Electroencephalographic features of elderly patients during anesthesia induction with remimazolam: a sub-study of a randomized controlled trial.

BACKGROUND: Although remimazolam is used as a general anesthetic in elderly patients due to its hemodynamic stability, the electroencephalogram (EEG) characteristics of remimazolam are not well-known. The purpose of this study was to identify the EEG features of remimazolam-induced unconsciousness in elderly patients and compare them with propofol. METHODS: Remimazolam (n=26) or propofol (n=26) were randomly administered for anesthesia induction in surgical patients. The hypnotic agent was blinded only to the patients. During the induction of anesthesia, remimazolam was administered at a rate of 6 mg/kg/h, and propofol was administered at a target effect-site concentration of 3.5 µg/ml. The EEG signals from 8 channels (Fp1,Fp2,Fz,F3,F4,Pz,P3,P4, referenced to A2, using the 10-20 system) were acquired during the induction of anesthesia and in the postoperative care unit. Power spectrum analysis was performed, and directed functional connectivity between frontal and parietal regions was evaluated using normalized symbolic transfer entropy. Functional connectivity in unconscious processes induced by remimazolam or propofol was compared with baseline. To compare each power of frequency over time of the two hypnotic agents, a permutation test with t statistic was conducted. RESULTS: Compared to the baseline in the alpha band, the feedback connectivity decreased by an average of 46% and 43%, respectively, after the loss of consciousness induced by remimazolam and propofol (95% CI for the mean difference:-0.073 to -0.044 for remimazolam, P<0.001,-0.068 to -0.042 for propofol,P<0.001). Asymmetry in the feedback and feedforward connectivity in the alpha band was suppressed after the loss of consciousness induced by remimazolam and propofol. There were no significant differences in the power of each frequency over time between the two hypnotic agents (minimum q-value=0.4235). CONCLUSIONS: Both regimens showed a greater decrease in feedback connectivity compared to a decrease in feedforward connectivity after loss of consciousness, leading to a disruption of asymmetry between the frontoparietal connectivity.

Neuromodulation of inhibitory control using phase-lagged transcranial alternating current stimulation.

BACKGROUND: Transcranial alternating current stimulation (tACS) is a prominent non-invasive brain stimulation method for modulating neural oscillations and enhancing human cognitive function. This study aimed to investigate the effects of individualized theta tACS delivered in-phase and out-of-phase between the dorsal anterior cingulate cortex (dACC) and left dorsolateral prefrontal cortex (lDLPFC) during inhibitory control performance. METHODS: The participants engaged in a Stroop task with phase-lagged theta tACS over individually optimized high-density electrode montages targeting the dACC and lDLPFC. We analyzed task performance, event-related potentials, and prestimulus electroencephalographic theta and alpha power. RESULTS: We observed significantly reduced reaction times following out-of-phase tACS, accompanied by reduced frontocentral N1 and N2 amplitudes, enhanced parieto-occipital P1 amplitudes, and pronounced frontocentral late sustained potentials. Out-of-phase stimulation also resulted in significantly higher prestimulus frontocentral theta and alpha activity. CONCLUSIONS: These findings suggest that out-of-phase theta tACS potently modulates top-down inhibitory control, supporting the feasibility of phase-lagged tACS to enhance inhibitory control performance.

Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice.

Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

The thalamocortical inhibitory network controls human conscious perception.

Although conscious perception is a fundamental cognitive function, its neural correlates remain unclear. It remains debatable whether thalamocortical interactions play a decisive role in conscious perception. To clarify this, we used functional magnetic resonance imaging (fMRI) where flickering red and green visual cues could be perceived either as a non-fused colour or fused colour. Here we show significantly differentiated fMRI neurodynamics only in higher-order thalamocortical regions, compared with first-order thalamocortical regions. Anticorrelated neurodynamic behaviours were observed between the visual stream network and default-mode network. Its dynamic causal modelling consistently provided compelling evidence for the involvement of higher-order thalamocortical iterative integration during conscious perception of fused colour, while inhibitory control was revealed during the non-fusion condition. Taken together with our recent magnetoencephalography study, our fMRI findings corroborate a thalamocortical inhibitory model for consciousness, where both thalamic inhibitory regulation and integrative signal iterations across higher-order thalamocortical regions are essential for conscious perception.

Effect of Echinochrome A on Submandibular Gland Dysfunction in Ovariectomized Rats.

Post-menopausal dry mouth or xerostomia is caused by reduced salivary secretion. This study aimed to investigate the efficacy of echinochrome A (Ech A) in alleviating submandibular gland dysfunctions in ovariectomized rats that mimic menopause. Female rats that were eight-weeks-old were randomly divided into SHAM-6, -12; OVX-6, -12; and ECH-6, -12 groups (consisting of 6- and 12-weeks post-sham-operated, ovariectomized, and Ech A-treated ovariectomized rats, respectively). The ECH groups had lower body weight than OVX but similar food intake and estradiol or estrogen receptor ß expression. However, the ECH groups had lower mRNA expression of sterol-regulatory element binding protein-1c (Srebp-1c), acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), cluster of differentiation 36 (Cd36), and lipid vacuole deposition than OVX mice. Moreover, reactive oxygen species (ROS), malondialdehyde (MDA), and iron accumulation were lower in the ECH than in the OVX groups. Fibrosis markers, transforming growth factor ß (Tgf-ßI and Tgf-ßII mRNA) increased in the OVX than SHAM groups but decreased in the ECH groups. Aquaporin (Aqp-1 and Aqp-5 mRNA) and mucin expressions were downregulated in the OVX groups but improved with Ech A. In addition, Ech A prevented post-menopausal salivary gland dysfunction by inhibiting lipogenesis and ferroptosis. These findings suggest Ech A as an effective remedy for treating menopausal dry mouth.

Echinochrome A Treatment Alleviates Fibrosis and Inflammation in Bleomycin-Induced Scleroderma.

Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.

Mechanisms of hysteresis in human brain networks during transitions of consciousness and unconsciousness: Theoretical principles and empirical evidence.

Hysteresis, the discrepancy in forward and reverse pathways of state transitions, is observed during changing levels of consciousness. Identifying the underlying mechanism of hysteresis phenomena in the brain will enhance the ability to understand, monitor, and control state transitions related to consciousness. We hypothesized that hysteresis in brain networks shares the same underlying mechanism of hysteresis as other biological and non-biological networks. In particular, we hypothesized that the principle of explosive synchronization, which can mediate abrupt state transitions, would be critical to explaining hysteresis in the brain during conscious state transitions. We analyzed high-density electroencephalogram (EEG) that was acquired in healthy human volunteers during conscious state transitions induced by the general anesthetics sevoflurane or ketamine. We developed a novel method to monitor the temporal evolution of EEG networks in a parameter space, which consists of the strength and topography of EEG-based networks. Furthermore, we studied conditions of explosive synchronization in anatomically informed human brain network models. We identified hysteresis in the trajectory of functional brain networks during state transitions. The model study and empirical data analysis explained various hysteresis phenomena during the loss and recovery of consciousness in a principled way: (1) more potent anesthetics induce a larger hysteresis; (2) a larger range of EEG frequencies facilitates transitions into unconsciousness and impedes the return of consciousness; (3) hysteresis of connectivity is larger than that of EEG power; and (4) the structure and strength of functional brain networks reconfigure differently during the loss vs. recovery of consciousness. We conclude that the hysteresis phenomena observed during the loss and recovery of consciousness are generic network features. Furthermore, the state transitions are grounded in the same principle as state transitions in complex non-biological networks, especially during perturbation. These findings suggest the possibility of predicting and modulating hysteresis of conscious state transitions in large-scale brain networks.

Neurophysiologic Correlates of Ketamine Sedation and Anesthesia: A High-density Electroencephalography Study in Healthy Volunteers.

BACKGROUND: Previous studies have demonstrated inconsistent neurophysiologic effects of ketamine, although discrepant findings might relate to differences in doses studied, brain regions analyzed, coadministration of other anesthetic medications, and resolution of the electroencephalograph. The objective of this study was to characterize the dose-dependent effects of ketamine on cortical oscillations and functional connectivity. METHODS: Ten healthy human volunteers were recruited for study participation. The data were recorded using a 128-channel electroencephalograph during baseline consciousness, subanesthetic dosing (0.5 mg/kg over 40 min), anesthetic dosing (1.5 mg/kg bolus), and recovery. No other sedative or anesthetic medications were administered. Spectrograms, topomaps, and functional connectivity (weighted and directed phase lag index) were computed and analyzed. RESULTS: Frontal theta bandwidth power increased most dramatically during ketamine anesthesia (mean power ± SD, 4.25 ± 1.90 dB) compared to the baseline (0.64 ± 0.28 dB), subanesthetic (0.60 ± 0.30 dB), and recovery (0.68 ± 0.41 dB) states; P < 0.001. Gamma power also increased during ketamine anesthesia. Weighted phase lag index demonstrated theta phase locking within anterior regions (0.2349 ± 0.1170, P < 0.001) and between anterior and posterior regions (0.2159 ± 0.1538, P < 0.01) during ketamine anesthesia. Alpha power gradually decreased with subanesthetic ketamine, and anterior-to-posterior directed connectivity was maximally reduced (0.0282 ± 0.0772) during ketamine anesthesia compared to all other states (P < 0.05). CONCLUSIONS: Ketamine anesthesia correlates most clearly with distinct changes in the theta bandwidth, including increased power and functional connectivity. Anterior-to-posterior connectivity in the alpha bandwidth becomes maximally depressed with anesthetic ketamine administration, suggesting a dose-dependent effect.

Vulnerability-Based Critical Neurons, Synapses, and Pathways in the Caenorhabditis elegans Connectome.

Determining the fundamental architectural design of complex nervous systems will lead to significant medical and technological advances. Yet it remains unclear how nervous systems evolved highly efficient networks with near optimal sharing of pathways that yet produce multiple distinct behaviors to reach the organism's goals. To determine this, the nematode roundworm Caenorhabditis elegans is an attractive model system. Progress has been made in delineating the behavioral circuits of the C. elegans, however, many details are unclear, including the specific functions of every neuron and synapse, as well as the extent the behavioral circuits are separate and parallel versus integrative and serial. Network analysis provides a normative approach to help specify the network design. We investigated the vulnerability of the Caenorhabditis elegans connectome by performing computational experiments that (a) "attacked" 279 individual neurons and 2,990 weighted synaptic connections (composed of 6,393 chemical synapses and 890 electrical junctions) and (b) quantified the effects of each removal on global network properties that influence information processing. The analysis identified 12 critical neurons and 29 critical synapses for establishing fundamental network properties. These critical constituents were found to be control elements-i.e., those with the most influence over multiple underlying pathways. Additionally, the critical synapses formed into circuit-level pathways. These emergent pathways provide evidence for (a) the importance of backward locomotion, avoidance behavior, and social feeding behavior to the organism; (b) the potential roles of specific neurons whose functions have been unclear; and

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress.

AIMS/HYPOTHESIS: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity. METHODS: Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. RESULTS: We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. CONCLUSIONS/INTERPRETATION: Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress.

The incidence and risk factors of acute kidney injury after hepatobiliary surgery: a prospective observational study.

BACKGROUND: Although intraperitoneal surgery is a major operation associated with postoperative acute kidney injury (AKI), the incidence, risk factors, and long-term renal outcome are not well known. We aimed to determine the risk factors and 6 months renal outcome in patients with clinical or subclinical AKI after hepatobiliary surgery. We also assessed the validity of urine neutrophil gelatinase-associated lipocalin (NGAL) in the early detection of AKI or prediction of renal outcome. METHODS: This prospective observational study enrolled patients with normal renal function who underwent hepatobiliary surgeries. Urine and serum samples were collected for NGAL measurement. RESULTS: Among 131 patients, 10 (7.6%) developed postoperative AKI. Urine NGAL at 12 h postsurgery was the most predictive parameter for the diagnosis of AKI (cutoff, 92.85 ng/mL). With the cutoff value, subclinical AKI was diagnosed in 42 (32.1%) patients. Patients with clinical AKI and those with subclinical AKI were assigned to the AKI group. The AKI group had significantly higher model for end-stage liver disease and sodium (MELD-Na) score, lower albumin level, and longer hospital stay after surgery than the non-AKI group. Older age and higher MELD-Na score were independent risk factors for the development of postoperative AKI. At 6 months postsurgery, the estimated glomerular filtration rate (eGFR) in the AKI group was significantly lower than that in the non-AKI group, although the baseline eGFR was not different. In multiple linear regression analysis, the maximum urine NGAL level during 24 h postsurgery, intraoperative fluid balance, and having liver transplantation were significantly associated with a poor 6 months renal outcome. CONCLUSION: Urine NGAL was useful in the early diagnosis of postoperative AKI as well as in predicting the 6 months renal outcome after hepatobiliary surgery. A considerable proportion of patients developed subclinical AKI, and these patients showed worse renal outcome compared with the non-AKI group.

Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model.

BACKGROUND: Cardiorenal syndrome is now frequently recognized, and the combined dysfunction of heart and kidney increases morbidity and mortality. This study aimed to investigate possible mechanisms that underlie renal damage following heart dysfunction using a rat myocardial infarction model, focusing on the inflammatory pathway. METHODS: Rats were randomized into four groups: normal, volume depletion, sham operation and myocardial infarction (MI). MI was induced by the ligation of the left coronary artery and a volume depletion model was produced by low-salt diet and furosemide injection. Biochemical, histological and flow cytometric analyses were performed at 3 days and 4 and 8 weeks after MI. RESULTS: On Day 3 following MI, the development of subclinical acute kidney injury was identified through significantly increased serum and urine neutrophil gelatinase-associated lipocalin level. We detected the increase of activated monocytes (CC chemokine receptor 2(+) ED-1(+)) in peripheral blood, along with the infiltration of ED-1(+) macrophages and the increment of nuclear p65 in the kidney of MI rats, suggesting the contribution of nuclear factor-kappa B-mediated inflammation in the development of Type 1 cardiorenal syndrome (CRS). The inflammatory cytokines, interleukin-6 and tumour necrosis factor-α (TNF-α) mRNA expression, as well as microvascular endothelial permeability and tubular cell apoptosis, significantly increased in the kidneys of MI rats. At 4 and 8 weeks after MI, tubular cell apoptosis, ED-1(+) macrophage infiltration and interstitial fibrosis increased in MI rats, and these chronic changes were significantly mitigated by systemic monocyte/macrophage depletion using liposome clodronate. CONCLUSION: This study identifies the possible important role of inflammatory response as a mediator of heart-kidney crosstalk in CRS.

The role of urinary liver-type fatty acid-binding protein in critically ill patients.

Although several urinary biomarkers have been validated as early diagnostic markers of acute kidney injury (AKI), their usefulness as outcome predictors is not well established. This study aimed to determine the diagnostic and prognostic abilities of urinary liver-type fatty acid-binding protein (L-FABP) in heterogeneous critically ill patients. We prospectively collected data on patients admitted to medical and surgical intensive care units (ICUs) from July 2010 to June 2011. Urine neutrophil gelatinase-associated lipocalin (NGAL) and L-FABP at the time of ICU admission were quantitated. Of the 145 patients, 54 (37.2%) had AKI defined by the Acute Kidney Injury Network (AKIN) criteria. AKI patients showed significantly higher level of urinary NGAL and L-FABP and also higher mortality than non-AKI patients. The diagnostic performances, assessed by the area under the ROC curve, were 0.773 for NGAL and 0.780 for L-FABP, demonstrating their usefulness in diagnosing AKI. In multivariate Cox analysis, urinary L-FABP was an independent predictor for 90-day mortality. Urinary L-FABP seems to be promising both for the diagnosis of AKI and for the prediction of prognosis in heterogeneous ICU patients. It needs to be further validated for clinical utility.

Distinct pathophysiologic mechanisms of septic acute kidney injury: role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury.

OBJECTIVE: Sepsis is the most common cause of acute kidney injury in critically ill patients; however, the mechanisms leading to acute kidney injury in sepsis remain elusive. Although sepsis has been considered an excessive systemic inflammatory response, clinical trials that inhibit inflammation have been shown to have no effect. The purpose of this study was to examine the pathophysiology of septic acute kidney injury focusing on immune responses and renal tubular cell apoptosis by providing an on-site quantitative comparison between septic- and ischemia/reperfusion-induced acute kidney injury. DESIGN: Twenty-four hours after cecal ligation and puncture or ischemia/reperfusion injury, biochemical, histologic, and cytokine changes were compared in C57BL/6 mice. Apoptosis was assessed, and the effect of caspase 3 inhibition on renal function was also examined. The percentage of regulatory T cells and the effect of depletion were determined and compared with ischemia/reperfusion-induced acute kidney injury. The effect of interleukin-10 blocking was also compared. MEASUREMENTS AND MAIN RESULTS: Despite comparable renal dysfunction, acute tubular necrosis or inflammation was minimal in septic kidneys. However, tubular cell apoptosis was prominent, and caspase 3 activity was positively correlated with renal dysfunction. A decrease in apoptosis by caspase 3 inhibitor resulted in attenuation of renal dysfunction. In assessment of systemic immunity, septic acute kidney injury was associated with an increase in interleukin-10, and also showed massive immune cell apoptosis with increased regulatory T cells. In contrast to ischemia/reperfusion injury in which depletion of regulatory T cells aggravated renal injury, depletion of regulatory T cells before cecal ligation and puncture resulted in renoprotection. In addition, blocking interleukin-10 rescued septic mice from the development of acute kidney injury, whereas it had no effect in ischemia/reperfusion injury. CONCLUSIONS: Pathogenesis of septic acute kidney injury is thought to be different from that of ischemia/reperfusion-induced acute kidney injury. Our data showed a link between apoptosis, immune suppression, and the development of acute kidney injury during sepsis and suggest that strategies targeting apoptosis or enhancing immunity might be a potential therapeutic strategy for septic acute kidney injury.

CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury.

BACKGROUND: The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs. METHODS: Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed. RESULTS: Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b( +) CD11c( +) DC and with maturation of spleen CD11c( +) DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4( +) CD25( +) Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non-Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720. CONCLUSION: These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI.

Primed monocytes: putative culprits of chronic low-grade inflammation and impaired innate immune responses in patients on hemodialysis.

BACKGROUND: End-stage renal disease patients are known to be in a state of chronic low-grade inflammation and to have high infection-related morbidity and mortality. However, the precise mechanisms are not understood. The purpose of this study was to determine the mechanisms underlying chronic low-grade inflammation and defects in innate immune responses in hemodialysis (HD) patients. METHOD: In 33 HD patients, we measured the basal status of toll-like receptor 4 (TLR4) positivity in the CD14-positive monocyte population in the peripheral blood (not strong, i.e., CD14(low)), with plasma levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-12p70 compared with 22 healthy controls. After stimulation by lipopolysaccharide (LPS), the plasma cytokine response was also compared. RESULTS: In the basal state, the percentage of peripheral blood TLR4(+)CD14(low) monocytes and plasma cytokines were significantly higher in HD patients (p < 0.05), suggesting that preactivated primed monocytes might be responsible for the chronic inflammatory state in HD patients. However, upon LPS challenge, the fold increase in plasma cytokine response was significantly reduced in HD patients (p < 0.05) compared with controls. More importantly, the fold increase of these cytokines showed a positive correlation with plasma albumin (p < 0.05) and a negative correlation with C-reactive protein (CRP) (p < 0.05), suggesting the presence of a possible link between chronic low-grade inflammation and suboptimal innate immune response. CONCLUSION: Chronic low-grade inflammation due to preactivated peripheral blood CD14(+) leukocyte subset might be a mechanism for impaired innate immune responses, thus resulting in the high rates of infection-related morbidity and mortality observed in HD patients.

Sphingosine-1-phosphate reduces hepatic ischaemia/reperfusion-induced acute kidney injury through attenuation of endothelial injury in mice.

AIM: Hepatic ischaemia/reperfusion injury (IRI) frequently complicates acute kidney injury (AKI) during the perioperative period. This study was to determine whether hepatic IRI causes AKI and the effect of the sphingosine-1-phosphate (S1P) on AKI. METHODS: S1P and vehicle were given to mice before ischaemia and mice were subjected to hepatic IRI. Plasma creatinine (PCr), alanine transaminase (ALT), urinary neutrophil gelatinase-associated lipocalin (NGAL) and renal histological changes were determined. As a marker of endothelial injury, vascular permeability was measured. The effect of VPC 23019, a S1P(1) receptor antagonist, was also assessed. RESULTS: Hepatic IRI resulted in liver injury (increased ALT) and systemic inflammation. Kidneys showed elevated inflammatory cytokines, leucocyte infiltration, increased vascular permeability, tubular cell apoptosis and increased urinary NGAL, although PCr did not increase. Pretreatment with S1P resulted in an attenuation of systemic inflammation and kidney injury without any effect on plasma ALT or peripheral lymphocytes. The protective effect of S1P was partially reversed by VPC 23019, suggesting the important contribution of the S1P/S1P(1) pathway to protect against hepatic IRI-induced AKI. CONCLUSION: The study data demonstrate the important contribution of systemic inflammation and endothelial injury to AKI following hepatic IRI. Modulation of the S1P/S1P(1) receptor pathway might have some therapeutic potential in hepatic IRI-induced kidney injury.

Mitochondrial peroxiredoxin III is a potential target for cancer therapy.

Mitochondria are involved either directly or indirectly in oncogenesis and the alteration of metabolism in cancer cells. Cancer cells contain large numbers of abnormal mitochondria and produce large amounts of reactive oxygen species (ROS). Oxidative stress is caused by an imbalance between the production of ROS and the antioxidant capacity of the cell. Several cancer therapies, such as chemotherapeutic drugs and radiation, disrupt mitochondrial homeostasis and release cytochrome c, leading to apoptosome formation, which activates the intrinsic pathway. This is modulated by the extent of mitochondrial oxidative stress. The peroxiredoxin (Prx) system is a cellular defense system against oxidative stress, and mitochondria in cancer cells are known to contain high levels of Prx III. Here, we review accumulating evidence suggesting that mitochondrial oxidative stress is involved in cancer, and discuss the role of the mitochondrial Prx III antioxidant system as a potential target for cancer therapy. We hope that this review will provide the basis for new strategic approaches in the development of effective cancer treatments.

Criticality Creates a Functional Platform for Network Transitions Between Internal and External Processing Modes in the Human Brain.

Continuous switching between internal and external modes in the brain appears important for generating models of the self and the world. However, how the brain transitions between these two modes remains unknown. We propose that a large synchronization fluctuation of brain networks, emerging only near criticality (i.e., a balanced state between order and disorder), spontaneously creates temporal windows with distinct preferences for integrating the network's internal information or for processing external stimuli. Using a computational model, electroencephalography (EEG) analysis, and functional magnetic resonance imaging (fMRI) analysis during alterations of consciousness in humans, we report that synchronized and incoherent networks, respectively, bias toward internal and external information with specific network configurations. In the brain network model and EEG-based network, the network preferences are the most prominent at criticality and in conscious states associated with the bandwidth 4-12 Hz, with alternating functional network configurations. However, these network configurations are selectively disrupted in different states of consciousness such as general anesthesia, psychedelic states, minimally conscious states, and unresponsive wakefulness syndrome. The network preference for internal information integration is only significant in conscious states and psychedelic states, but not in other unconscious states, suggesting the importance of internal information integration in maintaining consciousness. The fMRI co-activation pattern analysis shows that functional networks that are sensitive to external stimuli-such as default mode, dorsal attentional, and frontoparietal networks-are activated in incoherent states, while insensitive networks, such as global activation and deactivation networks, are dominated in highly synchronized states. We suggest that criticality produces a functional platform for the brain's capability for continuous switching between two modes, which is crucial for the emergence of consciousness.

Delirium, Caffeine, and Perioperative Cortical Dynamics.

Delirium is a major public health issue associated with considerable morbidity and mortality, particularly after surgery. While the neurobiology of delirium remains incompletely understood, emerging evidence suggests that cognition requires close proximity to a system state called criticality, which reflects a point of dynamic instability that allows for flexible access to a wide range of brain states. Deviations from criticality are associated with neurocognitive disorders, though the relationship between criticality and delirium has not been formally tested. This study tested the primary hypothesis that delirium in the postanesthesia care unit would be associated with deviations from criticality, based on surrogate electroencephalographic measures. As a secondary objective, the impact of caffeine was also tested on delirium incidence and criticality. To address these aims, we conducted a secondary analysis of a randomized clinical trial that tested the effects of intraoperative caffeine on postoperative recovery in adults undergoing major surgery. In this substudy, whole-scalp (16-channel) electroencephalographic data were analyzed from a subset of trial participants (n = 55) to determine whether surrogate measures of neural criticality - (1) autocorrelation function of global alpha oscillations and (2) topography of phase relationships via phase lag entropy - were associated with delirium. These measures were analyzed in participants experiencing delirium in the postanesthesia care unit (compared to those without delirium) and in participants randomized to caffeine compared to placebo. Results demonstrated that autocorrelation function in the alpha band was significantly reduced in delirious participants, which is important given that alpha rhythms are postulated to play a vital role in consciousness. Moreover, participants randomized to caffeine demonstrated increased alpha autocorrelation function concurrent with reduced delirium incidence. Lastly, the anterior-posterior topography of phase relationships appeared most preserved in non-delirious participants and in those receiving caffeine. These data suggest that early postoperative delirium may reflect deviations from neural criticality, and caffeine may reduce delirium risk by shifting cortical dynamics toward criticality.