Comorbidity and Treatment in Older Psychiatric In-patients-A Retrospective Study in a Chinese Psychiatric Hospital.

Background: Comorbid somatic diseases increase the death risk and affect the condition, treatment, and prognosis of older psychiatric patients. We investigated the comorbidity and drug treatment in older patients with psychosis. Methods: This retrospective study used data from 3,115 older psychiatric in-patients hospitalized at the Shanghai Mental Health Center Affiliated to Shanghai Jiaotong University School of Medicine, China discharged from 2005 to 2015. Descriptive analyses of patients' age, sex, treatment drugs, diagnoses (based on ICD-10), and time trend were performed. Results: Patients' median age was 56 (range, 50-98) years; 1,824 (58.6%) were female. The top five first-level diagnoses were schizophrenia (F20) (n = 1,818, 58.3%), depressive episode (F32) (n = 457, 14.6%), bipolar affective disorder (F31) (n = 151, 4.8%), manic episode (F30), (n = 143, 4.6%), and vascular dementia (F01) (n = 136, 4.4%). Mental (99.9%), central nervous system (85.2%), digestive system (83.5%), cardiovascular system (72.5%), and anti-infective (59.6%) drugs had the highest prescription rates. The combined use of antidepressants, anti-anxiety, anti-arrhythmic, hormones and endocrine system drugs were significantly higher in female than in male patients, while mood stabilizers and genitourinary system drugs significantly more frequent in men. With increasing age, the F20-F29 patients decreased, while F00-F09 patients increased, with the corresponding changes to prescription in those patients. In comparison to that in 2005-2010, the combined prescriptions for genitourinary and cardiovascular drugs increased between 2011 and 2015, and F00-F09 and F40-F48 older patients doubled, accordingly anti-Alzheimer's disease drugs and antidepressants more than doubled. F30-F39 patients increased by 49.1%, and anti-anxiety drugs, mood stabilizers, etc. increased by ≥50%; F20-F29 older patients decreased by 26.7%, while antipsychotics only increased by 4.4%. Conclusions: This study found the combined drug treatment of somatic diseases, particularly for central nervous, digestive, cardiovascular, respiratory and genitourinary drugs were extremely common among older psychiatric in-patients in China. With increasing age, the F20-F29 patients decreased, while F00-F09 patients increased; the antipsychotics prescriptions decreased, and almost all comorbidity drugs increased. Compared with that in 2005-2010, the older patients with all diagnosis except F20-F29 increased in 2011-2015, and the prescriptions for psychotropic, genitourinary, and cardiovascular drugs increased.

PAID study design on the role of PKC activation in immune/inflammation-related depression: a randomised placebo-controlled trial protocol.

BACKGROUND: Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression. Microglia activation can lead to an increase in the levels of proinflammatory cytokines, including TNF-α, which leads to neuronal apoptosis in the specific neural circuits of some brain regions, abnormal cognition and treatment-resistant depression (TRD). Protein kinase C (PKC) is a key regulator of the microglia activation process. We assume that the abnormality in PKC might result in abnormal microglia activation, neuronal apoptosis, significant changes in emotional and cognitive neural circuits, and TRD. In the current study, we plan to target at the PKC signal pathway to improve the TRD treatment outcome. METHODS AND ANALYSIS: This is a 12-week, ongoing, randomised, placebo-controlled trial. Patients with TRD (N=180) were recruited from Shanghai Mental Health Center, Shanghai Jiao Tong University. Healthy control volunteers (N=60) were recruited by advertisement. Patients with TRD were randomly assigned to 'escitalopram+golimumab (TNF-α inhibitor)', 'escitalopram+calcium tablet+vitamin D (PKC activator)' or 'escitalopram+placebo' groups. We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale (HAMD-17). The secondary outcome is defined as changes in anti-inflammatory effects, cognitive function and quality of life. DISCUSSION: This study might be the first randomised, placebo-controlled trial to target at the PKC signal pathway in patients with TRD. Our study might help to propose individualised treatment strategies for depression. TRIAL REGISTRATION NUMBER: The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

Lack of Association Between PLA2G6 Genetic Variation and Parkinson's Disease: A Systematic Review.

BACKGROUND: The phospholipase A2 Group 6 (PLA2G6, also known as PLA2, PARK14, and iPLA2) gene encodes a group VIA calcium-independent phospholipase A2. Genetic polymorphism of PLA2G6 has been indicated to be involved in conferring susceptibility for Parkinson's disease (PD), whereas conclusive results have not been obtained. Thus, we intended to conduct a systematic review to determine if PLA2G6 genetic variation confers a greater susceptibility to PD. METHODS: All case-control studies that investigated the association of the PLA2G6 polymorphisms with the risk of PD published before 15 July 2018 were included. The literature was comprehensively searched and identified in five English databases (EBSCO, Pubmed, OVID, EMBASE and ISI Web of Knowledge) and four Chinese databases (Wanfang database, Chinese Biomedical Literature Database, China Academic Journals Database and VIP database). We performed analyses of study characteristics, heterogeneity, and forest plot in analyses analogous to dominant, codominant and additive models with the pooled odds ratio (OR) in fixed- or random-effects models as the measure of association. RESULTS: A total of 664 potentially relevant studies were retrieved with the initial search, of which eight studies fulfilled the inclusion criteria, and included 2,779 PD patients and 3,291 control participants,. Among all the reported 27 genetic variants, 15 single nucleotide polymorphisms (SNPs) were present only in patients, and only five available SNPs (rs2267369, rs140758033, c.1959T>A (Gly653Gly), rs76718524, rs199935023) were pooled in the meta-analysis. However, there was no evidence for a significant association between the five SNPs and PD risk in dominant, codominant and allele models, suggesting a lack of association between PLA2G6 genetic variation and PD susceptibility. CONCLUSION: The present study assessed the association of PLA2G6 genetic polymorphism with the risk PD, and the result strongly demonstrates that PLA2G6 polymorphism is not associated with PD susceptibility.

Ifenprodil rapidly ameliorates depressive-like behaviors, activates mTOR signaling and modulates proinflammatory cytokines in the hippocampus of CUMS rats.

RATIONALE: The rapid-onset and long-lasting antidepressant properties of ketamine have prompted investigations into a variety of agents that target N-methyl-D-aspartate receptors (NMDARs) for the treatment of major depressive disorder (MDD). According to the literature, ifenprodil (a GluN2B-containing NMDAR antagonist) can potentiate the antidepressant-like effects of certain antidepressant drugs in mice. Here, we report that a single injection of ifenprodil (3 mg/kg, intraperitoneally (i.p.)) was sufficient to provoke rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS) rats. Moreover, ifenprodil activated mTOR signaling and reversed the CUMS-induced elevation of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, in our study, ifenprodil had no influence on corticosterone levels in the plasma. Our data indicate that ifenprodil per se might exert antidepressant-like effects by modulating neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors. OBJECTIVES: To explore the potential rapid antidepressant-like effects and mechanisms of ifenprodil, a GluN2B subunit-selective NMDAR antagonist. METHODS: Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, we used the forced swim test (FST) and sucrose preference test (SPT) to identify the rapid antidepressant-like effects of ifenprodil in chronic unpredictable mild stress (CUMS) rats after acute administration. In experiment 2, we assessed neurochemical changes involved in synaptic plasticity within the hippocampus of CUMS rats. In experiment 3, we assessed the levels of corticosterone in the plasma and proinflammatory cytokines in the hippocampus in CUMS rats after ifenprodil treatment. RESULTS: Ifenprodil rapidly ameliorated depressive-like behaviors in the FST and SPT, activated mTOR signaling, dephosphorylated eukaryotic elongation factor 2, enhanced BDNF expression, and promoted the synthesis of the synaptic protein GluA1 synthesis after acute administration. Moreover, ifenprodil reversed the CUMS-induced elevation of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, ifenprodil had no influence on corticosterone levels in the plasma in our study. CONCLUSIONS: Our data indicate that ifenprodil per se might exert antidepressant-like effects through its effects on neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors.

Causes of drug discontinuation in patients with major depressive disorder in China.

BACKGROUND: This research was designed to investigate patient-reported and doctor-reported reasons for the discontinuation of pharmacological treatment in Chinese patients with major depressive disorder (MDD), which was part of the National Survey on Symptomatology of Depression (NSSD) from 2014 to 2015. METHODS: This cross-sectional study included 649 patients who had discontinued antidepressant medications and 711 patients who had remained on them, selected from a group of 3516 candidates who have had at least one depressive episode. Differences in the two groups' sociodemographic factors, clinical characteristics, medication use, and self-reported reasons for drug discontinuation were compared via Student's t-test or chi-square test. Logistic regression analysis was then used to determine the association of all non-subjective dichotomous and ordinal categorical variables, including the additional 63 items of our physician-evaluated symptomatic assessment, with drug compliance. RESULTS: Compared to the spontaneous drug discontinuation (SDD) group, the drug adherence (DA) group had significantly lower rates of the following: family history of mental disease (9.0% vs 13.6%), highest level of education achieved being post-graduate or above (1.6% vs 4.7%), smoking (5.8% vs 9.7%), and other health problems (33.9% vs 42.4%) (p's < 0.05). On the other hand, first-episode depression (48.5% vs 21.9%) and taking of mood stabilizer(s) (8.3% vs 5.6%) were higher in the former group than in the latter (p's < 0.05). Logistic Regression Analysis showed that five symptoms, such as depressed mood, were correlated positively with SDD, while another six symptoms, such as psychomotor retardation, were correlated negatively with it. The receiver operating characteristic (ROC) curve of this model yielded an area under the curve (AUC) of 0.701 (95% CI, 0.673-0.729). Notably, there were three main reasons given by patients in the DA group as to why they discontinued their medication(s): (1) concern about long-term side effects (36.1%), (2) no perceived need for taking said medication(s) long-term (34.2%), and (3) believing oneself to have been cured completely (30.0%). CONCLUSIONS: The aforementioned factors may affect patient compliance and elicit maladaptive thinking even from patients with good educational backgrounds, increasing the risk of drug discontinuation. Compliance of pharmacological treatment might be improved by increasing clarification and elucidation of different symptom clusters to the patient and combating the main reasons for drug discontinuation.

Fabrication of Hierarchical Porous Carbon Nanoflakes for High-Performance Supercapacitors.

In the current work, the carbon nanoflakes (CNs-Fe/KOH) and porous carbon (PC-Ni/KOH) have been produced by using Fe(NO3)3/KOH and Ni(NO3)2/KOH as the cographitization/activation catalysts to treat the natural plane tree fluff, respectively. The as-prepared carbon materials show different morphologies when treated with different metal ions. Compared with PC-Ni/KOH, the CNs-Fe/KOH have both high graphitization degree (IG/ID = 1.53) and large SBET (1416 m2/g). In a three-electrode setup, the CNs-Fe/KOH electrode shows a high specific capacitance of 253 F/g at 10 A/g, with a capacitance retention of 92.64% after 10000 cycles in 2 M H2SO4 aqueous solution, which is far better than the sample without Fe3+ addition. In 1 M LiPF6 in ethylene carbonate/diethyl carbonate organic solution, CNs-Fe/KOH-based symmetric supercapacitor also presents an excellent specific capacitance of 32.2 F/g at 1 A/g. In addition, an energy density of 39.98 W h/kg can be achieved at the power density of 1.49 kW/kg. Influence of metal ions on the morphology and structure as well as electrochemical performance of the carbon materials are further analyzed in detail. The current work provides a novel path for design and fabrication of supercapacitor electrode materials with promising electrochemical performances.

Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells.

The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression. Autophagy inhibitors, 3-methyladenine (3-MA), chloroquine and bafilomycin A1, or ATG genes silencing in HepG2 cells significantly inhibited CA-induced autophagic cell death. The CA treatment decreased the levels of phosphorylated Akt and mTOR without any effects on PI3K or PTEN. Most importantly, overexpression of Akt and knockdown of PTEN attenuated autophagy induction in CA-treated cells. Taken together, our results indicated that CA induced autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. These findings suggest that CA has a great potential for the treatment of hepatoma via autophagic induction.

A dynamic plasma membrane proteome analysis of alcohol-induced liver cirrhosis.

Alcohol-induced injury has become one of the major causes for liver cirrhosis. However, the molecular mechanisms of ethanol-induced injury are not fully understood. To this end, we performed a dynamic plasma membrane proteomic research on rat model. A rat model from hepatitis to liver cirrhosis was developed. Plasma membrane from liver tissue with liver fibrosis stage of 2 and 4 (S2 and S4) was purified by sucrose density gradient centrifugation. Its purification was verified by western blotting. Proteins from plasma membrane were separated by two-dimensional electrophoresis (2DE) and differentially expressed proteins were identified by tandem mass spectrometry. 16 consistent differentially expressed proteins from S2 to S4 were identified by mass spectrometry. The expression of differentially expressed proteins annexin A6 and annexin A3 were verified by western blotting, and annexin A3 was futher verified by immunohistochemistry. Our research suggests a possible mechanism by which ethanol alters protein expression to enhance the liver fibrosis progression. These differentially expressed proteins might be new drug targets for treating alcoholic liver cirrhosis.

Alpha-1 antitrypsin variants in plasma from HIV-infected patients revealed by proteomic and glycoproteomic analysis.

Novel tools are necessary to explore proteins related to human immunodeficiency virus (HIV) infection. In this work, proteomic and glycoproteomic technology were employed to examine plasma samples from HIV-positive patients. Through comparative proteome analysis of normal and HIV-positive plasma samples, 19 differentially expressed protein spots related to 12 non-redundant proteins were identified by ESI-ion trap MS. Among these, the 130-kDa isoform of α-1-antitrypsin was found to be decreased in HIV-positive patients while another variant with a molecular weight of 40 kDa was increased. SWISS-2-D-PAGE reference gel and protein sequence comparisons of the 40-kDa protein showed homology with α-1-antitrypsin minus the N-terminus, and its identity was further confirmed by 1-D Western blotting and glycoproteomic analysis. In all, our results showed that proteomics and glycoproteomics are powerful tools for discovering proteins related to HIV infection. Furthermore, this 40-kDa variant of α-1-antitrypsin found in the plasma of HIV-positive individuals may prove to be a potentially useful biomarker for anti-HIV research according to bioinformatics analysis.

Development and validation of a liquid chromatography-mass spectrometry metabonomic platform in human plasma of liver failure caused by hepatitis B virus.

This paper presents an liquid chromatography (LC)/mass spectrometry (MS)-based metabonomic platform that combined the discovery of differential metabolites through principal component analysis (PCA) with the verification by selective multiple reaction monitoring (MRM). These methods were applied to analyze plasma samples from liver disease patients and healthy donors. LC-MS raw data (about 1000 compounds), from the plasma of liver failure patients (n = 26) and healthy controls (n = 16), were analyzed through the PCA method and a pattern recognition profile that had significant difference between liver failure patients and healthy controls (P < 0.05) was established. The profile was verified in 165 clinical subjects. The specificity and sensitivity of this model in predicting liver failure were 94.3 and 100.0%, respectively. The differential ions with m/z of 414.5, 432.0, 520.5, and 775.0 were verified to be consistent with the results from PCA by MRM mode in 40 clinical samples, and were proved not to be caused by the medicines taken by patients through rat model experiments. The compound with m/z of 520.5 was identified to be 1-Linoleoylglycerophosphocholine or 1-Linoleoylphosphatidylcholine through exact mass measurements performed using Ion Trap-Time-of-Flight MS and METLIN Metabolite Database search. In all, it was the first time to integrate metabonomic study and MRM relative quantification of differential peaks in a large number of clinical samples. Thereafter, a rat model was used to exclude drug effects on the abundance of differential ion peaks. 1-Linoleoylglycerophosphocholine or 1-Linoleoylphosphatidylcholine, a potential biomarker, was identified. The LC/MS-based metabonomic platform could be a powerful tool for the metabonomic screening of plasma biomarkers.

Proteomic analysis of PBMCs: characterization of potential HIV-associated proteins.

BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) pandemic has continued unabated for nearly 30 years. To better understand the influence of virus on host cells, we performed the differential proteome research of peripheral blood mononuclear cells (PBMCs) from HIV-positive patients and healthy controls. RESULTS: 26 protein spots with more than 1.5-fold difference were detected in two dimensional electrophoresis (2DE) gels. 12 unique up-regulated and one down-regulated proteins were identified in HIV-positive patients compared with healthy donors. The mRNA expression of 10 genes was analyzed by real time RT-PCR. It shows that the mRNA expression of talin-1, vinculin and coronin-1C were up-regulated in HIV positive patients and consistent with protein expression. Western blotting analysis confirmed the induction of fragments of vinculin, talin-1 and filamin-A in pooled and most part of individual HIV-positive clinical samples. Bioinformatic analysis showed that a wide host protein network was disrupted in HIV-positive patients. CONCLUSIONS: Together, this work provided useful information to facilitate further investigation of the underlying mechanism of HIV and host cell protein interactions, and discovered novel potential biomarkers such as fragment of vinculin, filamin-A and talin-1 for anti-HIV research.

[LC-MS/MS method for simultaneous quantification of lopinavir and ritonavir in human plasma].

A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of lopinavir and ritonavir in human plasma. Analytes were separated from plasma by a combination of alkalinized protein precipitation and liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a Agilent ZORBAX Eclipse XDB-C18 column with the mobile phase consisted of methanol-0.1% formic acid in water (80:20). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 629.6 --> 155.2, m/z 721.4 --> 268.2, and m/z 515.2 --> 276.2 for lopinavir, ritonavir and telmisartan (internal standard), respectively. The method showed a good linearity in a concentration range of 62.5 - 10000 ng mL(-1) for lopinavir, and 12.5 - 2000 ng mL(-1) for ritonavir. The lower limits of quantification were 15 pg mL(-1) and 8 pg mL(-1) for lopinavir and ritonavir, respectively. The intra- and inter-day precision was less than 15% and the absolute recovery was above 75%. This method was selective and rapid, sensitive for investigating blood drug concentrations in clinics.

Simultaneous determination of puerarin, daidzein, baicalin, wogonoside and liquiritin of GegenQinlian decoction in rat plasma by ultra-performance liquid chromatography-mass spectrometry.

A specific ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed for the simultaneous determination of puerarin, daidzein, baicalin, wogonoside and liquiritin in rat plasma. Chromatographic separation was performed on a C(18) column packed with 1.7 microm particles by a linear gradient elution. The analytes and carbamazepine (internal standard, I.S.) were monitored in a selected-ion reaction (SIR) mode with a positive electrospray ionization (ESI) interface by the following ions: m/z 417.2 for puerarin, m/z 255.2 for daidzein, m/z 271.0 for baicalin, m/z 461.0 for wogonoside, m/z 441.0 for liquiritin and m/z 237.2 for carbamazepine (I.S.), respectively. The calibration curves of these analytes were linear over the concentration ranges from 0.00254-1.02 microg mL(-1) to 0.0102-10.2 microg mL(-1). Within-batch and between-batch precisions (RSD%) were all within 15% and accuracy (RE%) ranged from -10% to 10%. The extraction recoveries were on average 79.8% for puerarin, 90.8% for daidzein, 74.4% for baicalin, 70.2% for wogonoside and 84.7% for liquiritin. The validated method was successfully applied to investigate the pharmacokinetics of five bioactive compounds of GegenQinlian decoction (GQD) in rats.