Microglia sense and suppress epileptic neuronal hyperexcitability.

Microglia are the resident immune cells of the central nervous system, undertaking surveillance role and reacting to brain homeostasis and neurological diseases. Recent studies indicate that microglia modulate epilepsy-induced neuronal activities, however, the mechanisms underlying microglia-neuron communication in epilepsy are still unclear. Here we report that epileptic neuronal hyperexcitability activates microglia and drives microglial ATP/ADP hydrolyzing ectoenzyme CD39 (encoded by Entpd1) expression via recruiting the cAMP responsive element binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) from cytoplasm to the nucleus and binding to CREB. Activated microglia in turn suppress epileptic neuronal hyperexcitability in a CD39 dependent manner. Disrupting microglial CREB/CRTC1 signaling, however, decreases CD39 expression and diminishes the inhibitory effect of microglia on epileptic neuronal hyperexcitability. Overall, our findings reveal CD39-dependent control of epileptic neuronal hyperexcitability by microglia is through an excitation-transcription coupling mechanism.

A method of motion estimation of segmental ventricular wall with tracking of ultrasonic echocardiogram.

BACKGROUND: Ultrasonic echocardiography is commonly used for monitoring myocardial dysfunction. However, it has limitations such as poor quality of echocardiography images and subjective judgment of doctors. METHODS: In this paper, a calculation model based on optical flow tracking of echocardiogram is proposed for the quantitative estimation motion of the segmental wall. To improve the accuracy of optical flow estimation, a method based on confidence-optimized multiresolution(COM) optical flow model is proposed to reduce the estimation errors caused by the large amplitude of myocardial motion and the presence of "shadows" and other image quality problems. In addition, motion vector decomposition and dynamic tracking of the ventricular region of interest are used to extract information regarding the myocardial segmental motion. The proposed method was validated using simulation images and 50 clinical cases (25 patients and 25 healthy volunteers) for myocardial motion analysis. RESULTS: The results demonstrated that the proposed method could track the motion information of myocardial segments well and reduce the estimation errors of optical flow caused due to the use of low-quality echocardiogram images. CONCLUSIONS: The proposed method improves the accuracy of motion estimation for the cardiac ventricular wall.

Valproic acid suppresses cuprizone-induced hippocampal demyelination and anxiety-like behavior by promoting cholesterol biosynthesis.

Myelin consists of several layers of tightly compacted membranes that form an insulating sheath around axons. These membranes are highly enriched in cholesterol, which is essential for the myelination process. Proper myelination is crucial for various neurophysiological functions while demyelination may cause CNS disease, such as multiple sclerosis (MS). Recent studies demonstrated that demyelination occurs not only in the white matter but also in the grey matter, such as the hippocampus, which may cause cognitive deficits and mental disorders. Valproic acid (VPA) is an anticonvulsant agent prescribed for the treatment of epilepsy and seizure. Recently, VPA was reported to alter cholesterol metabolism in neural cells, suggesting that it may play an important role in myelin biogenesis. Here in this study, we found significant demyelination in the hippocampus of the mouse cuprizone model, which is accompanied by reduced cholesterol biosynthesis and increased anxiety-like behavior. VPA treatment, however, suppressed cuprizone-induced hippocampal demyelination and anxiety-like behavior by promoting cholesterol biosynthesis. These data identify an important role of VPA in the hippocampal demyelination process and the hippocampal demyelination-related behavior deficit via regulation of cholesterol biosynthesis, which provides new insights into the mechanisms of VPA as a protective agent against CNS demyelination.

Automatic Lumen Border Detection in IVUS Images Using Deep Learning Model and Handcrafted Features.

In the clinical analysis of Intravascular ultrasound (IVUS) images, the lumen size is an important indicator of coronary atherosclerosis, and is also the premise of coronary artery disease diagnosis and interventional treatment. In this study, a fully automatic method based on deep learning model and handcrafted features is presented for the detection of the lumen borders in IVUS images. First, 193 handcrafted features are extracted from the IVUS images. Then hybrid feature vectors are constructed by combining handcrafted features with 64 high-level features extracted from U-Net. In order to obtain the feature subsets with larger contribution, we employ the extended binary cuckoo search for feature selection. Finally, the selected 36-dimensional hybrid feature subset is used to classify the test images using dictionary learning based on kernel sparse coding. The proposed algorithm is tested on the publicly available dataset and evaluated using three indicators. Through ablation experiments, mean value of the experimental results (Jaccard: 0.88, Hausdorff distance: 0.36, Percentage of the area difference: 0.06) prove to be effective improving lumen border detection. Furthermore, compared with the recent methods used on the same dataset, the proposed method shows good performance and high accuracy.

Metalloprotease Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation.

BACKGROUND: Mice with pilocarpine-induced temporal lobe epilepsy (TLE) are characterized by intense hippocampal neuroinflammation, a prominent pathological hallmark of TLE that is known to contribute to neuronal hyperexcitability. Recent studies indicate that Adam10, a member of a disintegrin and metalloproteinase domain-containing protein (Adam) family, has been involved in the neuroinflammation response. However, it remains unclear whether and how Adam10 modulates neuroinflammation responses in the context of an epileptic brain or whether Adam10 affects epileptogenesis via the neuroinflammation pathway. METHODS: Adult male C57BL/6J mice were subjected to intraperitoneal injection of pilocarpine to induce TLE. Adeno-associated viral (AAV) vectors carrying Adam10 (AAV-Adam10) or lentiviral vectors carrying short hairpin RNA, which is specific to the mouse Adam10 mRNA (shRNA-Adam10), were bilaterally injected into the hippocampus to induce overexpression or knockdown of Adam10, respectively. The specific anti-inflammatory agent minocycline was administered following status epilepticus (SE) to block hippocampal neuroinflammation. Continuous video EEG recording was performed to analyze epileptic behavior. Western blot, immunofluorescence staining, and ELISA were performed to determine Adam10 expression as well as hippocampal neuroinflammation. RESULTS: In this study, we demonstrate that overexpression of Adam10 in the hippocampus suppresses neuroinflammation and reduces seizure activity in TLE mice, whereas knockdown of Adam10 exacerbates hippocampal neuroinflammation and increases seizure activity. Furthermore, increased seizure activity in Adam10 knockdown TLE mice is dependent on hippocampal neuroinflammation. CONCLUSION: These results suggest that Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation. Our findings provide new insights into the Adam10 regulation of development of epilepsy via the neuroinflammation pathway and identify a potential therapeutic target for epilepsy.

A method of localization and segmentation of intervertebral discs in spine MRI based on Gabor filter bank.

BACKGROUND: Spine magnetic resonance image (MRI) plays a very important role in the diagnosis of various spinal diseases, such as disc degeneration, scoliosis, and osteoporosis. Accurate localization and segmentation of the intervertebral disc (IVD) in spine MRI can help accelerate the diagnosis time and assist in the treatment by providing quantitative parameters. In this paper, a method based on Gabor filter bank is proposed for IVD localization and segmentation. METHODS: First, the structural features of IVDs are extracted using a Gabor filter bank. Second, the Gabor features of spine are calculated and spinal curves are detected. Third, the Gabor feature images (GFI) of IVDs are calculated and adjusted according to the spinal curves. Fourth, the IVDs are localized by clustering analysis with GFI. Finally, an optimum grayscale-based algorithm with self-adaptive threshold, combined with the localization results and Gabor features of the spine, is performed for IVDs segmentation. RESULTS: The proposed method is verified by an MRI dataset consisting of 278 IVDs from 37 patients. The accuracy of localization is 98.23 % and the dice similarity index for segmentation evaluation is 0.9237. CONCLUSIONS: The proposed Gabor filter based method is effective for IVD localization and segmentation. It would be useful in computer-aided diagnosis of IVD diseases and computer-assisted spine surgery.

[Development of Terahertz Imaging Technology in the Assessment of Burn Injuries].

Terahertz waves have unique properties and advantages, which makes it gain increasing attention and applications in the biomedical field. Burns is a common clinical trauma. Since the water-sensitive and non-destructive characteristics of terahertz, terahertz imaging techniques can be used to detect burns. So far, terahertz imaging technology in the assessment of burn injuries has been developed from ex vivo to in vivo, and high-resolution images can be obtained through the gauzes and plasters. In this paper, we mainly introduces the application of terahertz imaging technology and development in the assessment of burn injuries.

Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression.

BACKGROUND: Although it has been documented that methamphetamine induces astrocyte activation, the mechanism(s) underlying this effect remain poorly understood. We thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1R) in this process. METHODS: The expression of σ-1R and glial fibrillary acidic protein (GFAP) was examined by reverse transcription PCR (RT-PCR), real-time PCR, Western blot, and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by Western blot analysis. Immunoprecipitation was used to determine the interaction between σ-1R and p-Src. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of cAMP-response element-binding protein (CREB) with the promoter of σ-1R. The role of σ-1R in astrocyte activation was further validated in σ-1R knockout (KO) mice by Western blot combined with immunofluorescent staining. RESULTS: Exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1R via the activation of Src, ERK mitogen-activated protein kinase, and downstream CREB pathways. Subsequently, CREB translocated into nucleus and interacted with the promoter of σ-1R resulting in increased expression of σ-1R with a concomitant increase in expression of GFAP. This effect was inhibited in cells treated with the σ-1R antagonist-BD1047, thereby implicating the role of σ-1R in the activation of astrocytes. In vivo relevance of these findings was further corroborated in σ-1R KO mice that were administered methamphetamine. In the methamphetamine administered mice, there was a failure of the drug to induce activation of astrocytes, an effect that was evident in wild-type (WT) mice exposed to methamphetamine. CONCLUSIONS: The study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1R through a positive-feedback mechanism. Understanding the regulation of σ-1R expression could provide insights into the development of potential therapeutic strategies for astrocyte activation induced by methamphetamine.

Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy.

OBJECTIVE: Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model. METHODS: Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREB(IR) ) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video-electroencephalography (EEG) to assess the effect of CREB suppression on seizures. RESULTS: Our findings indicate that activation of CREB(IR) shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREB(IR) induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREB(IR) , supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation. SIGNIFICANCE: Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy.

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.

[Method for Extracting Vascular Perfusion Region Based on Ultrasound Contrast Agent].

Vascular perfusion distribution in fibroids contrast-enhanced ultrasound images provides useful pathological and physiological information, because the extraction of the vascular perfusion area can be helpful to quantitative evaluation of uterine fibroids blood supply. The pixel gray scale in vascular perfusion area of fibroids contrast-enhanced ultrasound image sequences is different from that in other regions, and, based on this, we proposed a method of extracting vascular perfusion area of fibroids. Firstly, we denoised the image sequence, and then we used Brox optical flow method to estimate motion of two adjacent frames, based on the results of the displacement field for motion correction. Finally, we extracted vascular perfusion region from the surrounding background based on the differences in gray scale for the magnitude of the rich blood supply area and lack of blood supply area in ultrasound images sequence. The experimental results showed that the algorithm could accurately extract the vascular perfusion area, reach the precision of identification of clinical perfusion area, and only small amount of calculation was needed and the process was fairly simple.

The Safety and Efficacy of Abaloparatide on Postmenopausal Osteoporosis: A Systematic Review and Meta-analysis.

PURPOSE: The aging of the population increases the incidence of postmenopausal osteoporosis, which threatens the health of elderly women. Abaloparatide is a synthetic peptide analogue of the human parathyroid hormone-related protein that has recently been approved for the treatment of postmenopausal osteoporosis. Its efficacy and safety have not been systematically evaluated. Therefore, studies on the efficacy and safety of abaloparatide could be of assistance in the clinical medication of postmenopausal osteoporosis. The aim of this study was to evaluate the clinical efficacy and safety of abaloparatide in postmenopausal osteoporosis. METHODS: PubMed, Cochrane Library, EMBASE, and Web of Science databases were electronically searched from inception to July 6, 2023, for relevant randomized controlled trials. Two review authors independently conducted the study screening, quality assessment (based on the Risk of Bias Assessment Tool recommended in the Cochrane handbook), and data extraction. Outcome measures included bone mineral density (BMD), bone turnover and metabolic markers, incidence of fractures, and adverse events. Data analyses were processed by using Stata SE15. FINDINGS: Ultimately, 8 randomized controlled trials, involving a total of 3705 postmenopausal women, were included. Meta-analysis showed that abaloparatide administration significantly increased the BMD of the lumbar vertebrae (standardized mean difference [SMD], 1.28 [95% CI, 0.81-1.76); I2 = 78.5%]), femoral neck (SMD, 0.70 [95% CI, 0.17-1.23; I2 = 75.7%]), and hip bone (SMD, 0.86 [95% CI, 0.53-1.20; I2 = 60.4%]) in postmenopausal women compared with the control group. Type I procollagen N-terminal propeptide, a bone formation marker, was also elevated after abaloparatide administration. The incidence of vertebral fracture was lower in the abaloparatide group than in the control group (risk ratio, 0.13; 95% CI, 0.06-0.26; I2 = 0%). There was no significant difference in the incidence of adverse events between the abaloparatide and the placebo groups (risk ratio, 1.03; 95% CI, 0.99-1.06; I2 = 0%). IMPLICATIONS: Abaloparatide has a protective effect on women with postmenopausal osteoporosis. It could reduce their risk for vertebral fracture; increase their BMD of the lumbar spine, femoral neck, and hip; and alleviate symptoms and complications of postmenopausal osteoporosis with considerable safety. Limitations of this study include not searching the gray literature and not performing a subgroup analysis. PROSPERO Registration No.: CRD42022370944.

Epilepsy and demyelination: Towards a bidirectional relationship.

Demyelination stands out as a prominent feature in individuals with specific types of epilepsy. Concurrently, individuals with demyelinating diseases, such as multiple sclerosis (MS) are at a greater risk of developing epilepsy compared to non-MS individuals. These bidirectional connections raise the question of whether both pathological conditions share common pathogenic mechanisms. This review focuses on the reciprocal relationship between epilepsy and demyelination diseases. We commence with an overview of the neurological basis of epilepsy and demyelination diseases, followed by an exploration of how our comprehension of these two disorders has evolved in tandem. Additionally, we discuss the potential pathogenic mechanisms contributing to the interactive relationship between these two diseases. A more nuanced understanding of the interplay between epilepsy and demyelination diseases has the potential to unveiling the molecular intricacies of their pathological relationships, paving the way for innovative directions in future clinical management and treatment strategies for these diseases.

Diagnostic values of different musculoskeletal ultrasound signs, serum uric acid, and their combined detection for gouty arthritis.

Objectives: The study aimed to investigate the diagnostic values of different musculoskeletal ultrasound (MSUS) signs, serum uric acid (SUA), and their combined detection for gouty arthritis (GA). Patients and methods: In this retrospective study, 70 patients (62 males, 8 females; mean age: 46.1±14.1 years; range, 25 to 86 years) diagnosed with GA (the GA group) between August 2022 and March 2023 and 70 patients (54 females, 16 males; mean age: 49.0±14.1 years; range, 21 to 75 years) diagnosed with rheumatoid arthritis and osteoarthritis during the same period (the non-GA group) were included. The positive rate of MSUS signs and SUA in both groups was recorded to compare the differences. The correlations of MSUS signs and SUA with GA were analyzed using Spearman's rank correlation analysis. The diagnostic values of different MSUS signs, SUA, and their combined detection for GA were analyzed using a receiver operating characteristic, the area under the curve (AUC), sensitivity, specificity, and the Youden index. Results: The positive rate of the double contour (DC) sign (chi-squared [χ2 ]=102.935, p<0.001), hyperechoic spots (χ2=56.395, p<0.001), bone erosions (χ2 =10.080, p<0.001), and SUA (χ2 =41.117, p <0.001) were higher in the GA group than in the non-GA group. The positive rate of the DC sign (rs=0.829, p=0.001), hyperechoic spots (rs=0.631, p<0.001), bone erosion (rs=0.268, p=0.001), and SUA (rs=0.542, p<0.001) were positively correlated with GA. Among the single-indicator measures, the DC sign exhibited the highest diagnostic value (AUC=0.907, sensitivity=81.4%, specificity=100%, p<0.001). Among the combined-indicator measures, the DC sign combined with SUA exhibited the highest diagnostic value (AUC=0.929, sensitivity=91.4%, specificity=94.3%, p<0.001), higher than DC sign detection alone. Conclusion: The DC sign combined with SUA yielded a high diagnostic value and can thus provide a reliable basis for effectively and efficiently diagnosing GA.

Antibiotic resistance of Helicobacter pylori isolated in the Southeast Coastal Region of China.

BACKGROUND: The resistance of Helicobacter pylori (H. pylori) to antibiotics is increasing worldwide, lowering its efficacy in current eradication therapies. This study evaluated H. pylori resistance to antibiotics in the southeast coastal region of China and suggests appropriate alternatives. MATERIALS AND METHODS: Seventeen thousand seven hundred and thirty one H. pylori strains were collected from eight areas of two provinces in coastal southeast China from 2010 to 2012. The resistance of these strains to six antibiotics was tested using the agar dilution method. RESULTS: The resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, gentamicin and furazolidone were 21.5, 95.4, 20.6, 0.1, 0.1 and 0.1%, respectively. Double, triple and quadruple antibacterial resistant percentages were 25.5, 7.5 and 0.1%, respectively. A positive association between the resistance to levofloxacin and to clarithromycin was found, but there was a negative correlation in the resistances to levofloxacin and to metronidazole. CONCLUSIONS: The prevalence of H. pylori resistance to clarithromycin, metronidazole, levofloxacin and multiple antibiotics in coastal southeast China is high. Choice of therapy should be individualized based on a susceptibility test in this region of the country.

Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice.

Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1ß and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

CRISPR/Cas12a-assisted visible fluorescence for pseudo dual nucleic acid detection based on an integrated chip.

BACKGROUND: A false negative result is one of the major problems in nucleic acid detection. Failure to screen positive samples for pathogens or viruses poses a risk to public health. This situation will lead to more serious consequences for infectious pathogens or viruses. At present, the common solution is to introduce exogenous or endogenous internal control. Because it amplifies and is detected separately from the target gene, it cannot avoid false negative results caused by DNA extraction failure or reagent inactivation. There is an urgent need for a simple and reliable method to solve the false negative problem of nucleic acid detection. RESULTS: We established a chip and an on-chip detection method for the integrated detection of target genes and internal control using the CRISPR system in LAMP amplification products. The chip is processed from a low-cost PMMA board and has three chambers and some channels. After adding the sample, the chip only needs to be rotated twice, and the sample enters three chambers successively depending on its gravity for dual LAMP reaction and CRISPR detections. With a portable LED blue light exciter, visual fluorescence detection is realized. Whether the detection result is positive, negative, or invalid can be determined according to the fluorescence in the CRISPR chamber for target gene and CRISPR chamber for internal control. In this study, the detection of Salmonella enterica in Fenneropenaeus chinensis was taken as an example. The results showed good specificity and sensitivity. It could detect as low as 15 copies/µL of Salmonella enterica. SIGNIFICANCE: The on-chip detection solves the problem of aerosol contamination and false negative results. It has the advantages of high sensitivity, high specificity, high accuracy, and low cost. This research will advance the development of nucleic acid detection technology, providing a new and reliable strategy for POCT detection of pathogenic bacteria and viruses.

Clinical outcomes and risk factors of non-curative endoscopic submucosal dissection for early gastric cancer: a retrospective multicenter study in Zhejiang, China.

Background: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) does not always lead to curative resection. Risk factors of lymph node metastasis (LNM)/local cancer residue after non-curative ESD for EGC have not been fully elucidated. We therefore aimed to clarify them and evaluate whether the "eCura system" is reliable for the risk stratification of LNM after non-curative ESD. Methods: We conducted a multicenter retrospective study at seven institutions in Zhejiang, China, on 128 patients who underwent non-curative ESD for EGC. We divided the patients into two groups according to their therapeutic regimen after non-curative ESD. We analyzed the risk factors for LNM, local cancer residue, cancer recurrence, and cancer-specific mortality. Furthermore, we compared the outcomes in each risk category after applying the "eCura system". Results: Among 68 patients undergoing additional surgery, LNM was found in three (4.41%) patients, while local cancer residue was found in eight (11.76%) patients. Multivariate analysis showed that upper third location and deep submucosal invasion were independent risk factors of LNM and local cancer residue. Among 60 patients who underwent simple follow-up, local cancer recurrence was found in four (6.67%) patients and cancer-specific mortality was found in one (1.67%) patient. There were no independent risk factors of cancer recurrence and cancer-specific mortality in our study. During the follow-up period, 5-year overall survival (OS) and disease-free survival (DFS) were 93.8% and 88.9%, respectively. Additionally, LNM and cancer recurrence were significantly associated with the eCura scoring system (p = 0.044 and p = 0.017, respectively), while local cancer residue and cancer-specific mortality were not (p = 0.478 and p = 0.131, respectively). Conclusion: Clinicians should be aware of the risk factors for the prognosis of patients with non-curative ESD to determine subsequent treatment. Through the application of the "eCura system", additional surgery should be performed in patients with intermediate/high risk of LNM.

Decreased CREB levels suppress epilepsy.

Epilepsy is a common neurologic disorder yet no treatments aimed at preventing epilepsy have been developed. Several molecules including genes containing cAMP response elements (CREs) in their promoters have been identified that contribute to the development of epilepsy, a process called epileptogenesis. When phosphorylated cAMP response element binding protein (CREB) increases transcription from CRE regulated promoters. CREB phosphorylation is increased in rodent epilepsy models, and in the seizure onset region of humans with medically intractable epilepsy (Rakhade et al., 2005; Lee et al., 2007; Lund et al., 2008). Here we show that mice with decreased CREB levels (CREB(α∆) mutants) have a ~50% reduction in spontaneous seizures following pilocarpine induced status epilepticus (SE) and require more stimulation to electrically kindle. Following SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the CREB(α∆) mutants compared to wild-type mice, which may be contributing to differences in the severity of epilepsy. In contrast, we found no difference in KCC2 mRNA levels between the CREB(α∆) and wild-type mice after SE. The mechanism by which BDNF and ICER mRNAs increase specifically in the CREB(α∆) compared to wild-type mice following SE is not known. We did, however, find an increase in specific cAMP response element modulator (CREM) mRNA transcripts in the CREB(α∆) mutants that might be responsible for the differential regulation of BDNF and ICER after SE. Altering CREB activity following a neurologic insult provides a therapeutic strategy for modifying epileptogenesis.

Combined effects of levetiracetam and sodium valproate on paediatric patients with epilepsy: a systematic review and meta-analysis.

OBJECTIVE: To estimate the safety and efficacy of sodium valproate combined with levetiracetam in paediatric patients with epilepsy based on randomized controlled trials (RCTs). METHODS: The Cochrane Library, PubMed, Web of Science, Chinese Journal Full-Text Database (CNKI), WANGFANG DATA and Sino Med were searched between January 1946 and May 2021. The included literature was randomized controlled clinical trials focusing on sodium valproate combined with levetiracetam in paediatric patients with epilepsy. Two evaluators separately collected the data based on the retrieval strategy, filtered the literature in accordance with the inclusion and exclusion criteria, and summarized the literature that satisfied the criteria. The statistical programme used for the meta-analysis was Stata V14.0. RESULTS: Of 577 original titles screened, data were extracted from 7 studies (617 participants). Compared with sodium valproate alone or sodium valproate combined with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy significantly improved the overall therapeutic effect (RR=1.24, 95% CI: 1.16 to 1.33, p=0.927). The observation group significantly reduced the occurrence of adverse drug reactions (ADRs) (RR=0.54, 95% CI: 0.37 to 0.79, p=0.602). Egger's regression test of the overall therapeutic effect showed no potential publication bias (p=0.122). CONCLUSION: Based on this meta-analysis, compared with sodium valproate alone or sodium valproate with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy can significantly improve the overall therapeutic effect and simultaneously reduce the occurrence of ADR. Therefore, we recommend sodium valproate combined with levetiracetam for the therapy of paediatric patients with epilepsy.