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Accurate interpretation of in vivo wide-field fluorescent imaging (WFFI) data requires precise separation of raw fluorescence signals into neural and hemodynamic components. The classical Beer-Lambert law-based approach, which uses concurrent 530-nm illumination to estimate relative changes in cerebral blood volume (CBV), fails to account for the scattering and reflection of 530-nm photons from non-neuronal components leading to biased estimates of CBV changes and subsequent misrepresentation of neural activity. This study introduces a novel linear regression approach designed to overcome this limitation. This correction provides a more reliable representation of CBV changes and neural activity in fluorescence data. Our method is validated across multiple datasets, demonstrating its superiority over the classical approach., Competing Interests: Declaration of competing interest The authors have no relevant financial interests in the manuscript and no other potential conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Clinical manifestations of phlebosclerotic colitis (PC) exhibit significant variability, necessitating diverse treatment strategies depending on disease severity. However, there is limited research exploring the relationship between imaging findings and disease severity. Hence, this retrospective study aimed to analyze the correlation between computed tomography (CT) findings, colonoscopic features, and disease severity. This study compared the abdominal CT characteristics, colonoscopy findings, and treatment modalities of 45 PC patients. CT images were assessed for the severity of mesenteric venous calcification, maximum colonic wall thickness, number of involved colonic segments, and presence of pericolic inflammation. Colonoscopic images were assessed for dark purple discoloration mucosa, erosive and ulcerative lesions, mucosal edema, luminal narrowing, and the number of involved colonic segments. In addition, patients were categorized into three groups: the observation (n = 15), medical treatment (n = 19), and operation (n = 11) groups. In CT images, a significant difference in pericolic inflammation (p = 0.039) was observed among groups. Further, significant differences in dark purple discoloration mucosa (p = 0.033), erosive or ulcerative lesions (p < 0.001), mucosal edema (p < 0.001), luminal narrowing (p = 0.012), and the number of involved colonic segments (p = 0.001) were observed in colonoscopy. Moreover, we found positive correlations between CT and colonoscopy features. In conclusion, CT manifestations and colonoscopy findings exhibited correlation with disease severity in PC. When limited to one diagnostic tool, observations from that tool can infer potential manifestations of the alternative tool., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

The development of deep learning-based groundwater level forecast models can tackle the challenge of high dimensional groundwater dynamics, predict groundwater variation trends accurately, and manage groundwater resources effectively, thereby contributing to sustainable water resources management. This study proposed a novel ConvAE-LSTM model, which fused a Convolutional-based Autoencoder model (ConvAE) and a Long Short-Term Memory Neural Network model (LSTM), to provide accurate spatiotemporal groundwater level forecasts over the next three months. The HBV-light and LSTM models are chosen as benchmarks. An ensemble of point data and the corresponding derived images concerning the past (observations) and the future (forecasts from a conceptual model) of groundwater levels at 33 groundwater wells in Jhuoshuei River basin of Taiwan between 2000 and 2019 constituted the case study. The findings showcase the effectiveness of the ConvAE-LSTM model in extracting crucial features from both point and imagery datasets. This model successfully establishes spatiotemporal dependencies between regional images and groundwater level data over diverse time frames, leading to accurate multi-step-ahead forecasts of groundwater levels. Notably, the ConvAE-LSTM model exhibits a substantial improvement, with the R-squared values showing an increase of more than 18%, 22%, and 49% for the R1, R2, and R3 regions, respectively, compared to the HBV-light model. Additionally, it outperforms the LSTM model in this regard. This study represents a noteworthy milestone in environmental modeling, offering key insights for designing sustainable groundwater management strategies to ensure the long-term availability of this vital resource., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Fi-John Chang reports financial support was provided by National Science and Technology Council, Taiwan., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Response surface models (RSMs) are a new trend in modern anesthesia. RSMs have demonstrated significant applicability in the field of anesthesia. However, the comparative analysis between RSMs and logistic regression (LR) in different surgeries remains relatively limited in the current literature. We hypothesized that using a total intravenous anesthesia (TIVA) technique with the response surface model (RSM) and logistic regression (LR) would predict the emergence from anesthesia in patients undergoing video-assisted thoracotomy surgery (VATS). This study aimed to prove that LR, like the RSM, can be used to improve patient safety and achieve enhanced recovery after surgery (ERAS). This was a prospective, observational study with data reanalysis. Twenty-nine patients (American Society of Anesthesiologists (ASA) class II and III) who underwent VATS for elective pulmonary or mediastinal surgery under TIVA were enrolled. We monitored the emergence from anesthesia, and the precise time point of regained response (RR) was noted. The influence of varying concentrations was examined and incorporated into both the RSM and LR. The receiver operating characteristic (ROC) curve area for Greco and LR models was 0.979 (confidence interval: 0.987 to 0.990) and 0.989 (confidence interval: 0.989 to 0.990), respectively. The two models had no significant differences in predicting the probability of regaining response. In conclusion, the LR model was effective and can be applied to patients undergoing VATS or other procedures of similar modalities. Furthermore, the RSM is significantly more sophisticated and has an accuracy similar to that of the LR model; however, the LR model is more accessible. Therefore, the LR model is a simpler tool for predicting arousal in patients undergoing VATS under TIVA with Remifentanil and Propofol.

Derlin family members participate in the retrotranslocation of endoplasmic reticulum (ER) lumen proteins to the cytosol for ER-associated degradation (ERAD); however, the proteins facilitating this retrotranslocation remain to be explored. Using CRISPR library screening, we have found that derlin-2 and surfeit locus protein 4 (Surf4) are candidates to facilitate degradation of cyclooxygenase-2 (COX-2, also known as PTGS2). Our results show that derlin-2 acts upstream of derlin-1 and that Surf4 acts downstream of derlin-2 and derlin-1 to facilitate COX-2 degradation. Knockdown of derlin-2 or Surf4 impedes the ubiquitylation of COX-2 and the interaction of COX-2 with caveolin-1 (Cav-1) and p97 (also known as VCP) in the cytosol. Additionally, COX-2 degradation is N-glycosylation dependent. Although derlin-2 facilitates degradation of N-glycosylated COX-2, the interaction between derlin-2 and COX-2 is independent of COX-2 N-glycosylation. Derlin-1, Surf4 and p97 preferentially interact with non-glycosylated COX-2, whereas Cav-1 preferentially interacts with N-glycosylated COX-2, regardless of the N-glycosylation pattern. Collectively, our results reveal that Surf4 collaborates with derlin-2 and derlin-1 to mediate COX-2 translocation from the ER lumen to the cytosol. The derlin-2-derlin-1-Surf4-Cav-1 machinery might represent a unique pathway to accelerate COX-2 degradation in ERAD., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Objective: Focal epilepsy is thought to be a network disease, in which epileptiform activity can spread noncontiguously through the brain via highly interconnected nodes, or hubs, within existing networks. Animal models confirming this hypothesis are scarce, and our understanding of how distant nodes are recruited is also lacking. Whether interictal spikes (IISs) also create and reverberate through a network is not well understood., Methods: We injected bicuculline into the S1 barrel cortex and employed multisite local field potential and Thy-1 and parvalbumin (PV) cell mesoscopic calcium imaging during IISs to monitor excitatory and inhibitory cells in two monosynaptically connected nodes and one disynaptically connected node: ipsilateral secondary motor area (iM2), contralateral S1 (cS1), and contralateral secondary motor area (cM2). Node participation was analyzed with spike-triggered coactivity maps. Experiments were repeated with 4-aminopyridine as an epileptic agent., Results: We found that each IIS reverberated throughout the network, differentially recruiting both excitatory and inhibitory cells in all connected nodes. The strongest response was found in iM2. Paradoxically, node cM2, which was connected disynaptically to the focus, was recruited more intensely than node cS1, which was connected monosynaptically. The explanation for this effect could be found in node-specific excitatory/inhibitory (E/I) balance, as cS1 demonstrated greater PV inhibitory cell activation compared with cM2, where Thy-1 excitatory cells were more heavily recruited., Significance: Our data show that IISs spread noncontiguously by exploiting fiber pathways that connect nodes in a distributed network and that E/I balance plays a critical role in node recruitment. This multinodal IIS network model can be used to investigate cell-specific dynamics in the spatial propagation of epileptiform activity., (© 2023 International League Against Epilepsy.)

Objectives: Dexmedetomidine is an alpha-2 agonist with anti-anxiety, sedative, and analgesic effects and causes a lesser degree of respiratory depression. We hypothesized that the use of dexmedetomidine in non-intubated video-assisted thoracic surgery (VATS) may reduce opioid-related complications such as postoperative nausea and vomiting (PONV), dyspnea, constipation, dizziness, skin itching, and cause minimal respiratory depression, and stable hemodynamic status., Methods: Patients who underwent non-intubated VATS lung wedge resection with propofol combined with dexmedetomidine (group D) or alfentanil (group O) between December 2016 and May 2022 were enrolled in this retrospective propensity score matching cohort study. Intraoperative vital signs, arterial blood gas data, perioperative results and treatment outcomes were analyzed. Of 100 patients included in the study (group D, 50 and group O, 50 patients), group D had a significantly lower degree of decrement in the heart rate and the blood pressure than group O. Intraoperative one-lung arterial blood gas revealed lower pH and significant ETCO 2 . The common opioid-related side effects, including PONV, dyspnea, constipation, dizziness, and skin itching, all of which occurred more frequently in group O than in group D. Patients in group O had significantly longer postoperative hospital stay and total hospital stay than group D, which might be due to opioid-related side effects postoperatively., Conclusions: The application of dexmedetomidine in non-intubated VATS resulted in a significant reduction in perioperative opioid-related complications and maintenance with acceptable hemodynamic performance. These clinical outcomes found in our retrospective study may enhance patient satisfaction and shorten the hospital stay., (© 2023. The Author(s).)

Purpose: Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep sedation is ambiguous. Deep sedation offers patient comfort as well as greater safety concerns. Unintended deep sedation can occur if drug interactions are overlooked. We present a pharmacodynamic model for moderate sedation using midazolam, alfentanil and propofol. The model is suitable for training and devising rationales for appropriate dosing., Methods: The study consists of two parts: modeling and validation. In modeling, patients scheduled for esophagogastroduodenoscopy (EGD) or colonoscopy sedation are enrolled. The modified observer's assessment of alertness/sedation (MOAA/S) score < 4 is defined as loss of response to represent moderate sedation. Two patient groups receiving bronchoscopy or endoscopic retrograde cholangiopancreatography (ERCP) are used for validation. Model performance is assessed by receiver operating characteristic (ROC) curves and area under the curve (AUC). Simulations are performed to demonstrate how the model is used to rationally determine drug regimen for moderate sedation., Results: Interaction between propofol and alfentanil is stronger than the other pairwise combinations. Additional synergy is observed with three drugs. ROC AUC is 0.83 for the modeling group, and 0.96 and 0.93 for ERCP and bronchoscopy groups respectively. Model simulation suggests that 1 mg midazolam, 250 µg alfentanil and propofol maximally benefits from drug interactions and suitable for moderate sedation., Conclusion: We demonstrate the accurate prediction of a three-drug response surface model for moderate sedation and simulation suggests a rational dosing strategy for moderate sedation with midazolam, alfentanil and propofol., (© 2023. The Author(s).)

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pharmacodynamic models have described the interactions between anesthetics. Applying the models to clinical practice is still problematic due to inherent limitations: 1. modeling conditions are different from practice. 2. One model can only describe one endpoint. To tackle these, we propose a new method of model validation for recovery and intraprocedural sedation adequacy with a three-drug pharmacodynamic model using six published clinical studies that contain midazolam, opioid, and propofol. Mean drug dose, intraprocedural sedation level, procedure, and recovery time are extracted from each study. Simulated drug regimens are designed to best approximate study conditions. A published deep sedation model is used for simulation. Model-predicted recovery time and intraprocedural sedation scores are compared with the original clinical study outcomes. The model successfully predicted recovery times in eight out of nine regimens. Lower doses of midazolam are associated with faster recovery. Model prediction of intraprocedural sedation level was compatible with the clinical studies in five out of seven regimens. The three-drug pharmacodynamic model describes the course of gastrointestinal endoscopy sedations from clinical studies well. Model predictions are consistent with the results from clinical studies. The approach implies that large scale validation can be performed repeatedly.

Given the popularity of ketogenic diets, their potential long-term consequences deserve to be more carefully monitored. Mitochondrially derived formate has a critical role in mammalian one-carbon (1C) metabolism and development. The glycine cleavage system (GCS) accounts for another substantial source for mitochondrially derived 1C units., Objective: We investigated how the ketogenic state modulates mitochondrial formate generation and partitioning of 1C metabolic fluxes., Design: HepG2 cells treated with physiological doses (1 mM and 10 mM) of β-hydroxybutyrate (βHB) were utilized as the in vitro ketogenic model. Eight-week male C57BL/6JNarl mice received either a medium-chain fatty-acid-enriched ketogenic diet (MCT-KD) or a control diet AIN 93M for 8 weeks. Stable isotopic labeling experiments were conducted., Results and Conclusions: MCT-KD is effective in weight and fat loss. Deoxythymidine (dTMP) synthesis from the mitochondrial GCS-derived formate was significantly suppressed by βHB and consumption of MCT-KD. Consistently, plasma formate concentrations, as well as the metabolic fluxes from serine and glycine, were suppressed by MCT-KD. MCT-KD also decreased the fractional contribution of mitochondrially derived formate in methionine synthesis from serine. With the worldwide application, people and medical professionals should be more aware of the potential metabolic perturbations when practicing a long-term ketogenic diet.

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Although they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus., Competing Interests: ES, JL, EM, TD, KT, BG, RE, RG, CS No competing interests declared, PH is affiliated with Neurosurgical Associates, LLC. The author has no financial interests to declare, GM reports fees from Koh Young, Inc, SS consulting for Boston Scientific, Abbott, Neuropace, Zimmer Biomet, JR reports fees from Medtronic, Inc, (© 2022, Smith et al.)

We present Rydberg-state electromagnetically-induced-transparency (EIT) measurements examining the effects of laser polarization, magnetic fields, laser intensities, and the optical density of the thermal 87 Rb medium. Two counter-propagating laser beams with wavelengths of 480 nm and 780 nm were employed to sweep the spectrum across the Rydberg states |33D 3/2 〉 and |33D 5/2 〉. An analytic transmission expression well fits the Rydberg-EIT spectra with multiple transitions under different magnetic fields and laser polarization after accounting for the relevant Clebsch-Gordan coefficients, Zeeman splittings, and Doppler shifts. In addition, the high-contrast Rydberg EIT can be optimized with the probe laser intensity and optical density. Rydberg EIT peak height was achieved at 13%, which is more than twice as high as the maximum peak height at room temperature. A quantitative theoretical model is employed to represent the spectra properties and to predict well the optimization conditions. A Rydberg EIT spectrum with high contrast in real time can be served as a quantum sensor to detect the electromagnetic field within an environment.

5-methoxytryptophan (5-MTP) is a recently discovered tryptophan (Trp) metabolite with anti-inflammatory and tumor-suppressing actions. Its synthesis is catalyzed by hydroxyindole O-methyltransferase (HIOMT). HIOMT levels were reported to be decreased in some patients with colorectal, pancreatic and breast cancer. It is unclear whether tissue HIOMT levels is altered in hepatocellular carcinoma (HCC). It is also unclear whether serum 5-MTP concentration is influenced by HCC. In this study, 150 HCC and adjacent normal liver tissues and serum samples were obtained from the HCC biobank established by a prospective multicenter study. Serum samples from 47 healthy subjects were included as a reference. HIOMT mRNA was measured by real time PCR. Serum 5-MTP and selected Trp metabolites were analyzed by quantitative LC-MS. HCC tissue HIOMT mRNA levels adjusted for adjacent normal tissue HIOMT mRNA levels was associated with overall and relapse-free (RF) survival. Combined serum 5-MTP or tissue HIOMT mRNA and serum kynurenine (Kyn) analysis predicted prolonged overall and RF survival following liver resection. A high serum 5-MTP or tissue HIOMT mRNA and low serum Kyn is associated with long-term survival. In conclusion, tumor tissue HIOMT mRNA and serum 5-MTP are potential biomarkers of HCC, especially when analyzed in combination with serum Kyn.

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

Background: Ultrasound-guided minimally invasive procedures are widely used to treat thyroid diseases. The objective of this study was to assess the efficacy and safety of ethanol ablation (EA) in comparison with other non-surgical options in the treatment of benign thyroid cystic nodules., Methods: We conducted a systematic search of studies on EA for thyroid cystic nodules, mainly in the Ovid-MEDLINE and Embase, Web of Science, and Cochrane databases. The standardized mean difference (SMD) of the volume reduction ratio (VRR) after EA versus other non-surgical treatments comprised the primary outcome, whereas the odds ratio (OR) of therapeutic success rates between the two groups comprised the secondary outcome., Results: The meta-analysis included 19 studies (four randomized controlled trials and 15 non-randomized studies) with 1,514 participants. The cumulative VRR of EA was 83.908% (95% confidence interval [CI], 79.358% to 88.457%). EA had a significantly higher pooled VRR (SMD, 0.381; 95% CI, 0.028 to 0.734; P=0.030), but not a significantly higher pooled therapeutic success rate (OR, 0.867; 95% CI, 0.132 to 5.689; P=0.880), than other forms of non-surgical management including radiofrequency ablation (RFA), polidocanol sclerotherapy, and simple aspiration with or without saline flush. However, the VRR and therapeutic success rate were not significantly different between EA and RFA. Major complications were recorded only in six patients (0.53%) with self-limiting dysphonia., Conclusion: The role of EA as the first-line treatment for benign thyroid cysts and predominantly cystic nodules is supported by its high effectiveness and good safety profile compared to other currently available non-surgical options.

Background: Inhalational anesthetic-induced burst suppression (BS) is classically considered a bilaterally synchronous rhythm. However, local asynchrony has been predicted in theoretical studies and reported in patients with pre-existing focal pathology. Method: We used high-speed widefield calcium imaging to study the spatiotemporal dynamics of isoflurane-induced BS in rats. Results: We found that isoflurane-induced BS is not a globally synchronous rhythm. In the neocortex, neural activity first emerged in a spatially shifting, variably localized focus. Subsequent propagation across the whole cortex was rapid, typically within <100 milliseconds, giving the superficial resemblance to global synchrony. Neural activity remained locally asynchronous during the bursts, forming complex recurrent propagating waves. Despite propagation variability, spatial sequences of burst propagation were largely preserved between the hemispheres, and neural activity was highly correlated between the homotopic areas. The critical role of the thalamus in cortical burst initiation was demonstrated by using unilateral thalamic tetrodotoxin injection. Conclusion: The classical impression that anesthetics-induced BS is a state of global brain synchrony is inaccurate. Bursts are a series of shifting local cortical events facilitated by thalamic projection that unfold as rapid, bilaterally asynchronous propagating waves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ming, Liou, Yang, Li, Chu, Zhou, Wu, Xu, Luo, Liang, Li, Pryor, Lin, Schwartz and Ma.)

High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.

5-methoxytryptophan (5-MTP) is an endothelial factor with anti-inflammatory properties. It is synthesized from L-tryptophan via two enzymatic steps: tryptophan hydroxylase-1 (TPH-1) and hydroxyindole O-methyltransferase. Lipopolysaccharide (LPS) and pro-inflammatory cytokines suppress endothelial 5-MTP production by inhibiting TPH-1 expression. 5-MTP protects endothelial barrier function and promotes endothelial repair, while it blocks vascular smooth muscle cell migration and proliferation by inhibiting p38 MAPK activation. 5-MTP controls macrophage transmigration and activation by inhibiting p38 MAPK and NF-κB activation. 5-MTP administration attenuates arterial intimal hyperplasia, defends against systemic inflammation and prevents renal fibrosis in relevant murine models. Serum 5-MTP level is depressed in human sepsis as well as in mice with sepsis-like disorder. It is reduced in chronic kidney disease and acute myocardial infarction in humans. The reported data suggest that serum 5-MTP may be a theranostic biomarker. In summary, 5-MTP represents a new class of tryptophan metabolite which defends against inflammation and inflammation-mediated tissue damage and fibrosis. It may be a valuable lead compound for developing new drugs to treat complex human inflammatory disorders.

Inflammation of the vascular microenvironment modulates distinct types of vascular cells, and plays important roles in promoting atherosclerosis, stenosis/restenosis, and vascular-related diseases. Nik-related kinase (Nrk), a member of the Ste20-type kinase family, has been reported to be selectively expressed in embryonic skeletal muscle. However, whether Nrk is expressed in adult vascular smooth muscle, and if it influences intimal hyperplasia is unclear. Here, we found that Nrk is abundantly expressed in cultured vascular smooth muscle cells (VSMC) and mouse arterial intima. Treatment of mouse VSMCs with lipopolysaccharide (LPS) or platelet-derived growth factor significantly reduced Nrk expression. In addition, expression of Nrk was significantly reduced in regions of neointimal formation caused by guide-wire carotid artery injuries in mice, as well as in human atherosclerotic tissues, when compared to normal vessels. We identified that expression of matrix metalloproteinases (MMP3, MMP8 and MMP12) and inflammatory cytokines/chemokines (CCL6, CCL8, CCL11, CXCL1, CXCL3, CXCL5 and CXCL9) are synergistically induced by Nrk siRNA in LPS-treated mouse VSMCs. Moreover, we found that resveratrol significantly impaired LPS- and Nrk siRNA-induced expression of MMP3, CCL8, CCL11, CXCL3 and CXCL5. These results suggested that Nrk may play important roles in regulating pathological progression of atherosclerosis or neointimal- hyperplasia-related vascular diseases.

Chronic kidney disease (CKD) accelerates the development of neointima formation at the anastomosis site of arteriovenous (AV) fistulas. Accumulation of certain uremic toxins has a deleterious effect on the cardiovascular system. The oral charcoal adsorbent, AST-120, reduces circulating and tissue uremic toxins, but its effect on neointima formation at an AV fistula is unknown. To understand the effect of CKD and AST-120 on neointima formation, we created AV fistulas (common carotid artery to the external jugular vein in an end-to-side anastomosis) in mice with and without CKD. AST-120 was administered in chow before and after AV fistula creation. Administration of AST-120 significantly decreased serum indoxyl sulfate levels in CKD mice. CKD mice had a larger neointima area than non-CKD mice, and administration of AST-120 in CKD mice attenuated neointima formation. Both smooth muscle cell and fibrin components were increased in CKD mice, and AST-120 decreased both. RNA expression of MMP-2, MMP-9, TNFα, and TGFβ was increased in neointima tissue of CKD mice, and AST-120 administration neutralized the expression. Our results provided in vivo evidence to support the role of uremic toxin-binding therapy on the prevention of neointima formation. Peri-operative AST-120 administration deserves further investigation as a potential therapy to improve AV fistula patency.

We developed a neural network model that can account for major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus, and postulates a role for synaptic plasticity in the emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this model can provide a roadmap and potentially an in silico testbed for future explorations of seizure mechanisms and clinical therapies., Competing Interests: JL, ES, LB, SB, GM, RG, RE, CS, LA No competing interests declared, (© 2020, Liou et al.)

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg 2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Burst suppression is an electroencephalogram pattern of globally symmetric alternating high amplitude activity and isoelectricity that can be induced by general anaesthetics. There is scattered evidence that burst suppression may become spatially non-uniform in the setting of underlying pathology. Here, we induced burst suppression with isoflurane in rodents and then created a neocortical acute seizure focus with injection of 4-aminopyridine (4-AP) in somatosensory cortex. Burst suppression events were recorded before and after creation of the focus using bihemispheric wide-field calcium imaging and multielectrode arrays. We find that the seizure focus elicits a rapid alteration in triggering, initiation, and propagation of burst suppression events. Compared with the non-seizing brain, bursts are triggered from the thalamus, initiate in regions uniquely outside the epileptic focus, elicit marked increases of multiunit activity and propagate towards the seizure focus. These findings support the rapid, widespread impact of focal epilepsy on the extended brain network., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Here, we found that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. We identified that 14-3-3ε induced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3ε-suppressed MT-1 expression. ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation. ZNF479-suppressed MT-1 expression was restored by silencing of ASH2L and DNMT1. Furthermore, ZNF479 expression was higher in HCC tissues than that in the non-cancerous tissues. Expression analyses revealed a positive correlation between the expression of ZNF479 and DNMT1, UHRF1, ASH2L, and Menin, and an inverse correlation with that of ZNF479, ASH2L, Menin, and MT-1 isoforms. Moreover, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B. Here, we found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC. Approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC.

Background: Awake craniotomy (AC) is performed to identify cerebral language center. The challenge of anesthesia is to maintain a calm, comfortable, and cooperative patient during the mapping phase. Response surface models (RSMs) are multidrug modeling algorithms. In this pharmacodynamic study, we investigate the first use of RSM with bispectral index (BIS) to predict patient's response to name calling (RNC) and wakefulness (complete neurological tests) during AC., Methods: The study is performed in two phases. We prospectively enrolled 40 patients who received video-assisted thoracoscopic surgery (VATS) using propofol and fentanyl as the modeling group. Effect-site concentrations (Ce) and BIS values were recorded and a RSM is built from the data set. We verified the RSM retrospectively in AC patients, designated as the validation group. Corresponding BIS values were analyzed for RNC and wakefulness., Results: A total of 155 data sets of propofol Ce, fentanyl Ce, and BIS pairs were available for modeling. The range of propofol and fentanyl Ce were 0 to 9.95 μg/mL and 0 to 3.69 ng/mL, respectively. Observed BIS ranged from 21 to 98. The model identified an additive interaction between propofol and an opioid. RNC at BIS 64 is predicted by the model and 70 is required for wakefulness., Conclusion: RSM built from VATS patients is verified with a separate group of AC patient. The BIS target advised for RSM-predicted wakefulness is 70. The model illustrates the timeline to wakefulness during AC under propofol and an opioid. It has implications in guiding, dosing, and estimation of time to wakefulness with propofol and an opioid.

Response surface models (RSMs) were used to predict effects of multiple drugs interactions. Our study was aimed to validate accuracy of the previous published volunteer models during transoesophageal echocardiography (TEE). This is a cross-sectional study with 20 patients scheduled for transesophageal echocardiography in Taipei Veterans General Hospital, Taiwan. Effect-site concentration pairs of alfentanil and propofol were recorded and converted to equivalent remifentanil and propofol effect-site concentrations. Observer's Assessment of Alertness/Sedation (OAA/S) scores were assessed every 2 minutes. Using these data, previous published models of loss of response (LOR), intolerable ventilatory depression (IVD), and loss of response to esophageal instrumentation (LREI) were then estimated. Accuracy of prediction is assessed by calculating the difference between the true response and the model-predicted probability. Clinical events such as interruption of TEE were recorded. The average procedure time was 11 minutes. Accuracy for prediction of LOR and LREI is 63.6% and 38.5%, respectively. There were four patients experienced desaturation for less than 1 minute, which were not predicted by IVD model, and one interruption of TEE due to involuntary movement. The previous published drug-interaction RSMs predict LOR well but not LREI for TEE sedation. Further studies using response surface methodology are needed to improve quality for TEE sedation and clinical implementation.

Focal adhesion kinase (FAK) plays an important role in vascular development, including the regulation of endothelial cell (EC) adhesion, migration, proliferation, and survival. 3'-deoxyadenosine (cordycepin) is known to suppress FAK expression, cell migration, and the epithelial⁻mesenchymal transition in hepatocellular carcinoma (HCC). However, whether cordycepin affects FAK expression and cellular functions in ECs and the specific molecular mechanism remain unclear. In this study, we found that cordycepin suppressed FAK expression and the phosphorylation of FAK (p-FAK) at Tyr397 in ECs. Cordycepin inhibited the proliferation, wound healing, transwell migration, and tube formation of ECs. Confocal microscopy revealed that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. The suppressed expression of FAK was accompanied by induced p53 and p21 expression in ECs. Finally, we demonstrated that cordycepin suppressed angiogenesis in an in vivo angiogenesis assay and reduced HCC tumor growth in a xenograft nude mice model. Our study indicated that cordycepin could attenuate cell proliferation and migration and may result in the impairment of the angiogenesis process and tumor growth via downregulation of FAK and induction of p53 and p21 in ECs. Therefore, cordycepin may be used as a potential adjuvant for cancer therapy.

Objective: The dynamics of the postictal period, which may demonstrate such dramatic clinical phenomena as focal neurological deficits, prolonged coma and immobility, and even sudden death, are poorly understood. We sought to classify and characterize postictal phases of bilateral tonic-clonic seizures based on electroencephalographic (EEG) criteria and associated clinical features., Methods: We performed a detailed electroclinical evaluation of the postictal period in a series of 31 bilateral tonic-clonic seizures in 16 patients undergoing epilepsy surgery evaluations for focal pharmacoresistant epilepsy with intracranial electrodes and time-locked video., Results: The postictal EEG demonstrated three clearly differentiated phases as follows: attenuation, a burst-attenuation pattern, and a return to continuous background, with abrupt, synchronized transitions between phases. Postictal attenuation was common, occurring in 84% of seizures in 94% of patients in this study. There was increased power in gamma frequencies (>25 Hz) during postictal attenuation periods relative to preictal baseline in 88% of seizures demonstrating the attenuation pattern (n = 25 seizures, P < 0.002). Such increases were seen in >90% of channels in 13 seizures (52%) and <10% of channels in three seizures (12%). Postictal immobility was seen in 87% of seizures, with either a flaccid (58%) or rigid/dystonic (29%) appearance. Clinical motor manifestations, including focal dystonic posturing, automatisms, head and eye deviation, and myoclonic jerking, continued or emerged within the first minute following seizure termination in 48% of seizures, regardless of EEG appearance., Significance: Intracranial postictal attenuation, which may be diffuse or focal, is so common that it should be regarded as a ubiquitous feature of bilateral tonic-clonic seizures, rather than an unusual event. The prominence of high-frequency activity coupled with emerging clinical features, including rigid immobility and semiologies such as automatisms, during the postictal period supports the presence of ongoing seizure-related neuronal activity in unrecorded brain regions., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Background: Sedation for esophagogastroduodenoscopy (EGD) and colonoscopy is characterized by rapid patient induction and emergence. The drugs midazolam and alfentanil have long been used for procedural sedation; however, the relationship between plasma or effect-site concentrations (Cp or Ce, respectively) and emergence remains unclear. The aim of this study is to develop patient wake-up prediction models for both Cp and Ce using response surface modeling, a pharmacodynamics tool for assessing patients' responses., Methods: The Observer's Alertness/Sedation (OAA/S) score was used to monitor sedation depth during the examinations. Concentration pairs of midazolam and alfentanil were calculated for each of Cp and Ce using pharmacokinetic simulation software. Response surface models were developed using the Greco construct. Temporal analysis was done by comparing model-predicted wake-up time with true patient wake-up time., Results: Thirty-three patients with an average body mass index of 21.85 ± 2.3 kg/m 2 were pooled for analysis. The average duration of examination were 2.9 ± 1.4 min for EGD and 6.6 ± 2.7 min for colonoscopy. Seventy-five concentration pairs of midazolam and alfentanil were obtained for each Cp and Ce. The Cp-based Greco response surface model showed significant synergy between midazolam and alfentanil and was a better predictor of patient wake-up time, with an average deviation of 1.0 ± 3.9 min, while the Ce model show time deviation greater than 20 min., Conclusion: The early phases of drug distribution are unique and complicated by nonsteady-state concentrations, and our study revealed that Ce-based wake-up time prediction is more difficult under these circumstances., (Copyright © 2018. Published by Elsevier B.V.)

Background/aim: Expression of 14-3-3ε is associated with prognostic outcomes of hepatocellular carcinoma (HCC) patients. Metallothionein-1 (MT-1) proteins and aldo-keto-reductase family 1 B10 (AKR1B10) are considered potential tumor regulators of HCC. The aim of this study, was to examine the prognostic value of 14-3-3ε, MT-1 and AKR1B10 expression in HCC., Materials and Methods: The expression levels of 14-3-3ε, MT-1 and AKR1B10 in HCC cell lines and paraffin-embedded tissues were examined by western blotting and immunohistochemical analysis., Results: 14-3-3ε positivity was significantly associated with decreased MT-1 expression in HCC. Patients with decreased MT-1 expression had worse survival rates and a higher risk of metastasis than 14-3-3ε-positive HCC patients with unchanged MT-1 expression. Distinct expression patterns of 14-3-3ε/MT-1/AKR1B10 were significantly associated with the metastatic incidence and survival rates of HCC patients. Patients with negative 14-3-3ε staining in primary tumors had better prognostic outcomes. In contrast, patients with positive 14-3-3ε staining, decreased MT-1 expression and no increase in AKR1B10 expression in primary tumors had the worst overall and disease-free survival rates and the highest metastatic risk., Conclusion: 14-3-3ε, AKR1B10, and MT-1 act as potential prognostic biomarkers of HCC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Researchers have used logistic regression (LR) and non-linear response surface models (RSMs) to predict patient responses to sedation. The reduced Greco and hierarchy RSMs have proven to be more appropriate than other RSMs in gastrointestinal endoscopies using midazolam and alfentanil. In this study, we evaluate the performance of a simpler model, LR, and compared it with that of RSM., Methods: Thirty-three patients who received esophagogastroduodenoscopy (EGD) and colonoscopy sedation with midazolam and alfentanil were enrolled in the study. LR was performed for the EGD group and validated using the colonoscopy group. The two RSMs were performed using the same process, and performances and receiver operating characteristic (ROC) curves of the models were evaluated., Results: The native EGD LR model had an ROC curve area of 0.94. For external validation, the ROC curves were 0.92, 0.94, and 0.94 for the reduced Greco, hierarchy, and LR models, respectively. Pairwise comparison between models was not significant., Conclusion: The LR model performed as well as RSM in generalizing the predicted sedative effect of midazolam and alfentanil during gastrointestinal endoscopies. LR may be used for generalization across patients experiencing procedures with similar stimulus intensities., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Acute hepatic injury caused by inflammatory liver disease is associated with high mortality. This study examined the role of caveolin-1 (Cav-1) in lipopolysaccharide (LPS) and D-galactosamine (GalN)-induced fulminant hepatic injury in wild type and Cav-1-null (Cav-1 -/- ) mice. Hepatic Cav-1 expression was induced post-LPS/GalN treatment in wild-type mice. LPS/GalN-treated Cav-1 -/- mice showed reduced lethality and markedly attenuated liver damage, neutrophil infiltration and hepatocyte apoptosis as compared to wild-type mice. Cav-1 deletion significantly reduced LPS/GalN-induced caspase-3, caspase-8 and caspase-9 activation and pro-inflammatory cytokine and chemokine expression. Additionally, Cav-1 -/- mice showed suppressed expression of Toll-like receptor 4 (TLR4) and CD14 in Kupffer cells and reduced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 in liver cells. Cav-1 deletion impeded LPS/GalN-induced inducible nitric oxide synthase expression and nitric oxide production and hindered nuclear factor-κB (NF-κB) activation. Taken together, Cav-1 regulated the expression of mediators that govern LPS-induced inflammatory signalling in mouse liver. Thus, deletion of Cav-1 suppressed the inflammatory response mediated by the LPS-CD14-TLR4-NF-κb pathway and alleviated acute liver injury in mice., (© 2018 Institute of Biomedical Sciences, Academia Sinica. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

[This corrects the article DOI: 10.18632/oncotarget.5734.].

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3-mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

Background: The non-linear mixed amount with zero amounts response surface model can be used to describe drug interactions and predict loss of response to noxious stimuli and respiratory depression. We aimed to determine whether this response surface model could be used to model sedation with the triple drug combination of midazolam, alfentanil and propofol., Methods: Sedation was monitored in 56 patients undergoing gastrointestinal endoscopy (modelling group) using modified alertness/sedation scores. A total of 227 combinations of effect-site concentrations were derived from pharmacokinetic models. Accuracy and the area under the receiver operating characteristic curve were calculated. Accuracy was defined as an absolute difference <0.5 between the binary patient responses and the predicted probability of loss of responsiveness. Validation was performed with a separate group (validation group) of 47 patients., Results: Effect-site concentration ranged from 0 to 108 ng ml -1 for midazolam, 0-156 ng ml -1 for alfentanil, and 0-2.6 μg ml -1 for propofol in both groups. Synergy was strongest with midazolam and alfentanil (24.3% decrease in U 50 , concentration for half maximal drug effect). Adding propofol, a third drug, offered little additional synergy (25.8% decrease in U 50 ). Two patients (3%) experienced respiratory depression. Model accuracy was 83% and 76%, area under the curve was 0.87 and 0.80 for the modelling and validation group, respectively., Conclusion: The non-linear mixed amount with zero amounts triple interaction response surface model predicts patient sedation responses during endoscopy with combinations of midazolam, alfentanil, or propofol that fall within clinical use. Our model also suggests a safety margin of alfentanil fraction <0.12 that avoids respiratory depression after loss of responsiveness., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

We report the lateral order and self-organized morphology of diblock copolymer polystyrene- block -poly(2-vinylpyridine), P(S- b -2VP), and micelles on silicon substrates (SiO x /Si). These micellar films were prepared by spin coating from polymer solutions of varied concentration of polymer in toluene onto SiO x /Si, and were investigated with grazing-incidence small-angle X-ray scattering (GISAXS) and an atomic force microscope (AFM). With progressively increased surface coverage with increasing concentration, loosely packed spherical micelles, ribbon-like nanostructures, and a second layer of spherical micelles were obtained sequentially. Quantitative analysis and simulations of the micellar packing demonstrates that the spatial ordering of the loosely packed spherical micelles altered from short-range order to hexagonal order when the micellar coverage increased from small to moderate densities of the covered surface. At large densities, anisotropic fusion between spherical micelles caused the ribbon-like nanostructures to have a short-range spatial order; the ordering quality of the second layer was governed by the rugged surface of the underlying layer because the valleys between the ribbon-like nanostructures allowed for further deposition of spherical micelles.

Background/purpose: The Stagnara wake-up test assesses neurological deficits during scoliosis surgery, and response surface interaction models for opioids and inhaled agents predicts anesthetic drug effects. We hypothesized that there is an optimal desflurane-fentanyl dosing regimen that can provide a faster and more predictable wake-up time, while also ensuring adequate analgesia during wake-up testing., Methods: Twenty-three American Society of Anesthesiologists Class I-II scoliosis patients who received desflurane-fentanyl anesthetic regimens were enrolled in this posthoc study, and their intraoperative drug administration data were collected retrospectively. Desflurane and fentanyl effect site concentrations were calculated using pharmacokinetic models, and converted to equivalent remifentanil-sevoflurane concentrations., Results: Results were fitted into Greco models for predicting the probability of an Observers Assessment of Alertness/Sedation score of <2. At time of wake-up, the models correctly predicted the probability that patients would respond to voice prompts and prodding was approximately 50%. The probability of pain intensity was distributed between 50% and 95%, indicating a low degree of pain at emergence. When comparing subgroups defined by calculated effect-site fentanyl concentrations, the wake-up time in the intermediate concentration group was significantly shorter than that in the high concentration group (p = 0.024)., Conclusion: This study provides evidence that desflurane-fentanyl-based anesthesia is conducive to rapid emergence followed by an immediate neurological evaluation. Intermediate fentanyl effect-site concentrations (1-2 ng/mL) at time of wake-up were associated with good balance between rapid emergence and adequate analgesia. Furthermore, we believe that generalizing response surface models to a variety of inhalation agent-opioid combinations using simple relative potency relationships is possible and practical., (Copyright © 2016. Published by Elsevier B.V.)

It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after both neuronal and hemodynamic onset. Glial calcium waves exhibited a stereotypical spread that terminated prior to seizure offset and propagated to an area ~60% greater than the propagation area of neural and vascular signals. Complete blockage of glial activity with fluoroacetate resulted in no change in either neuronal or hemodynamic activity. These ictal glial waves were blocked by carbenoxolone, a gap junction blocker. Our in vivo data reveal that ictal events trigger a slowly propagating, stereotypical glial calcium wave, mediated by gap junctions, that is spatially and temporally independent of neuronal and hemodynamic activities. We introduce a novel ictally triggered propagating glial calcium wave calling into question the criticality of glial calcium wave in both ictal onset and neurovascular coupling., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Modern anesthesia usually employs a hypnotic and an analgesic to produce synergistic sedation and analgesia. Two remifentanil-propofol interaction response surface models were used to predict sedation using Observer's Assessment of Alertness/Sedation (OAA/S) scores; one predicts an OAA/S <2 and the other <4. We hypothesized that both models would predict regained responsiveness (RR) after video-assisted thoracic surgery (VATS) to reduce total anesthesia time and make early extubation clinically relevant. We included 30 patients undergoing VATS received total intravenous anesthesia (TIVA) combined with thoracic epidural anesthesia (TEA). Pharmacokinetic profiles were calculated using Tivatrainer. Model predictions were compared with observations to evaluate the accuracy and precision of emergence model predictions. The mean (standard deviation) differences between when a patient responded to their name and the time when the model predicted a 50% probability of patient response were 30.80 ± 17.77 and 13.71 ± 11.35 minutes for the OAA/S <2 model and <4 model, respectively. Both models had a limited ability to predict patient response in our patients. Both models identified target concentration pairs predicting time of RR in volunteers and some elective surgeries, but another model of epidural and intravenous anesthetic combinations may be needed to predict time of RR after VATS under TIVA with TEA.

Background: Although antenatal steroids and early use nasal continuous positive airway pressure (NCPAP) have significantly improved outcomes of neonatal respiratory distress syndrome, intubation with ventilator support is still commonly required in extremely low birth weight (ELBW) infants. The optimal timing of extubation in ELBW infants remains unclear., Methods: We retrospectively analyzed all ELBW preterm infants who were admitted to our neonatal intensive care unit (NICU) from January 2009 to December 2013. Demographic, ventilation, and arterial blood gas analysis results prior to and 2 hours after extubation were collected. Extubation failure was defined as reintubation due to deterioration of respiratory condition within 7 days after extubation. Risk factors for extubation failure were analyzed., Results: In total, 173 ELBW infants were born and admitted to our NICU during these 5 years. Among these 173 infants, 77 (44.5%) used NCPAP only during their hospitalization (20 diagnosed with chronic lung disease (CLD), 25.9%). Among the 95 patients that required intubation, 27 patients expired so extubation was not attempted. Sixteen of 68 (23.5%) survival cases required reintubation within 7 days after extubation. We found that gestational age, birth body weight, and sex ratio did not differ between the successful extubation group and the failed extubation group. Univariate analysis showed that the failed extubation group had a lower arterial pH right before and 2 hours after extubation, with a lower bicarbonate level after extubation. Further multivariate logistic regression analysis revealed an association between poor acid-base homeostasis 2 hours after extubation (pH < 7.3 and HCO 3  < 18 mM/L) and extubation failure (odds ratio 4.56 and 6.187 and 95% confidence interval: 1.263∼16.462 and 1.68∼22.791, respectively)., Conclusion: This study shows that nearly half of ELBW infants do not require intubation. Among ELBW infants who require invasive ventilator support, those who have lower postextubation arterial pH and bicarbonate levels are at high risk of extubation failure., (Copyright © 2016. Published by Elsevier B.V.)

Maintaining stemness of leukemic stem cells (LSCs) and reciprocal interactions between leukemia and stromal cells support leukemic progression and resistance to chemotherapy. Targeting the niche-based microenvironment is thus a new approach for leukemia therapy. Cordycepin is an analogue of adenosine and has been suggested to possess anti-leukemia properties. However, whether cordycepin influences association of leukemia and mesenchymal stromal cells has never been investigated. Here we show that cordycepin reduces CD34 + CD38 - cells in U937 and K562 cells and induces Dkk1 expression via autocrine and paracrine regulation in leukemia and mesenchymal stromal/stem cells (MSCs). Cordycepin suppresses cell attachment of leukemia with MSCs and downregulates N-cadherin in leukemia and VCAM-1 in MSCs. Moreover, incubation with leukemic conditioned media (CM) significantly induces IL-8 and IL-6 expression in MSCs, which is abrogated by cordycepin. Suppression of leukemic CM-induced VCAM-1 and IL-8 by cordycepin in MSCs is mediated by impairing NFκB signaling. Finally, cordycepin combined with an adenosine deaminase inhibitor prolongs survival in a leukemic mouse model. Our results indicate that cordycepin is a potential anti-leukemia therapeutic adjuvant via eliminating LSCs and disrupting leukemia-stromal association.

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy., Competing Interests: The authors have declared that no conflict of interest exists.