The Salmonella effector SifA initiates a kinesin-1 and kinesin-3 recruitment process mirroring that mediated by Arl8a and Arl8b.

When intracellular, pathogenic Salmonella reside in a membrane compartment composed of interconnected vacuoles and tubules, the formation of which depends on the translocation of bacterial effectors into the host cell. Cytoskeletons and their molecular motors are prime targets for these effectors. In this study, we show that the microtubule molecular motor KIF1Bß (a splice variant of KIF1B), a member of the kinesin-3 family, is a key element for the establishment of the Salmonella replication niche as its absence is detrimental to the stability of bacterial vacuoles and the formation of associated tubules. Kinesin-3 interacts with the Salmonella effector SifA but also with SKIP (also known as PLEKHM2), a host protein complexed to SifA. The interaction with SifA is essential for the recruitment of kinesin-3 on Salmonella vacuoles whereas that with SKIP is incidental. In the non-infectious context, however, the interaction with SKIP is essential for the recruitment and activity of kinesin-3 only on a fraction of the lysosomes. Finally, our results show that, in infected cells, the presence of SifA establishes a kinesin-1 and kinesin-3 recruitment pathway that is analogous to and functions independently of that mediated by the Arl8a and Arl8b GTPases. This article has an associated First Person interview with the first author of the paper.

Regulation of kinesin-1 activity by the Salmonella enterica effectors PipB2 and SifA.

Salmonella enterica is an intracellular bacterial pathogen. The formation of its replication niche, which is composed of a vacuole associated with a network of membrane tubules, depends on the secretion of a set of bacterial effector proteins whose activities deeply modify the functions of the eukaryotic host cell. By recruiting and regulating the activity of the kinesin-1 molecular motor, Salmonella effectors PipB2 and SifA play an essential role in the formation of the bacterial compartments. In particular, they allow the formation of tubules from the vacuole and their extension along the microtubule cytoskeleton, and thus promote membrane exchanges and nutrient supply. We have developed in vitro and in cellulo assays to better understand the specific role played by these two effectors in the recruitment and regulation of kinesin-1. Our results reveal a specific interaction between the two effectors and indicate that, contrary to what studies on infected cells suggested, interaction with PipB2 is sufficient to relieve the autoinhibition of kinesin-1. Finally, they suggest the involvement of other Salmonella effectors in the control of the activity of this molecular motor.This article has an associated First Person interview with the first author of the paper.

Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS).

Changes in the expression of HCN ion channels leading to changes in Ih function and neuronal excitability are considered to be possible mechanisms involved in epileptogenesis in kinds of human epilepsy. In previous animal studies of febrile seizures and temporal lobe epilepsy, changes in the expression of HCN1 and HCN2 channels at different time points and in different parts of the brain were not consistent, suggesting that transcriptional disorders involving HCNs play a crucial role in the epileptogenic process. Therefore, we aimed to assess the transcriptional regulation of HCN channels in Medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. This study included eight nonhippocampal sclerosis patients and 40 MTLE-HS patients. The mRNA expression of HCN channels was evaluated by qRT-PCR, while the protein expression was quantitatively analyzed by Western blotting. The subcellular localization of HCN channels in the hippocampus was explored by immunofluorescence. We demonstrated that the mRNA and protein expression of HCN1 and HCN2 are downregulated in controls compared to that in MTLE-HS patients. In the hippocampal CA1/CA4 subregion and GCL, in addition to a large decrease in neurons, the expression of HCN1 and HCN2 on neuronal cell membranes was also downregulated in MTLE-HS patients. These findings suggest that the expression of HCN channels are downregulated in MTLE-HS, which indicates that the decline in HCN channels in the hippocampus during chronic epilepsy in MTLE-HS patients leads to the downregulation of Ih current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.

Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

PURPOSE: This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). METHODS: A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. RESULTS: We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. CONCLUSION: Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

Prevalence and risk factors for depression in outpatient departments of three general hospitals in China: a cross-sectional study.

Objectives: To determine the prevalence and risk factors associated with depression of outpatients in three general hospitals in southern China.Methods: This hospital-based, cross-sectional descriptive study was conducted in outpatient departments of Neurology, Gastroenterology, Cardiology and Gynaecology of three general hospitals between March and June 2016. A total of 5294 adult respondents (≥18 years) in clinic waiting rooms were recruited, and 4976 were eligible to participate in the study. The nine-item Patient Health Questionnare-9 (PHQ-9) Scale was used to assess the presence of depressive symptoms. Binary logistic regression analysis was performed to identify the risk factors associated with depressive symptoms.Results: The prevalence of depressive symptoms among outpatients was 26.0% (95% CI: 24.8-27.3%). Risk factors associated with depressive symptoms included younger age (OR = 0.960; 95% CI: 0.95-0.971), social alcohol drinking (OR = 1.339; 95% CI: 1.074-1.668) and sleep disturbance (OR = 3.678; 95% CI: 3.025-4.471).Conclusions: This study provides evidence that depressive symptoms are prevalent among outpatients of general hospitals. Moreover, younger age, alcohol consumption and sleep disturbance may potentially be useful for targeted screening and prevention for outpatients with depression seen in general hospitals.KeypointsThe prevalence of self-reported depressive symptoms is common in outpatients in clinical settings.Younger age, current alcohol drinking and sleep disturbance are the associated risk factors for depression in outpatient population.Alcohol prevention and sleep quality improvement need to be incorporated into strategies aimed at the prevention and management of depression.

A single CRD C-type lectin from Eriocheir sinensis (EsLecB) with microbial-binding, antibacterial prophenoloxidase activation and hem-encapsulation activities.

C-type lectins (CTLs) exist widely in crustaceans. To date, thirteen CTLs have been reported in crustaceans, and play significant roles in pathogen recognition, encapsulation of hemocytes and antimicrobial activity in the innate immune response. Based on the initial expressed sequence tags (EST) of a hepatopancreatic cDNA library, a novel CTL, designated as EsLecB, with a 470 bp open reading frame encodes a polypeptide of 156 amino acids, including a signal peptide of 19 amino acid residues and one carbohydrate-recognition domain of 131 aa residues, was cloned from the crustacean Eriocheir sinensis. By qRT-PCR analysis, EsLecB was detected in all tested tissues, and showed highest expression in hemocytes, hepatopancreas and heart. The expression of EsLecB was up-regulated following injections of PAMPs or bacteria. The recombinant protein (rEsLecB) expressed in Escherichia coli had a calcium-independent but carbohydrate-dependent microbial-binding and microbial-agglutinating, microorganism growth inhibitory and hem-encapsulation activities. Moreover, the rEsLecB could stimulate the activation of prophenoloxidase in vitro. These results indicated that EsLecB, as an antibacterial pattern recognition receptor is involved in innate immunity, and may act as an upstream detector of the prophenoloxidase activating system, which can detect pathogen invasion in E. sinensis.

[Effects of carbamazepine on plasma concentrations of valproic acid and its toxic metabolite in epileptic patients].

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.

Frontal Theta Asymmetry may be a new target for reducing the severity of depression and improving cognitive function in depressed patients.

BACKGROUND: The prevalence of depressive disorder is increasing due to a variety of factors, which brings a huge strain on individuals, families and society. This study aims to investigate whether there is Frontal Theta Asymmetry (FTA) in depressed patients, and whether FTAs are related to depression severity and cognitive function changes in depressed patients. METHODS: Participants who met the inclusion criteria were enrolled in this study. Socio-demographic data of each participant were recorded. Zung's self-rating Depression Scale was used to assess the depression status of participants. P300 was used to evaluate the cognitive function of participants. EEG data from participants were collected by the NeuroScan SynAmps RT EEG system. t-test, Wilcoxon rank-sum test and Chi-square test were used to detect the differences of different variables between the two groups. Multiple linear regression analysis and multiple logistic regression analysis were used to analyze relationships between FTAs in different regions and participants' depression status and cognitive function. RESULTS: A total of 66 depressed participants and 47 healthy control participants were included in this study. The theta spectral power of the left frontal lobe was slightly stronger than that of the right frontal lobe in the depression group, while the opposite was true in the healthy control group. The FTA in F3/F4 had certain effects on the emergence of depression in participants, the emergence of depression in participants and Changes in cognitive function. CONCLUSIONS: FTAs are helpful to assess the severity of depression and early identify cognitive impairment in patients with depression.

Standardized Treatment and Shortened Depression Course can Reduce Cognitive Impairment in Adolescents With Depression.

Objectives: This study aimed to explore the influence of depression severity, disease course, treatment status, and other factors on cognitive function in adolescents with depressive disorders. Methods: Participants who met the inclusion criteria were enrolled in the study. Sociodemographic data of each participant were recorded, including age, sex, and family history of mental disorders. Zung's Self-Rating Depression Scale was used to assess depression status in adolescents. Moreover, P300 and mismatch negativity (MMN) were used to objectively evaluate the participants' cognitive function. Results: Only 26.8% of the adolescents with depression received standard antidepressant treatment. The latencies of N2 (267.80±23.34 ms), P3 (357.71±32.09 ms), and MMN (212.10±15.61 ms) in the adolescent depression group were longer than those in the healthy control group (p<0.01). Further analysis revealed that the latency of MMN was extended with increased levels of depression in adolescents. The MMN latency was short in participants with depression receiving standardized treatment. Furthermore, the latency of MMN was positively correlated with the severity and duration of depression (correlation coefficients were 0.465 and 0.479, respectively) (p<0.01). Conclusion: Receiving standardized treatment and shortening the course of depression can reduce cognitive impairment in adolescents with depression.

Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection.

Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.

Pluronic P85 decreases the delivery of phenytoin to the brain in drug-resistant rats with P-glycoprotein overexpressed chronic mesial temporal lobe epilepsy.

P-glycoprotein (Pgp) overexpressed in blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Pluronic P85 (P85) was proved to enhance the delivery of drugs into the brain by inhibition of Pgp. To determine whether the surfactant P85 [versus Pgp inhibitor tariquidar (TQD)] enhance phenytoin (PHT) into the brain in drug-resistant rats with chronic mesial temporal lobe epilepsy (MTLE) induced by lithium-pilocarpine, in brain of which Pgp were overexpressed, then direct verification of PHT transport via measurement of PHT concentration in brain using microdialysis. The drug-resistant model rats were randomly divided into three groups, which were treated with PHT, 1%P85 + PHT, or PHT+TQD, respectively. 1%P85 + PHT treatment displayed a lower ratio of the area under the curve (AUC) of the PHT concentration in the brain/plasma even than that of the PHT treatment in model rats (p < 0.05), while PHT+TQD showed the highest ratio of the AUC of all treatments. However, the ratio of the PHT concentration in the liver/plasma was similar in three model groups (p > 0.05). For the ratio of the kidney/plasma, PHT+TQD treatment model group had the highest ratio of the other treatments in model rats. Thus, P85 oppositely decreased PHT concentration in brain in drug-resistant model rats with Pgp overexpressed MTLE while TQD could increase PHT distribution in brain.

Sex differences in the association of plasma cytokines and neurocognition in first-episode major depressive disorder.

BACKGROUND: Peripheral cytokines were found to be involved in the pathophysiology of neurocognition in individuals with major depressive disorder (MDD). However, whether there are sex differences in this association between cytokines and cognition in MDD remains unknown. Our aim is to examine sex differences in the relationship between plasma cytokines and cognition in MDD. METHOD: One hundred and twenty-seven first episode drug naïve patients with MDD and sixty healthy controls (HCs) were recruited for present study. The MATRICS Consensus Cognitive Battery was administered to measure the cognition. Plasma concentrations of nineteen cytokines were measured using high sensitivity multiplex bead-based assays. RESULTS: Both female and male patients with MDD had significant cognitive impairment in verbal learning and visual learning and had higher levels of a range of cytokines than HCs (all p < 0.05). Female patients performed worse in trail making (F = 4.442, p = 0.018) and had higher concentration of interleukin (IL)-4 (F = 7.775, p = 0.006) than males. In female MDD, a significant positive association between category frequency and level of IL-4 was observed (B = 8.040, p = 0.031). However, this association was not present in male MDD or HCs (p > 0.05). LIMITATION: Present study used a cross-sectional design. CONCLUSION: Female MDD patients had worse trail making performance and higher level of IL-4 than males. The elevated IL-4 in female MDD was positively associated with category fluency, suggesting that IL-4 may be involved in the pathophysiology related to specific cognitive domain in female MDD patients.

Ag Nanoparticle-Thiolated Chitosan Composite Coating Reinforced by Ag-S Covalent Bonds with Excellent Electromagnetic Interference Shielding and Joule Heating Performances.

Conductive composite coatings are an important element in flexible electronics research and are widely used in energy transformation, artificial intelligence, and electronic skins. However, the comparatively low electrical conductivity limits their performance in many specific applications, such as electromagnetic interference (EMI) shielding and Joule heating devices. Therefore, the preparation of ultrahigh-electrical conductivity composite coatings with good flexibility and durability remains a great challenge. Herein, we fabricated multifunctional conductive composite coatings based on thiolated chitosan (TCS) and Ag nanoparticles (AgNPs) by an eco-friendly drop-coating method. The three-dimensional conductive network constructed by thermal sintering imparted the coating with an ultrahigh electrical conductivity of up to 67079.4 S/m. Moreover, the coating reinforced by Ag-S covalent bonding exhibits good stability, including heat resistance, chemical resistance, and mechanical stability. In addition, based on the ultrahigh electrical conductivity, the coating exhibits superior EMI shielding effectiveness and Joule heating capability. With 30 wt % of AgNPs in the coating, the EMI shielding effectiveness of the coating reaches 70.2 dB, far exceeding commercial standards. Additionally, the coating can quickly reach a saturation temperature (Ts) of 195.9 °C at a safe drive voltage of 3 V. These excellent performances demonstrate that the robust and flexible highly conductive composite coatings prepared by this method have attractive potential for EMI shielding and thermal management applications as well as in wearable electronics.

Exploring the nonlinear piezoresistive effect of 4H-SiC and developing MEMS pressure sensors for extreme environments.

Microelectromechanical system (MEMS) pressure sensors based on silicon are widely used and offer the benefits of miniaturization and high precision. However, they cannot easily withstand high temperatures exceeding 150 °C because of intrinsic material limits. Herein, we proposed and executed a systematic and full-process study of SiC-based MEMS pressure sensors that operate stably from -50 to 300 °C. First, to explore the nonlinear piezoresistive effect, the temperature coefficient of resistance (TCR) values of 4H-SiC piezoresistors were obtained from -50 to 500 °C. A conductivity variation model based on scattering theory was established to reveal the nonlinear variation mechanism. Then, a piezoresistive pressure sensor based on 4H-SiC was designed and fabricated. The sensor shows good output sensitivity (3.38 mV/V/MPa), accuracy (0.56% FS) and low temperature coefficient of sensitivity (TCS) (-0.067% FS/°C) in the range of -50 to 300 °C. In addition, the survivability of the sensor chip in extreme environments was demonstrated by its anti-corrosion capability in H2SO4 and NaOH solutions and its radiation tolerance under 5 W X-rays. Accordingly, the sensor developed in this work has high potential to measure pressure in high-temperature and extreme environments such as are faced in geothermal energy extraction, deep well drilling, aeroengines and gas turbines.

Endomembrane remodeling and dynamics in Salmonella infection.

Salmonellae are bacteria that cause moderate to severe infections in humans, depending on the strain and the immune status of the infected host. These pathogens have the particularity of residing in the cells of the infected host. They are usually found in a vacuolar compartment that the bacteria shape with the help of effector proteins. Following invasion of a eukaryotic cell, the bacterial vacuole undergoes maturation characterized by changes in localization, composition and morphology. In particular, membrane tubules stretching over the microtubule cytoskeleton are formed from the bacterial vacuole. Although these tubules do not occur in all infected cells, they are functionally important and promote intracellular replication. This review focuses on the role and significance of membrane compartment remodeling observed in infected cells and the bacterial and host cell pathways involved.

An ultrasensitive and stretchable strain sensor based on a microcrack structure for motion monitoring.

Flexible strain sensors are promising candidates for intelligent wearable devices. Among previous studies, although crack-based sensors have attracted a lot of attention due to their ultrahigh sensitivity, large strain usually causes fractures in the conductive paths. Because of the unstable crack structure, the tradeoff between sensitivity and workable strain range is still a challenge. As carbon nanotubes (CNTs) and silver nanowires (AgNWs) can form a strong interface with the thermoplastic substrate and strengthen the conductive network by capillary force during water evaporation, CNTs and AgNWs were deposited on electrospun TPU fiber mats via vacuum-assisted filtration in this work. The prestretching treatment constructed a microcrack structure that endowed the sensor with the combined characteristics of a wide working range (0~171% strain), ultrahigh sensitivity (a gauge factor of 691 within 0~102% strain, ~2 × 104 within 102~135% strain, and >11 × 104 within 135~171% strain), a fast response time (~65 ms), small hysteresis, and superior durability (>2000 cycles). Subsequently, the sensing mechanism of the sensor was studied. Distributed microcrack propagation based on the "island-bridge" structure was explained in detail, and its influence on the strain-sensing behavior of the sensor was analyzed. Finally, the sensor was assembled to monitor various vibration signals and human motions, demonstrating its potential applications in the fields of electronic skin and human health monitoring.

Production of Murine Macrophages from Hoxb8-Immortalized Myeloblasts: Utility and Use in the Context of Salmonella Infection.

Salmonella enterica is a Gram-negative intracellular pathogen that causes a range of life-threatening diseases in humans and animals worldwide. In a systemic infection, the ability of Salmonella to survive/replicate in macrophages, particularly in the liver and spleen, is crucial for virulence. Transformed macrophage cell lines and primary macrophages prepared from mouse bone marrow are commonly used models for the study of Salmonella infection. However, these models raise technical or ethical issues that highlight the need for alternative methods. This chapter describes a technique for immortalizing early hematopoietic progenitor cells derived from wild-type or transgenic mice and using them to produce macrophages. It validates, through a specific example, the interest of this cellular approach for the study of Salmonella infection.

Medial temporal lobe atrophy as a predictor of poor cognitive outcomes in general paresis.

BACKGROUND: The effect of penicillin therapy on clinical outcomes vary among patients with general paresis (GP). We sought to explore biomarkers that might serve as predictors of clinical outcomes in GP and identify patients requiring early intervention. METHODS: Thirty-five inpatients with GP were recruited. Each GP patient underwent comprehensive neuropsychological, neuroimaging and laboratory assessments before receiving penicillin therapy, and returned for follow-up evaluations after 6 months. The visual rating of medial temporal lobe atrophy (MTA) and the Fazekas scale was used to analyze the neuroimaging abnormalities. RESULTS: MTA scores were correlated with the pre-treatment cognitive scores and change in Mini Mental State Examination scores. GP patients with a Clinical Dementia Rating Scale (CDR) ≤1 or MTA scores ≤2 achieved significant improvement in neuropsychological test scores, as compared with patients with CDR >1 or MTA scores >2. Fazekas scale scores correlated with the pre-treatment attention scores. Significant improvements in cognitive test scores were observed in GP patients with normalization of serum rapid plasma regain (RPR) titers, but not those without normalization of RPR titers. CONCLUSIONS: Severe MTA may serve as a predictor of poor cognitive outcome and an indicator of severe cognitive impairment in GP patients. Thus, early interventions for improving cognitive function may be considered for GP patients with severe MTA. White matter hyperintensities may associated with attention impairment. Serum RPR titer may serve as a sensitive indicator of therapeutic effect in GP.

Structural and functional brain abnormalities in drug-naive, first-episode, and chronic patients with schizophrenia: a multimodal MRI study.

BACKGROUND: Structural and functional brain abnormalities in schizophrenia (SZ) have been widely reported. However, a few studies have investigated both structural and functional characteristics in SZ patients at different stages to understand the neuropathology of SZ. METHODS: In this study, we recruited 44 first-episode drug-naive SZ (FESZ) patients, 44 medicated chronic SZ (CSZ) patients, and 56 normal controls (NCs) and acquired their structural and resting-state functional magnetic resonance imaging (MRI). We then made group comparisons on structural and functional characteristics, including regional gray matter volume (GMV), regional homogeneity, amplitude of low-frequency fluctuation, and degree centrality. A linear support vector machine (SVM) combined with a recursive feature elimination (RFE) algorithm was implemented to discriminate three groups. RESULTS: Our results indicated that the regional GMV was significantly decreased in patients compared with that in NCs; CSZ patients have more diffused GMV decreases primarily involved in the frontal and temporal lobes when compared with FESZ patients. Both FESZ and CSZ patients showed significant functional alterations compared with NCs; when compared with FESZ patients, CSZ patients showed significant reductions in functional characteristics in several brain regions associated with auditory, visual processing, and sensorimotor functions. Moreover, a linear SVM combined with a RFE algorithm was implemented to discriminate three groups. The accuracies of the three classifiers were 79.80%, 83.16%, and 81.71%, respectively. The performance of classifiers in this study with multimodal MRI was better than that of previous discriminative analyses of SZ patients with single-modal MRI. CONCLUSION: Our findings bring new insights into the understanding of the neuropathology of SZ and contribute to stage-specific biomarkers in diagnosis and interventions of SZ.

Effect of lamotrigine on seizure development in a rat pentylenetetrazole kindling model.

INTRODUCTION: Epileptogenesis is a process of seizure development. Lamotrigine is a novel antiepileptic drug which is also used for antiepileptogenic research. Kindling models are recommended as potentially useful tools for antiepileptogenic treatment discovery. However, previous studies demonstrated that the antiepileptogenic effect of lamotrigine is controversial in the electrical kindling model. Chemical kindling such as with pentylenetetrazole is another kindling model. The aims of this study were to examine whether lamotrigine could prevent the development of seizure in pentylenetetrazole kindling rats. METHODS: Female rats were kindled by subconvulsive doses of pentylenetetrazole (35 mg/kg) once every other day for 15 times. Thereafter, the kindled rats received different doses of lamotrigine (5, 10 and 20 mg/kg) before pentylenetetrazole to observe the anticonvulsant effect. For the antiepileptogenic experiment, rats were kindled as the same way while pretreated (1 h) with different doses of lamotrigine (5, 10 and 20 mg/kg) before each injection of pentylenetetrazole. After a washout period for 1 week, the rats were administrated with pentylenetetrazole again for 3 times. The seizures were recorded each time. Later it was in vivo electrophysiological experiments followed with histologic analysis. RESULTS: For the anticonvulsant experiment lamotrigine dose-dependently suppressed pentylenetetrazole-induced seizures. Here, 20 mg/kg of lamotrigine pretreatment significantly blocked the seizure development in rats for their seizure stages remained longer in 1-3 during the kindling phase. Mean seizure stages or generalized seizure durations in the 10 and 20 mg/kg lamotrigine pretreated groups were significantly lower or shorter when received 3 times of pentylenetetrazole after the washout period. Electrophysiological study also demonstrated 20 mg/kg of lamotrigine pretreatment obviously eliminated increased population spike amplitude in hippocampus. However, different doses of lamotrigine pretreatment could not alleviate severity of hippocampal neuronal damage. CONCLUSIONS: The results suggest that adequate doses of lamotrigine can prevent seizure development in the pentylenetetrazole kindling rat model.