Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.

Expression profiles of α-synuclein in cortical lesions of patients with FCD IIb and TSC, and FCD rats.

Background: Focal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC. Methods: Surgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques. Result: Our results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats. Conclusion: These results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.

Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells.

BACKGROUND: Liver fibrosis is the common pathological process associated with the occurrence and development of various chronic liver diseases. At present, there is still a lack of effective prevention and treatment methods in clinical practice. Hepatic stellate cell (HSC) plays a key role in liver fibrogenesis. In recent years, the study of liver fibrosis targeting HSC autophagy has become a hot spot in this research field. Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of renin-angiotensin system, and its specific molecular mechanism on autophagy and liver fibrosis needs to be further explored. AIM: To investigate the effect of ACE2 on hepatic fibrosis in mice by regulating HSC autophagy through the Adenosine monophosphate activates protein kinases (AMPK)/mammalian target of rapamycin (mTOR) pathway. METHODS: Overexpression of ACE2 in a mouse liver fibrosis model was induced by injection of liver-specific recombinant adeno-associated virus ACE2 vector (rAAV2/8-ACE2). The degree of liver fibrosis was assessed by histopathological staining and the biomarkers in mouse serum were measured by Luminex multifactor analysis. The number of apoptotic HSCs was assessed by terminal deoxynucleoitidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunofluorescence staining. Transmission electron microscopy was used to identify the changes in the number of HSC autophagosomes. The effect of ACE2 overexpression on autophagy-related proteins was evaluated by multicolor immunofluorescence staining. The expression of autophagy-related indicators and AMPK pathway-related proteins was measured by western blotting. RESULTS: A mouse model of liver fibrosis was successfully established after 8 wk of intraperitoneal injection of carbon tetrachloride (CCl4). rAAV2/8-ACE2 administration reduced collagen deposition and alleviated the degree of liver fibrosis in mice. The serum levels of platelet-derived growth factor, angiopoietin-2, vascular endothelial growth factor and angiotensin II were decreased, while the levels of interleukin (IL)-10 and angiotensin- (1-7) were increased in the rAAV2/8-ACE2 group. In addition, the expression of alpha-smooth muscle actin, fibronectin, and CD31 was down-regulated in the rAAV2/8-ACE2 group. TUNEL and immunofluorescence staining showed that rAAV2/8-ACE2 injection increased HSC apoptosis. Moreover, rAAV2/8-ACE2 injection notably decreased the number of autophagosomes and the expression of autophagy-related proteins (LC3I, LC3II, Beclin-1), and affected the expression of AMPK pathway-related proteins (AMPK, p-AMPK, p-mTOR). CONCLUSION: ACE2 overexpression can inhibit HSC activation and promote cell apoptosis by regulating HSC autophagy through the AMPK/mTOR pathway, thereby alleviating liver fibrosis and hepatic sinusoidal remodeling.

Plexin-mediated neuronal development and neuroinflammatory responses in the nervous system.

Plexins are a large family of single-pass transmembrane proteins that mediate semaphorin signaling in multiple systems. Plexins were originally characterized for their role modulating cytoskeletal activity to regulate axon guidance during nervous system development. Thereafter, different semaphorin-plexin complexes were identified in the nervous system that have diverse functions in neurons, astrocytes, glia, oligodendrocytes, and brain derived-tumor cells, providing unexpected but meaningful insights into the biological activities of this protein family. Here, we review the overall structure and relevant downstream signaling cascades of plexins. We consider the current knowledge regarding the function of semaphorin-plexin cascades in the nervous system, including the most recent data regarding their roles in neuronal development, neuroinflammation, and glioma.

Percutaneous transhepatic intraportal biopsy using gastroscope biopsy forceps for diagnosis of a pancreatic neuroendocrine neoplasm: A case report.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PNENs) are a rare group of neoplasms originating from the islets of the Langerhans. Portal vein tumor thrombosis has been reported in 33% of patients with PNENs. While the histopathological diagnosis of PNENs is usually based on percutaneous biopsy or endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), these approaches may be impeded by gastric varices, poor access windows, or anatomically contiguous critical structures. Obtaining a pathological diagnosis using a gastroscope biopsy forceps via percutaneous transhepatic intravascular pathway is an innovative method that has rarely been reported. CASE SUMMARY: A 72-year-old man was referred to our hospital for abdominal pain and melena. Abdominal contrast-enhanced magnetic resonance imaging revealed a well-enhanced tumor (size: 2.4 cm × 1.2 cm × 1.2 cm) in the pancreatic tail with portal vein invasion. Traditional pathological diagnosis via EUS-FNA was not possible because of diffuse gastric varices. We performed a percutaneous transportal biopsy of the portal vein tumor thrombus using a gastroscope biopsy forceps. Histopathologic examination revealed a pancreatic neuroendocrine neoplasm (G2) with somatostatin receptors 2 (+), allowing systemic treatment. CONCLUSION: Intravascular biopsy using gastroscope biopsy forceps appears to be a safe and effective method for obtaining a histopathological diagnosis. Although well-designed clinic trials are required to obtain more definitive evidence, this procedure may help improve the diagnosis of portal vein thrombosis and related diseases.

Olmesartan Improves Hepatic Sinusoidal Remodeling in Mice with Carbon Tetrachloride-Induced Liver Fibrosis.

Aim: In mice with liver fibrosis produced by carbon tetrachloride (CCl4), the effects of olmesartan on intrahepatic angiogenesis and sinusoidal remodeling will be evaluated. Methods: By injecting CCl4 into the peritoneal cavity, we established a mouse model of liver fibrosis. Using Sirius red and Masson trichrome staining, the extent of liver fibrosis in the animals was determined. Using immunohistochemical labeling and western blotting, the level of α-smooth muscle actin (α-SMA) expression, a characteristic of hepatic stellate cell activation, was assessed. Electron microscopy was used to determine the effect of olmesartan on hepatic sinusoidal capillarization, and immunohistochemical labeling was used to determine the expression levels of endothelial and basement membrane proteins in mouse liver tissues. Platelet-derived growth factor (PDGF), IL-10, vascular endothelial growth factor (VEGF), and angiotensin II levels in mouse serum were measured by Luminex multifactor analysis and ELISA. Olmesartan's effect on the angiotensin II type 1 receptor (AT1R) and the VEGF receptor (VEGFR) was evaluated using western blotting. Results: Olmesartan reduced CCl4-induced inflammatory cell infiltration and collagen deposition to alleviate liver fibrosis. α-SMA expression was decreased, and HSC activation was inhibited in mouse liver tissues by olmesartan treatment. In addition, hepatic sinusoidal capillarization was improved under the action of olmesartan. The expression of collagen IV, fibronectin, CD31, and von Willebrand factor (VWF) in the olmesartan group was also markedly downregulated. In fibrotic mice, olmesartan medication decreased the levels of PDGF, VEGF, and angiotensin II, but it increased the level of IL-10. Moreover, olmesartan reduced the expression of VEGFR-1, VEGFR-2, and AT1R relative to CCl4-induced liver fibrosis. Conclusions: In mice with CCl4-induced fibrosis, olmesartan lowers angiogenesis and improves hepatic sinusoidal remodeling, according to our findings. By acting on the angiotensin II-AT1R-VEGF axis, this is achieved.

Vascular endothelial growth factor-C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia.

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents.

Predictors of Seizure Freedom in Patients Undergoing Surgery for Central Nervous System Infection-Related Epilepsy: A Systematic Review and Meta-Analysis.

Objective: Central nervous system infections (CNSIs), especially viral encephalitis and meningitis, are well-recognized causes of medically refractory epilepsy. Although surgery is an effective and durable intervention against these infections, the seizure control outcomes described in previous surgical series have been variable. Accordingly, it is not clear which variables are most valuable in predicting seizure control following surgery for CNSI. The aim of this meta-analysis was to identify the predictors of favorable surgical outcomes in CNSI-related epilepsy. Methods: The PubMed, EMBASE, Cochrane Library, WANGFANG, VIP, CBM, and CNKI databases were searched for studies according to the inclusion criteria. Prognostic factors, surgical outcomes, and patient characteristics were extracted. Heterogeneity was detected by the I2 and Q statistics. Results: Seventeen studies were included in our meta-analysis. Eight predictors of favorable outcomes (Engel Class I/II) were determined, including abnormal MRI findings, meningitis, temporal location only, regional ictal pattern, unilateral ictal pattern, older age at epilepsy, longer silent period, and longer time from infection, as follows: OR = 3.34 (95% CI 1.44-7.74), OR = 0.31 (95% CI 0.13-0.70), OR = 0.34 (95% CI 0.16-0.74), OR = 5.65 (95% CI 1.75-18.30), and OR = 9.53 (95% CI 2.36-38.48), respectively, and MD = 2.15 (95% CI 0.20-4.11), MD = 2.40 (95% CI 0.09-4.70), and MD = 8.49 (95% CI 1.50-15.48), respectively. A subgroup analysis found the following associations: regional and unilateral ictal patterns in viral encephalitis, a younger age at infection in parasitic encephalopathy, an older age at surgery, a longer time from onset, and a longer time from infection in unexplained meningitis. A sensitivity analysis restricted to studies that included each variable yielded robust results. Little evidence of publication bias was observed. Conclusions: This meta-analysis suggests that abnormal MRI findings, meningitis, temporal location only, regional and unilateral ictal patterns, older age at epilepsy, longer silent period, and longer time from infection are predictive factors in patients with favorable surgical outcomes in CNSI-related epilepsy. In addition, different infective agents influenced the results in regional and unilateral ictal patterns in ictal electroencephalography, as well as the relationship between age at infection and surgery and the time from epilepsy onset and infection.

Sarcopenia as a prognostic predictor of liver cirrhosis: a multicentre study in China.

BACKGROUND: Diagnostic criteria for sarcopenia have not been established in Chinese. This study established criteria based on the L3-skeletal muscle index (L3-SMI) and assessed its value for outcomes predicting in cirrhotic Chinese patients. METHODS: Totally 911 subjects who underwent a CT scan at two centres were enrolled in Cohort 1 (394 male and 417 female subjects, aged 20-80 years). The data of those subjects younger than 60 years (365 male and 296 female subjects) were used to determine the reference intervals of the L3-SMI and its influencing factors. Cohort 2 consisted of 480 patients (286 male and 184 female patients) from three centres, and their data were used to investigate the prevalence of sarcopenia and evaluate the value of L3-SMI for predicting the prognosis and complications of cirrhosis. RESULTS: Age and sex had the greatest effects on the L3-SMI (P < 0.001). The L3-SMI scores were clearly higher in male patients than in female patients (52.94 ± 8.41 vs. 38.91 ± 5.65 cm2 /m2 , P < 0.001) and sharply declined in subjects aged ≥ 60 years. Based on the mean -1.28 × SD among adults aged < 60 years, the L3-SMI cut-off value for sarcopenia was 44.77 cm2 /m2 in male patients and 32.50 cm2 /m2 in female patients. Using these values, 22.5% of the cirrhotic patients (28.7% of male patients and 11.9% of female patients) were diagnosed with sarcopenia. Compared with non-sarcopenia individuals, sarcopenia patients had lower body mass index (21.28 ± 3.01 vs. 24.09 ± 3.39 kg/m2 , P < 0.001) and serum albumin levels (31.54 ± 5.93 vs. 32.93 ± 5.95 g/L, P = 0.032), longer prothrombin times (16.39 ± 3.05 vs. 15.71 ± 3.20 s, P = 0.049), higher total bilirubin concentrations (41.33 ± 57.38 vs. 32.52 ± 31.48 µmol/L, P = 0.039), worse liver function (Child-Pugh score, 8.05 ± 2.11 vs. 7.32 ± 2.05, P = 0.001), higher prevalence of cirrhosis-related complications (81.82% vs. 62.24%, P < 0.001) and mortality (30.68% vs. 11.22%, P < 0.001). Overall survival was significantly lower in the sarcopenia group [risk ratio (RR) = 2.643, 95% confidence interval (CI) 1.646-4.244, P < 0.001], accompanied with an increased cumulative incidence of ascites (RR = 1.827, 95% CI 1.259-2.651, P = 0.002), spontaneous bacterial peritonitis (RR = 3.331, 95% CI 1.404-7.903, P = 0.006), hepatic encephalopathy (RR = 1.962, 95% CI 1.070-3.600, P = 0.029), and upper gastrointestinal varices (RR = 2.138, 95% CI 1.319-3.466, P = 0.002). Subgroup analysis showed sarcopenia shortened the survival of the patients with Model For End-Stage Liver Disease score > 14 (RR = 4.310, 95% CI 2.091-8.882, P < 0.001) or Child-Pugh C (RR = 3.081, 95% CI 1.516-6.260, P = 0.002). CONCLUSIONS: Sarcopenia is a common comorbidity of cirrhosis and can be used to predict cirrhosis-related complications and the prognosis.

Doxazosin Attenuates Liver Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via Activation of the PI3K/Akt/mTOR Signaling Pathway.

PURPOSE: To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism. METHODS: In vivo, a mouse liver fibrosis model was induced by the intraperitoneal injection of carbon tetrachloride (CCl4). Doxazosin was administered at doses of 2.5, 5 and 10 mg/(kg*day) by gavage. After 20 weeks, blood and liver tissues were collected for serological and histological analysis, respectively. Blood analysis, hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry and immunofluorescence staining were used to measure the extent of liver fibrosis in model and control mice. In vitro, the human HSC cell line LX-2 was cultured and treated with different doses of doxazosin for the indicated times. The effects of doxazosin on LX-2 cell proliferation and migration were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The number of autophagosomes in LX-2 cells was observed by transmission electron microscopy (TEM). Infection with green fluorescent protein (GFP)-LC3B adenovirus, GFP-red fluorescent protein (RFP)-LC3B adenovirus and mCherry-EGFP-LC3 adeno-associated virus was performed to examine changes in autophagic flux in vitro and in vivo. Cell apoptosis was measured by flow cytometry in vitro and by TUNEL assays both in vitro and in vivo. Immunoblotting was performed to evaluate the expression levels of proteins related to fibrosis, autophagy, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). RESULTS: Doxazosin inhibited HSC proliferation and migration. HSC activation was attenuated by doxazosin in a concentration-dependent manner in vivo and in vitro. Doxazosin also blocked autophagic flux and induced apoptosis in HSCs. In addition, the PI3K/Akt/mTOR pathway was activated by doxazosin and regulated fibrosis, autophagy and apoptosis in HSCs. CONCLUSION: The study confirmed that doxazosin could inhibit autophagy by activating the PI3K/Akt/mTOR signaling pathway and attenuate liver fibrosis.

Expression and cellular distribution of FGF13 in cortical tubers of the tuberous sclerosis complex.

Cortical tubers in patients with tuberous sclerosis complex (TSC) are highly associated with intractable epilepsy. Recent evidence suggests a close relationship between FGF13 and seizures. To understand the role of FGF13 in the pathogenesis of cortical tubers, we investigated the expression pattern of FGF13 in cortical tubers of TSC compared with normal control cortices (CTX). We found that both the mRNA and protein levels of FGF13 were significantly higher in the cortical tubers from patients with TSC than in the control cortices. The immunohistochemical results showed strong FGF13 immunoreactivity in abnormal cells, including dysplastic neurons (DNs) and giant cells (GCs). Moreover, double-label immunofluorescence analyses confirmed that FGF13 was mainly localized in neurons and nearly absent in glia-like cells. The protein levels of FGF13 in the TSC samples were positively correlated with the frequency of seizures before surgery. Taken together, these results suggest that the overexpression and distribution pattern of FGF13 may be related to intractable epilepsy caused by TSC.

A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. METHODS: In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. RESULTS: A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as "pathogenic" according to the American College of Medical Genetics (ACMG) guidelines. CONCLUSION: WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

An Update on Physical Activity Research among Children in Hong Kong: A Scoping Review.

Similar to their Western counterparts, children in Hong Kong generally fail to reach the recommended levels of physical activity (PA). As an ultra-dense metropolis, Hong Kong is different from most Western cities. It is therefore important to update and appraise previous PA research in order to inform future PA promotion for Hong Kong children. Using a scoping review, the current study aimed to evaluate PA research among preschool and school-aged children in Hong Kong aged 3-12 years old who are at a critical development stage. Literature was searched from four English databases: Medline via EBSCOhost, SPORTDiscus, ERIC and PsycINFO via ProQuest; and three Chinese databases: CNKI, CQVIP and WAN-FANG. PA research among Hong Kong children published from 1 January 1997 to the searching date, 31 March 2020 was included. A total of 63 studies were identified, with the majority of studies focused on school-aged children as compared to preschoolers, adopted a cross-sectional design, using self-reported PA measures, and with small to medium sample sizes. We classified eligible studies into five main categories: (a) Health benefits of PA (k = 12). Consistent evidence on the health benefits of skeletal and cardiovascular capacity, quality of life, cognitive function, and sleep quality was revealed. However, inconsistent evidence was found on the benefits of weight-related indicators and academic performance. (b) Patterns of PA (k = 12). There is a general pattern of low levels of PA among Hong Kong children, in particular girls and children with special educational needs. (c) Measures of PA and related constructs (k = 11). The Chinese versions of self-reported measures of PA, PA-related social environment, and PA-related psychological constructs showed acceptable reliabilities and validities. (d) Correlates of PA (k = 18). The correlates of PA include physical environment, social environment, physical factors, psychological factors, and multiple correlates, which is in line with the social-ecological model. (e) Interventions for promoting PA (k = 10). PA interventions among Hong Kong children were conducted for healthy children, children with special educational needs, and children with cancer. Overall, there is a growing volume of PA research among children in Hong Kong in the recent decade. Yet, there is a lack of high-quality research for measuring, understanding, and promoting PA among Hong Kong children. It is highly recommended that future PA research among children should pay more attention on the preschoolers, adopting robust research design (e.g., randomized controlled trials), recruiting large and representative sample, and collecting device-assessed data.

Subtemporal selective amygdalohippocampectomy in patients with mesial temporal lobe epilepsy: Systematic review of seizure and neuropsychological outcomes.

In addition to standard anterior temporal lobectomy (ATL), subtemporal selective amygdalohippocampectomy (sSAH) is also a common technique for the treatment of medically intractable mesial temporal lobe epilepsy (MTLE). We conducted a systematic literature review to determine the seizure and neuropsychological outcomes in patients with MTLE who underwent sSAH. We searched PubMed and Embase using Medical Subject Headings and keywords related to sSAH, seizure outcome, and neuropsychological outcome. Titles, abstracts, and full-texts were screened in light of inclusion and exclusion criteria that were established a priori. Potential papers were reviewed by 3 reviewers, who reached a consensus on the final papers to be included. Literature review identified 208 abstracts from which a total of 29 full-text articles were reviewed. Six studies containing data from 4 countries (3 continents) met our inclusion criteria. The seizure-free rates at 12 months after sSAH ranged from 59.1% to 61.5% in 4 studies. Four studies showed that seizure-free rates ranged from 56% to 82.6% at 24 months after surgery. Six studies evaluated the neuropsychological changes of patients with MTLE after sSAH, including intelligence, verbal memory, nonverbal memory, language function, and so on. In terms of neuropsychological outcomes, there are some differences among the 6 studies. Taken together, sSAH can provide a considerable rate of seizure freedom. In addition, the neuropsychological outcomes of patients who underwent sSAH were slightly different among 6 studies. Therefore, large-scale case series or randomized controlled trials (RCTs) are needed to clarify the advantages and disadvantages of the sSAH.

Expression of TRPC3 in cortical lesions from patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the main causes of medically intractable epilepsy. Some studies have reported that transient receptor potential canonical channel 3 (TRPC3) may play an important role in the occurrence of seizures. In this study, we investigated the expression patterns of TRPC3 in different types of FCD. Forty-five FCD specimens and 12 control samples from autopsies were used in our study. Western blotting, immunohistochemistry, and immunofluorescence staining were employed to detect protein expression and distribution. The amount of TRPC3 protein was markedly elevated in the FCD group. The immunohistochemistry results revealed that TRPC3 staining was strong in the malformed cells and microcolumns. Most of the TRPC3-positive cells were colabeled with glutamatergic and GABAergic markers. The overexpression and altered cellular distribution of TRPC3 in the FCD samples suggest that TRPC3 may be related to epileptogenesis in FCD.

Differential Expression Hallmarks of Interneurons in Different Types of Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is the main cause of medically intractable pediatric epilepsy. Previous studies have suggested that alteration of cortical interneurons and abnormal cytoarchitecture have been linked to initiation and development for seizure. However, whether each individual subpopulation of cortical interneurons is linked to distinct FCD subtypes remains largely unknown. Here, we retrospectively analyzed both control samples and epileptic specimens pathologically diagnosed with FCD types Ia, IIa, or IIb. We quantified three major interneuron (IN) subpopulations, including parvalbumin (PV)-, somatostatin (Sst)-, and vasoactive intestinal peptide (Vip)-positive INs across all the subgroups. Additionally, we calculated the ratio of the subpopulations of INs to the major INs (mINs) by defining the total number of the PV-, Sst-, and Vip-INs as mINs. Compared with the control, the density of the PV-INs in FCD type IIb was significantly lower, and the ratio of PV/mINs was lower in the superficial part of the cortex of the FCD type Ia and IIb groups. Interestingly, we found a significant increase in the ratio of Vip/mINs only in FCD type IIb. Overall, these results suggest that in addition to a reduction in PV-INs, the increase in Vip/mINs may be related to the initiation of epilepsy in FCD type IIb. Furthermore, the increase in Vip/mINs in FCD type IIb may, from the IN development perspective, indicate that FCD type IIb forms during earlier stages of pregnancy than FCD type Ia.

Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

A meta-analysis of the health action process approach.

OBJECTIVE: The health action process approach (HAPA) is a social-cognitive model specifying motivational and volitional determinants of health behavior. A meta-analysis of studies applying the HAPA in health behavior contexts was conducted to estimate the size and variability of correlations among model constructs, test model predictions, and test effects of past behavior and moderators (behavior type, sample type, measurement lag, study quality) on model relations. METHOD: A literature search identified 95 studies meeting inclusion criteria with 108 independent samples. Averaged corrected correlations among HAPA constructs and multivariate tests of model predictions were computed using conventional meta-analysis and meta-analytic structural equation modeling, with separate models estimated in each moderator group. RESULTS: Action and maintenance self-efficacy and outcome expectancies had small-to-medium sized effects on health behavior, with effects of outcome expectancies and action self-efficacy mediated by intentions, and action and coping planning. Effects of risk perceptions and recovery self-efficacy were small by comparison. Past behavior attenuated the intention-behavior relationship. Few variations in model effects were observed across moderator groups. Effects of action self-efficacy on intentions and behavior were larger in studies on physical activity compared with studies on dietary behaviors, whereas effects of volitional self-efficacy on behavior were larger in studies on dietary behaviors. CONCLUSIONS: Findings highlight the importance of self-efficacy in predicting health behavior in motivational and volitional action phases. The analysis is expected to catalyze future research including experimental studies targeting change in individual HAPA constructs, and longitudinal research to examine change and reciprocal effects among constructs in the model. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Predictors of seizure recurrence in patients with surgery for focal cortical dysplasia: pairwise and network meta-analysis and trial sequential analysis.

OBJECT: The aim of this study was to determine the predictors of seizure recurrence in surgery for focal cortical dysplasia (FCD) by conducting a meta-analysis. METHODS: Publications that met the pre-stated inclusion criteria were selected from PubMed and CNKI databases. Two authors extracted data independently about prognostic factors, surgical outcome, and clinical characteristics of participants. A fixed-effects model was used to calculate the summary of odds ratio (OR) with 95% confidence interval (CI). RESULTS: Forty-eight studies were included in our meta-analysis. Three predictors of seizure recurrence (Engel class III/IV)-histological FCD type I, incomplete resection, and extratemporal location were determined; combined OR with 95% CI were 1.94 (95%CI 1.53-2.46), 12.06 (95%CI 7.32-19.88), and 1.91 (95%CI 1.06-3.44), respectively. Trial sequential analysis revealed that the outcomes had a sufficient sample size to reach firm conclusions. Furthermore, seizure location was not substantially modified by geographic region, while histological FCD type I and incomplete resection showed a significant association with seizure recurrence in different continents except Asia for incomplete resection. Sensitivity analyses restricted to studies for each variable yielded robust results. Little evidence of publication bias was observed. Meanwhile, the difference in the standard for outcome failed to influence the results for prognosis. Network meta-analysis including 13 trials comparing subtypes of FCD found the FCD IIb had the lowest seizure recurrence rate. CONCLUSIONS: This meta-analysis suggests that histological FCD type I, incomplete resection, and extratemporal location are recurrence factors in patients with epilepsy surgery for FCD. In addition, FCD IIb is associated with the highest rates of postoperative seizure control among the subtypes of FCD, type I and type II.

Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells in vivo and in vitro by activating AMP-activated protein kinase.

AIM: To investigate the effect of metformin on activated hepatic stellate cells (HSCs) and the possible signaling pathways involved. METHODS: A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride (CCl4) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation (CCK8 assay), motility (scratch test and Transwell assay), contraction (collagen gel contraction assay), extracellular matrix (ECM) secretion (Western blot), and angiogenesis (ELISA and tube formation assay) was investigated. We also analyzed the possible signaling pathways involved by Western blot analysis. RESULTS: Mice developed marked liver fibrosis after intraperitoneal injection with CCl4 for 6 wk. Metformin decreased the activation of HSCs, reduced the deposition of ECM, and inhibited angiogenesis in CCl4-treated mice. Platelet-derived growth factor (PDGF) promoted the fibrogenic response of HSCs in vitro, while metformin inhibited the activation, proliferation, migration, and contraction of HSCs, and reduced the secretion of ECM. Metformin decreased the expression of vascular endothelial growth factor (VEGF) in HSCs through inhibition of hypoxia inducible factor (HIF)-1α in both PDGF-BB treatment and hypoxic conditions, and it down-regulated VEGF secretion by HSCs and inhibited HSC-based angiogenesis in hypoxic conditions in vitro. The inhibitory effects of metformin on activated HSCs were mediated by inhibiting the Akt/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) pathways via the activation of adenosine monophosphate-activated protein kinase (AMPK). CONCLUSION: Metformin attenuates the fibrogenic response of HSCs in vivo and in vitro, and may therefore be useful for the treatment of chronic liver diseases.