Risk factors of elevated blood ammonia level in epilepsy patients treated with lamotrigine.

AbstractThe aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level. This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for 3 years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Total of 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils affected blood ammonia level. Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

Comparison of Electroencephalography in Patients With Seizures Caused by Neurosyphilis and Viral Encephalitis.

Background: Neurosyphilis (NS) lacks specificity in clinical and imaging features, and patients are frequently misdiagnosed as viral encephalitis when they present with seizures. This study aimed to compare electroencephalography (EEG) in patients with seizures resulting from the two diseases and provide guidance for differential diagnosis. Methods: A retrospective study on patients diagnosed with neurosyphilis and viral encephalitis with seizures in the Department of Neurology, Zhongshan Hospital, Xiamen University from 2012 to 2020. Results: A total of 39 patients with seizures caused by neurosyphilis and 40 patients with seizures caused by viral encephalitis were included. Chi-square test analysis showed that compared with patients with viral encephalitis, patients with neurosyphilis mainly developed in middle-aged and elderly people (p < 0.001), were more likely to have temporal epileptiform discharges (p < 0.001), and less likely to have status epilepticus (SE) (p = 0.029). There was difference between two groups in the EEG performance of lateralized periodic discharges (LPDs) (p = 0.085). The two groups were matched for age and sex by case-control matching, and 25 cases in each group were successfully matched. Patients with neurosyphilis were more likely to have temporal epileptiform discharges than those with viral encephalitis (p = 0.002), and there were no significant differences in LPDs (p = 0.077) and SE (p = 0.088) between two groups. Conclusion: When EEG shows temporal epileptiform discharges, especially in the form of LPDs, we should consider the possibility of neurosyphilis.

Preliminary Study on the Effect of Impaired Glucose Tolerance on Blood-Brain Barrier Permeability in Non-Neurosyphilis Patients.

Background: Blood-brain barrier (BBB) is frequently disrupted in patients with diabetes mellitus (DM) and/or neurosyphilis (NS). Clinical cases reflect a trend that non-neurosyphilis (non-NS) patients with impaired glucose tolerance (IGT) are likely to develop NS and/or DM. Objective: To investigate whether IGT promotes BBB disruption in patients with non-NS. Methods and Material: A total of 21 subjects were enrolled, including six with IGT, nine with non-NS, and six with both IGT and non-NS. BBB permeability was evaluated by dynamic contrast-enhanced (DCE) MRI and the secretion of biomarkers from cerebrospinal fluid (CSF) were measured by colorimetric method, immune turbidimetric method, and enzyme-linked immunosorbent assay (ELISA) method. Results: The non-NS patients with IGT have higher BBB permeability at cortex superior frontal gyrus, white matter, and thalamus than non-NS patients without IGT or IGT patients without non-NS. The CSF-serum albumin-quotient (Qalb) levels and CSF secretion are highest in non-NS patients with IGT, including matrix metalloproteinase 9 (MMP9), soluble intercellular cell adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1). Conclusions: Significant correlations between CSF biomarkers and BBB permeability were found.

Predictors of hemorrhagic complications after intravenous thrombolysis in acute cerebral infarction patients: A single-center study of 391 cases.

ABSTRACT: For patients with ischemic stroke, intravenous (IV) thrombolysis with Urokinase within 6 hours has been accepted as beneficial, but its application is limited by high risk of hemorrhagic complications after thrombolysis. This study aimed to analyze the risk factors of hemorrhagic complications after intravenous thrombolysis using Urokinase in acute cerebral infarction (ACI) patients.Total 391 consecutive ACI patients were enrolled and divided into 2 groups: the hemorrhagic complications group and the non-hemorrhagic complications group. The related data were collected and analyzed.Univariate analysis showed significant differences in prothrombin time, atrial fibrillation (AF), Mean platelet volume, large platelet ratio (L-PLR), triglyceride (TG), Lactate dehydrogenase, alanine aminotransferase (ALT), high-density lipoprotein, and baseline National Institute of Health Stroke Scale score between the hemorrhagic complications and the non-hemorrhagic complications group (P < .1). Multivariate logistic regression analysis indicated that AF (odds ratio [OR] = 2.91, 95% confidence interval [CI] = 1.06-7.99 P = .039) was the risk factor of hemorrhagic complications, while ALT (OR = 0.27, 95% CI = 0.10-0.72 P = .009) and TG (OR = 0.16, 95% CI = 0.06-0.45 P = .000) were protective factors of hemorrhagic complications.For patients with AF and lower levels of ALT or TG, the risk of hemorrhagic complications might increase after ACI.

Organelle-Partitioned Sugar-Rhodamine Diad for In Vivo Tumor Imaging.

Current tumor imaging agents are often limited by their liability to dissipate from tumor tissues. As cell sugar sorting enables exogenous sugars to be delivered into predetermined subcellular locations, we synthesized sialic acid (Sia) derivatives with rhodamine-X conjugated at C-9 (ROXSia), which hitchhikes cell sialic acid sorting to target tumor cell lysosomes, exhibiting pH-independent long-term probe retention in lysosomes. ROXSia gives selective, bright, and endured fluorescence signals in subcutaneous tumors and orthotopic tumors in mice models. These results indicate the potential of ROXSia as a lysosome-targeted optical agent for fluorescence-guided tumor resection.

Predictors of Outcome in Juvenile Myoclonic Epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy syndrome, accounting for 10% of all epilepsy. However, there is limited information regarding the predictors of seizure outcome. The aim of this study was to determine the predictors of seizure outcome in JME patients. METHODS: A population-based retrospective study of JME patients who were treated at the Department of Neurology of affiliated Zhongshan Hospital, Xiamen University from 2008 to 2013. RESULTS: Sixty-three patients (30 women and 33 men) were enrolled in this study. The median age at seizure onset was 14 years old, and the average duration of epilepsy was 5 years. The onset of JME at age <16 years was found in 63.5% of patients. The epileptiform runs ≥3 s were observed in 35.8% patients. Febrile seizure was noted in 28.9% of patients. Among 63 patients, 40 patients (63.5%) had remission. Multivariate analysis identified the following factors as significant predictors of seizure outcome: the onset of JME at age <16 years, epileptiform runs ≥3 s runs, and febrile seizure. CONCLUSION: The onset of JME at age <16 years, febrile seizures and epileptiform runs ≥3 s might be associated with poor long-term seizure outcome in patients with JME.

Influencing Factors of Recanalization after Intravenous Thrombolysis with Urokinase in Acute Cerebral Infarction Patients.

BACKGROUND: Intravenous thrombolysis (IVT) with urokinase is the standard reperfusion therapy for acute cerebral infarction (ACI) in China. Only about 30% patients who use urokinase for IVT can recanalize. Therefore, this study aimed to analyze the influencing factors of recanalization after IVT using urokinase in ACI patients. METHODS: A total of 391 consecutive patients with a diagnosis of ACI from January 2013 to October 2019 were enrolled and divided into 2 groups: patients without recanalization and patients with recanalization. Related data were collected and analyzed. RESULTS: Univariate analysis showed that there were significant differences in gender, atrial fibrillation, erythrocyte mean corpuscular volume, platelet large cell ratio (P-LCR), glucose (GLU), and severity of ICAS between patients without recanalization and patients with recanalization (p < 0.05). Multivariate logistic regression analysis indicated that P-LCR (odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.03-0.89, p = 0.04), GLU (OR = 0.28, 95% CI = 0.11-0.67, p = 0.004), and ICAS severity (OR = 0.48, 95% CI = 0.32-0.76, p = 0.001) were the influencing factors of recanalization. CONCLUSION: For patients with higher levels of P-LCR, GLU, or ICAS severity, the recanalization rate might decrease after ACI.

TIPE Regulates DcR3 Expression and Function by Activating the PI3K/AKT Signaling Pathway in CRC.

Tumor necrosis factor-induced protein-8 (TIPE) is highly expressed in colorectal cancer (CRC). Decoy receptor 3 (DcR3) is a soluble secreted protein that can antagonize Fas ligand (FasL)-induced apoptosis and promote tumorigenesis. It remains unclear whether TIPE can regulate DcR3 expression. In this study, we examined this question by analyzing the relationship between these factors in CRC. Bioinformatics and tissue microarrays were used to determine the expression of TIPE and DcR3 and their correlation in CRC. The expression of TIPE and DcR3 in colon cancer cells was detected. Plasma samples were collected from CRC patients, and DcR3 secretion was measured. Then, dual-luciferase reporter gene analysis was performed to assess the interaction between TIPE and DcR3. We exogenously altered TIPE expression and analyzed its function and influence on DcR3 secretion. Lipopolysaccharide (LPS) was used to stimulate TIPE-overexpressing HCT116 cells, and alterations in signaling pathways were detected. Additionally, inhibitors were used to confirm molecular mechanisms. We found that TIPE and DcR3 were highly expressed in CRC patients and that their expression levels were positively correlated. DcR3 was highly expressed in the plasma of cancer patients. We confirmed that TIPE and DcR3 were highly expressed in HCT116 cells. TIPE overexpression enhanced the transcriptional activity of the DcR3 promoter. TIPE activated the PI3K/AKT signaling pathway to regulate the expression of DcR3, thereby promoting cell proliferation and migration and inhibiting apoptosis. In summary, TIPE and DcR3 are highly expressed in CRC, and both proteins are associated with poor prognosis. TIPE regulates DcR3 expression by activating the PI3K/AKT signaling pathway in CRC, thus promoting cell proliferation and migration and inhibiting apoptosis. These findings may have clinical significance and promise for applications in the treatment or prognostication of CRC.

High HbA1c level is correlated with blood-brain barrier disruption in syphilis patients.

Diabetes mellitus (DM) and neurosyphilis (NS) may both damage the blood-brain barrier (BBB). It seems that non-neurosyphilis (non-NS) patients with high HbA1c levels are likely to develop into NS. However, the correlation of HbA1c level with BBB disruption in syphilis (non-NS) patients is unclear. In this study, we used dynamic contrast-enhanced (DCE) MRI to quantify regional BBB permeability in syphilis (non-NS) patients and detected several molecular biomarkers of cerebrospinal fluid (CSF). We found that BBB permeability values in the hippocampus, white matter, and cortex inferior temporal gyrus were correlated with albumin quotient (Qalb), CSF concentrations of interleukin IL-6 and IL-10. Moreover, BBB breakdown in white matter was correlated with CSF concentrations of sICAM-1 and sVCAM-1. In conclusion, our data suggest that BBB integrity may be liable to be disrupted in syphilis (non-NS) patients, patients with high HbA1c levels, as well as syphilis (non-NS) patients with high HbA1c levels, and it is particularly important to control blood glucose in these patients.

Pleiotrophin regulates functional heterogeneity of microglia cells in EAE animal models of multiple sclerosis by activating CCr-7/CD206 molecules and functional cytokines.

Multiple sclerosis (MS) is a neurodegenerative and immune-mediated disorder that characterizes by demyelination and neuro-inflammation. This study aimed to investigate the effects of pleiotrophin (PTN) on treatment of early injuries of white matter of MS patients. Experimental autoimmune encephalomyelitis (EAE) animal models were established by injecting 200 µg myelinoligodendrocyte glyeoprotein 33-35 (MOG35-55) and were divided into PTN+MOG group and PBS+MOG group. Meanwhile, normal mice group was assigned as control group (NC group). Immunofluorescence double label was used to examined co-expression of molecules. LV5-PTN and LV3-siPTN were established and transfected into microglia cells. All brain imaging data was acquired with MRI scanner. Quantitative real-time RT-PCR (qRT-PCR) and western blot were used to evaluate mRNA and protein expression, respectively. Lesion sites mainly appeared in NAWM of bilateral occipital lobes in EAE models. PTN treatment significantly enhanced CCr7 and reduced CD206 expression compared to PBS+MOG group (P<0.05). PTN participated in mitogen-activated protein kinase (MAPK) signaling pathway in EAE models. PTN treatment significantly regulated levels of functional cytokines in both M1 and M2 type microglia cells compared to PBS+MOG group (P<0.05). LV5-PTN and LV3-siPTN transfection modulated levels of PTN and MAPK molecule in microglia cells undergoing treatment of M1 or M2 inducer. PTN strengthened M1/M2 transformation by regulating functional cytokines. In conclusion, PTN regulated functional heterogeneity of microglia cells in EAE animal models of MS by activating CCr-7/CD206 molecules and functional cytokines. PTN could be considered as a promising candidate molecule for treating early injuries of white matter of patients with MS.

High Stress Hyperglycemia Ratio Predicts Poor Outcome after Mechanical Thrombectomy for Ischemic Stroke.

OBJECTIVE: The present study aimed to evaluate the association between stress hyperglycemia ratio (SHR) and outcome at 3 months after mechanical thrombectomy (MT) for acute occlusion in the anterior circulation. METHODS: Data from 160 consecutive patients with large vessel occlusion in the anterior circulation who underwent MT from May 2013 to March 2018 were retrospectively reviewed. SHR was calculated as the fasting glucose concentration divided by the estimated average glucose concentration (derived from the glycosylated hemoglobin level). Patients were dichotomized into 2 groups in accordance with the median SHR. Univariate and multivariate analyses were used to identify predictors of functional outcome. Good and poor outcomes were defined as modified Rankin Scale scores of 0-2 and 3-6, respectively. RESULTS: patients with unfavorable outcome had significantly higher levels of SHR than those with favorable outcome (median in SHR = 1.02 versus .84, P = .000). The median SHR was .96. Univariate analysis showed that significantly more patients with a poor outcome had SHR ≥ .96 compared with those with a good outcome (65.2% versus 31.0%, P = .000). After adjusting for potential covariates, Increased SHR (odds ratio [OR] 6.97, 95% confidence intervals [CI] 1.22-39.65, P = .029, for continuous SHR levels) and SHR ≥ .96 (OR 3.12, 95% CI 1.39-6.96, P = .006) remained independent predictors of poor outcome. CONCLUSIONS: Increased SHR is strongly correlated with poor outcome at 3 months after MT for proximal artery occlusion in the anterior circulation.

Association of the Apolipoprotein E polymorphism with migraine: a meta-analysis.

BACKGROUND: Apolipoprotein E (ApoE) gene has been reported to be associated with migraine and tension-type headache (TTH), but the results are conflicting. This study aimed to evaluate the association of ApoE with migraine by a meta-analysis. METHODS: MEDLINE, ISI Web of Knowledge, The Cochrane Central Register of Controlled Trials, and EMBASE databases were searched to identify eligible studies published in English from 2000 to 2014. Data were extracted using standardized forms. The association was assessed by relative risk (RR) with 95% confidence intervals (CIs) using a fixed or random effects model. RESULTS: Four studies, comprising 649 migraineurs, 229 TTH subjects and 975 controls, met all the criteria and were included in the meta-analysis. No significant difference was found comparing genotypic and allelic frequencies in the case of migraineurs versus controls and TTH subjects versus controls. Only when migraineurs and TTH subjects were considered as a whole group, ApoE4 was found to increase the relative risk of headache by 1.48 (95% CI 1.16, 1.90; P = 0.002), compared to controls. CONCLUSIONS: ApoE ε4 allele is not associated with migraine susceptibility, but is positively related to headache (including migraine and TTH).

Association of 231G>A polymorphism of endothelin type A receptor gene with migraine: a meta-analysis.

BACKGROUND/AIMS: Vascular dysfunction is implied in migraine. Endothelin type A receptor (EDNRA) is a receptor for endothelin-1, a potent vasoconstrictor. Several studies have investigated the association between EDNRA -231G>A SNP and migraine, but showed conflicting results. This study aimed to evaluate the association between EDNRA -231A allele and migraine by meta-analysis. METHODS: Relevant databases were searched to identify eligible studies published in English from 2000 to 2012. Data were extracted using standardized forms. The association was assessed by relative risk (RR) with 95% confidence intervals (CIs) using a fixed or random effects model to determine the strength of the genetic association. RESULTS: Three studies comprising 440 migraineurs, 222 subjects with tension-type headaches (TTHs) and 1323 controls were included in the meta-analysis. A significant difference was found between migraineurs and controls with AA genotype vs. AG+GG, and pooled RR with fixed effect was 4.04 (95% CI 1.173, 1.585; p=0.000, I(2)=15.1%). However, there was no statistically significant difference between TTH and controls (p=0.774). CONCLUSIONS: This meta-analysis provides evidence suggesting a significant association between EDNRA -231G>A polymorphism and migraine.

Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway.

Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1ß and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke.

Selective inhibition of 5-HT7 receptor reduces CGRP release in an experimental model for migraine.

OBJECTIVE: To investigate the role of 5-HT(7) receptors on the release of calcitonin gene-related peptide (CGRP) in an animal model of migraine. BACKGROUND: Calcitonin gene-related peptide has been identified as a key neuropeptide in the pathophysiology of migraine. It is elevated in the external jugular vein during migraine attacks in humans and after stimulation of the trigeminal ganglion in animal models of migraine. This can be treated with the 5-HT(1B/1D) receptor agonist sumatriptan concomitant with headache relief. Nevertheless, triptans, the most effective agents for the treatment of acute migraine attacks, are not effective in more than 1/3 of migraineurs and less than 50% of migraineurs achieve complete pain freedom. This indicates other serotonin receptors may be involved in the pathophysiology of migraine. Increasing evidence has shown that 5-HT(7) receptors may be involved in migraine pathogenesis. However, direct evidence for the role of 5-HT(7) receptors in migraine is still lacking. METHODS: Unilateral electrical stimulation of the trigeminal ganglion (TGES) was performed in anesthetized male Sprague-Dawley rats. Animals were pretreated with sumatriptan (300 microg/kg, i.v.), selective 5-HT(7) receptor antagonist SB269970 (5, 10 mg/kg, s.c.), potential 5-HT(7) receptor agonist AS19 (5, 10 mg/kg, s.c.) or co-administration of SB269970 and AS19 (10 mg/kg, s.c.). Serum CGRP concentrations in the ipsilateral jugular vein were determined before and at 2 and 5 minutes after the start of TGES. RESULTS: Our results showed that sumatriptan almost completely inhibited the release of CGRP evoked by TGES. Pre-administration of SB269970 (5, 10 mg/kg) caused a significant decrease in serum CGRP concentrations at 2 and 5 minutes following the onset of TGES, with a less inhibitory effect compared with sumatriptan. AS19 had no significant effect on CGRP release, while the SB269970-induced inhibitory effect was reversed by AS19. CONCLUSIONS: Selective inhibition of 5-HT(7) receptors partly reduced CGRP release evoked by TGES. These findings suggest that 5-HT(7) receptors may play a role in the pathophysiology of migraine.