Vascular calcification and cellular signaling pathways as potential therapeutic targets.

Increased vascular calcification (VC) is observed in patients with cardiovascular diseases such as atherosclerosis, diabetes, and chronic kidney disease. VC is divided into three types according to its location: intimal, medial, and valvular. Various cellular signaling pathways are associated with VC, including the Wnt, mitogen-activated protein kinase, phosphatidylinositol-3 kinase/Akt, cyclic nucleotide-dependent protein kinase, protein kinase C, calcium/calmodulin-dependent kinase II, adenosine monophosphate-activated protein kinase/mammalian target of rapamycin, Ras homologous GTPase, apoptosis, Notch, and cytokine signaling pathways. In this review, we discuss the literature concerning the key cellular signaling pathways associated with VC and their role as potential therapeutic targets. Inhibitors to these pathways represent good candidates for use as potential therapeutic agents for the prevention and treatment of VC.

Deuterium Magnetic Resonance Imaging Using Deuterated Water-Induced 2H-Tissue Labeling Allows Monitoring Cancer Treatment at Clinical Field Strength.

PURPOSE: An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field MRI using deuterium-labeled molecules. The study aim was to use 2H tissue labeling and deuterium MRI at clinical field strength for tumor visualization and assessment of three anticancer therapies in pancreatic cancer model mice. EXPERIMENTAL DESIGN: MIA PaCa-2 pancreatic carcinoma and C26 colorectal carcinoma models of BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days of free drinking of 30% D2O to track 2H distribution in tissues. 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration was also measured in MIA PaCa-2-bearing mice. Confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS, and histopathology were performed. RESULTS: The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI, and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments. CONCLUSIONS: Deuterium MRI at 1.5T proved feasible to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for preliminary assessment of radiotherapy and chemotherapy of cancer.

Observation of the phase-separation multiphase flow using a polyethylene glycol/phosphate mixed solutions and the aqueous two-phase distribution of red blood cells in the flow system.

Phase-separation multiphase flow at a liquid-liquid interface was successfully formed in an aqueous two-phase system of polyethylene glycol/phosphate mixed solutions when fed into a microchannel (100 µm wide and 40 µm deep) on a microchip and a fused-silica capillary tube (100 µm ID). As one example, tube radial distribution flow (annular flow) was observed when 10.0 wt% polyethylene glycol 6000 and 8.5 wt% dipotassium hydrogen phosphate aqueous solution containing 1.0 mM Rhodamine B was fed at 40 â„ƒ, recorded by bright field microscopy. It exhibited a dipotassium hydrogen phosphate-rich inner phase and polyethylene glycol-rich outer phase. Effects of conditions including composition, flow rate, viscosity, and contact angle on tube radial distribution flow were analyzed. It was found out that although the viscosity of PEG-rich solution was much higher than that of phosphate-rich one, the phase configuration in tube radial distribution flow did not necessarily obey the viscous dissipation law in untreated microchannel and capillary tube, as well as for all the types of PEG/phosphate mixed solution the PEG-rich solution occupied the outer phase near the ODS-treated inner wall of both microchannel and capillary tube against the law. To assess the use of microfluidic flow in applications, we examined the distribution of red blood cells in the inner and outer phases fed into double capillary tubes with different inner diameters. Cell distribution was found to concentrate in the inner (dipotassium hydrogen phosphate-rich) phase compared to the outer (polyethylene glycol-rich) phase at a ratio of 1.8.

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer.

Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, ßI, ßII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers.

Noninvasive Diagnosis of the Mitochondrial Function of Doxorubicin-Induced Cardiomyopathy Using In Vivo Dynamic Nuclear Polarization-Magnetic Resonance Imaging.

Doxorubicin (DOX) induces dose-dependent cardiotoxicity via oxidative stress and abnormal mitochondrial function in the myocardium. Therefore, a noninvasive in vivo imaging procedure for monitoring the redox status of the heart may aid in monitoring diseases and developing treatments. However, an appropriate technique has yet to be developed. In this study, we demonstrate a technique for detecting and visualizing the redox status of the heart using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with 3-carbamoyl-PROXYL (CmP) as a molecular imaging probe. Male C57BL/6N mice were administered DOX (20 mg/kg) or saline. DNP-MRI clearly showed a slower DNP signal reduction in the DOX group than in the control group. Importantly, the difference in the DNP signal reduction rate between the two groups occurred earlier than that detected by physiological examination or clinical symptoms. In an in vitro experiment, KCN (an inhibitor of complex IV in the mitochondrial electron transport chain) and DOX inhibited the electron paramagnetic resonance change in H9c2 cardiomyocytes, suggesting that the redox metabolism of CmP in the myocardium is mitochondrion-dependent. Therefore, this molecular imaging technique has the potential to monitor the dynamics of redox metabolic changes in DOX-induced cardiomyopathy and facilitate an early diagnosis of this condition.

Microfluidic behavior of ternary mixed solutions of water/acetonitrile/ethyl acetate through experiments and computer simulations.

When ternary mixed solutions of water/acetonitrile/ethyl acetate are delivered into a microspace under laminar flow conditions, the solvent molecules show specific microfluidic flows, such as microfluidic inverted flow and tube radial distribution flow, which have been applied to novel analytical methods. In this paper, inverted flow was examined using various Y-type microchannels that had mixing angles of 0°, 90°, 180°, and 270°. Inverted flow was experimentally observed and the trigger phenomenon was also successfully expressed through computer simulations. Tube radial distribution flow, that is, annular flow, in a capillary tube is reported to cause exchange of the inner and outer phases based on the solvent composition of the ternary mixed solution. Tube radial distribution flow for an organic solvent-rich inner and a water-rich outer phases, as well as for a water-rich inner and an organic solvent-rich outer phases, could be well recreated by computer simulations for a ternary mixed solution. This highlights the effectiveness of computer simulations for such flow scenarios and will allow optimization of the operating conditions and design of microfluidic analytical devices.

Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions.

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFß signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFß and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

Neonatal Morbidity of Monoamniotic Twin Pregnancies: A Systematic Review and Meta-analysis.

OBJECTIVE: This study was aimed to report the incidence of neonatal morbidity in monochorionic monoamniotic (MCMA) twin pregnancies according to gestational age at birth and type of management adopted (inpatient or outpatient). STUDY DESIGN: Medline and Embase databases were searched. Inclusion criteria were nonanomalous MCMA twins. The primary outcome was a composite score of neonatal morbidity, defined as the occurrence of at least one of the following outcomes: respiratory morbidity, overall neurological morbidity, severe neurological morbidity, and infectious morbidity, necrotizing enterocolitis at different gestational age windows (24-30, 31-32, 33-34, and 35-36 weeks). Secondary outcomes were the individual components of the primary outcome and admission to neonatal intensive care unit (NICU). Subanalysis according to the type of surveillance strategy (inpatient compared with outpatient) was also performed. Random effect meta-analyses were used to analyze the data. RESULTS: A total of 14 studies including 685 MCMA twin pregnancies without fetal anomalies were included. At 24 to 30, 31 to 32, 33 to 34, and 35 to 36 weeks of gestation, the rate of composite morbidity was 75.4, 65.5, 37.6, and 18.5%, respectively, the rate of respiratory morbidity was 74.2, 59.1, 35.5, and 12.2%, respectively, while overall neurological morbidity occurred in 15.3, 10.2, 4.3, and 0% of the cases, respectively. Infectious morbidity complicated 13, 4.2, 3.1, and 0% of newborns while 92.1, 81.6, 58.7, and 0% of cases required admission to NICU. Morbidity in pregnancies delivered between 35 and 36 weeks of gestation was affected by the very small sample size of cases included. When comparing the occurrence of overall morbidity according to the type of management (inpatient or outpatient), there was no difference between the two surveillance strategies (p = 0.114). CONCLUSION: MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity that gradually decreases with increasing gestational age at delivery with a significant reduction for pregnancies delivered between 33 and 34 weeks. We found no difference in the occurrence of neonatal morbidity between pregnancies managed as inpatient or outpatient. KEY POINTS: · MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity.. · Neonatal morbidity gradually decreases with increasing GA at delivery, mostly between 33 and 34 weeks.. · There is no difference in the occurrence of neonatal morbidity between in- or outpatient management..

In Vivo Dynamic Nuclear Polarization Magnetic Resonance Imaging for the Evaluation of Redox-Related Diseases and Theranostics.

Significance:In vivo molecular and metabolic imaging is an emerging field in biomedical research that aims to perform noninvasive detection of tissue metabolism in disease states and responses to therapeutic agents. The imbalance in tissue oxidation/reduction (Redox) states is related to the onset and progression of several diseases. Tissue redox metabolism provides biomarkers for early diagnosis and drug treatments. Thus, noninvasive imaging of redox metabolism could be a useful, novel diagnostic tool for diagnosis of redox-related disease and drug discovery. Recent Advances:In vivo dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) is a technique that enables the imaging of free radicals in living animals. DNP enhances the MRI signal by irradiating the target tissue or solution with the free radical molecule's electron paramagnetic resonance frequency before executing pulse sequence of the MRI. In vivo DNP-MRI with redox-sensitive nitroxyl radicals as the DNP redox contrast agent enables the imaging of the redox metabolism on various diseases. Moreover, nitroxyl radicals show antioxidant effects that suppress oxidative stress. Critical Issues: To date, considerable progress has been documented preclinically in the development of animal imaging systems. Here, we review redox imaging of in vivo DNP-MRI with a focus on the recent progress of this system and its uses in patients with redox-related diseases. Future Directions: This technique could have broad applications in the study of other redox-related diseases, such as cancer, inflammation, and neurological disorders, and facilitate the evaluation of treatment response as a theranostic tool. Antioxid. Redox Signal. 36, 172-184.

Spatiotemporal imaging of redox status using in vivo dynamic nuclear polarization magnetic resonance imaging system for early monitoring of response to radiation treatment of tumor.

In general, the effectiveness of radiation treatment is evaluated through the observation of morphological changes with computed tomography (CT) or magnetic resonance imaging (MRI) images after treatment. However, the evaluation of the treatment effects can be very time consuming, and thus can delay the verification of patient cases where treatment has not been fully effective. It is known that the treatment efficacy depends on redox modulation in tumor tissues, which is an indirect effect of oxidizing redox molecules such as hydroxyl radicals and of reactive oxygen species generated by radiation treatment. In vivo dynamic nuclear polarization-MRI (DNP-MRI) using carbamoyl-PROXYL (CmP) as a redox sensitive DNP probe enables the accurate monitoring of the anatomical distribution of free radicals based on interactions of electrons and nuclear spin, known as Overhauser effect. However, spatiotemporal response of the redox status in tumor tissues post-irradiation remains unknown. In this study, we demonstrate the usefulness of spatiotemporal redox status as an early imaging biomarker of tumor response after irradiation using in vivo DNP-MRI. Our results highlight that in vivo DNP-MRI/CmP allowed us to visualize the tumor redox status responses significantly faster and earlier compared to the verification of morphological changes observed with 1.5 T MRI and cancer metabolism (Warburg effect) obtained by hyperpolarized 13C pyruvate MRS. Our findings suggest that the early assessment of redox status alterations with in vivo DNP-MRI/CmP probe may provide very efficient information regarding the effectiveness of the subsequent radiation treatment.

Bioinspired macrophage-targeted anti-inflammatory nanomedicine: A therapeutic option for the treatment of myocarditis.

Myocarditis is a disease characterized by inflammation of the heart muscle, which increases the risk of dilated cardiomyopathy and heart failure. Macrophage migration is a major histopathological hallmark of myocarditis, making macrophages a potential therapeutic target for the management of this disease. In the present study, we synthesized a bioinspired anti-inflammatory nanomedicine conjugated with protein G (PSL-G) that could target macrophages and induce macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Notably, PSL-G exhibited a higher affinity for macrophages than non-macrophage cells. The addition of PSL-G decreased the levels of pro-inflammatory cytokines (e.g., IL-1α, IL-6, and TNF-α), but increased the level of the anti-inflammatory cytokine IL-10 in macrophages treated with lipopolysaccharide and/or interferon-γ. Furthermore, the lifetime of PSL-G in murine blood circulation was found to be significantly higher than that of PSL. Systemic injection of PSL-G into a mouse model of experimental autoimmune myocarditis remarkably reduced macrophage migration in the myocardium (16-fold compared with the positive control group) and myocardial fibrosis (8-fold). Based on these results and the fact that macrophages play a critical role in the pathogenesis of various diseases, we believe that bioinspired macrophage-targeted anti-inflammatory nanomedicines may be effective therapeutic options for the treatment of autoimmune and autoinflammatory diseases, especially myocarditis.

Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials.

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, ßI, ßII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.

Consecutive Sample Injection Analysis in Tube Radial Distribution Chromatography.

Tube radial distribution chromatography based on the tube radial distribution flow, or annular flow, in an open-tubular capillary has been reported, where the annular flow is created through phase-separation multiphase flow. We have proposed the first-ever procedure for consecutive sample injection analysis using chromatography. In basic terms, a commercially available HPLC system could be used with a sample injector (0.2 µL volume) and a fused-silica capillary tube (250 cm long) as a separation column instead of a normal packed one, while the built-in detection cell was replaced by improved on-capillary detection. A ternary mixed solution of water/acetonitrile/ethyl acetate (3:8:4 volume ratio) was delivered into the capillary tube as an eluent at a flow rate of 2.0 µL min-1. Model sample solutions of 1-naphthol and 2,6-naphthalenedisulfonic acid were consecutively analyzed by the present chromatography with a processing rate of 6 samples per hour. Simple and rapid consecutive analysis could be performed because washing and initialization of the separation tube was no longer necessary. The obtained results provide clues to developing new methodologies which combine features of both chromatography (separation) and the flow injection method (consecutive analysis).

Identification of Activated Protein Kinase Cα (PKCα) in the Urine of Orthotopic Bladder Cancer Xenograft Model as a Potential Biomarker for the Diagnosis of Bladder Cancer.

Bladder cancer has a high recurrence rate; therefore, frequent and effective monitoring is essential for disease management. Cystoscopy is considered the gold standard for the diagnosis and continuous monitoring of bladder cancer. However, cystoscopy is invasive and relatively expensive. Thus, there is a need for non-invasive, relatively inexpensive urinary biomarker-based diagnoses of bladder cancer. This study aimed to investigate the presence of activated protein kinase Cα (PKCα) in urine samples and the possibility of PKCα as a urinary biomarker for bladder cancer diagnosis. Activated PKCα was found to be present at higher levels in bladder cancer tissues than in normal bladder tissues. Furthermore, high levels of activated PKCα were observed in urine samples collected from orthotopic xenograft mice carrying human bladder cancer cells compared to urine samples from normal mice. These results suggest that activated PKCα can be used as a urinary biomarker to diagnose bladder cancer. To the best of our knowledge, this is the first report describing the presence of activated PKCα in the urine of orthotopic xenograft mice.

Reflectance spectra analysis for mucous assessment.

This review report represents an overview of research and development on medical hyperspectral imaging technology and its applications. Spectral imaging technology is attracting attention as a new imaging modality for medical applications, especially in disease diagnosis and image-guided surgery. Considering the recent advances in imaging, this technology provides an opportunity for two-dimensional mapping of oxygen saturation (SatO2) of blood with high accuracy, spatial spectral imaging, and its analysis and provides detection and diagnostic information about the tissue physiology and morphology. Multispectral imaging also provides information about tissue oxygenation, perfusion, and potential function during surgery. Analytical algorithm has been examined, and indication of accurate map of relative hemoglobin concentration and SatO2 can be indicated with preferable resolution and frame rate. This technology is expected to provide promising biomedical information in practical use. Several studies suggested that blood flow and SatO2 are associated with gastrointestinal disorders, particularly malignant tumor conditions. The use and analysis of spectroscopic images are expected to potentially play a role in the detection and diagnosis of these diseases.

Protein Nanoparticles Modified with PDGF-B as a Novel Therapy After Acute Cerebral Infarction.

Treatment options for cerebral infarction beyond the time window of reperfusion therapy are limited, and novel approaches are needed. PDGF-B is considered neuroprotective; however, it is difficult to administer at effective concentrations to infarct areas. Nanoparticles (NPs) are small and stable; therefore, we modified PDGF-B to the surface of naturally occurring heat shock protein NPs (HSPNPs) to examine its therapeutic effect in cerebral infarction. PDGF-B modified HSPNPs (PDGF-B HSPNPs) were injected 1 d after transient middle cerebral artery occlusion (t-MCAO) in CB-17 model mice. We analyzed the infarct volume and motor functional recovery at 3 and 7 d. PDGF-B HSPNPs were specifically distributed in the infarct area, and compared with HSPNPs alone, they significantly reduced infarct volumes and improved neurologic function 3 and 7 d after administration. PDGF-B HSPNP administration was associated with strong phosphorylation of Akt in infarct areas and significantly increased neurotrophin (NT)-3 production as well as reduced cell apoptosis compared with HSPNPs alone. Moreover, astrogliosis in peri-infarct area was significantly upregulated with PDGF-B HSPNPs compared with HSPNPs alone. Treatment with PDGF-B HSPNPs might be a novel approach for treating cerebral infarction.

Development of 20 cm sample bore size dynamic nuclear polarization (DNP)-MRI at 16 mT and redox metabolic imaging of acute hepatitis rat model.

Tissue redox metabolism is involved in various diseases, and an understanding of the spatio-temporal dynamics of tissue redox metabolism could be useful for diagnosis of progression and treatment. In in vivo dynamic nuclear polarization (DNP)-MRI, electron paramagnetic resonance (EPR) irradiation at the resonance frequency of nitroxyl radicals administered as a redox probe for induction of DNP, increases the intensity of MRI signals. For electron spin, it is necessary to apply a resonant frequency 658 times higher than that required for nuclear spin because of the higher magnetic moment of unpaired electrons. Previous studies using a disease model of small animals and in vivo DNP-MRI have revealed that an abnormal redox status is involved in many diseases, and that it could be used to visualize the dynamics of alterations in redox metabolism. To use the current methods in clinical practice, the development of a prototype DNP-MRI system for preclinical examinations of large animals is indispensable for clarifying the problems peculiar to the increase in size of the DNP-MRI device. Therefore, we developed a in vivo DNP-MRI system with a sample bore size of 20 cm and a 16-mT magnetic field using a U-shaped permanent magnet. Because the NMR frequency is very low, we adopted a digital radiofrequency transmission/reception system with excellent filter and dynamic range characteristics and equipped with a digital eddy current compensation system to suppress large eddy currents. The pulse sequence was based on the fast spin-echo sequence, which was improved for low frequency and large-eddy current equipment. The in vivo DNP-MRI system developed was used to non-invasively image the redox reaction of a carbamoyl-PROXYL probe in the livers of large rats weighing 800 g. Furthermore, DNP-MRI analysis was able to capture significant changes in redox metabolism in hepatitis-model rats.

A Novel Hyperspectral Imaging System for Intraoperative Prediction of Cerebral Hyperperfusion Syndrome after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis in Patients with Moyamoya Disease.

BACKGROUND: Postoperative cerebral hyperperfusion syndrome (CHS) may occur after superficial temporal artery (STA)-middle cerebral artery (MCA) bypass for moyamoya disease (MMD). Predicting postoperative CHS is challenging; however, we previously reported the feasibility of using a hyperspectral camera (HSC) for monitoring intraoperative changes in brain surface hemodynamics during STA-MCA bypass. OBJECTIVE: To investigate the utility of HSC to predict postoperative CHS during STA-MCA bypass for patients with MMD. METHODS: Hyperspectral images of the cerebral cortex of 29 patients with MMD who underwent STA-MCA bypass were acquired by using an HSC before and after anastomosis. We then analyzed the changes in oxygen saturation after anastomosis and assessed its correlation with CHS. RESULTS: Five patients experienced transient neurological deterioration several days after surgery. 123I-N-Isopropyl-iodoamphetamine single-photon emission computed tomography scan results revealed an intense, focal increase in cerebral blood flow at the site of anastomosis without any cerebral infarction. Patients with CHS showed significantly increased oxygen saturation (SO2) in the cerebral cortex after anastomosis relative to those without CHS (33 ± 28 vs. 8 ± 14%, p < 0.0001). Receiver operating characteristic analysis results show that postoperative CHS likely occurs when the increase rate of cortical SO2 value is >15% (sensitivity, 85.0%; specificity, 81.3%; area under curve, 0.871). CONCLUSIONS: This study indicates that hyperspectral imaging of the cerebral cortex may be used to predict postoperative CHS in patients with MMD undergoing STA-MCA bypass.

Protective and healing effects of apoptotic mimic-induced M2-like macrophage polarization on pressure ulcers in young and middle-aged mice.

Pressure ulcers (PUs) have no cure and are of significant health and economic concern worldwide, owing to the increasing population of elderly individuals at high risk for PU and who have impaired tissue repair. Macrophages play a pivotal role in PU development and healing. Imbalances between M1 (inflammatory) and M2 (anti-inflammatory/reparative) macrophages result in delayed resolution of inflammation and wound healing. We hypothesized that M1-to-M2 macrophage polarization mediated by artificial apoptotic cell mimics, phosphatidylserine-containing liposomes (PSLs), would protect against PU formation and accelerate PU healing in young (2-month-old) and middle-aged (12-month-old) mice. We used a clinically relevant murine model of ischemia-reperfusion-induced PU. Middle-aged mice displayed the delayed wound healing associated with increased inflammation, decreased collagen deposition, reduced angiogenesis, and delayed wound closure relative to their younger counterparts. PSL treatment significantly inhibited PU formation and promoted tissue remodeling in both age groups. These effects were mediated by increased M1-to-M2 macrophage polarization, induced by the PSLs. Thus, this study suggests, for the first time, that PSL-induced M2-like macrophage polarization is a promising strategy to protect against PU formation and promote PU repair in human patients of all ages.

Histidine-Rich Glycoprotein Alleviates Liver Ischemia/Reperfusion Injury in Mice With Nonalcoholic Steatohepatitis.

Hepatic ischemia/reperfusion injury (IRI) is a major complication of liver surgery and transplantation, especially in patients with nonalcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to IRI has not been fully clarified. We investigated the role of liver-produced histidine-rich glycoprotein (HRG) in NASH IRI. A NASH mouse model was established using C57BL/6J mice fed a methionine-choline-deficient diet (MCDD) for 6 weeks. The MCDD and standard diet groups were exposed to 60 minutes of partial hepatic ischemia/reperfusion (I/R). We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. IRI increased HRG expression in the standard diet group, but not in the MCDD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and the formation of neutrophil extracellular traps (NETs). HRG KD mice showed severe liver injury with neutrophil infiltration and the formation of NETs. Pretreatment with supplementary HRG protected against I/R with the inhibition of neutrophil infiltration and the formation of NETs. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/reoxygenation conditions, but not in response to oleic acid-treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased farnesoid X receptor and hypoxia inducible factor 2 alpha subunit expression. HRG is a hepatoprotective factor during hepatic IRI because it decreases neutrophil infiltration and the formation of NETs. The decrease in HRG is a cause of susceptibility to IRI in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in patients with NASH.