Liquid chromatography-mass spectrometry-based metabolomic profiling reveals sex differences of lipid metabolism among the elderly from Southwest China.

BACKGROUND: The sexual dimorphism represents one of the triggers of the metabolic disparities while the identification of sex-specific metabolites in the elderly has not been achieved. METHODS: A group of aged healthy population from Southwest China were recruited and clinical characteristics were collected. Fasting plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomic analyses were performed. Differentially expressed metabolites between males and females were identified from the metabolomic analysis and metabolite sets enrichment analysis was employed. RESULTS: Sixteen males and fifteen females were finally enrolled. According to clinical characteristics, no significant differences can be found except for smoking history. There were thirty-six differentially expressed metabolites between different sexes, most of which were lipids and lipid-like molecules. Twenty-three metabolites of males were increased while thirteen were decreased compared with females. The top four classes of metabolites were fatty acids and conjugates (30.6%), glycerophosphocholines (22.2%), sphingomyelins (11.1%), and flavonoids (8.3%). Fatty acids and conjugates, glycerophosphocholines, and sphingomyelins were significantly enriched in metabolite sets enrichment analysis. CONCLUSIONS: Significant lipid metabolic differences were found between males and females among the elderly. Fatty acids and conjugates, glycerophosphocholines, and sphingomyelins may partly account for sex differences and can be potential treatment targets for sex-specific diseases.

Serum levels of lipocalin-2 in patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Evidence has shown that lipocalin-2 (LCN2) is involved in the pathological process of PD. We aimed to explore whether serum levels of LCN2 could be a biomarker of PD. METHODS: We recruited consecutive PD patients and healthy controls (HC) in our hospital from June 2020 to July 2020. Serum LCN2 levels were detected using the LCN2 enzyme-linked immunosorbent assay (ELISA) kit. The motor section of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Hoehn and Yahr Staging Scale (H&Y) were assessed on admission to evaluate disease severity in patients with PD. Cognitive status was measured by the Montreal Cognitive Assessment (MoCA). RESULTS: We finally recruited 75 patients, including 40 PD patients and 35 HC. Serum LCN2 levels were not significantly increased in PD patients compared with HC (4.9 [- 0.7 to 18.6] vs 1.9 [- 1.5 to 16.9] ng/mL, P = 0.33). Besides, there was no significant difference in LCN2 levels between patients at early and advanced stage of PD (P = 0.75), as well as between cognitively impaired PD patients, PD patients with normal cognition, and HC (P = 0.30). Moreover, LCN2 had no correlation with disease duration (r = - 0.1, P = 0.37), UPDRS III score (r = 0.07, P = 0.65), and MoCA score (r = 0.221, P = 0.17). CONCLUSIONS: Overall, our study suggests that serum LCN2 levels may not be a biomarker for PD.

The disturbance of lipid metabolism is correlated with neuropsychiatric symptoms in patients with Parkinson's disease.

OBJECTIVE: We aimed to identify the detailed relationships between serum lipid levels and neuropsychiatric symptoms in patients with Parkinson's disease (PD). METHODS: Consecutive PD patients and healthy controls were recruited and demographic data were collected. The disease stages of PD patients were assessed using Hoehn-Yahr scale while neuropsychiatric symptoms were determined using Hamilton depression rating scale (HAMD), Hamilton anxiety rating scale (HAMA), and mini-mental state examination scale. Fast serum samples were obtained and the serum levels of lipids were identified. Linear regression analyses and correlation analyses were performed to explore the relationships between serum lipid levels and neuropsychiatric symptoms. RESULTS: The serum levels of triglyceride had significantly decreased while the levels of HDL-c and lipoprotein a had increased in PD patients. Linear regression analyses confirmed that the levels of triglyceride were mainly correlated with age and HAMA score, the levels of HDL-c were correlated with disease duration and gender, and the levels of lipoprotein a were correlated with HAMD score. Correlation analyses further confirmed that the levels of triglyceride were negatively correlated with HAMA score when the levels of lipoprotein a were negatively correlated with HAMD score. CONCLUSIONS: Lipid metabolism is significantly correlated with neuropsychiatric disorders in PD patients.

Metabolomics profiling reveals altered lipid metabolism and identifies a panel of lipid metabolites as biomarkers for Parkinson's disease related anxiety disorder.

OBJECTIVES: Anxiety disorder is a common non-motor symptom in patient with Parkinson's disease (PD). We aimed to explore its pathogenesis and identify plasma biomarkers using untargeted metabolomics analysis. METHODS: Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients with Parkinson's disease related anxiety disorder (PDA) were recognized. Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the differentially expressed metabolites from the above metabolomics analysis, correlation analyses and receiver operating characteristic curves (ROC) were further employed. RESULTS: According to the clinical data, PDA patients had lower plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were thirty-nine differentially expressed metabolites in PDA patients when compared with the other two groups from the metabolomics analysis, respectively. Fourteen lipid metabolites were simultaneously altered between these two groups, and all of them were significantly decreased. They can be further subcategorized into fatty acyls, glycerolipids, sterol lipids, sphingolipids, and prenol lipids. The plasma levels of thirteen metabolites were negatively correlated with HAMA scores except 10-oxo-nonadecanoic acid. Based on the ROC curves, the fourteen lipid metabolites can be diagnostic biomarkers for PDA patients separately and the areas under the curve of the fourteen lipid metabolites ranged from 0.681 to 0.798. CONCLUSIONS: Significantly lower plasma lipoproteins can be found in PDA patients. A panel of fourteen lipid metabolites were also significantly decreased and can be clinical biomarkers for the diagnosis of PDA patients.

Lipid metabolic dysregulation is involved in Parkinson's disease dementia.

Dementia is very common in the late stage of patient with Parkinson's disease (PD). We aim to explore its underlying pathogenesis and identify candidate biomarkers using untargeted metabolomics analysis. Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients were categorized into Parkinson's disease without dementia (PDND) and Parkinson's disease dementia (PDD). Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the identified differentially-expressed metabolites from the metabolomics analysis, multivariate linear regression analyses and receiver operating characteristic (ROC) curves were further employed. According to the clinical data, the mean ages of PDND and PDD patients were significantly higher than those of healthy controls. The incidence of hypercholesterolemia was decreased in PDD patients. PDD patients also had lower levels of triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were 24 and 57 differentially expressed metabolites in PDD patients when compared with the healthy controls and PDND patients from the metabolomics analysis. Eleven lipid metabolites were simultaneously decreased between these two groups, and can be further subcategorized into fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and prenol lipids. The plasma levels of the eleven metabolites were positively correlated with MMSE score and can be candidate biomarkers for PDD patients with areas under the curve ranging from 0.724 to 0.806 based on the ROC curves. Plasma lipoproteins are significantly lower in PDD patients. A panel of eleven lipid metabolites were also decreased and can be candidate biomarkers for the diagnosis of PDD patients. Lipid metabolic dysregulation is involved in the pathogenesis of Parkinson's disease dementia.

Integrated Metabolomics and Proteomics Analysis Reveals Plasma Lipid Metabolic Disturbance in Patients With Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson's disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

Gamma-hydroxybutyrate (GHB) for narcolepsy in adults: an updated systematic review and meta-analysis.

BACKGROUND: Narcolepsy is a chronic and debilitating sleep disorder characterized by cataplexy and excessive daytime sleeping. Gamma-hydroxybutyrate (GHB) has been widely used to treat narcolepsy, and new findings have been published in recent years. OBJECTIVE: A meta-analysis was conducted to assess the efficacy and tolerability of GHB treatment in adults with narcolepsy. METHODS: A systematic search of PubMed, Cochrane, Embase, Web of Science, and clinical-trials.gov from inception to June 2018 was performed. Change in daily diaries and polysomnographic data of narcoleptic patients were defined as the efficacy outcomes. The tolerability and acceptability outcomes were the rates of adverse events and dropping out for adverse effects or other reasons. RESULTS: Fifteen randomized controlled trials involving 2104 participants were identified. GHB was found to improve cataplexy attacks (P = 0.001), subjective daytime sleepiness (P < 0.0001), daytime sleep latency (P < 0.0001), inadvertent naps/sleep attacks (P < 0.00001), effective rates (Clinical Global Impression of change) (P < 0.00001), hypnagogic hallucinations (P = 0.004), sleep paralysis (P = 0.004), stage 1 sleep (P = 0.04), slow wave sleep (P = 0.003), REM sleep (P = 0.0006), sleep shifts (P = 0.005), nocturnal awakenings (P = 0.004), quality of nocturnal sleep (P < 0.00001), chin muscle activity, and quality of life, but had no effect on stage 2 sleep (P = 0.88). GHB was less well tolerated than placebo because of side effects that occurred in a dose-dependent fashion (RR = 6.08; 95% CI = 2.18 to 16.97; P = 0.0006). CONCLUSIONS: GHB was effective in improving narcolepsy-cataplexy and related symptoms in adults but was less well tolerated than placebo because of dose-dependent side effects.

Integrated Analysis Reveals Altered Lipid and Glucose Metabolism and Identifies NOTCH2 as a Biomarker for Parkinson's Disease Related Depression.

Depression is a common comorbidity in Parkinson's disease (PD) but is underdiagnosed. We aim to investigate the altered metabolic pathways of Parkinson's disease-related depression (PDD) in plasma and to identify potential biomarkers for clinical diagnosis. Consecutive patients with PD were recruited, clinically assessed, and patients with PDD identified. Fasting plasma samples were collected from 99 patients and differentially expressed metabolites and proteins between patients with PDD and PD were identified using non-targeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and tandem mass tag (TMT)-based proteomics analysis, followed by an integrated analysis. Based on the above results, enzyme-linked immune sorbent assay (ELISA) tests were then performed to identify potential biomarkers for PDD. In clinics, patients with PDD suffered less hypertension and had lower serum low-density lipoprotein cholesterol and apolipoprotein B levels when compared to the other patients with PD. A total of 85 differentially expressed metabolites were identified in metabolomics analysis. These metabolites were mainly lipids and lipid-like molecules, involved in lipid and glucose metabolic pathways. According to proteomics analysis, 17 differentially expressed proteins were identified, and 12 metabolic pathways were enriched, which were predominantly related to glucose metabolism. Integrated analysis indicated that altered lipid and glucose metabolism in PDD may induce cellular injury through oxidative stress. Additionally, plasma levels of several proteins were confirmed to be significantly altered and correlated with depressive severity. NOTCH2 may be a potential blood biomarker for PDD, with an optimal cut-off point of 0.91 ng/ml, a sensitivity value of 95.65%, and a specificity value of 81.58%. Depressive symptoms are associated with lipid and glucose metabolism in patients with PD and NOTCH2 may be a potential blood biomarker for the clinical diagnosis of PDD.

Complementary and alternative therapies for restless legs syndrome: An evidence-based systematic review.

Restless legs syndrome (RLS) is defined as an irresistible urge to move the legs, which is usually accompanied by paresthesias or dysesthesias at least twice weekly, and affects 2%-4% of adults in Europe and North America. This systematic review assesses the current complementary and alternative options for RLS and the potential benefits of those treatments on sleep quality, mood disorder, and quality of life. A systematic search of the PubMed, Embase, Cochrane, and Web of Science databases was conducted. Eighteen studies met the inclusion criterion, which included the use of the international RLS study group criteria. Complementary and alternative therapies have been found to be effective in both primary and secondary RLS. The severity of primary RLS symptoms can be significantly ameliorated by exercise training, transcutaneous spinal direct current stimulation, pneumatic compression devices, light therapy, repetitive transcranial magnetic stimulation, and acupuncture. Pneumatic compression devices and yoga also improve RLS-related disorders. Exercise training is highly efficacious in the reduction of symptom severity in uremic RLS and related effects such as poor quality of life. Endovenous laser ablation may be a good choice for patients with concurrent RLS and superficial venous insufficiency.

Decreased serum proNGF concentration in patients with Parkinson's disease.

Parkinson's disease (PD), a progressive and age-related neurodegenerative condition, is a common neurodegenerative disorder. However, no validated biomarkers for PD have been identified to date. Accumulating evidence supports the role of proNGF-p75NTR-sortilin signaling in the neurodegeneration and pathogenesis of PD. The aim of our study was to investigate alterations in serum proNGF concentrations in PD patients and related anxiety. Seventy-seven consecutive PD patients and 39 healthy controls were enrolled, and clinical data were collected. Modified Hoehn-Yahr Staging Scale, Unified Parkinson's Disease Rating Scale (UPDRS), and Hamilton Anxiety (HAMA) Scale scores were assessed upon admission. Serum proNGF concentration was compared between that of PD patients and healthy controls. Pearson correlation coefficients were determined to explore the relationship between proNGF concentration and UPDRS, Hoehn-Yahr, and HAMA scores. Received operating characteristic (ROC) curves and proNGF optimal cutoff point were used to distinguish PD and related anxiety. The median concentration of proNGF was significantly lower (p = 0.000) in PD patients (94.91 ng/L, range 85.92-118.06 ng/L) compared with that of healthy controls (106.67 ng/L, range 102.39-122.06 ng/L). The optimal proNGF cutoff point for distinguishing PD patients was 102.29 ng/L, and the sensitivity and specificity values were 87.0 and 100%, respectively. proNGF concentration positively correlated with UPDRS (r = 0.281, p = 0.013), Hoehn-Yahr (r = 0.260, p = 0.023), and HAMA (r = 0.276, p = 0.015) scores. Our results indicate that serum proNGF concentration may represent a biomarker for PD and its role in the pathogenesis of PD thus warrants further investigation.

Recombinant tissue plasminogen activator induces long-term anxiety-like behaviors via the ERK1/2-GAD1-GABA cascade in the hippocampus of a rat model.

OBJECTIVES: Recombinant tissue plasminogen activator (rtPA) is widely used for patients with thromboembolic disease, and increasing evidence indicates that it can directly induce neurotoxicity independent of its thrombolysis property. Here, we aimed to confirm the long-term effect of rtPA on animal's behavior, and investigate the underlying pathogenesis. METHODS AND RESULTS: Male Sprague-Dawley rats randomly received a dose of rtPA (10 mg/kg) or sterile saline. Three months later, the animals receiving rtPA displayed anxiety-like behaviors in the open field and novelty-suppressed feeding tests. To investigate the possible pathogenesis, gas chromatography-mass spectrometry-based metabolomics analysis was performed, with 18 differential metabolites identified in the hippocampus 24 h after the treatments. Based upon these differential metabolites, a metabolite-protein integrated network was generated, which indicated that ERK1/2-glutamic acid decarboxylase (GAD) 1-γ aminobutyric acid (GABA) cascade may be related to long-term anxiety-like behaviors. The GABA levels in hippocampus were decreased 24 h post-treatment and three months later, confirmed by a high performance liquid chromatography method. We also examined the expression of GAD1 and GAD2 using western blotting or immunohistochemical staining. Levels of GAD1 were persistently decreased after treatment, while GAD2 levels, GAD1-immunoreactive, and GAD2-immunoreactive neurons showed no significant differences. The underlying pathogenesis also involved activation of ERK1/2, confirmed by increased phospho-ERK1/2 24 h post-treatment. CONCLUSIONS: RtPA can induce long-term anxiety-like behaviors after a clinical injected dose. The underlying pathogenesis involves the ERK1/2-GAD1-GABA cascade in the hippocampus. This pharmacological side effect of rtPA may further exacerbate post-stroke anxiety disorder for stroke patients.

Serum Butyrylcholinesterase Activity: A Biomarker for Parkinson's Disease and Related Dementia.

OBJECTIVE: This study aim to determine changes of serum butyrylcholinesterase (BChE) activity in PD patients and related dementia. PATIENTS AND METHODS: Consecutive PD patients and healthy controls were included and clinical data were collected. Fast serum BChE activity was determined and compared between healthy controls and PD patients. Independent risk factors were performed for BChE activity, PD, and related dementia. The relationship between BChE activity and disease severity was also evaluated. Receiver operating characteristic (ROC) curves were obtained to explore serum BChE activity in distinguishing PD patients and related dementia. RESULTS: Serum BChE activity mainly independently correlated with gender, albumin, triglyceride, body mass index, and PD. Serum BChE activity decreased in PD patients compared with healthy controls. Based on the ROC curve, the optimal cut-off point was 6864.08 IU/L for distinguishing PD patients, and the sensitivity and specificity values were 61.8% and 72.1%. It inversely correlated with Unified Parkinson's Disease Rating Scale score. BChE activity decreased in PD-related dementia compared with those without dementia. The sensitivity and specificity values were 70.6% and 76.3%, respectively, with an optimal cut-off point of 6550.00 IU/L. CONCLUSIONS: Serum BChE activity can be regarded as a biomarker for PD and related dementia.

Cerebrovascular risk factors for patients with cerebral watershed infarction: A case-control study based on computed tomography angiography in a population from Southwest China.

To determine cerebrovascular risk factors for patients with cerebral watershed infarction (CWI) from Southwest China.Patients suffering from acute ischemic stroke were categorized into internal CWI (I-CWI), external CWI (E-CWI), or non-CWI (patients without CWI) groups. Clinical data were collected and degrees of steno-occlusion of all cerebral arteries were scored. Arteries associated with the circle of Willis were also assessed. Data were compared using Pearson chi-squared tests for categorical data and 1-way analysis of variance with Bonferroni post hoc tests for continuous data, as appropriate. Multivariate binary logistic regression analysis was performed to determine independent cerebrovascular risk factors for CWI.Compared with non-CWI, I-CWI had higher degrees of steno-occlusion of the ipsilateral middle cerebral artery, ipsilateral carotid artery, and contralateral middle cerebral artery. E-CWI showed no significant differences. All the 3 arteries were independent cerebrovascular risk factors for I-CWI confirmed by multivariate binary logistic regression analysis. I-CWI had higher degrees of steno-occlusion of the ipsilateral middle cerebral artery compared with E-CWI. No significant differences were found among arteries associated with the circle of Willis.The ipsilateral middle cerebral artery, carotid artery, and contralateral middle cerebral artery were independent cerebrovascular risk factors for I-CWI. No cerebrovascular risk factor was identified for E-CWI.

Tricyclic antidepressants for preventing migraine in adults.

BACKGROUND: Migraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing. METHODS: A computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes. RESULTS: In total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P < .00001). Participants receiving TCAs were more likely to experience an ≥50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P = .14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P = .94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P = .05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P = .06) on account of adverse events. CONCLUSIONS: This research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects.

Efficacy and feasibility of antidepressant treatment in patients with post-stroke depression.

BACKGROUND: Depression greatly impacts the quality of life in most stroke survivors. Therefore, effective treatment of post-stroke depression (PSD) is critically important. However, evidence supporting the effectiveness and feasibility of antidepressant treatment in this population is limited and somewhat confusing. METHODS: A comprehensive literature search of the Cochrane, PubMed, Web of Science, and Embase databases from inception up to November 2015 was conducted. We reviewed all randomized controlled trials (RCTs) that assigned patients with a clinical diagnosis of PSD to antidepressant or placebo treatment. Reduction in depression rating scale scores and response rate to antidepressants were defined as the efficacy outcomes. Rates of dropout for any reason and for adverse effects were defined as the acceptability outcomes. We also assessed improvements in activities of daily living (ADL) as functional outcomes. RESULTS: In total, 11 trials consisting of 740 participants were indentified. A significant advantage of antidepressants compared with placebo treatment in PSD was observed in overall pooled effect size analysis (SMD = -0.96; 95% CI = -1.41 to -0.51; P <0.0001). In addition, patients receiving antidepressants presented a much greater improvement in various depressive symptoms than those with placebo (RR = 1.36; 95% CI = 1.01-1.83; P = 0.04). However, antidepressants were less well tolerated than placebo because of some adverse events (RR = 2.72; 95% CI = 1.37-5.43; P = 0.04). Intriguingly, no consistent evidence was found for a positive effect of antidepressants on ADL in our analysis. CONCLUSIONS: This meta-analysis suggests that antidepressants treatment confers potentially positive effects in patients with PSD as compared with simple placebo treatment. However, this must be carefully considered in light of its possible adverse events in some individual patients.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. METHODS: Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias. RESULTS: We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. CONCLUSIONS: This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Divergent Urinary Metabolic Phenotypes between Major Depressive Disorder and Bipolar Disorder Identified by a Combined GC-MS and NMR Spectroscopic Metabonomic Approach.

Bipolar disorder (BD) is a complex debilitating mental disorder that is often misdiagnosed as major depressive disorder (MDD). Therefore, a large percentage of BD subjects are incorrectly treated with antidepressants in clinical practice. To address this challenge, objective laboratory-based tests are needed to discriminate BD from MDD patients. Here, a combined gas chromatography-mass spectrometry (GC-MS)-based and nuclear magnetic resonance (NMR) spectroscopic-based metabonomic approach was performed to profile urine samples from 76 MDD and 43 BD subjects (training set) to identify the differential metabolites. Samples from 126 healthy controls were included as metabolic controls. A candidate biomarker panel was identified by further analyzing these differential metabolites. A testing set of, 50 MDD and 28 BD subjects was then used to independently validate the diagnostic efficacy of the identified panel using an area under the receiver operating characteristic curve (AUC). A total of 20 differential metabolites responsible for the discrimination between MDD and BD subjects were identified. A panel consisting of six candidate urinary metabolite biomarkers (propionate, formate, (R*,S*)2,3-dihydroxybutanoic acid, 2,4-dihydroxypyrimidine, phenylalanine, and ß-alanine) was identified. This panel could distinguish BD from MDD subjects with an AUC of 0.913 and 0.896 in the training and testing sets, respectively. These results reveal divergent urinary metabolic phenotypes between MDD and BD. The identified urinary biomarkers can aid in the future development of an objective laboratory-based diagnostic test for distinguishing BD from MDD patients.