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Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota–gut–brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota.

Objective Focal cortical dysplasia (FCD) appears to be strongly associated with intractable epilepsy. Although patients with FCD are candidates for epilepsy surgery, gray matter structural abnormalities can extend beyond the primary lesion, which makes surgery less effective. The objective of this study was to evaluate functional connectivity patterns in epilepsy associated with FCD to explore the underlying pathological mechanism of this disorder. Methods A total of 34 patients (14 men) with FCD and epilepsy [mean age ± standard deviation (SD), 24.5 ± 9.8 years; range, 8–47 years] and 34 age-matched healthy controls (14 men, 24.6 ± 9.7 years) underwent functional magnetic resonance imaging. Independent component analysis (ICA), seed-based functional connectivity, and graph theory were applied to analyze functional connectivity patterns in the brain. Results Patients showed more connections among dorsal attention network, anterior default mode network, and sensorimotor brain networks than healthy controls based on ICA. Analysis of connectivity between regions of interest (ROIs) showed greater functional connectivity in patients between frontal and temporal regions, but lower connectivity between the cerebellum and frontal regions. The normalized characteristic path length was significantly higher in group of patients, but the two groups showed no significant differences in global or regional efficiency, clustering coefficient or characteristic path length. Conclusions Analysis of ICA-derived and ROI-based functional connectivity suggests that disrupted interactions and dysconnectivity in large-scale neural networks and frontotemporal-cerebellar regions may contribute to underlying pathological mechanisms in FCD-related epilepsy.

To figure out the spectra features of malformations of cortical development (MCDs) and the differences between MCDs subcategories. Twenty patients and 18 controls were studied. The patients included two subcategories: disorders of migration (DOM) and postmigration (DOPM). Spectra of patients were acquired from both the lesion and the normal-appearing contralateral side (NACS), and they were compared to those of the controls obtained from the frontal lobe. Compared to the controls, a decreased NAA (P = 0.002) was identified in MCDs. After dividing the MCDs into the DOM and DOPM, we found that NAA reduction was only notable in the DOM (P = 0.007). Moreover, Ins and Cr of the DOPM were higher than those of the controls (P = 0.017 and 0.013) and the DOM (P = 0.027 and 0.001). Compared to the NACS, a decreased NAA (P = 0.042) and an increased Ins (P = 0.039) were identified in the lesion of MCDs. After dividing the MCDs into the DOM and DOPM, we found no significant differences in the DOM, but Ins, Cr, and Glx of the lesion were higher than those of the NACS (P = 0.007, 0.005 and 0.047) in the DOPM. In addition, we found that Cr and Glx correlated positively to the seizure frequency (P = 0.003 and 0.016). Decreased NAA was the prominent abnormality confirmed in MCDs. Spectra of different MCDs subcategories were different: the DOM was characterized by decreased NAA, while the DOPM was characterized by increased Ins.

Combining isocitrate dehydrogenase mutation (IDHmut) with O6 -methylguanine-DNA methyltransferase promoter methylation (MGMTmet) has been identified as a critical prognostic molecular marker for gliomas. The aim of this study was to determine the ability of glioma radiomics features from magnetic resonance imaging (MRI) to predict the co-occurrence of IDHmut and MGMTmet by applying the tree-based pipeline optimization tool (TPOT), an automated machine learning (autoML) approach. This was a retrospective study, in which 162 patients with gliomas were evaluated, including 58 patients with co-occurrence of IDHmut and MGMTmet and 104 patients with other status comprising: IDH wildtype and MGMT unmethylated (n = 67), IDH wildtype and MGMTmet (n = 36), and IDHmut and MGMT unmethylated (n = 1). Three-dimensional (3D) T1-weighted images, gadolinium-enhanced 3D T1-weighted images (Gd-3DT1WI), T2-weighted images, and fluid-attenuated inversion recovery (FLAIR) images acquired at 3.0 T were used. Radiomics features were extracted from FLAIR and Gd-3DT1WI images. The TPOT was employed to generate the best machine learning pipeline, which contains both feature selector and classifier, based on input feature sets. A 4-fold cross-validation was used to evaluate the performance of automatically generated models. For each iteration, the training set included 121 subjects, while the test set included 41 subjects. Student's t-test or a chi-square test was applied on different clinical characteristics between two groups. Sensitivity, specificity, accuracy, kappa score, and AUC were used to evaluate the performance of TPOT-generated models. Finally, we compared the above metrics of TPOT-generated models to identify the best-performing model. Patients' ages and grades between two groups were significantly different (p = 0.002 and p = 0.000, respectively). The 4-fold cross-validation showed that gradient boosting classifier trained on shape and textual features from the Laplacian-of-Gaussian-filtered Gd-3DT1 achieved the best performance (average sensitivity = 81.1%, average specificity = 94%, average accuracy = 89.4%, average kappa score = 0.76, average AUC = 0.951). Using autoML based on radiomics features from MRI, a high discriminatory accuracy was achieved for predicting co-occurrence of IDHmut and MGMTmet in gliomas. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

Given the rarity in the population with adult thalamic gliomas (ATGs), comprehensive characteristics, treatments and survival outcome are not well characterized. This study was conducted to investigate the comprehensive characteristic and treatment of ATGs and identify the prognostic factors associated with overall survival (OS). A retrospective analysis of newly diagnosed ATGs who underwent surgical resection consecutively was conducted. Survival analysis of OS was performed by Kaplan–Meier analysis. Cox proportional hazard model was used to investigate the possible prognostic factors associated with OS. A total of 102 patients with ATG were enrolled in this study. The median age was 41 years (range 18–68 years). There were 56 (54.9%) males. Sixty-two patients (60.8%) had glioblastoma (GBM). Among these patients, 46 patients (45.1%) had GTR/NTR, 50 patients (49.0%) had STR and 6 patients (5.9%) had PR. Postoperatively, 71.6% of these patients received adjuvant therapy. The median OS was 13.6 months (range 1 week–75 months). COX regression analysis revealed that ATG patients with longer duration of symptoms (p = 0.024), better pre-KPS (p = 0.045), maximal resection (p = 0.013), or lower tumor grade (p = 0.002) had longer OS, and these predictors are considered as independent prognostic factors. Survival analysis showed that ATGs with GTR/NTR plus chemoradiotherapy had significant OS advantage compared with other treatment regimens. This study comprehensively summarized the characteristics, treatments and survival outcomes of ATGs in the largest sample size. Maximal surgical resection can bring survival benefit. Combined-modality therapy regimen of GTR/NTR plus chemoradiotherapy may be better beneficial for OS than other regimens.

Background Aldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger pendrin is unclear, as are potassium's role in this response and the receptor's effect on intercalated and principal cell function in the cortical collecting duct (CCD). Methods We measured CCD chloride absorption, transepithelial voltage, epithelial sodium channel activity, and pendrin abundance and subcellular distribution in wild-type and intercalated cell-specific mineralocorticoid receptor knockout mice. To determine if the receptor directly regulates pendrin, as well as the effect of serum aldosterone and potassium on this response, we measured pendrin label intensity and subcellular distribution in wild-type mice, knockout mice, and receptor-positive and receptor-negative intercalated cells from the same knockout mice. Results Ablation of the intercalated cell mineralocorticoid receptor in CCDs from aldosterone-treated mice reduced chloride absorption and epithelial sodium channel activity, despite principal cell mineralocorticoid receptor expression in the knockout mice. With high circulating aldosterone, intercalated cell mineralocorticoid receptor gene ablation directly reduced pendrin's relative abundance in the apical membrane region and pendrin abundance per cell whether serum potassium was high or low. Intercalated cell mineralocorticoid receptor ablation blunted, but did not eliminate, aldosterone's effect on pendrin total and apical abundance and subcellular distribution. Conclusions With high circulating aldosterone, intercalated cell mineralocorticoid receptor ablation reduces chloride absorption in the CCD and indirectly reduces principal cell epithelial sodium channel abundance and function. This receptor directly regulates pendrin's total abundance and its relative abundance in the apical membrane region over a wide range in serum potassium concentration. Aldosterone regulates pendrin through mechanisms both dependent and independent of the IC MR receptor.

Oxaliplatin is a first-line clinical drug in cancer treatment and its side effects of peripheral neuropathic pain have also attracted much attention. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in the course. Current studies have shown that curcumin has various biological activities like antioxidant, anti-inflammatory, antitumor and so on, while few studies were conducted about its role in oxaliplatin-induced peripheral neuropathic pain. The aim of this study is to verify the mechanism of curcumin alleviating oxaliplatin-induced peripheral neuropathic pain. Intraperitoneal injection with oxaliplatin (4 mg/kg body weight) was given to the rats twice a week and last for four weeks to establish the model rats. Gavage administration of curcumin (12.5, 25, and 50 mg/kg body weight, respectively) was conducted for consecutive 28 d to explore the effects and potential mechanism. Our results showed that curcumin administration could increase mechanical withdrawal threshold and decrease the paw-withdrawal times of cold allodynia significantly; meanwhile, motor nerve conduction velocity (MNCV) and sense nerve conduction velocity (SNCV) were both increased and the injured neurons of the spinal cord were repaired. In addition, curcumin administration increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and reduced malondialdehyde (MDA). Moreover, the curcumin operation inhibited the activated of NF-κB and level of inflammatory factors like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In conclusion, these findings suggested that curcumin could alleviate oxaliplatin-induced peripheral neuropathic pain; the mechanism might be inhibiting oxidative stress-mediated activation of NF-κB and mitigating neuroinflammation.

Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.

PURPOSE To develop and validate a dual-energy CT (DECT)-based radiomics nomogram from multicenter trials for predicting the histological differentiation of head and neck squamous cell carcinoma (HNSCC). METHODS A total of 178 patients (112 in the training and 66 in the validation cohorts) from eight institutions with histologically proven HNSCCs were included in this retrospective study. Radiomics-signature models were constructed from features extracted from virtual monoenergetic images (VMI) and iodine-based material decomposition images (IMDI), reconstructed from venous-phase DECT images. Clinical factors were also assessed to build a clinical model. Multivariate logistic regression analysis was used to develop a nomogram combining the radiomics signature models and clinical model for predicting poorly differentiated HNSCC and moderately well-differentiated HNSCC. The predictive performance of the clinical model, radiomics signature models, and nomogram was compared. The calibration degree of the nomogram was also assessed. RESULTS The tumor location, VMI-signature, and IMDI-signature were associated with the degree of HNSCC differentiation, and areas under the ROC curves (AUCs) were 0.729, 0.890, and 0.833 in the training cohort and 0.627, 0.859, and 0.843 in the validation cohort, respectively. The nomogram incorporating tumor location and two radiomics-signature models yielded the best performance in training (AUC = 0.987) and validation (AUC = 0.968) cohorts with a good calibration degree. CONCLUSION The nomogram that integrated the DECT-based radiomics-signature models and tumor location showed good performance in predicting histological differentiation degree of HNSCC, providing a novel combination for predicting HNSCC differentiation.

We have previously shown that blockade of ATP-binding cassette transporter A1 (ABCA1) with cyclosporine A (CsA) stimulates the epithelial sodium channel (ENaC) in cultured distal nephron cells. Here we show that CsA elevated systolic blood pressure in both wild-type and apolipoprotein E (ApoE) knockout (KO) mice to a similar level. The elevated systolic blood pressure was completely reversed by inhibition of cholesterol (Cho) synthesis with lovastatin. Inside-out patch-clamp data show that intracellular Cho stimulated ENaC in cultured distal nephron cells by interacting with phosphatidylinositol‑4,5‑bisphosphate (PIP2), an ENaC activator. Confocal microscopy data show that both α‑ENaC and PIP2 were localized in microvilli via a Cho-dependent mechanism. Deletion of membrane Cho reduced the levels of γ‑ENaC in the apical membrane. Reduced ABCA1 expression and elevated intracellular Cho were observed in old mice, compared to young mice. In parallel, cell-attached patch-clamp data from the split-open cortical collecting ducts (CCD) show that ENaC activity was significantly increased in old mice. These data suggest that elevation of intracellular Cho due to blockade of ABCA1 stimulates ENaC, which may contribute to CsA-induced hypertension. This study also implies that reduced ABCA1 expression may mediate age-related hypertension by increasing ENaC activity via elevation of intracellular Cho.

Frontal lobe epilepsy (FLE) is the second most common type of the focal epilepsies. Our understanding of this disease has been revolutionized over the past decade, but variable treatment outcomes persist and the underlying functional mechanisms responsible for this have yet to be deciphered. This study was designed to determine how intrinsic brain connectivity related to treatment response in patients with FLE. 50 patients with FLE and 28 healthy controls were enrolled in this study and underwent functional MRI at baseline. At the end of 12-month follow up period, all patients with FLE were classified, based on their responses to AEDs treatment, into drug-responsive and drug-refractory groups. The amplitude of low-frequency fluctuation (ALFF) was calculated amongst the three groups in order to detect regional neural function integration. The responsive group showed decreased ALFF only in the left ventromedial prefrontal cortex (vmPFC), while the refractory group showed decreased ALFF in the left vmPFC, right superior frontal gyrus (SFG), and supramarginal gyrus (SMG) relative to healthy controls. In addition, both the responsive and refractory groups showed increased ALFF in the precuneus and postcentral gyrus when compared to the healthy controls. Furthermore, the refractory group exhibited significantly decreased ALFF in the left vmPFC, right SFG and SMG, relative to the responsive group. Focal spontaneous activity, as assessed by ALFF, was associated with response to antiepileptic treatment in patients with FLE. Patients with refractory frontal lobe epilepsy exhibited decreased intrinsic brain activity. Our findings provide novel neuroimaging evidence into the mechanisms of medically-intractable FLE at the brain level.

In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GEC) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel (ENaC), which is expressed by GEC, upon binding to the channel’s α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E(2) and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation.

A large number of studies have demonstrated that the hippocampus has important influences on stress response and memory. The abundant expressions of apelin and its receptor APJ in the hippocampus may imply potential involvement of apelin/APJ signaling in modulating stress-related memory performance deficit. In our previous study, apelin-13 ameliorates memory performance deficit in acute stressed rats. Here, we further examined whether apelin-13 can ameliorate memory performance deficit in chronic stressed rats. Rats were exposed to chronic water-immersion restraint stress (CWIRS) for 4 weeks. After stress withdrawal, apelin-13 was intracerebroventricularly infused once a day for one week. The novel object recognition test (NORT) and Y-maze test (YMT), two hippocampus-dependent memory tasks, were performed to assess memory performance. We found that apelin-13 restored CWIRS-induced decline in the discrimination index and alternation ratio in NORT and YMT, respectively. Furthermore, apelin-13 ameliorated CWIRS-induced hippocampal BDNF expression deficit, and the TrkB receptor antagonist ANA-12 blocked the ameliorative effect of apelin-13 on memory performance deficit in CWIRS rats. The current observations indicate that apelin-13 ameliorates CWIRS-induced memory performance deficit through upregulation of BDNF in rats.

Tourette syndrome (TS) is a neurobehavioral disorder for which the neurological mechanism has not been elucidated. Voxel-based morphometry (VBM) studies have revealed abnormalities in gray matter volume (GMV) in patients with TS; however, consistent results have not been obtained. The current study attempted to provide a voxel wise meta-analysis of gray matter changes using seed-based d mapping (SDM). We identified ten relevant studies that investigated gray matter alterations in TS patients and performed a meta-analysis using the SDM method to quantitatively estimate regional gray matter abnormalities. Next, we examined the relationships between GMV abnormalities and demographic and clinical characteristics. Our results demonstrated that TS patients had smaller GMV in the bilateral inferior frontal gyri and greater GMV in the cerebellum, right striatum (putamen), and bilateral thalami (pulvinar nucleus) than healthy controls. A meta-regression analysis did not identify correlations between GMV changes and demographic or clinical variables. This meta-analysis confirmed significant and consistent GMV changes in several brain regions of TS patients, primarily in the cortico-striato-thalamo-cortical network.

Diffuse tenosynovial giant cell tumor (D-TSGCT) is a benign but locally destructive tumor of synovium that may involve joints, tendon sheaths, and bursae. Its occurrence in the temporomandibular joint (TMJ) is extremely rare. The authors reported a case of 48-year-old man with an extra-articular D-TSGCT in the TMJ with medial cranial fossa extension. computed tomography (CT) and magnetic resonance imaging (MRI) features are described. The lesion was a cystic-solid mass centered at the temporal bone without involvement of the condylar head, and its solid component presented high-density on CT and hypointensity on MRI. No signs of recurrence or metastasis was observed during 12-months of follow-up. The present report suggested the potential characteristics of radiologic imaging of D-TSGCT in TMJ.

The epithelial sodium channel (ENaC) regulates blood pressure by fine-tuning distal nephron sodium reabsorption. Our previous work has shown that ENaC gating is regulated by anionic phospholipid phosphates, including phosphatidylinositol 4,5-bisphosphate (PIP2). The PIP2-dependent regulation of ENaC is mediated by the myristoylated alanine-rich protein kinase C substrate-like protein-1 (MLP-1). MLP-1 binds to and is a reversible source of PIP2at the plasma membrane. We examined MLP-1 regulation of ENaC in distal convoluted tubule clonal cell line DCT-15 cells. Wild-type MLP-1 runs at an apparent molecular mass of 52 kDa despite having a predicted molecular mass of 21 kDa. Native MLP-1 consists of several distinct structural elements: an effector domain that is highly positively charged, sequesters PIP2, contains serines that are the target of PKC, and controls MLP-1 association with the membrane; a myristoylation domain that promotes association with the membrane; and a multiple homology 2 domain of previously unknown function. To further examine MLP-1 in DCT-15 cells, we constructed several MLP-1 mutants: WT, a full-length wild-type protein; S3A, three substitutions in the effector domain to prevent phosphorylation; S3D mimicked constitutive phosphorylation by replacing three serines with aspartates; and GA replaced the myristoylation site glycine with alanine, so GA could not be myristoylated. Each mutant was tagged with either NH2-terminal 3XFLAG or COOH-terminal mCherry or V5. Transfection with MLP mutants modified ENaC activity in DCT-15 cells: activity was highest in S3A and lowest in S3D, and the activity after transfection with either construct was significantly different from WT. In Western blots, when transfected with 3XFLAG-tagged MLP-1 mutants, the expression of the full length of MLP-1 at 52 kDa increased in mutant S3A-MLP-1-transfected DCT-15 cells and decreased in S3D-MLP-1-transfected DCT-15 cells. Several lower molecular mass bands were also detected that correspond to potential presumptive calpain cleavage products. Confocal imaging shows that the different mutants localize in different subcellular compartments consistent with their preferred location in the membrane or in the cytosol. Activation of protein kinase C increases phosphorylation of endogenous MLP-1 and reduces ENaC activity. Our results suggest a complicated role for proteolytic processing in MLP-1 regulation of ENaC.

The red peony root derived from Paeonia lactiflora has been applied to treat human inflammatory diseases. To investigate its therapeutic potential in treating moderately severe acute pancreatitis (MSAP), which has been rarely studied, this study was designed as a double-blinded, placebo-controlled, randomized clinical trial. A total of 60 MSAP patients were enrolled and randomly divided into an experimental (n = 30) group and a control group (n = 30), who received a coloclyster of 15 g of red peony root or placebo granules dissolved in 150 mL of water, respectively. The patients’ demographic and clinical characteristics were recorded. The results showed that the experimental group had a shorter remission time of fever (p<0.05) and abdominal pain (p<0.01) and faster resumption of self-defecation (p<0.01) than did the control group. In addition, the coloclyster of red peony root decreased the modified Balthazar CT score as well as the serum interleukin-6 and tumor necrosis factor-alpha levels to a greater extent than did the placebo coloclyster (p<0.05). The remission times for the normalization of white blood cells and percentage of neutrophils and lymphocytes in the experimental group were also significantly shorter than those in the control group (p<0.05). In conclusion, a coloclyster of red peony root could help alleviate the clinical symptoms and shorten the course of MSAP by possibly attenuating systematic inflammation. This trial is registered with 14004664.

Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy whose neurobiological underpinnings remain poorly understood. The present study aimed to identify possible neurochemical alterations in the dorsolateral prefrontal cortex (DLPFC) in participants with SHE using proton magnetic resonance spectroscopy (1 H MRS). Thirty-nine participants with SHE (mean age, 30.7 years ± 11.3 [standard deviation], 24 men) and 59 controls (mean age, 29.4 years ± 10.4, 29 men) were consecutively and prospectively recruited and underwent brain magnetic resonance imaging and 1 H MRS in the bilateral DLPFCs. Brain concentrations of metabolites, including N-acetyl aspartate (NAA), myo-inositol (mI), choline, creatine, the sum of glutamate and glutamine, glutathione (GSH) and γ-aminobutyric acid, were estimated with LCModel and corrected for the partial volume effect of cerebrospinal fluid using tissue segmentation. ANCOVA analyses revealed lower concentration of NAA in the left DLPFC in participants with SHE compared with controls. A significant difference of NAA concentration between DLPFC in the two hemispheres (left > right) was observed only in the control group. We further confirmed a higher GSH concentration in men than in women in SHE participants, which probably indicates that men are more susceptible to this disease. The mI concentration in the right DLPFC was negatively correlated with epilepsy duration. This study demonstrates that DLPFC is an important brain region involved in the pathophysiology of SHE, in which both neurons and astrocytes appear impaired, and the elevated GSH level may suggest an abnormality related to oxidative stress.

Background: Anorexia nervosa (AN) is a debilitating illness whose neural basis remains unclear. Studies using tract-based spatial statistics (TBSS) with diffusion tensor imaging (DTI) have demonstrated differences in white matter (WM) microarchitecture in AN, but the findings are inconclusive and controversial. Objectives: To identify the most consistent WM abnormalities among previous TBSS studies of differences in WM microarchitecture in AN. Methods: By systematically searching online databases, a total of 11 datasets were identified, including 245 patients with AN and 246 healthy controls (HC). We used Seed-based d Mapping to analyze fractional anisotropy (FA) differences between AN patients and HC, and performed meta-regression analysis to explore the effects of clinical characteristics on WM abnormalities in AN. Results: The pooled results of all AN patients showed robustly lower FA in the corpus callosum (CC) and the cingulum compared to HC. These two regions preserved significance in the sensitivity analysis as well as in all subgroup analyses. Fiber tracking showed that the WM tracts primarily involved were the body of the CC and the cingulum bundle. Meta-regression analysis revealed that the body mass index and mean age were not linearly correlated with the lower FA. Conclusions: The most consistent WM microstructural differences in AN were in the interhemispheric connections and limbic association fibers. These common "targets" advance our understanding of the complex neural mechanisms underlying the puzzling symptoms of AN, and may help in developing early treatment approaches.

Background/Aims. In previous studies, it has been observed that Xiaotan Jieyu (XTJY) prescription may inhibit the proliferation of human breast precancerous lesion MCF-10AT cells by inhibiting the PI3K/Akt signaling pathway. The purpose of this study is to further verify the therapeutic effect and the possible mechanism of XTJY on precancerous lesions of breast cancer in vivo. Methods. The successfully established breast precancerous lesion rat model and normal healthy rats were randomly assigned into the blank (BLA), model (MOD), XTJY-low (LD), XTJY-medium (MD), XTJY-high (HD), and tamoxifen (TAM) groups. Different concentrations of XTJY and saline were supplied by intragastric administration for 4 consecutive weeks to assess the protective effect of XTJY on the progress of the breast precancerous lesion in rats involving the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Results. In this study, it determined that 10 mg/each rat DMBA-combined estrogen and progesterone induction for 10 weeks was the optimal condition for the establishment of the breast precancerous lesion rat model. In vivo administration of XTJY or TAM was found to inhibit the development of the breast precancerous lesion, and the occurrence rate of breast invasive carcinomas was decreased by about 50%. Furthermore, XTJY or TAM markedly reduced protein expressions of PI3K and p-Akt and increased protein expressions of PTEN. Conclusion. These data indicated that XTJY can significantly alleviate the development of breast precancerous lesions by inhibiting the activation of the PI3K/Akt signaling pathway. XTJY may be a promising drug for the treatment of precancerous lesions in breast cancer.

To characterize possible metabolic changes of the dorsolateral prefrontal cortex (DLPFC) in patients with temporal lobe epilepsy (TLE). Quantitative proton magnetic resonance spectroscopy (1H-MRS) studies were performed on 24 TLE patients and 22 healthy controls. Metabolite concentrations were calculated using a linear combination model (LCModel) and corrected for cerebrospinal fluid contamination. Comparisons were performed between the TLE patients and the controls and between the left DLPFC and right DLPFC in each group. Pearson correlation coefficients were calculated between the metabolite concentrations and epilepsy duration and between the metabolite concentrations and voxel tissue composition: [gray matter (GM)/(GM+white matter (WM))]. Metabolic asymmetry was found in controls between the left and right DLPFC, i.e., the NAA concentration of the left DLPFC was significantly higher than that of the right. However, such metabolic asymmetry was not observed in TLE patients. Compared with the controls, TLE patients showed significantly decreased NAA and Ins, and the reductions were greater in the left DLPFC. No significant correlation was found between the metabolite concentrations and epilepsy duration or between the metabolite concentrations and voxel tissue composition [GM/(GM+WM)]. This study suggests that TLE can produce metabolic changes to DLPFC that is remote from the seizure focus. • Magnetic resonance spectroscopy probes the brain metabolism noninvasively. • Dorsolateral prefrontal reductions in NAA (a neuronal marker) and Ins are observed in TLE. • Temporal lobe epilepsy can result in metabolic changes remote from the seizure focus.

Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

This meta-analysis investigated the effectiveness of Tai Chi on cancer-related fatigue (CRF). Nine databases (PubMed, Web of Science, Ovid, the Cochrane Library, Embase, and four Chinese databases) were searched to identify randomized controlled trials (RCTs) that evaluated the effects of Tai Chi on CRF. The reference lists given in the identified RCTs were also reviewed to identify potentially relevant studies. Six RCTs involving 373 patients were included. The change in short- and long-term CRF (SCRF and LCRF, respectively) was calculated as the change in the mean score for CRF from baseline to the end of intervention period and to the end of post-intervention follow-up, respectively. Pooled results suggested that Tai Chi had a significant positive effect on standard mean difference (i.e., SCRF; SMD = − 0.54; p

BACKGROUND: Focal epilepsy accounts for most epilepsy cases, and frontal lobe epilepsy (FLE) accounts for the largest proportion of cases of extratemporal epilepsy syndrome. The epileptogenic zone is usually not easy to locate, contributing to a lack of imaging studies. The objective of this study was to evaluate functional connectivity patterns to explore the underlying pathological mechanisms of this disorder. METHODS: Forty-three patients with focal extratemporal epilepsy [mean age ± standard deviation (SD): 29.51±8.04 years, 19 males] and the same number of healthy controls (mean age ± SD: 29.56±8.02 years, 19 males) were recruited to undergo functional magnetic resonance imaging. Mean regional homogeneity (ReHo) was measured, and regions showing significant alterations in ReHo in patients were identified to examine functional connectivity (FC). In particular, FC within the default mode network (DMN) in patients was analyzed. RESULTS: Patients with extratemporal lobe epilepsy showed significantly higher ReHo in the bilateral precentral gyrus, and lower ReHo in frontal-cerebellum regions than healthy controls [P

PAR-1 is expressed not only in epithelium, neurons, astrocytes, immune cells, but also in cancer-associated fibroblasts, ECs (epithelial cells), myocytes of blood vessels, mast cells, and macrophages in tumor microenvironment, whereas PAR-1 stimulates macrophages to synthesize and secrete thrombin as well as other growth factors, resulting in enhanced cell proliferation, tumor growth and metastasis. Therefore, considerable effort has been devoted to the development of inhibitors targeting PAR-1. Here, we provide a comprehensive review of PAR-1's role in cancer invasiveness and dissemination, as well as potential therapeutic strategies targeting PAR-1 signaling.

Background An overlap of clinical symptoms between major depressive disorder (MDD) and social anxiety disorder (SAD) suggests that the two disorders exhibit similar brain mechanisms. However, few studies have directly compared the brain structures of the two disorders. The aim of this study was to assess the gray matter volume (GMV) and cortical thickness alterations between non-comorbid medication-naive MDD patients and SAD patients. Methods High-resolution T1-weighted images were acquired from 37 non-comorbid MDD patients, 24 non-comorbid SAD patients and 41 healthy controls (HCs). Voxel-based morphometry analysis of the GMV (corrected with a false discovery rate of p, Highlights • MDD and SAD share common gray matter abnormalities in the orbitofrontal-striatal-thalamic circuit, salience and dorsal attention network. • MDD patients show disorder-specific involvement of the visual processing regions. • SAD patients show disorder-specific involvement of the precentral cortex. An overlap of clinical symptoms between major depressive disorder (MDD) and social anxiety disorder (SAD) suggests similar brain mechanisms for the two disorders. However, few studies have directly compared the brain structures of the two disorders. The aim of this study was to assess gray matter volume and cortical thickness alterations between non-comorbid medication-naive MDD patients and SAD patients. We found that MDD and SAD shared a common pattern of gray matter abnormalities in the orbitofrontal-striatal-thalamic circuit, salience network and dorsal attention network. MDD patients showed disorder-specific involvement of the visual processing regions. SAD patients showed disorder-specific involvement of the precentral cortex.

Abnormally high epithelial Na+ channel (ENaC) activity in the aldosterone-sensitive distal nephron and collecting duct leads to hypertension. Myelin and lymphocyte (Mal) is a lipid raft-associated protein that has been previously shown to regulate Na+-K-2Cl− cotransporter and aquaporin-2 in the kidney, but it is not known whether it regulates renal ENaC. ENaC activity is positively regulated by the anionic phospholipid phosphate phosphatidylinositol 4,5-bisphosphate (PIP2). Members of the myristoylated alanine-rich C-kinase substrate (MARCKS) family increase PIP2 concentrations at the plasma membrane, whereas hydrolysis of PIP2 by phospholipase C (PLC) reduces PIP2 abundance. Our hypothesis was that Mal protein negatively regulates renal ENaC activity by stabilizing PLC protein expression at the luminal plasma membrane. We investigated the association between Mal, MARCKS-like protein, and ENaC. We showed Mal colocalizes with PLC-β3 in lipid rafts and positively regulates its protein expression, thereby reducing PIP2 availability at the plasma membrane. Kidneys of 129Sv mice injected with MAL shRNA lentivirus resulted in increased ENaC open probability in split-open renal tubules. Overexpression of Mal protein in mouse cortical collecting duct (mpkCCD) cells resulted in an increase in PLC-β3 protein expression at the plasma membrane. siRNA-mediated knockdown of MAL in mpkCCD cells resulted in a decrease in PLC-β3 protein expression and an increase in PIP2 abundance. Moreover, kidneys from salt-loaded mice showed less Mal membrane protein expression compared with non-salt-loaded mice. Taken together, Mal protein may play an essential role in the negative feedback of ENaC gating in principal cells of the collecting duct.

Flow-related bending of cilia results in Ca2+ influx through a polycystin-1 (Pkd1) and polycystin-2 (Pkd2) complex, both of which are members of the transient receptor potential (TRP) family (TRPP1 and TRPP2, respectively). Deletion of this complex as well as cilia result in polycystic kidney disease. The Ca2+ influx pathway has been previously characterized in immortalized collecting duct cells without cilia and found to be a 23-pS channel that was a multimere of TRPP2 and TRPV4. The purpose of the present study was to determine if this TRPP2 and TRPV4 multimere exists in vivo. Apical channel activity was measured using the patch-clamp technique from isolated split-open cortical collecting ducts from adult conditional knockout mice with ( Ift88flox/flox) or without ( Ift88−/−) cilia. Single tubules were isolated for measurements of mRNA for Pkd1, Pkd2, Trpv4, and epithelial Na+ channel subunits. The predominant channel activity from Ift88flox/flox mice was from epithelial Na+ channel [5-pS Na+-selective channels with long mean open times (475.7 ± 83.26 ms) and open probability > 0.2]. With the loss of cilia, the predominant conductance was a 23-pS nonselective cation channel (reversal potential near 0) with a short mean open time (72 ± 17 ms), open probability < 0.08, and a characteristic flickery opening. Loss of cilia increased mRNA levels for Pkd2 and Trpv4 from single isolated cortical collecting ducts. In conclusion, 23-pS channels exist in vivo, and activity of this channel is elevated with loss of cilia, consistent with previous finding of an elevated-unregulated Ca2+-permeable pathway at the apical membrane of collecting duct cells that lack cilia.

A known cause of seizure-induced respiratory arrest is the deficiency in serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of central serotonin (5-hydroxytryptamine) synthesis which converts l-tryptophan to 5-hydroxytryptophan. A recent study revealed a reduction in TPH2 protein expression in the brainstems of DBA/1 mice that developed recurrent seizure-induced respiratory arrest, whereas the activity of this protein was unexplored. Thus this study aims to investigate the association between intrinsic 5-hydroxytryptamine synthesis in the brainstem and the susceptibility for sudden unexpected death in epilepsy in DBA/1 mice. The effect of LY393558, a potent 5-hydroxytryptamine reuptake inhibitor with 5-HT1B/1D receptor antagonist properties, on seizure-induced respiratory arrest evoked by acoustic stimulation was also examined in DBA/1 mice. ELISA results showed significantly decreased TPH2 activity in the brainstems of untreated DBA/1 mice than that of C57BL/6J mice. Moreover, the concentrations of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-HIAA in the brainstems of DBA/1 mice with or without acoustic stimulation were significantly lower than that of C57BL/6J mice. Acute administration of LY393558 also significantly reduced seizure-induced respiratory arrest in DBA/1 mice. These observations provide novel evidences for the hypothesis that 5-hydroxytryptamine deficiency might be a potential cause of seizure-induced respiratory arrest.

Previous studies have shown that posttraumatic stress disorder (PTSD) is associated with dysfunction of the limbic system, in which the amygdala plays an important role. The purpose of this study was to evaluate whether the neurochemical concentrations assessed by proton magnetic resonance spectroscopy (1H-MRS) in the amygdala are abnormal in children and adolescents with PTSD. Twenty-eight pediatric PTSD patients (11 boys, 17 girls) and 24 matched trauma-exposed control subjects (9 boys, 15 girls) underwent magnetic resonance brain imaging and 1H-MRS of the bilateral amygdalae. The concentrations of N-acetylaspartate (NAA), myo-inositol (mI), total creatine (tCr) and total choline (tCho) in the right amygdala were significantly increased in PTSD patients compared with trauma-exposed control subjects. There were significant group-by-age interactions in the left amygdala NAA and right amygdala mI concentrations: older pediatric patients with PTSD had higher left amygdala NAA concentration and younger patients had higher right amygdala mI concentration than trauma-exposed control subjects. There was also a significant correlation between right mI concentration and time since trauma in PTSD patients. Finally, there was significant group-by-age interaction in the left amygdala volume; intragroup analysis revealed that the right amygdala volume was significantly lower than the left in the PTSD group, but not in the control group. These neurochemical abnormalities of the amygdala may indicate that dysfunctions of both neurons and glial cells are involved in the pathology of pediatric PTSD.

Juvenile xanthogranuloma (JXG) is a benign, self-limiting histiocytic disorder of infancy and early childhood, usually presented as a single or multiple cutaneous lesions. The central nervous system is rarely affected by JXG. There were only a few reports of intracranial JXG cases which described its features on MR spectroscopy (MRS) and diffusion-weighted imaging (DWI), but its features on susceptibility-weighted imaging (SWI) and perfusion-weighted imaging (PWI) have not been reported yet. Here, we reported an intracranial JXG case which underwent multimodal MRI examinations including DWI, SWI, and PWI. The multimodal MRI provided a thorough insight into this disease and we found that intense enhancement and high perfusion may be important clues for the diagnosis.

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality. The underlying neurobiological mechanisms are not well understood, and high-resolution structural magnetic resonance brain imaging studies have given inconsistent results. Here we aimed to psychoradiologically define the most prominent and replicable abnormalities of gray matter volume (GMV) in AN patients, and to examine their relationship to demographics and clinical characteristics, by means of a new coordinate-based meta-analytic technique called seed-based d mapping (SDM). In a pooled analysis of all AN patients we identified decreased GMV in the bilateral median cingulate cortices and posterior cingulate cortices extending to the bilateral precuneus, and the supplementary motor area. In subgroup analysis we found an additional decreased GMV in the right fusiform in adult AN, and a decreased GMV in the left amygdala and left anterior cingulate cortex in AN patients without comorbidity (pure AN). Thus, the most consistent GMV alterations in AN patients are in the default mode network and the sensorimotor network. These psychoradiological findings of the brain abnormalities might underpin the neuropathophysiology in AN.

Although the role of urea in urine concentration is known, the effect of urea handling by the urea transporters (UTs), UT-A1 and UT-A3, on sodium balance remains elusive. Serum and urinary sodium concentration is similar between wild-type mice (WT) and UT-A3 null (UT-A3 KO) mice; however, mice lacking both UT-A1 and UT-A3 (UT-A1/A3 KO) have significantly lower serum sodium and higher urinary sodium. Protein expression of renal sodium transporters is unchanged among all three genotypes. WT, UT-A3 KO, and UT-A1/A3 KO acutely respond to hydrochlorothiazide and furosemide; however, UT-A1/A3 KO fail to show a diuretic or natriuretic response following amiloride administration, indicating that baseline epithelial Na+channel (ENaC) activity is impaired. UT-A1/A3 KO have more ENaC at the apical membrane than WT mice, and single-channel analysis of ENaC in split-open inner medullary collecting duct (IMCD) isolated in saline shows that ENaC channel density and open probability is higher in UT-A1/A3 KO than WT. UT-A1/A3 KO excrete more urinary nitric oxide (NO), a paracrine inhibitor of ENaC, and inner medullary nitric oxide synthase 1 mRNA expression is ~40-fold higher than WT. Because endogenous NO is unstable, ENaC activity was reassessed in split-open IMCD with the NO donor PAPA NONOate [1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine)], and ENaC activity was almost abolished in UT-A1/A3 KO. In summary, loss of both UT-A1 and UT-A3 (but not UT-A3 alone) causes elevated medullary NO production and salt wasting. NO inhibition of ENaC, despite elevated apical accumulation of ENaC in UT-A1/A3 KO IMCD, appears to be the main contributor to natriuresis in UT-A1/A3 KO mice.

Plasmacytoma is a malignant tumor originating from the plasma cells of the bone marrow. Those discovered after a head injury is rare. We report a case of a 48-year-old female who complained of scalp mass without other symptoms after head injury. Meningioma was considered preoperatively based on imaging findings, and surgical resection was performed. Postoperatively, multiple myeloma complicated by skull plasmacytoma was diagnosed by histopathology and systematic examinations in succession. When evaluating a head mass that appeared after a head injury, plasmacytoma should be considered at times. Osteolytic changes and biconvex form on imaging are beneficial to differentiation.

Tea tree oil (TTO) inclusion complexes were prepared by co-precipitation with β-cyclodextrin (β-CD). After the complexation protocol was optimized using response surface methodology, the physicochemical and anti-fungal properties of the TTO-β-CD inclusion complex were investigated. The optimal complexation time (4 h), temperature (62 °C), and β-CD/TTO mass ratio (7), provided a TTO complexation efficiency of 87.47 %. Fourier transform infrared spectroscopy showed that the spectra of TTO complexations and β-CD are quite similar, suggesting that TTO molecules enter β-CD cavities during the formation of inclusion complexes. Scanning electron micrographs revealed that particles of TTO-β-CD complexes are smoother and smaller than the amorphous structures of β-CD. Thermogravimetric analysis demonstrated that the thermal stability of TTO is enhanced after complexation with β-CD, which reduces TTO volatility and oxidation. Complexed TTO inhibit mycelial growth of B. cinerea in a dose-dependent manner in vitro. In cherry tomato fruit, complexed TTO can control artificially-induced B. cinerea infection and extend shelf life. It was concluded that TTO complexation might be benefit for the commercial application of TTO to control the postharvest grey mold of fruits.

Background and purpose We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP-binding cassette transporter A1; ABCA1). Experimental approach We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell-attached patch-clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail-cuff method. Key results Specific deletion of ABCA1 elevated BP and ENaC single-channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. Conclusions and implications These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol-dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4-2, increased furin expression, and reduced cilium-mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA-induced hypertension.

Background Meningeal melanoma is a rare tumor of the central nervous system, whose amelanotic variant is called “amelanotic meningeal melanoma” (AMM). AMM does not produce melanin and therefore does not exhibit typical short T1 and short T2 signal on magnetic resonance imaging and thus can be easily misdiagnosed and be inappropriately managed. To date, only 4 AMM cases have been reported in the English literature. Here, we report the fifth case. Case Description A 26-year-old female patient presented with a 4-month history of progressive headache and nausea, the conventional magnetic resonance imaging demonstrated a posterior fossa mass accompanied by diffuse leptomeningeal dissemination. Repeated cerebrospinal fluid cytology screening showed negative results. The functional magnetic resonance examinations, including diffusion-weighted imaging, proton magnetic resonance spectroscopy, and dynamic susceptibility contrast perfusion-weighted imaging, provided complementary information. The final diagnosis of AMM was made by immunohistochemistry. Despite gross total excision of the tumor, the disease progressed, and the patient died 10 months after diagnosis. Conclusions Our experience with this case demonstrated that meningeal melanoma should be included in the differential diagnosis when an intracranial mass is accompanied by leptomeningeal dissemination, and especially when proton magnetic resonance spectroscopy and dynamic susceptibility contrast perfusion-weighted imaging indicate a malignant tumor whereas diffusion-weighted imaging does not. And the loss of a typical melanin signal should not server as an excluding criterion for meningeal melanoma.

Background Previous psychoradiological studies of posttraumatic stress disorder (PTSD) were mainly of patients at a chronic stage, focusing on brain regions outside the amygdala. The goals of this study were to investigate the early biochemical and structural changes of anterior cingulate cortex (ACC) and amygdala in patients with PTSD and to explore their relationships. Methods Seventy-eight drug-naive PTSD subjects and 71 non-PTSD age- and sex-matched control subjects were enrolled, all of whom had suffered the same earthquake about one year before. Single-voxel proton magnetic resonance spectroscopy (1H-MRS) was performed and absolute metabolite concentrations in ACC and bilateral amygdalae were estimated with LCModel. Bilateral amygdalae were manually outlined and their volumes were calculated and corrected for the total intracranial volume. Results The PTSD group showed significantly increased N-acetylaspartate (NAA) concentration in the ACC, increased creatine (Cr) concentration in the left amygdala, and increased myo-inositol (mI) concentration in the right amygdala, compared to non-PTSD controls. The NAA concentration in ACC was negatively correlated with the time since trauma. The PTSD group showed significantly decreased volumes of bilateral amygdalae compared to non-PTSD controls, but amygdala volumes were not correlated with metabolite concentrations. Limitations Longitudinal studies are needed to explore the metabolic and structural changes of PTSD at different stages. The volume of ACC was not measured. Conclusions This concurrent increase in some metabolite concentrations and decrease of amygdala volumes may represent a pattern of biochemical and morphological changes in recent-onset PTSD which is different from that reported in chronic PTSD.

In recent years, Chinese medicine has played an important role in the prognosis of gastric cancer. Precancerous lesions of gastric carcinoma (PLGC) is a class of gastric cancer which is closely related to the gastric mucosal pathology changes in the role of carcinogenic incentives, and plays key role in the progression of normal gastric mucosal cells into gastric cancerous cells. In current experiment, we explore the relationship between Chinese traditional medicine (Xiao Tan He Wei Decoction) and gastric cancer in the PLGC rat animal models and epithelial-mesenchymal transitioned GES-1 cells which were induced useing 1- Methyl-3-nitro-1-nitrosoguanidine (MNNG). PLGC rat model showed significant deterioration in the gastric mucosa with terrible growth rate in body weight and more atypical hyperplasia in gastric mucosa. MC cells, MNNG induced GES-1 cells which epithelial- mesenchymal-transition (EMT)-related proteins have a great change compare with normal GES-1 cells. The cells had characteristics of malignant cells including proliferation, invasion and metastasis ability. Our research founds that Xiao Tan He Wei Decoction could inhibit cell proliferation and increased apoptosis by increase the level of pro-apoptotic proteins like Bax and caspase-3 and decreased the level of anti-apoptotic protein Bcl-2, block the cells in G0/G1 phase simultaneously. Furthermore, Xiao Tan He Wei Decoction could inhibit nuclear factor kappa-light-chain-enhancer (NF-kB) activity and inhibit its transfer from the cytoplasm to the nucleus. However, when we incubated with NF-κB activator PMA, the effect of Xiao Tan He Wei Decoction was reversed. These results suggested that Xiao Tan He Wei Decoction could be used as a method for the treatment of gastric precancerous lesions, and possibly provide a theoretical basis for the clinical treatment of gastric cancer and gastric precancerous lesions.

Pulmonary permeability edema is characterized by reduced alveolar Na⁺ uptake capacity and capillary barrier dysfunction and is a potentially lethal complication of listeriosis. Apical Na⁺ uptake is mainly mediated by the epithelial sodium channel (ENaC) and initiates alveolar liquid clearance. Here we examine how listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, impairs the expression and activity of ENaC. To that purpose, we studied how sub-lytic concentrations of LLO affect negative and positive regulators of ENaC expression in the H441 airway epithelial cell line. LLO reduced expression of the crucial ENaC-α subunit in H441 cells within 2 h and this was preceded by activation of PKC-α, a negative regulator of the channel's expression. At later time points, LLO caused a significant reduction in the phosphorylation of Sgk-1 at residue T256 and of Akt-1 at residue S473, both of which are required for full activation of ENaC. The TNF-derived TIP peptide prevented LLO-mediated PKC-α activation and restored phospho-Sgk-1-T256. The TIP peptide also counteracted the observed LLO-induced decrease in amiloride-sensitive Na⁺ current and ENaC-α expression in H441 cells. Intratracheally instilled LLO caused profound pulmonary edema formation in mice, an effect that was prevented by the TIP peptide; thus indicating the therapeutic potential of the peptide for the treatment of pore-forming toxin-associated permeability edema.

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This investigation was conducted to study the relationship between intracellular Ca(2+) and activation of large conductance Ca(2+)-activated K(+) (BK) currents by unoprostone, the first synthetic docosanoid. We used HEK293 cells stably transfected with two BK channel splice variants, one sensitive to unoprostone and the other insensitive. We examined the effects of unoprostone on channel activity in excised inside-out patches and cell-attached patches. The half-maximal stimulation of the sensitive BK channels by Ca(2+) was shifted from 3.4±0.017 nM to 0.81±.0058 nM in the presence of 10 nM unoprostone. There was no effect on insensitive channels even at unoprostone concentrations as high as 1000 nM. There was no effect of unoprostone on the voltage dependence of the BK channels. Changes in open probability and effects of Ca(2+) and unoprostone were best described by a synergistic binding model. These data would suggest that Ca(2+) and unoprostone were binding to sites close to one another on the channel protein and that unoprostone binding causes the affinity of the calcium binding site to increase. This idea is consistent with three dimensional models of the Ca(2+) binding site and a putative unoprostone binding domain. Our results have important implications for the clinical use of unoprostone to activate BK channels. Channel activation will be limited if intracellular Ca(2+) is not elevated.

Recent functional magnetic resonance spectroscopy (fMRS) studies have shown changes in glutamate/glutamine (Glx) concentrations between resting-state and active-task conditions. However, the types of task used have been limited to sensory paradigms, and the regions from which Glx con- centrations have been measured limited to sensory ones. This leaves open the question as to whether the same effect can be seen in higher-order brain regions during cognitive tasks. Cortical midline structures, especially the medial prefrontal cortex (MPFC), have been suggested to be involved in various such cognitive tasks. We, therefore set out to use fMRS to investigate the dynamics of Glx