Associations of evening-type and insomnia symptoms with depressive symptoms among youths.

BACKGROUND: Evening-type and insomnia symptoms are significantly related to each other and independently associated with depressive symptoms, yet few studies have examined the potential interaction between these two conditions. Therefore, we aimed to examine the associations of evening-type and insomnia symptoms with depressive symptoms among Chinese youths, with a specific focus on the joint effects of the two conditions on depressive symptoms. METHODS: Participants aged between 12 and 25 were invited to participate in an online survey from December 15, 2022, to May 26, 2023. Multivariate logistic regression models and additive interaction models were used to examine the independent and joint effects of chronotypes and insomnia symptoms on depressive symptoms, respectively. RESULTS: Of the 6145 eligible youths, the prevalence of evening-type and insomnia symptoms were 24.9 % and 29.6 %, respectively. Both evening-type (adjusted OR, [AdjOR]: 3.21, 95 % CI: 2.80-3.67) and insomnia symptoms (AdjOR: 10.53, 95 % CI: 9.14-12.12) were associated with an increased risk of depressive symptoms. In addition, the additive interaction models showed that there is an enhanced risk of depression related to interaction between evening-type and insomnia symptoms (relative excess risk due to interaction, [RERI]: 11.66, 95 % CI: 7.21-16.11). CONCLUSIONS: The present study provided additional evidence demonstrating the presence of interaction between evening-type and insomnia symptoms, which can lead to a higher risk of depressive symptoms. Our findings argue the need for addressing both sleep and circadian factors in the management of depressive symptoms in young people.

Pedigree-based study to identify GOLGB1 as a risk gene for bipolar disorder.

Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.

The association between sibling bullying and psychotic-like experiences among children age 11-16 years in China.

BACKGROUND: Few studies exist on sibling bullying or even sibling aggression more generally in the past 30 years. Studies of sibling bullying have shown that sibling bullying may associate with depression, anxiety, self-harm, suicide ideation in early adulthood. Nevertheless, few studies have explored the relationship between sibling victimization types and the occurrence of psychosis, not to mention that psychotic-like experiences (PLEs) always occur before psychotic disorders. Therefore, the current study aims to examine the association between sibling bullying and PLEs among children age 11-16 years in China. METHOD: This is a cross-sectional study which included 3231 students from eight junior middle schools in three cities of Hunan Province, China. Frequency and types of sibling bullying was assessed with Sibling Bullying Questionnaire and PLEs was assessed with Community Assessment Psychic Experiences-42. RESULTS: The percentage of sibling bullying were 12.9% for victimization and 10.8% for perpetration. Sibling bullying plays as an independent influence factor for all subtypes of PLEs, and verbal victimization was the most important risk factor in developing different subtypes of PLEs followed by physical victimization and verbal perpetration. CONCLUSION: The current study found that sibling bullying is associated with PLEs. Intervention programs should be conducted to focus on those children and adolescents who are involved in multiple types of sibling victimization or perpetration.

RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation.

Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer's disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.

Rapid Simultaneous Determination of 14 Antidepressants and 13 Antipsychotics in Human Plasma by Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry With Dynamic Multiple Reaction Monitoring and Its Application to Therapeutic Drug Monitoring.

BACKGROUND: A comprehensive, stable, and efficient high-performance liquid chromatography-tandem mass spectrometry method was developed for rapidly analyzing 14 antidepressants and 13 antipsychotics in human plasma for routine clinical therapeutic drug monitoring. METHODS: Simple protein precipitation was used for the pretreatment of plasma samples; dynamic multiple reaction monitoring was used to avoid the loss of sensitivity caused by numerous ion transitions. In all, 80 ion transitions of 40 compounds were quantitatively determined in 6 minutes. RESULTS: The limit of detection for the 27 analytes was in the range of 0.1-30 ng/mL, and all calibration lines prepared using blank plasma were linear with a correlation coefficient of r2 ≥ 0.99. The method was accurate and precise with acceptable intraday and interday precisions (coefficients of variation, ≤20% for a lower limit of quantification and ≤15% for other quality control samples) and an accuracy of 85.51%-114.77%. This analysis method has been completely validated and successfully used in routine clinical therapeutic drug monitoring for more than 9963 samples [including 488 samples having drug concentrations above the laboratory alert level (supra-alert-level samples)] at Xiamen Xianyue Hospital. CONCLUSIONS: This dynamic method is comprehensive (includes most antidepressants and antipsychotics listed in China), reliable (stably used for almost 2 years), and efficient (convenient sample processing and short run time) and provides a large amount of meaningful data for optimized pharmacotherapy. Our experimental data from the plasma concentrations of supra-alert-level samples could serve as a reference for the interpretation of the pharmacokinetics of patients with a high risk of toxicity or loss of tolerability.

Fluoxetine attenuates prepulse inhibition deficit induced by neonatal administration of MK-801 in mice.

Increasing evidence supports schizophrenia may be a neurodevelopmental and neurodegenerative disorder. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to have neuroprotective effects and be effective in treating neurodegenerative disorders including schizophrenia. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of fluoxetine on the sensorimotor gating deficit, a schizophrenia-like behavior in a neurodevelopmental schizophrenic mouse model induced by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. On postnatal day 7, mouse pups were treated with a total seven subcutaneous daily injections of MK-801 (1 mg/kg/day), followed by intraperitoneal injection of fluoxetine (5 or 10 mg/kg/day) starting on postnatal day 14 in the MK-801-injected mice for 4 weeks. The sensorimotor gating deficit in mice was measured by prepulse inhibition (PPI) behavioral test on postnatal day 43. After the behavioral test, the protein expression of brain-derived neurotrophic factor (BDNF) was measured by western blot or ELISA in the frontal cortex of mice. Our results showed fluoxetine attenuated PPI deficit and the decrease of cerebral BDNF expression in the MK-801-injected mice. These results suggest that fluoxetine can be used to treat sensorimotor gating deficit in a neurodevelopmental mouse model of schizophrenia, and the attenuating effect of fluoxetine on sensorimotor gating deficit may be related to fluoxetine's neuroprotective effect targeting on the modulation of cerebral BDNF.

The prevalence of confirmed childhood trauma and its' impact on psychotic-like experiences in a sample of Chinese adolescents.

Adolescents with childhood trauma may be associated with psychotic-like experiences (PLEs) and is at high risk for later development of psychoses. Exploring early age risk factors for childhood trauma may provide useful information for prevention of mental disorders and improvement of mental health, yet no studies have examined the association between exposure to specific forms of trauma and different types of PLEs in a sample of Chinese adolescents. Thus, the Childhood Trauma Questionnaire-Short Form was used to measure five types of childhood trauma (emotional abuse, EA; physical abuse, PA; sexual abuse, SA; emotional neglect, EA; physical neglect, PA) in junior middle school students. And the positive subscale of Community Assessment of Psychic Experiences divided into four types (bizarre experiences, perceptual abnormalities, persecutory ideation and magical thinking) was used to measure PLEs. Then the possible associations among demographic information and specific types of childhood trauma on specific forms of PLEs was compared. The rates of EA, PA, SA, EA and PA were 14.2%, 13.0%, 16.1%, 60.0%, and 78.6%, respectively. Moreover, childhood trauma seems to be a main role in the development of PLE, and EA and SA patients are particularly likely to experience PLEs.

Lower serum nicotinamide N-methyltransferase levels in patients with bipolar disorder during acute episodes compared to healthy controls: a cross-sectional study.

BACKGROUND: Nicotinamide N-methyltransferase (NNMT) has been implicated in the pathogenesis of neuropsychiatric diseases. Bipolar disorder (BD) is associated with metabolic abnormalities and NNMT regulates energy metabolism and may also exert a causal role in metabolic disorders. The present study aimed to determine serum NNMT levels in patients with BD and compared the results with that of healthy controls, to explore the correlation between NNMT and clinical and metabolic characteristics. METHODS: The NNMT levels of 80 patients having a manic episode of BD and 65 non-psychiatric control individuals were measured using enzyme-linked immunosorbent assay. Metabolic parameters were evaluated using standard laboratory methods. RESULTS: The serum NNMT levels of bipolar mania patients were significantly lower than that of non-psychiatric controls. Furthermore, the serum levels of NNMT were found to be negatively correlated with Young Mania Rating Scale (YMRS) scores and the duration of the illness. Moreover, lower NNMT serum levels were found in patients with a history of antipsychotic medication and dyslipidemia. Our results also demonstrated the different patterns of correlation that exist between the study groups. Serum NNMT levels were found to be negatively correlated with triglyceride, cholesterol, and apolipoprotein B levels in the BD group, while the same was found to be negatively associated only with high-density lipoprotein cholesterol in the control group. CONCLUSIONS: These findings support the suggestion that lower NNMT serum levels are significantly associated with BD and that serum NNMT has the potential to regulate lipid metabolism in BD patients.

Plasma levels of Interleukin 18 but not amyloid-ß or Tau are elevated in female depressive patients.

BACKGROUND: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-ß (Aß) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aß40, Aß42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. METHODS: We measured plasma IL18, Aß40, Aß42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. RESULTS: We found that none of the plasma levels of IL18, Aß40, Aß42, and Tau, the ratio of Aß42/Aß40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aß42/Aß40 ratio and standardized Tau in depressive patients. CONCLUSIONS: Plasma IL18 may be a potential biomarker for depression in women.

High serum levels of FGF21 are decreased in bipolar mania patients during psychotropic medication treatment and are associated with increased metabolism disturbance.

Bipolar disorder (BD), a psychiatric illness, results partly as a side effect of psychotropic medications and presents a high risk of metabolic disturbance. Fibroblast growth factor 21 (FGF21) is as an important regulator in carbohydrate and lipid metabolism. In this study, we investigated the serum levels of FGF21 and analyzed its association with metabolic parameters in bipolar mania patients at pre- and post-treatment with psychotropic medications. Bipolar mania inpatients (n = 99) and healthy controls (n = 99) were included at baseline; the patients were followed up after four-week treatment. Serum levels of FGF21 and several metabolic parameters were measured by appropriate detection methods. We found that baseline serum FGF21 levels were significantly higher in bipolar manic patients when compared to that in controls. After four-week medication, FGF21 levels were found to be decreased in patients when compared to the baseline suggesting that FGF21 may be associated with the psychopathology of bipolar mania. Moreover, FGF21 levels were found to be negatively correlated with the serum triglycerides (TG), cholesterol (CHO), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), glucose (Glu), and Body Mass Index (BMI). In addition, our data also indicates that FGF21 may monitor and/or prevent the metabolic abnormalities induced by psychotropic drugs.

RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits.

BACKGROUND: Although synaptic impairment is a prerequisite to cognitive deficiencies in Alzheimer's disease (AD), mechanisms underlying the dysregulation of essential synaptic scaffolding components and their integrity remain elusive. RPS23RG1 is a newly identified protein implicated in AD. However, the physiological function of RPS23RG1 has yet to be determined. METHODS: We investigated the role of RPS23RG1 in maintaining synaptic structure and function in cell cultures and in Rps23rg1 knockout mice and determined whether targeting RPS23RG1-mediated pathways has therapeutic potential in APP/PS1 AD model mice. RESULTS: Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of postsynaptic structure and function, with marked reductions in postsynaptic densities-93 and -95 (PSD-93 and PSD-95) levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from murine double minute 2-mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PS-D95 levels reversed synaptic and memory deficits in Rps23rg1 knockout mice. We further observed attenuated RPS23RG1 expression in human AD, which positively correlated with PSD-93/PSD-95 levels. Importantly, an RPS23RG1-derived peptide comprising a unique PSD-93/PSD-95 interaction motif rescued synaptic and cognitive defects in Rps23rg1 knockout and AD mouse models. CONCLUSIONS: Our results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in AD pathogenesis. This demonstrates that RPS23RG1-mediated pathways show good therapeutic potential in AD intervention.

Histopathologic tumor invasion of superior mesenteric vein/ portal vein is a poor prognostic indicator in patients with pancreatic ductal adenocarcinoma: results from a systematic review and meta-analysis.

BACKGROUND: The impact of histopathologic tumor invasion of the superior mesenteric vein (SMV)/portal vein (PV) on prognosis in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreatectomy remains controversial. A meta-analysis was performed to assess this issue. RESULTS: Eighteen observational studies comprising 5242 patients were eligible, of whom 2199 (41.9%) patients received SMV/PV resection. Histopathologic tumor invasion was detected in 1218 (58.1%) of the 2096 resected SMV/PV specimens. SMV/PV invasion was associated with higher rates of poor tumor differentiation (P = 0.002), lymph node metastasis (P < 0.001), perineural invasion (P < 0.001), positive resection margins (P = 0.004), and postoperative tumor recurrence (P < 0.001). SMV/PV invasion showed a significantly negative effect on survival in total patients who underwent pancreatectomy with and without SMV/PV resection (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 1.08-1.35; P = 0.001) and in patients who underwent pancreatectomy with SMV/PV resection (HR: 1.88, 95% CI, 1.48-2.39; P < 0.001). MATERIALS AND METHODS: A systematic literature search was performed to identify articles published from January 2000 to August 2016. Data were pooled for meta-analysis using Review Manager 5.3. CONCLUSIONS: Histopathologic tumor invasion of the SMV/PV is associated with more aggressive biologic behavior and could be used as an indicator of poor prognosis after PDAC resection.

Clinicopathological characteristics, treatment, and survival outcomes of cystadenocarcinoma of the salivary gland: a population-based study.

BACKGROUND: The aim of this study was to investigate the clinicopathological characteristics, treatment, and survival of cystadenocarcinoma of the salivary gland. PATIENTS AND METHODS: Cases in the Surveillance, Epidemiology, and End Results database from 1991 to 2012 were identified. Factors significantly associated with survival were identified using Kaplan-Meier survival analysis and Cox proportional hazard regression. RESULTS: A total of 65 patients were identified; of these patients, 64 received surgical treatment, 25 underwent lymphadenectomy, and four (16.0%) patients had nodal metastasis and only one (2.1%) patient had poorly differentiated disease. The most common tumor location was the parotid gland (87.7%). The median follow-up was 55 months. None of the patients died of salivary gland malignant-tumor-related disease. The 5- and 10-year cause-specific survival rates were 97.0% and 81.4%, respectively. The 5- and 10-year overall survival rates were 84.6% and 60.7%, respectively. Surgical procedures, lymphadenectomy, and adjuvant radiotherapy did not affect survival. CONCLUSION: Salivary gland cystadenocarcinoma is extremely rare but has an excellent prognosis, and surgery is the mainstay of treatment.

[A clinical study of paclitaxel combined with FOLFOX4 regimen as neoadjuvant chemotherapy for advanced gastric cancer].

OBJECTIVE: To evaluate the clinical efficacy and the toxicity of neoadjuvant chemotherapy with paclitaxel and FOLFOX4 (5-fluorouracil/leucovorin combined and oxaliplatin) regimen for advanced gastric cancer. METHODS: Seventy-eight patients with cTNM stage III or IV (M0) gastric cancer were enrolled and 39 were randomized into the treatment arm (n=39, paclitaxel combined with FOLFOX4 regimen neoadjuvant chemotherapy every two weeks in each cycle) and control group (n=39). Clinical response was evaluated with RECIST criteria after 3 cycles. Patients in experimental group received surgery after 2-4 weeks and postoperative chemotherapy of 3 cycles of the original regimen. When disease progressed, postoperative chemotherapy regimen was changed into ECF regimen. The control group of 39 patients received surgery within 2 weeks and postoperative chemotherapy of 6 cycles of paclitaxel combined with FOLFOX4 regimen. RESULTS: The clinical response rate was 66.7% in the treatment arm. The R0 resection rate (59.0%) was significantly higher than that in the control group (P=0.025) and the number of lymph node metastasis in the treatment arm(3.23±2.80) was significantly lower than that in the control group (5.79±2.69, P=0.001). There were no significant differences in postoperative complication rate (5.1% vs. 2.6%) and the number of lymph node dissection (19.69±2.95 vs. 20.59±3.22) between the two groups (P>0.05). The median survival time and 2-year survival rate in the treatment arm [(27.10±2.32) months and 59.0%] was significantly higher than that in the control group[(18.20±1.30) months and 28.2%] (P=0.001, P=0.006). Cox regression multivariable analysis showed that tumor differentiation, R0 resection, lymph node metastasis were independent prognostic factors. Adverse reaction of chemotherapy, mainly hematological adverse reactions, and peripheral nerve toxicity, were tolerable. No significant differences were noted between the two groups in adverse reactions (P>0.05). CONCLUSIONS: The efficacy of paclitaxel combined with FOLFOX4 as neoadjuvant chemotherapy is high. Patients tolerance and compliance are satisfactory. It can improve in patients with advanced gastric cancer the R0 resection rate, reduce lymph node metastasis and improve survival.