Impact of preoperative white blood cell count on outcomes in different stage colorectal cancer patients undergoing surgical resection: a single-institution retrospective cohort study.

PURPOSE: To explore the association between preoperative WBC count and the long-term survival outcomes and clinical outcomes in different stage patients who underwent surgical resection for colorectal cancer (CRC). PATIENTS AND METHODS: A cohort of 8121 Chinese patients who underwent surgical resection for CRC from January 1, 2008 to December 31, 2014 were enrolled as part of the retrospective cohort were retrospectively analyzed. Based on that the preoperative WBC optimal cut-off value was 7*109/L (7,000/µL), the high preoperative WBC group and the low preoperative WBC group was defined. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. The impact of preoperative WBC count on overall survival (OS) and disease-free survival (DFS) was investigated using the Kaplan-Meier method and Univariate Cox proportional hazards models in different stage subgroup respectively. RESULTS: After IPTW, the clinical characters in the high preoperative WBC count group and the low preoperative WBC count group were balanced. Kaplan-Meier analysis showed that the 5-year OS rate were significantly lower in the high preoperative WBC count group overall, in stage II and IV. The 5-year DFS rate was significantly lower overall, in stage II and III in the high preoperative WBC count group. High preoperative WBC count was associated with poorer OS overall in stage II and stage IV. CONCLUSIONS: This study suggests that preoperative WBC count is an independent risk factor for survival in patients undergoing colorectal surgery and may need to consider the stage of cancer when applied to predict long-term adverse outcome prognosis.

Changes in information integration and brain networks during propofol-, dexmedetomidine-, and ketamine-induced unresponsiveness.

BACKGROUND: Information integration and network science are important theories for quantifying consciousness. However, whether these theories propose drug- or conscious state-related changes in EEG during anaesthesia-induced unresponsiveness remains unknown. METHODS: A total of 72 participants were randomised to receive i.v. infusion of propofol, dexmedetomidine, or ketamine at a constant infusion rate until loss of responsiveness. High-density EEG was recorded during the consciousness transition from the eye-closed baseline to the unresponsiveness state and then to the recovery of the responsiveness state. Permutation cross mutual information (PCMI) and PCMI-based brain networks in broadband (0.1-45 Hz) and sub-band frequencies were used to analyse drug- and state-related EEG signature changes. RESULTS: PCMI and brain networks exhibited state-related changes in certain brain regions and frequency bands. The within-area PCMI of the frontal, parietal, and occipital regions, and the between-area PCMI of the parietal-occipital region (median [inter-quartile ranges]), baseline vs unresponsive were as follows: 0.54 (0.46-0.58) vs 0.46 (0.40-0.50), 0.58 (0.52-0.60) vs 0.48 (0.44-0.53), 0.54 (0.49-0.59) vs 0.47 (0.42-0.52) decreased during anaesthesia for three drugs (P<0.05). Alpha PCMI in the frontal region, and gamma PCMI in the posterior area significantly decreased in the unresponsive state (P<0.05). The frontal, parietal, and occipital nodal clustering coefficients and parietal nodal efficiency decreased in the unresponsive state (P<0.05). The increased normalised path length in delta, theta, and gamma bands indicated impaired global integration (P<0.05). CONCLUSIONS: The three anaesthetics caused changes in information integration patterns and network functions. Thus, it is possible to build a quantifying framework for anaesthesia-induced conscious state changes on the EEG scale using PCMI and network science.

Consistency of limb preference across unimanual feeding, bipedal locomotion, and social grooming in golden snub-nosed monkeys (Rhinopithecus roxellana).

The golden snub-nosed monkey (Rhinopithecus roxellana) is a typical arboreal group-living Old World primate. While limb preference has been extensively studied in this species, limb preference consistency has not yet been explored. Here, based on 26 R. roxellana adults, we investigated whether individuals exhibit consistent motor biases in manual- (e.g., unimanual feeding and social grooming) and foot-related (e.g., bipedal locomotion) tasks and whether limb preference consistency is influenced by increased social interactions during social grooming. Results showed no consistency in the direction or strength of limb preference among tasks, except for lateral strength in handedness for unimanual feeding and footedness in the initiation of locomotion. Population-level foot preference was only found among right-handers. Marked lateral bias was found in unimanual feeding, indicating that it may be a sensitive behavioural measure for assessing manual preference, especially for provisioned populations. This study not only improves our understanding of the relationship between hand and foot preference in R. roxellana but also reveals potential differential hemispheric regulation of limb preference and the influence of increased social interaction on handedness consistency.

MM-associated circular RNA downregulates microRNA-19a through methylation to suppress proliferation of pancreatic adenocarcinoma cells.

Opposite roles of circular RNA MM-associated circular RNA (circ-MYBL2) have been observed in different malignancies, and its role in pancreatic adenocarcinoma (PA) is unknown. Our preliminary sequencing data revealed its inverse correlation with microRNA-19a (miR-19a). This study was performed to explore the role of circ-MYBL2 in PA and its crosstalk with miR-19a. The accumulation of circ-MYBL2 and miR-19a in PA was detected by RT-qPCR. Participation of circ-MYBL2 in the regulation of miR-19a and its RNA gene methylation was studied with an overexpression assay, followed by RT-qPCR and MSP analyses. The role of miR-19a and circ-MYBL2 in PA cell proliferation and movement was evaluated using the BrdU assay and the Transwell assay, respectively. Downregulation of circ-MYBL2 and upregulation of miR-19a were observed in PA. In PA cells, circ-MYBL2 decreased the accumulation of miR-19a but increased its RNA gene methylation. Overexpression of circ-MYBL2 decreased PA cell proliferation and movement, while overexpression of miR-19a showed an opposite effect. In addition, circ-MYBL2 suppressed the role of miR-19a in cell proliferation, migration, and invasion. In conclusion, circ-MYBL2 was downregulated in PA and it downregulated miR-19a through methylation to suppress PA cell proliferation.

Protective effect of Alpinetin on rats with chronic obstructive pulmonary disease.

To investigate the function and mechanism of Alpinetin on chronic obstructive pulmonary disease (COPD) in rat model. The markers of lung injury (body weight/pulmonary function) were measured, and the protein levels of inflammatory-, apoptosis-, and fibrotic-related were determined by Western blot. HE/TUNEL/Masson staining was performed to investigate the mechanisms involved. The levels of inflammatory factors lung injury were detected by ELISA. The in vivo activities of all molecules were determined using a rat model. Alpinetin suppressed the injury of alveolus pulmonis cells occurred in vivo due to the decrease in inflammatory factors and biochemical markers by reduced the expression of TGF-ß1, α-SMA, and TNF-α (p < .05), associated with the declined of Caspase-3 and Caspase-9 (p < .01). Additionally, protective affection of Alpinetin downregulated the IL-6 and upregulated the IL-10 (p < .01). Protective affection of Alpinetin inhibits the apoptosis, inflammation, and fibrosis of alveolus pulmonis cells in rat models.

Altered Global Brain Signal during Physiologic, Pharmacologic, and Pathologic States of Unconsciousness in Humans and Rats.

BACKGROUND: Consciousness is supported by integrated brain activity across widespread functionally segregated networks. The functional magnetic resonance imaging-derived global brain signal is a candidate marker for a conscious state, and thus the authors hypothesized that unconsciousness would be accompanied by a loss of global temporal coordination, with specific patterns of decoupling between local regions and global activity differentiating among various unconscious states. METHODS: Functional magnetic resonance imaging global signals were studied in physiologic, pharmacologic, and pathologic states of unconsciousness in human natural sleep (n = 9), propofol anesthesia (humans, n = 14; male rats, n = 12), and neuropathological patients (n = 21). The global signal amplitude as well as the correlation between global signal and signals of local voxels were quantified. The former reflects the net strength of global temporal coordination, and the latter yields global signal topography. RESULTS: A profound reduction of global signal amplitude was seen consistently across the various unconscious states: wakefulness (median [1st, 3rd quartile], 0.46 [0.21, 0.50]) versus non-rapid eye movement stage 3 of sleep (0.30 [0.24, 0.32]; P = 0.035), wakefulness (0.36 [0.31, 0.42]) versus general anesthesia (0.25 [0.21, 0.28]; P = 0.001), healthy controls (0.30 [0.27, 0.37]) versus unresponsive wakefulness syndrome (0.22 [0.15, 0.24]; P < 0.001), and low dose (0.07 [0.06, 0.08]) versus high dose of propofol (0.04 [0.03, 0.05]; P = 0.028) in rats. Furthermore, non-rapid eye movement stage 3 of sleep was characterized by a decoupling of sensory and attention networks from the global network. General anesthesia and unresponsive wakefulness syndrome were characterized by a dissociation of the majority of functional networks from the global network. This decoupling, however, was dominated by distinct neuroanatomic foci (e.g., precuneus and anterior cingulate cortices). CONCLUSIONS: The global temporal coordination of various modules across the brain may distinguish the coarse-grained state of consciousness versus unconsciousness, while the relationship between the global and local signals may define the particular qualities of a particular unconscious state.

Novel circular RNAs expressed in brain microvascular endothelial cells after oxygen-glucose deprivation/recovery.

Circular RNAs (circRNAs) are generated by head-to-tail splicing and are ubiquitously expressed in all multicellular organisms. Their important biological functions are increasingly recognized. Cerebral ischemia reperfusion injury-induced brain microvascular endothelial cell dysfunction is an initial stage of blood-brain barrier disruption. The expression profile and potential function of circRNAs in brain microvascular endothelial cells is unknown. Rat brain microvascular endothelial cells were extracted and cultured in glucose-free medium for 4 hours with 5% CO2 and 95% N2, and the medium was then replaced with complete growth medium for 6 hours. The RNA in these cells was then extracted. The circRNA was identified by Find_circ and CIRI2 software. Functional and pathway enrichment analysis of genes that were common to differentially expressed mRNAs and circRNA host genes was performed by the Database for Annotation, Visualization and Integrated Discovery Functional Annotation Tool. Miranda software was used to predict microRNAs that were potentially spong-ed by circRNAs. Furthermore, cytoscape depicted the circR-NA-microRNA interaction network. The results showed that there were 1288 circRNAs in normal and oxygen-glucose deprived/recovered primary brain microvascular endothelial cells. There are 211 upregulated and 326 downregulated differentially expressed circRNAs. The host genes of these differentially expressed circRNAs overlapped with those of differentially expressed mRNAs. The shared genes were further studied by functional enrichment analyses, which revealed that circRNAs may contribute to calcium ion function and the cyclic guanosine 3',5'-monophosphate (CAMP) dependent protein kinase (PKα) signaling pathway. Next, quantitative reverse transcription polymerase chain reaction assays were performed to detect circRNA levels transcribed from the overlapping host genes. Eight out of the ten circRNAs with the highest fold-change identified by sequencing were successfully verified. Subsequently, the circRNA-microRNA interaction networks of these eight circRNAs were explored by bioinformatic analysis. These results demonstrate that altered circRNAs may be important in the pathogenesis of cerebral ischemia reperfusion injury and consequently may also be potential therapeutic targets for cerebral ischemia diseases. All animal experiments were approved by the Chongqing Medical University Committee on Animal Research, China (approval No. CQMU20180086) on March 22, 2018.

Disrupted neural variability during propofol-induced sedation and unconsciousness.

Variability quenching is a widespread neural phenomenon in which trial-to-trial variability (TTV) of neural activity is reduced by repeated presentations of a sensory stimulus. However, its neural mechanism and functional significance remain poorly understood. Recurrent network dynamics are suggested as a candidate mechanism of TTV, and they play a key role in consciousness. We thus asked whether the variability-quenching phenomenon is related to the level of consciousness. We hypothesized that TTV reduction would be compromised during reduced level of consciousness by propofol anesthetics. We recorded functional magnetic resonance imaging signals of resting-state and stimulus-induced activities in three conditions: wakefulness, sedation, and unconsciousness (i.e., deep anesthesia). We measured the average (trial-to-trial mean, TTM) and variability (TTV) of auditory stimulus-induced activity under the three conditions. We also examined another form of neural variability (temporal variability, TV), which quantifies the overall dynamic range of ongoing neural activity across time, during both the resting-state and the task. We found that (a) TTM deceased gradually from wakefulness through sedation to anesthesia, (b) stimulus-induced TTV reduction normally seen during wakefulness was abolished during both sedation and anesthesia, and (c) TV increased in the task state as compared to resting-state during both wakefulness and sedation, but not anesthesia. Together, our results reveal distinct effects of propofol on the two forms of neural variability (TTV and TV). They imply that the anesthetic disrupts recurrent network dynamics, thus prevents the stabilization of cortical activity states. These findings shed new light on the temporal dynamics of neuronal variability and its alteration during anesthetic-induced unconsciousness.

Breakdown in the temporal and spatial organization of spontaneous brain activity during general anesthesia.

Which temporal features that can characterize different brain states (i.e., consciousness or unconsciousness) is a fundamental question in the neuroscience of consciousness. Using resting-state functional magnetic resonance imaging (rs-fMRI), we investigated the spatial patterns of two temporal features: the long-range temporal correlations (LRTCs), measured by power-law exponent (PLE), and temporal variability, measured by standard deviation (SD) during wakefulness and anesthetic-induced unconsciousness. We found that both PLE and SD showed global reductions across the whole brain during anesthetic state comparing to wakefulness. Importantly, the relationship between PLE and SD was altered in anesthetic state, in terms of a spatial "decoupling." This decoupling was mainly driven by a spatial pattern alteration of the PLE, rather than the SD, in the anesthetic state. Our results suggest differential physiological grounds of PLE and SD and highlight the functional importance of the topographical organization of LRTCs in maintaining an optimal spatiotemporal configuration of the neural dynamics during normal level of consciousness. The central role of the spatial distribution of LRTCs, reflecting temporo-spatial nestedness, may support the recently introduced temporo-spatial theory of consciousness (TTC).

Multilevel Thoracic Paravertebral Block Using Ropivacaine With/Without Dexmedetomidine in Video-Assisted Thoracoscopic Surgery.

OBJECTIVES: Thoracic paravertebral block (TPVB) is reported to have advantages in postoperative pain management in unilateral thoracic surgeries. Previous studies have demonstrated that dexmedetomidine could be used as an adjuvant to local anesthetics, with the aim of prolonging the duration of neural blockade. However, little is known about whether such a combination could improve the quality of postoperative analgesia compared with local anesthetic only when TPVB is used for patients undergoing video-assisted thoracoscopic surgery (VATS). DESIGN: A prospective, randomized, controlled study. SETTING: Single-center university hospital. PARTICIPANTS: The study included 60 patients undergoing VATS under general anesthesia. INTERVENTIONS: The patients were allocated randomly into the following 2 groups: 0.375% ropivacaine, 20 mL only (group R, n = 30), and 0.375% ropivacaine, 20 mL plus 1 µg/kg of dexmedetomidine (group RD, n = 30). At the end of surgery, TPVB guided using ultrasound was performed at 4 points-T4-5, T5-6, T6-7, and T7-8-of the surgical side; 5 mL of solution were injected at each point. Postoperatively, the intravenous nonsteroidal anti-inflammatory drug flurbiprofen was used as part of multimodal analgesia. MEASUREMENTS AND MAIN RESULTS: Pain scores at rest and during coughing were evaluated by a blinded observer in the postanesthesia care unit postoperatively at 1, 2, 4, 8, 12, 24, 36, and 48 hours, and the dermatomal levels of sensory blockade, postoperative requirements for rescue analgesia, adverse events, and patient satisfaction also were recorded. There was a significant reduction in postoperative pain scores at rest starting from the postoperative 8th hour until the 48th hour and during coughing starting at the postoperative 4th hour until the 48th hour in the group RD compared with those in group R (p = 0.043). The dermatomal levels of sensory blockade were comparable in the 2 groups. Patient satisfaction after surgery was significantly higher in the group RD than in group R (p < 0.001). Total consumption of the intravenous rescue analgesic morphine and adverse events were not significantly different between the 2 groups. CONCLUSIONS: Compared with ropivacaine only, the addition of dexmedetomidine, 1 µg/kg, to local anesthetic for multilevel TPVB in patients undergoing VATS prolonged the duration of postoperative analgesia and improved patient satisfaction without serious side effects when combined with postoperative intravenous nonsteroidal anti-inflammatory drug administration.

A comparison report of three advanced methods for drug-cyclodextrin interaction measurements.

Three advanced methods, high performance affinity chromatography (HPAC), surface plasmon resonance (SPR) and surface plasmon resonance imaging (SPRi) were compared and evaluated for determining the drug-cyclodextrin (CD) interactions herein. In total, 18 sparingly soluble drugs were selected for this comparative study. The three methods share a unique connection in the working principles and strategies. The same strategies of CD fixation onto solid phase were used in HPAC and SPR for the measurements, whereas, the SPR and SPRi share identical working principles. However, whilst these relationships are evident, no strong correlation was found between kinetic constants obtained from the three methods: Four drugs, namely, prednisolone, pseudolaric acid B, diazepam and gramisetron failed to show any response on SPR, whereas, the kinetics parameters from SPRi and HPAC were successfully measured. From a comparative review of all the kinetic data, random results without any trends were observed (ka, kd and KA) regardless of the relationships between the three methods: It is apparent that the measurement conditions (volume, flow rate, buffers), non-specific adsorption and experimental procedures had a strong impact on the generated data. The relative advantages and limitations of each method are critically presented on the basis of generated data. This comparative study provides a basis to further upgrade these techniques for confident measurement of drug-CDs interactions.

Solvents effects on crystallinity and dissolution of ß-artemether.

ß-artemether (ARM) is a widely used anti-malarial drug isolated from the Chinese antimalarial plant, Artemisia annua. The solvent effects on crystal habits and dissolution of ARM were thoroughly investigated and discussed herein. The ARM was recrystallized in nine different solvents of varied polarity, namely, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, acetone and hexane by solvent evaporation method. The obtained crystals were morphologically characterized using scanning electron microscope (SEM). The average sizes of crystals were 1.80-2.64 µm calculated from microscopic images using Image-Pro software. No significant change in chemical structure was noticed after recrystallization and the specific band at 875 cm-1 wavenumber (C-O-O-C) confirmed the presence of most sensitive functional group in the ARM chemical structure. The existence and production of two polymorphic forms, polymorph A and polymorph B, was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The data suggested that the fabrication of polymorph B can be simply obtained from the recrystallization of ARM in a specific solvent. Significant effects of solvent polarity, crystals shapes and sizes on drug dissolution were noticed during in vitro dissolution test. The release kinetics were calculated and well fitted by the Higuchi and Hixon-Crowell models. The ARM-methanol and ARM-hexane showed highest and slowest dissolution, respectively, due to the effects of solvent polarity and crystal morphologies. Overall, proper selection of the solvents for the final crystallization of ARM helps to optimize dissolution and bioavailability for a better delivery of anti-malarial drug.

Sodium dodecyl sulfate/ß-cyclodextrin vesicles embedded in chitosan gel for insulin delivery with pH-selective release.

In an answer to the challenge of enzymatic instability and low oral bioavailability of proteins/peptides, a new type of drug-delivery vesicle has been developed. The preparation, based on sodium dodecyl sulfate (SDS) and ß-cyclodextrin (ß-CD) embedded in chitosan gel, was used to successfully deliver the model drug-insulin. The self-assembled SDS/ß-CD vesicles were prepared and characterized by particle size, zeta potential, appearance, microscopic morphology and entrapment efficiency. In addition, both the interaction of insulin with vesicles and the stability of insulin loaded in vesicles in the presence of pepsin were investigated. The vesicles were crosslinked into thermo-sensitive chitosan/ß-glycerol phosphate solution for an in-situ gel to enhance the dilution stability. The in vitro release characteristics of insulin from gels in media at different pH values were investigated. The insulin loaded vesicles-chitosan hydrogel (IVG) improved the dilution stability of the vesicles and provided pH-selective sustained release compared with insulin solution-chitosan hydrogel (ISG). In vitro, IVG exhibited slow release in acidic solution and relatively quick release in neutral solutions to provide drug efficacy. In simulated digestive fluid, IVG showed better sustained release and insulin protection properties compared with ISG. Thus IVG might improve the stability of insulin during its transport in vivo and contribute to the bioavailability and therapeutic effect of insulin.

A novel combination of the Arndt endobronchial blocker and the laryngeal mask airway ProSeal™ provides one-lung ventilation for thoracic surgery.

In this study, the feasibility and performance of the combination of the Arndt endobronchial blocker and the laryngeal mask airway (LMA) ProSeal™ in airway establishment, ventilation, oxygenation and lung isolation was evaluated. Fifty-five patients undergoing general anesthesia for elective thoracic surgeries were randomly allocated to group Arndt (n=26) or group double-lumen tube (DLT; n=29). Data concerning post-operative airway morbidity, ease of insertion, hemodynamics, lung collapse, ventilators, oxygenation and ventilation were collected for analysis. Compared with group DLT, group Arndt showed a significantly attenuated hemodynamic response to intubation (blood pressure, 149±31 vs. 115±16 mmHg; heart rate, 86±15 vs. 68±15 bpm), less severe injuries to the bronchus (injury score, 1.4±0.2 vs. 0.4±0.1) and vocal cords (injury score, 1.3±0.2 vs. 0.6±0.1), and lower incidences of post-operative sore throat and hoarseness. Furthermore, the novel combination of the Arndt and the LMA ProSeal showed similar ease of airway establishment, comparable ventilation and oxygenation performance, and an analogous lung isolation effect to DLT. The novel combined use of the Arndt endobronchial blocker and the LMA ProSeal can serve as a promising alternative for thoracic procedures requiring one-lung ventilation. The less traumatic properties and equally ideal lung isolation are likely to promote its use in rapidly spreading minimally invasive thoracic surgeries.