Serum biomarkers in patients with drug-resistant epilepsy: a proteomics-based analysis.

Objective: To investigate the serum biomarkers in patients with drug-resistant epilepsy (DRE). Methods: A total of 9 DRE patients and 9 controls were enrolled. Serum from DRE patients was prospectively collected and analyzed for potential serum biomarkers using TMT18-labeled proteomics. After fine quality control, bioinformatics analysis was conducted to find differentially expressed proteins. Pathway enrichment analysis identified some biological features shared by differential proteins. Protein-protein interaction (PPI) network analysis was further performed to discover the core proteins. Results: A total of 117 serum differential proteins were found in our study, of which 44 were revised upwards and 73 downwards. The up-regulated proteins mainly include UGGT2, PDIA4, SEMG1, KIAA1191, CCT7 etc. and the down-regulated proteins mainly include ROR1, NIF3L1, ITIH4, CFP, COL11A2 etc. Pathway enrichment analysis identified that the upregulated proteins were mainly enriched in processes such as immune response, extracellular exosome, serine-type endopeptidase activity and complement and coagulation cascades, and the down-regulated proteins were enriched in signal transduction, extracellular exosome, zinc/calcium ion binding and metabolic pathways. PPI network analysis revealed that the core proteins nodes include PRDX6, CAT, PRDX2, SOD1, PARK7, GSR, TXN, ANXA1, HINT1, and S100A8 etc. Conclusion: The discovery of these differential proteins enriched our understanding of serum biomarkers in patients with DRE and potentially provides guidance for future targeted therapy.

Correlation of glymphatic system abnormalities with Parkinson's disease progression: a clinical study based on non-invasive fMRI.

BACKGROUND: The glymphatic system is reportedly involved in Parkinson's disease (PD). Based on previous studies, we aimed to confirm the correlation between the glymphatic system and PD progression by combining two imaging parameters, diffusion tensor image analysis along the perivascular space (DTI-ALPS), and enlarged perivascular spaces (EPVS). METHODS: Fifty-one PD patients and fifty healthy control (HC) were included. Based on the Hoehn-Yahr scale, the PD group was divided into early-stage and medium-to late-stage. All PD patients were scored using the Unified PD Rating Scale (UPDRS). We assessed the DTI-ALPS indices in the bilateral hemispheres and EPVS numbers in bilateral centrum semiovale (CSO), basal ganglia (BG), and midbrain. RESULTS: The DTI-ALPS indices were significantly lower bilaterally in PD patients than in the HC group, and EPVS numbers in any of the bilateral CSO, BG, and midbrain were significantly higher, especially for the medium- to late-stage group and the BG region. In PD patients, the DTI-ALPS index was significantly negatively correlated with age, while the BG-EPVS numbers were significantly positively correlated with age. Furthermore, the DTI-ALPS index was negatively correlated with UPDRS II and III scores, while the BG-EPVS numbers were positively correlated with UPDRS II and III scores. Similarly, the correlation was more pronounced in the medium- to late-stage group. CONCLUSION: The DTI-ALPS index and EPVS numbers (especially in the BG region) are closely related to age and PD progression and can serve as non-invasive assessments for glymphatic dysfunction and its interventions in clinical studies.

Efficacy and Safety of SPN-812 (Extended-Release Viloxazine) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: SPN-812 has been approved for attention-deficit/hyperactivity disorder (ADHD) treatment in children and adolescents. OBJECTIVE: We aimed to analyze the efficacy and safety of different doses of SPN-812 for ADHD pediatric patients of different ages, verify its clinical efficacy, and evaluate its safety. METHODS: Up until 30 August 2023, randomized controlled trials (RCTs) were searched in EMBASE, MEDLINE, the Cochrane Library, and clinicaltrials.gov to evaluate different doses of SPN-812 and a placebo. RESULTS: We pooled 1619 patients from five RCTs with a duration of 6-8 weeks. Patients (6-17 years old) in SPN-812 (100, 200, and 400 mg/d) groups were superior to the control group in all efficacy outcomes with lower attention-deficit/hyperactivity disorder rating scale-5 (ADHD-RS-5), Conners 3-parent short form composite T score (Conners 3-PS), Weiss functional impairment rating scale-parent (WFIRS-P), and increased clinical global impression-improvement (CGI-I) score (both p < 0.05). At the same time, only SPN-812 300 mg/d did not show a significantly high risk of the adverse events (AEs) such as somnolence and decreased appetite (p = 0.09). There was no significant difference between placebo and SPN-812 groups (100, 200, and 400 mg/d) in serious adverse events (SAEs) such as syncope. The subgroup analyses showed that, both in children and adolescents subgroups, SPN-812 showed better efficacy than the placebo. The two age subgroups showed a significantly higher risk of AEs and an insignificant risk of SAEs than the placebo. CONCLUSION: At present, SPN-812 (100, 200, and 400 mg/d) is superior to the corresponding control in efficacy measures. However, the safety problem cannot be ignored.

Altered brain networks and connections in chronic heart failure patients complicated with cognitive impairment.

Objective: Accumulating evidence shows that cognitive impairment (CI) in chronic heart failure (CHF) patients is related to brain network dysfunction. This study investigated brain network structure and rich-club organization in chronic heart failure patients with cognitive impairment based on graph analysis of diffusion tensor imaging data. Methods: The brain structure networks of 30 CHF patients without CI and 30 CHF patients with CI were constructed. Using graph theory analysis and rich-club analysis, changes in global and local characteristics of the subjects' brain network and rich-club organization were quantitatively calculated, and the correlation with cognitive function was analyzed. Results: Compared to the CHF patients in the group without CI group, the CHF patients in the group with CI group had lower global efficiency, local efficiency, clustering coefficient, the small-world attribute, and increased shortest path length. The CHF patients with CI group showed lower nodal degree centrality in the fusiform gyrus on the right (FFG.R) and nodal efficiency in the orbital superior frontal gyrus on the left (ORB sup. L), the orbital inferior frontal gyrus on the left (ORB inf. L), and the posterior cingulate gyrus on the right (PCG.R) compared with CHF patients without CI group. The CHF patients with CI group showed a smaller fiber number of edges in specific regions. In CHF patients with CI, global efficiency, local efficiency and the connected edge of the orbital superior frontal gyrus on the right (ORB sup. R) to the orbital middle frontal gyrus on the right (ORB mid. R) were positively correlated with Visuospatial/Executive function. The connected edge of the orbital superior frontal gyrus on the right to the orbital inferior frontal gyrus on the right (ORB inf. R) is positively correlated to attention/calculation. Compared with the CHF patients without CI group, the connection strength of feeder connection and local connection in CHF patients with CI group was significantly reduced, although the strength of rich-club connection in CHF patients complicated with CI group was decreased compared with the control, there was no statistical difference. In addition, the rich-club connection strength was related to the orientation (direction force) of the Montreal cognitive assessment (MoCA) scale, and the feeder and local connection strength was related to Visuospatial/Executive function of MoCA scale in the CHF patients with CI. Conclusion: Chronic heart failure patients with CI exhibited lower global and local brain network properties, reduced white matter fiber connectivity, as well as a decreased strength in local and feeder connections in key brain regions. The disrupted brain network characteristics and connectivity was associated with cognitive impairment in CHF patients. Our findings suggest that impaired brain network properties and decreased connectivity, a feature of progressive disruption of brain networks, predict the development of cognitive impairment in patients with chronic heart failure.

Brain diffusion tensor imaging reveals altered connections and networks in epilepsy patients.

Introduction: Accumulating evidence shows that epilepsy is a disease caused by brain network dysfunction. This study explored changes in brain network structure in epilepsy patients based on graph analysis of diffusion tensor imaging data. Methods: The brain structure networks of 42 healthy control individuals and 26 epilepsy patients were constructed. Using graph theory analysis, global and local network topology parameters of the brain structure network were calculated, and changes in global and local characteristics of the brain network in epilepsy patients were quantitatively analyzed. Results: Compared with the healthy control group, the epilepsy patient group showed lower global efficiency, local efficiency, clustering coefficient, and a longer shortest path length. Both healthy control individuals and epilepsy patients showed small-world attributes, with no significant difference between groups. The epilepsy patient group showed lower nodal local efficiency and nodal clustering coefficient in the right olfactory cortex and right rectus and lower nodal degree centrality in the right olfactory cortex and the left paracentral lobular compared with the healthy control group. In addition, the epilepsy patient group showed a smaller fiber number of edges in specific regions of the frontal lobe, temporal lobe, and default mode network, indicating reduced connection strength. Discussion: Epilepsy patients exhibited lower global and local brain network properties as well as reduced white matter fiber connectivity in key brain regions. These findings further support the idea that epilepsy is a brain network disorder.

Effect of cognitive behavioral intervention on anxiety, depression, and quality of life in patients with epilepsy.

OBJECTIVE: This study aimed to investigate the effect of cognitive behavioral therapy (CBT) on quality of life, anxiety, and depression in patients with epilepsy. METHODS: Each study subject was randomly assigned to a CBT (n=46) or control (n=49) group (1:1 ratio), and the first group underwent an 8-week CBT treatment. Anxiety, depression, and quality of life (QOLIE-31) were assessed at both baseline and endpoint using the Self-Rating Anxiety Scale (SAS), Hamilton Depression Scale (HDMA) and quality of life in Epilepsy-31 (QOLIE-31) scales. The statistical analyses included between-and within-group comparisons of the effects of CBT on these measures and associations with demographic and clinical variables. RESULTS: No differences were found between variables at baseline (P>0.05). The repeated-measures analyses found that CBT group had greater improvement in depression score compared to the control group (P<0.05). The analysis of anxiety score showed that compared to the control group, CBT intervention had no statistical significance in the total anxiety population. However, the CBT intervention decreased anxiety in women and Combined-drug group (P<0.05). The CBT group had greater improvement in overall score, medication effect, and seizure worry score than the control group (P<0.05). Stratified analysis found total and medication effects score of CBT intervention group for the combined-drug group were higher than those of the single drug group (P<0.05). CONCLUSION: Increases in overall scores, seizure worry, cognitive functioning, and medication effect were better in the CBT group. CBT can improve anxiety, depression, and quality of life in patients with epilepsy. Women and combined-drug patients with epilepsy benefit most from CBT.

Study of brain network alternations in non-lesional epilepsy patients by BOLD-fMRI.

Objective: To investigate the changes of brain network in epilepsy patients without intracranial lesions under resting conditions. Methods: Twenty-six non-lesional epileptic patients and 42 normal controls were enrolled for BOLD-fMRI examination. The differences in brain network topological characteristics and functional network connectivity between the epilepsy group and the healthy controls were compared using graph theory analysis and independent component analysis. Results: The area under the curve for local efficiency was significantly lower in the epilepsy patients compared with healthy controls, while there were no differences in global indicators. Patients with epilepsy had higher functional connectivity in 4 connected components than healthy controls (orbital superior frontal gyrus and medial superior frontal gyrus, medial superior frontal gyrus and angular gyrus, superior parietal gyrus and paracentral lobule, lingual gyrus, and thalamus). In addition, functional connectivity was enhanced in the default mode network, frontoparietal network, dorsal attention network, sensorimotor network, and auditory network in the epilepsy group. Conclusion: The topological characteristics and functional connectivity of brain networks are changed in in non-lesional epilepsy patients. Abnormal functional connectivity may suggest reduced brain efficiency in epilepsy patients and also may be a compensatory response to brain function early at earlier stages of the disease.

A tract-based spatial statistics study of white matter integrity in epilepsy.

OBJECTIVE: To explore the changes of cerebral white matter diffusion tensor in epilepsy. METHODS: This study was a retrospective study based on diffusion tensor imaging (DTI). Twenty-six epileptic patients and 42 normal controls matched for sex, age and handedness were enrolled in our research. Based on the method of tract-based spatial statistics (TBSS), we analyzed the changes of each relevant parameter index of DTI in white matter of the brain in all subjects, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). RESULTS: In comparison with the control group, epileptic patients had decreased FA and elevated MD, AD, and RD in the anterior thalamic radiation, corticospinal tract, forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus and uncinate fasciculus (P < 0.05). CONCLUSION: Widespread white matter integrity was observed in epileptic patients, which may be the structural basis for the development of affective disorders, impaired cognition, and motor abnormalities.

Long noncoding RNA Nespas inhibits apoptosis of epileptiform hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway.

Epilepsy is one of the most common neurological diseases with spontaneous recurrent seizures. Long noncoding RNAs (lncRNAs) are crucial modulators in numerous diseases, including epilepsy. However, the functional role and potential mechanism of lncRNA Nespas in epilepsy remain unknown. Our study clarified that Nespas was underexpressed in epileptiform hippocampal tissues and neurons. Furthermore, Nespas promoted hippocampal neuron viability and proliferation, and inhibited hippocampal neuron apoptosis. Mechanistically, Nespas interacted with microRNA 615-3p (miR-615-3p) in epileptiform hippocampal neurons. 26S proteasome non-ATPase regulatory subunit 11 (Psmd11) was a downstream target of miR-615-3p, and Nespas elevated Psmd11 expression via competitively binding to miR-615-3p in epileptiform hippocampal neurons. In addition, rescue assays suggested that Nespas promoted hippocampal neuron viability and proliferation, and suppressed hippocampal neuron apoptosis by upregulation of Psmd11. Furthermore, Nespas suppressed the PI3K/Akt/mTOR pathway via upregulating Psmd11 in epileptiform hippocampal neurons. This report explored the function and regulatory mechanism of Nespas in epileptiform hippocampal neurons for the first time. Our findings revealed that Nespas suppressed the apoptosis of epileptiform hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway via upregulation of Psmd11 at a miR-615-3p dependent way, indicating that Nespas may offer a new direction for the treatment of epilepsy.

Clinical characteristics of the first known cases of death caused by COVID-19 pneumonia.

Severe pneumonia caused by COVID-19 has resulted in many deaths worldwide. Here, we analyzed the clinical characteristics of the first 17 reported cases of death due to COVID-19 pneumonia in Wuhan, China. Demographics, initial symptoms, complications, chest computerized tomography (CT) images, treatments, and prognoses were collected and analyzed from the National Health Committee of China data. The first 17 reported deaths from COVID-19 were predominately in older men; 82.35% of patients were older than 65 years, and 76.47% were males. The most common initial symptoms were fever or fatigue (14 cases, 82.35%), respiratory symptoms, such as cough (12 cases, 70.59%), and neurological symptoms, such as headache (3 cases, 17.65%). The most common finding of chest CT was viral pneumonia (5 cases, 29.41%). Anti-infectives (11 cases, 64.71%) and mechanical ventilation (9 cases, 52.94%) were commonly used for treatment. Most of the patients (16 cases, 94.12%) died of acute respiratory distress syndrome (ARDS). Our findings show that advanced age and male gender are effective predictors of COVID-19 mortality, and suggest that early interventions to reduce the incidence of ARDS may improve prognosis of COVID-19 pneumonia patients.

Triiodothyronine levels were positively correlated with opening of collateral circulation in cerebral infarction patients with large artery atherosclerosis.

INTRODUCTION: Non-thyroidal illness syndrome (NTIS) is one of the signs for poor prognosis of cerebral infarction (CI), but its risk factors had never been explored. In this study, we analyzed the potential effect of collateral circulation on prognosis prediction of triiodothyronine for large artery atherosclerosis cerebral infarction (LAA-CI) patients. MATERIAL AND METHODS: Clinical data of CI patients between 2012 and 2014 were collected. Imaging inspection was used for determining TOAST classification and evaluating collateral circulation. One-year follow-up was conducted for mRS score by telephone. RESULTS: T3 level in the NTIS group (p = 0.001) was significantly decreased while TSH level (p < 0.001) was increased. Patients in the NTIS group had a poorer prognosis (p = 0.008) and the main reason was the high mortality (p = 0.002). NTIS predicted poor collateral circulation (p = 0.026) and good collateral circulation tended to be less likely concomitant with NTIS (p = 0.001). Logistic regression analysis showed that triiodothyronine concentrations (OR = 4.760, 95% CI: 1.981-11.456, p < 0.001) were positively correlated with but advanced age (OR = 0.756, 95% CI: 0.645-0.886, p = 0.001) negatively with opening of collateral circulation. CONCLUSIONS: Poor opening of collateral circulation was likely to mediate the prediction of NTIS for prognosis of LAA-CI patients.

Long-noncoding RNA Peg13 alleviates epilepsy progression in mice via the miR-490-3p/Psmd11 axis to inactivate the Wnt/ß-catenin pathway.

Epilepsy, one of the most common neurological diseases with spontaneous recurrent seizures, is a severe health problem globally. The present study aimed to study the role and upstream mechanism of 26S proteasome non-ATPase regulatory subunit 11 (Psmd11) in epilepsy. In the current paper, epileptic mice models were successfully established. Hematoxylin and eosin (HE) staining was performed to reveal morphology of hippocampal tissues. Nissl's staining was performed for detection of neuron injury. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect concentrations of pro-inflammatory cytokines. The expression of Psmd11 was downregulated in the hippocampal tissues of epileptic mice, and overexpression of Psmd11 improved the spatial learning and memory of epileptic mice. Further, upregulation of Psmd11 protected epileptic hippocampal neurons from injury. Moreover, Psmd11 overexpression inhibited cell apoptosis, suppressed the activities of microglia and astrocytes, as well as reduced inflammatory response in epileptic hippocampi. Psmd11 was a downstream target of miR-490-3p. Long noncoding RNA (lncRNA) Peg13 bound with miR-490-3p to upregulate Psmd11. Subsequently, rescue experiments revealed that Peg13 suppressed the progression of epilepsy via upregulating Psmd11. Furthermore, Psmd11 was verified to inactivate the Wnt/ß-catenin pathway. Peg13 repressed the Wnt/ß-catenin pathway via upregulation of Peg13. In conclusion, this paper illuminated the function and upstream mechanism of Psmd11 in epilepsy. Psmd11 was upregulated by Peg13 at a miR-490-3p dependent way, thus inactivating the Wnt/ß-catenin pathway and alleviating epilepsy course in mice, which may be a promising approach for epilepsy treatment.

T-lymphocyte subsets as a predictive biomarker for stroke-associated pneumonia.

The aim of this study was to facilitate the clinical treatment and prognosis of stroke-associated pneumonia (SAP) by examining changes in T-lymphocyte subsets. Stroke patients admitted in Suzhou Hospital between 2014 and 2016 participated in the study. Patients were divided into a pneumonia group (50 patients) and a non-pneumonia group (254 patients) based on a diagnosis of pneumonia. Information regarding risk factors for ischemic stroke was collected from all patients using a questionnaire. Compared with non-SAP patients, SAP patients were older, dysphagic, smokers, had higher NIH stroke scale (NIHSS) scores and neutrophil: lymphocyte ratio, had higher leukocyte, neutrophil, and CD8 levels, had lower CD3, CD4, and lymphocyte levels, and had a lower CD4:CD8 ratio. Patients with a higher NIHSS score had higher CD8 levels, lower CD3 and CD4 levels, and a lower CD4:CD8 ratio. No significant differences in T-lymphocyte subsets were found between the left and right cerebral hemispheres. After adjusting for other variables, smoking, dysphagia, NIHSS score, and CD4:CD8 ratio were positively associated with SAP. The areas under the receiver operating characteristic curve for dysphagia, NIHSS score, CD4:CD8 ratio, CD4:CD8 ratio + NIHSS score, and Dysphagia+ CD4:CD8 ratio + NIHSS score were 0.583 (95% CI: 0.490-0.675), 0.791 (95% CI: 0.724-0.859), 0.676 (95% CI: 0.593-0.759), 0.846 (95% CI: 0.790-0.902), and 0.867 (95% CI: 0.815-0.918), respectively. A few T-lymphocyte subsets may increase susceptibility to pneumonia after acute ischemic stroke. Thus, the detection of T-lymphocyte subsets may predict the risk of SAP in such patients.

Association between hyperhomocysteinemia and stroke with atherosclerosis and small artery occlusion depends on homocysteine metabolism-related vitamin levels in Chinese patients with normal renal function.

This study was conducted to investigate the role of different homocysteine metabolism-related vitamin (HMRV) levels in the correlation between hyperhomocysteinemia (HHCY) and ischemic stroke (IS) subtypes. Three hundred and forty-eight IS patients manifesting different vascular subtypes were subclassified on the basis of HMRV deficiencies. Correlation between HHCY and IS subtypes was investigated in all the subgroups. In this study, HHCY was significantly correlated with the IS subtypes in large artery atherosclerosis (OR 1.126, 95%CI: 1.051 ~ 1.206, P = 0.001) and small artery occlusion (OR 1.105, 95%CI: 1.023 ~ 1.193, P = 0.012). Subgroup analysis revealed a correlation between HHCY and IS subgroup (OR 1.201, 1.178, 95%CI: 1.081 ~ 1.334, 1.058 ~ 1.313, P = 0.001, P = 0.003, respectively) in HMRV deficiency, but not significantly with the IS subgroup in normal HMRV levels. Serum vitamin B12 concentrations are inversely correlated with both IS subtypes in HMRV deficiency subgroups (OR 0.992, 0.995, 95%CI: 0.987 ~ 0.996, 0.991 ~ 0.999, P < 0.001, P = 0.007, respectively), which may contribute to HHCY incidence in these populations. The correlation between HHCY and IS subtypes is affected by HMRV levels in this case-control study. Our findings are helpful to understand the inconsistency in prior homocysteine studies. Serum vitamin B12 levels may play a critical role in HHCY incidence in this Chinese population.Cerebrovascular disease has emerged as the leading cause of disability and mortality in both urban and rural areas of China (Neurology branch of Chinese Medical Association 2015). Ischemic stroke (IS) constitutes 60% to 80% of all cerebrovascular disease (Neurology branch of Chinese Medical Association 2014). Among a variety of risk factors, hyperhomocysteinemia (HHCY) has been closely correlated with IS due to intracranial small-vessel disease and extracranial large-artery disease (Selhub et al. 1995; Eikelboom et al. 2000; Alvarez et al. 2012; Jeon et al. 2014). However, the failure to lower homocysteine (HCY) via homocysteine metabolism-related vitamin (HMRV, including folic acid and vitamin B12 but not vitamin B6 in this study) supplementation to reduce stroke morbidity questions the role of HCY as a risk factor for stroke (Lonn et al. 2006; Hankey et al. 2010). Theoretically, HMRV supplementation merely lowers the incidence of stroke induced by HHCY resulting from HMRV deficiency, whereas HHCY-induced stroke concomitant with normal HMRV levels may be refractory to treatment. The correlation between HCY varying with HMRV levels and IS subtypes is still unclear. In this study, we investigated the impact of variation in HMRV levels on the correlation between HHCY and IS subtypes in 348 acute IS patients with large and small vessel diseases. We sought to determine the factors underlying the conflicting results associated with lowering HCY by HMRV supplementation to reduce stroke incidence.

Evaluating the diagnostic value of vWF:Ag, D-D and FDP in patients with acute cerebral infarction using ROC curves.

Cerebral infarction is usually associated with arteriosclerosis, vascular endothelial cell injury and blood flow through the vascular system. The diagnostic value of markers, including von Willebrand factor antigen (vWF:Ag), D-dimer (D-D) and fibrinogen/fibrin degradation product (FDP), have not been studied in patients with acute cerebral infarction. Thus, the aim of the present study was to use receiver operating characteristic (ROC) curves to evaluate the diagnostic significance of vWF:Ag, D-D and FDP in 94 cases of acute cerebral infarction. The results revealed that vWF:Ag and D-D concentrations were significantly higher in acute cerebral infarction patients as compared with the normal controls (P<0.01), whereas no statistically significant difference in FDP was observed between the groups (P>0.01). Plasma vWF:Ag and D-D concentrations significantly correlated with the National Institute of Health Stroke Scale (NIHSS) scores (r=0.625 and 0.582, respectively; P<0.01). In addition, the vWF:Ag concentration significantly correlated with the D-D concentration (r=0.320; P<0.01), whereas FDP concentration did not correlate with D-D or vWF:Ag concentrations or the NIHSS scores (r=0.172, 0.188 and 0.065, respectively; P>0.05). The area under the ROC curve using vWF:Ag as a diagnostic marker in patients with acute cerebral infarction was 0.900, while for D-D the area was 0.795 and for FDP the area was 0.465. Logistic regression analysis revealed that the odds ratios of vWF:Ag and D-D were 16.727 and 2.324, respectively, which were statistically significant (P<0.001 and 0.023, respectively). These results indicated that using vWF:Ag as a diagnostic marker is likely to significantly improve the sensitivity of diagnosing patients with acute cerebral infarction. The diagnostic value of vWF:Ag concentration was significantly higher compared with D-D and FDP levels.

Low T3 syndrome predicts severe neurological deficits of cerebral infarction inpatients with large artery artherosclerosis in internal carotid artery system.

OBJECTIVES: The low triiodothyronine (T3) syndrome indicates poor prognosis for patients with cerebral infarction. It is unknown, however, whether basic conditions or severities in the patients with the low T3 syndrome are different compared to those without the low T3 syndrome. METHODS: We compared the risk factors and the severity of the disease using the National Institutes of Health stroke scale (NIHSS) score at the worst condition for cerebral infarction in patients with or without the low T3 syndrome in order to better understand the characteristics underlying the worse prognosis in patients with the low T3 syndrome. RESULTS: We found that cerebral infarction patients with the low T3 syndrome were significantly older (p<0.001) and significantly more likely to be female (p=0.002) and had hypertension (p=0.04) or homocystinemia (p=0.001), but less likely to smoke (p=0.008), compared to patients without the low T3 syndrome. The proportion of NIHSS score ≥8 in the patients with LAA-ICA-associated cerebral infarction accompanied by the low T3 syndrome was significantly higher than in those without the low T3 syndrome (p=0.001). CONCLUSION: We concluded that increased numbers of risk factors for cerebral infarction and more severe neurological deficits may be important causes for worse prognosis in the patients with the low T3 syndrome which may more likely occur in patients with LAA-ICA cerebral infarction. Intense secondary prevention in cerebral infarction especially in older women are needed.

Time-course of GDNF and its receptor expression after brain injury in the rat.

The aim of the present work was to perform, by in situ hybridization, a time-course analysis of the glial cell line-derived neurotrophic factor (GDNF) and its receptor mRNA expression in two models of brain injury in the rat: (a) excitotoxic lesion by ibotenic acid injection in the hippocampal formation; (b) mechanical lesion by needle insertion through the cerebral cortex including the white matter of the corpus callosum. The time-course analysis, ranging from 6h to 8 days, showed that the GDNF and its receptor (RET, GFRalpha-1 and GFRalpha-2) mRNA expressions were differentially up-regulated in both models of lesion. This in vivo regulation of the GDNF and its receptor mRNA expression indicates their involvement in the process of neuronal protection and regeneration occurring after brain injury.

Cellular localization of mGluR3 and mGluR5 mRNAs in normal and injured rat brain.

In order to understand the role of metabotropic glutamate receptors (mGluRs) in the brain, it is important to know how the mGluRs are differentially expressed among the different cell types. At present, the cellular expression of mGluR3 and mGluR5 has been mostly studied in terms of proteins with observations suggesting the expression of both mGluR3 and mGluR5 in neuronal and in glial cells. In order to verify the brain cell type-expressing mGluR3 and mGluR5 mRNAs, both in normal and injured brain, we performed a double labeling analysis, by in situ hybridization for mGluR3 or mGluR5 mRNA and immunohistochemistry for specific cellular markers. This approach allowed us to find mGluR3 mRNA expressed in neurons (NeuN-positive cells), and in glial cells, such as astrocytes (GFAP-positive cells) and oligodendrocytes (CNPase-positive cells). The same analysis showed that only NeuN-positive cells express mGluR5 mRNA. The time course of mGluR3 mRNA expression in two models of hippocampal formation lesion, kainate-induced seizures or ibotenic acid injection, showed an increased expression of mGluR3 in the area of lesion. This effect appears 1 week after the injury and was localized in GFAP- and CNPase-positive cells. In contrast, mGluR5 was not found expressed in the area of lesion. The present results contribute to extend available data on cell type-expressing mGluR3 and mGluR5 in normal and injured brain and could be relevant to understand the mechanisms that drive neuron-glial cells interaction both in normal and repairing processes.

Munc-18-2 regulates exocytosis of H(+)-ATPase in rat inner medullary collecting duct cells.

Exocytic insertion of H(+)-ATPase into the apical membrane of inner medullary collecting duct (IMCD) cells is dependent on a soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein target receptor (SNARE) complex. In this study we determined the role of Munc-18 in regulation of IMCD cell exocytosis of H(+)-ATPase. We compared the effect of acute cell acidification (the stimulus for IMCD exocytosis) on the interaction of syntaxin 1A with Munc-18-2 and the 31-kDa subunit of H(+)-ATPase. Immunoprecipitation revealed that cell acidification decreased green fluorescent protein (GFP)-syntaxin 1A and Munc-18-2 interaction by 49 +/- 7% and increased the interaction between GFP-syntaxin 1A and H(+)-ATPase by 170 +/- 23%. Apical membrane Munc-18-2 decreased by 27.5 +/- 4.6% and H(+)-ATPase increased by 246 +/- 22%, whereas GP-135, an apical membrane marker, did not increase. Pretreatment of IMCD cells with a PKC inhibitor (GO-6983) diminished the previously described changes in Munc-18-2-syntaxin 1A interaction and redistribution of H(+)-ATPase. In a pull-down assay of H(+)-ATPase by glutathione S-transferase (GST)-syntaxin 1A bound to beads, preincubation of beads with an approximately twofold excess of His-Munc-18-2 decreased H(+)-ATPase pulled down by 64 +/- 16%. IMCD cells that overexpress Munc-18-2 had a reduced rate of proton transport compared with control cells. We conclude that Munc-18-2 must dissociate from the syntaxin 1A protein for the exocytosis of H(+)-ATPase to occur. This dissociation leads to a conformational change in syntaxin 1A, allowing it to interact with H(+)-ATPase, synaptosome-associated protein (SNAP)-23, and vesicle-associated membrane protein (VAMP), forming the SNARE complex that leads to the docking and fusion of H(+)-ATPase vesicles.