-secretase inhibitors would be an attractive therapy for perinatal ischemia.

Postnatal maternal separation enhances tonic GABA current of cortical layer 5 pyramidal neurons in juvenile rats and promotes genesis of GABAergic neurons in neocortical molecular layer and subventricular zone in adult rats.

Postnatal maternal separation (PMS) has been shown to be associated with an increased vulnerability to psychiatric illnesses in adulthood. However, the underlying neurological mechanisms are not well understood. Here we evaluated its effects on neurogenesis and tonic GABA currents of cortical layer 5 (L5) pyramidal neurons. PMS not only increased cell proliferation in the subventricular zone, cortical layer 1 and hippocampal dentate gyrus in the adult brain, but also promoted the newly generated cells to differentiate into GABAergic neurons, and PMS adult brain maintained higher ratios of GABAergic neurons in the survival of newly generated cells within 5 days immediately post PMS. Additionally, PMS increased the tonic currents at P7-10 and P30-35 in cortical L5 pyramidal cells. Our results suggest that the newly generated GABAergic neurons and the low GABA concentration-activated tonic currents may be involved in the development of psychiatric disorders after PMS.

The membrane molecule RCAS1 induces immune cell apoptosis via the RCAS1-RCAS1R pathway.

Tumor-associated antigen receptor-binding cancer antigen expressed on SiSo cells (RCAS1) has been identified as an estrogen-responsive gene and reportedly acts as a ligand for a putative receptor present in a variety of human cell lines and peripheral lymphocytes, thus leading them to apoptosis. In this study, we investigated the biological function of RCAS1 in vitro in inducing the apoptosis of immune cells. We detected the expression of the RCAS1 receptor (RCAS1R) in the cell lines, and investigated the mechanisms behind the apoptosis induced by RCAS1. HeLa cells were transfected with recombinant adenovirus Ad-RCAS1. RCAS1 induced the apoptosis of activated T cells, K562 cells and phytohemagglutinin (PHA)-activated Jurkat cells via the RCAS1-RCAS1R pathway. The expression of RCAS1R was induced. The intracellular overexpression of RCAS1 inhibited the growth of Jurkat and K562 cells. The expression of RCAS1 negatively correlated with the expression of glycogen synthase kinase 3ß (GSK3ß), but positively correlated with the expression of phosphorylated GSK3ß (phGSK3ß). RCAS1 expression was identified as a brown staining pattern in the breast cancer specimens. These findings may provide insight into the mechanisms through which tumor cells escape from immune surveillance.

Opening of astrocytic mitochondrial ATP-sensitive potassium channels upregulates electrical coupling between hippocampal astrocytes in rat brain slices.

Astrocytes form extensive intercellular networks through gap junctions to support both biochemical and electrical coupling between adjacent cells. ATP-sensitive K(+) (K(ATP)) channels couple cell metabolic state to membrane excitability and are enriched in glial cells. Activation of astrocytic mitochondrial K(ATP) (mitoK(ATP)) channel regulates certain astrocytic functions. However, less is known about its impact on electrical coupling between directly coupled astrocytes ex vivo. By using dual patch clamp recording, we found that activation of mitoK(ATP) channel increased the electrical coupling ratio in brain slices. The electrical coupling ratio started to increase 3 min after exposure to Diazoxide, a mitoK(ATP) channel activator, peaked at 5 min, and maintained its level with little adaptation until the end of the 10-min treatment. Blocking the mitoK(ATP) channel with 5-hydroxydecanoate, inhibited electrical coupling immediately, and by 10-min, the ratio dropped by 71% of the initial level. Activation of mitoK(ATP) channel also decreased the latency time of the transjunctional currents by 50%. The increase in the coupling ratio resulting from the activation of the mitoK(ATP) channel in a single astrocyte was further potentiated by the concurrent inhibiting of the channel on the recipient astrocyte. Furthermore, Meclofenamic acid, a gap-junction inhibitor which completely blocked the tracer coupling, hardly reversed the impact of mitoK(ATP) channel's activation on electrical coupling (by 7%). The level of mitochondrial Connexin43, a gap junctional subunit, significantly increased by 70% in astrocytes after 10-min Diazoxide treatment. Phospho-ERK signals were detected in Connexin43 immunoprecipitates in the Diazoxide-treated astrocytes, but not untreated control samples. Finally, inhibiting ERK could attenuate the effects of Diazoxide on electrical coupling by 61%. These findings demonstrate that activation of astrocytic mitoK(ATP) channel upregulates electrical coupling between hippocampal astrocytes ex vivo. In addition, this effect is mainly via up-regulation of the Connexin43-constituted gap junction coupling by an ERK-dependent mechanism in the mitochondria.

Transient elevation of hepatic enzymes in volunteers after intake of alcohol.

BACKGROUND: In the organs that mediate alcohol effects on the human body and its health, the liver plays a particular important role. This study was designed to detect the changes of hepatic enzymes after alcohol intake and evaluate the corresponding damage to the human body. METHODS: Fifteen volunteers were included according to the criteria. After the intake of 80 g ethanol containing beverage, alcohol levels were detected and blood samples were collected at 0.5- to 3-hour interval to detect the levels of hepatic enzymes simultaneously. RESULTS: After the intake of 80 g ethanol, various symptoms occurred in volunteers while the concentration of blood alcohol peaked at 1 hour and normalized within 24 hours. The ratio of alanine aminotransferase (ALT) to aspartate aminotransferase (AST) increased significantly when the venous alcoholic concentration increased from 0 g/L to 1.2 g/L and the levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GT) were elevated when the alcoholic concentration reached 0.4 g/L. No significant changes were noticed in ALT, AST or cholinesterase (CHE). CONCLUSION: Acute alcohol intoxication may cause the changes of hepatic enzymes and prove the existence of reversible hepatic injury.

Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats.

The purpose of this study was to investigate whether or not clobenpropit, a selective and potent histamine H(3) receptor antagonist, can protect from pentylenetetrazole (35 mg/kg)-kindled seizures in rats. I.c.v. injection with clobenpropit (10 and 20 microg) significantly delayed the seizure stage and prolonged the latency to the onset of myoclonic jerks and the latency to the clonic generalized seizure in a dose-dependent manner. The protection by clobenpropit (20 microg) was completely antagonized by both immepip (5 and 10 microg, i.c.v.), a selective potent histamine H(3) receptor agonist, and alpha-fluoromethylhistidine (alpha-FMH, 50 microg, i.c.v.), a selective histidine decarboxylase inhibitor. In addition, clobenpropit markedly potentiated the histidine (100 and 200 mg/kg)-induced inhibition of pentylenetetrazole-kindled seizures. Pyrilamine (2 and 5 microg, i.c.v.) reversed the inhibition of pentylenetetrazole-kindled seizures induced by clobenpropit, whereas cimetidine had no effect even at a high dose of 5 microg. These results indicate that clobenpropit protects against pentylenetetrazole-kindled seizures in rats, and that its action is mainly due to the activation of endogenous histamine by blocking autoinhibitory presynaptic histamine H(3) receptors.