Hierarchical rhythmic propagation of corticothalamic interactions for consciousness: A computational study.

Clarifying the mechanisms of loss and recovery of consciousness in the brain is a major challenge in neuroscience, and research on the spatiotemporal organization of rhythms at the brain region scale at different levels of consciousness remains scarce. By applying computational neuroscience, an extended corticothalamic network model was developed in this study to simulate the altered states of consciousness induced by different concentration levels of propofol. The cortex area containing oscillation spread from posterior to anterior in four successive time stages, defining four groups of brain regions. A quantitative analysis showed that hierarchical rhythm propagation was mainly due to heterogeneity in the inter-brain region connections. These results indicate that the proposed model is an anatomically data-driven testbed and a simulation platform with millisecond resolution. It facilitates understanding of activity coordination across multiple areas of the conscious brain and the mechanisms of action of anesthetics in terms of brain regions.

Geriatric nutritional risk index predicts all-cause mortality in the oldest-old patients with acute coronary syndrome: A 10-year cohort study.

Background and objective: Nutritional status assessment in acute coronary syndrome (ACS) patients has been neglected for a long time. The geriatric nutritional risk index (GNRI) is a sensitive indicator for assessing the nutritional status of the elderly. This study aims to explore the association between GNRI and all-cause mortality in the oldest-old patients with ACS. Methods: The patients who met the inclusion criteria were consecutively enrolled from January 2006 to December 2012. Clinical data were collected on admission, and all subjects were followed after being discharged. The nutritional status was evaluated using GNRI. The relationship between GNRI and all-cause mortality was assessed by using different analyses. Results: A total of 662 patients with a mean age of 81.87 ± 2.14 years old were included in our study, and followed (median: 63 months, IQR 51-71). Patients whose GNRI ≤ 98 were reported as at risk of malnutrition (31.11%, n = 206). In multivariable analysis, we found that for each SD increase in GNRI, the risk of all-cause mortality lowered by 23%, and the HR for GNRI ≤ 98 was 1.39 (95% CI 1.04-1.86). After stratifying patients into three groups by tertiles of GNRI, we found that the HRs for tertile 2 and tertile 3 were 1.49 (95% CI 1.02-2.19) and 1.74 (95% CI 1.22-2.50), respectively. The trend test revealed a dose-response relationship between GNRI and all-cause mortality in the oldest-old with ACS. Lastly, in subgroup analyses, we found a reliable association between GNRI and all-cause mortality. Conclusion: Malnutrition is common in the oldest-old patients with ACS, and GNRI could predict their long-term all-cause mortality in a dose-dependent manner. GNRI may be a prospective index for risk-stratification and secondary-prevention in the oldest-old patients with ACS.

IntraCoronary Artery Retrograde Thrombolysis vs. Thrombus Aspiration in ST-Segment Elevation Myocardial Infarction: Study Protocol for a Randomized Controlled Trial.

Background: Type 2 diabetes (T2DM) is a major risk factor for myocardial infarction. Thrombus aspiration was considered a good way to deal with coronary thrombus in the treatment of acute myocardial infarction. However, recent studies have found that routine thrombus aspiration is not beneficial. This study is designed to investigate whether intracoronary artery retrograde thrombolysis (ICART) is more effective than thrombus aspiration or percutaneous transluminal coronary angioplasty (PTCA) in improving myocardial perfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Methods/Design: IntraCoronary Artery Retrograde Thrombolysis (ICART) vs. thrombus aspiration or PTCA in STEMI trial is a single-center, prospective, randomized open-label trial with blinded evaluation of endpoints. A total of 286 patients with STEMI undergoing PPCI are randomly assigned to two groups: ICART and thrombus aspiration or PTCA. The primary endpoint is the incidence of >70% ST-segment elevation resolution. Secondary outcomes include distal embolization, myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, and in-hospital bleeding. Discussion: The ICART trial is the first randomized clinical trial (RCT) to date to verify the effect of ICART vs. thrombus aspiration or PTCA on myocardial perfusion in patients with STEMI undergoing PPCI. Clinical Trial Registration: [https://www.chictr.org.cn/], identifier [ChiCTR1900023849].

Intracoronary artery retrograde thrombolysis combined with percutaneous coronary interventions for ST-segment elevation myocardial infarction complicated with diabetes mellitus: A case report and literature review.

Background: The management of a large thrombus burden in patients with acute myocardial infarction and diabetes is still a worldwide problem. Case presentation: A 74-year-old Chinese woman presented with ST-segment elevation myocardial infarction (STEMI) complicated with diabetes mellitus and hypertension. Angiography revealed massive thrombus formation in the mid-segment of the right coronary artery leading to vascular occlusion. The sheared balloon was placed far from the occlusion segment and urokinase (100,000 u) was administered for intracoronary artery retrograde thrombolysis, and thrombolysis in myocardial infarction (TIMI) grade 3 blood flow was restored within 7 min. At last, one stent was accurately implanted into the culprit's vessel. No-reflow, coronary slow flow, and reperfusion arrhythmia were not observed during this process. Conclusion: Intracoronary artery retrograde thrombolysis (ICART) can be effectively and safely used in patients with STEMI along with diabetes mellitus and hypertension, even if the myocardial infarction exceeds 12 h (REST or named ICART ClinicalTrials.gov number, ChiCTR1900023849).

Wnt 3a Protects Myocardial Injury in Elderly Acute Myocardial Infarction by Inhibiting Serum Cystatin C/ROS-Induced Mitochondrial Damage.

Aging represents an independent risk factor affecting the poor prognosis of patients with acute myocardial infarction (AMI). This present research aimed to explore the molecular mechanism of myocardial injury in elderly AMI by animals and cells experiment. Our previous clinical study found the serum Cystatin C (Cys-C) increased in the elderly AMI population, while the mechanism underlying high Cys-C induced myocardial injury of AMI remains unclear. In the in-vitro study, we confirmed that Wnt/ß-catenin could significantly reduce the expression of cytoplasmic Cys-C through transnuclear action, and highly attenuate the occurrence of mitochondrial oxidative stress injury induced via Cys-C/reactive oxygen species (ROS). Furthermore, the addition of exogenous Wnt3a and inhibition of Cys-C expression could effectively inhibit mitochondrial oxidative stress injury and relieve the acute myocardial hypoxia injury. These results indicate that Cys-C exerted damaging effects on the hypoxic aging cardiomyocyte through the ROS/mitochondrial signaling pathway. Inhibition of this pathway effectively reduced the apoptosis of aging cardiomyocytes. In the in-vivo study, we also explored the function of the Wnt/Cys-C pathway on the ischemic infarction heart. We confirmed that Wnt/ß-catenin served as the upstream protective protein of this pathway, and the promotion of this pathway improved the cardiac structure and function of the elderly AMI mice effectively.

Intracoronary artery retrograde thrombolysis for ST-segment elevation myocardial infarction with a tortuous coronary artery: A case report and review of the literature.

Background: How to deal with large thrombus burdens of culprit's blood vessel remains a great challenge in the treatment of acute myocardial infarction. Case presentation: A 32-year-old Chinese man was diagnosed with ST-segment elevation myocardial infarction (STEMI). Coronary angiography revealed that the distal end of a tortuous left circumflex was completely occluded by a large amount of thrombus. Cutted balloon-directed intracoronary artery retrograde thrombolysis (ICART) with urokinase led to the restoration of coronary blood flow. Because there was no obvious plaque rupture or artery stenosis in the coronary artery, it was only dilated, and no stent was implanted. Conclusion: Cutted balloon-directed ICART can be performed effectively and safely in some STEMI patients with tortuous coronary vessels and large thrombus. (REST or named ICART ClinicalTrials.gov number, ChiCTR1900023849).

Chemical Targeting of Rhodol Voltage-Sensitive Dyes to Dopaminergic Neurons.

Optical imaging of changes in the membrane potential of living cells can be achieved by means of fluorescent voltage-sensitive dyes (VSDs). A particularly challenging task is to efficiently deliver these highly lipophilic probes to specific neuronal subpopulations in brain tissue. We have tackled this task by designing a solubilizing, hydrophilic polymer platform that carries a high-affinity ligand for a membrane protein marker of interest and a fluorescent VSD. Here, we disclose an improved design of polymer-supported probes for chemical, nongenetic targeting of voltage sensors to axons natively expressing the dopamine transporter in ex vivo mouse brain tissue. We first show that for negatively charged rhodol VSDs functioning on the photoinduced electron transfer principle, poly(ethylene glycol) as a carrier enables targeting with higher selectivity than the polysaccharide dextran in HEK cell culture. In the same experimental setting, we also demonstrate that incorporation of an azetidine ring into the rhodol chromophore substantially increases the brightness and voltage sensitivity of the respective VSD. We show that the superior properties of the optimized sensor are transferable to recording of electrically evoked activity from dopaminergic axons in mouse striatal slices after averaging of multiple trials. Finally, we suggest the next milestones for the field to achieve single-scan recordings with nongenetically targeted VSDs in native brain tissue.

Evaluation of the long-term prognostic ability of triglyceride-glucose index for elderly acute coronary syndrome patients: a cohort study.

BACKGROUND: With the advancement of the world population aging, more attention should be paid to the prognosis of elderly patients with acute coronary syndrome (ACS). Triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance (IR) and is closely related to traditional risk factors of cardiovascular disease (CVD). However, the effect of TyG index on the prognosis of long-term adverse events in elderly ACS patients has not been reported. This study evaluated the prognostic power of TyG index in predicting adverse events in elderly ACS patients. METHODS: In this study, 662 ACS patients > 80 years old who were hospitalized from January 2006 to December 2012 were enrolled consecutively and the general clinical data and baseline blood biochemical indicators were collected. The follow-up time after discharge was 40-120 months (median, 63 months; interquartile range, 51‒74 months). In addition, the following formula was used to calculate the TyG index: Ln [fasting TG (mg/dL) × FBG (mg/dL)/2], and patients were divided into three groups according to the tertile of the TyG index. RESULTS: The mean age of the subjects was 81.87 ± 2.14 years, the proportion of females was 28.10%, and the mean TyG index was 8.76 ± 0.72. The TyG index was closely associated with the traditional risk factors of CVD. In the fully-adjusted Cox regression model, the Hazard ratio (95% CI) of all-cause mortality (in tertile 3) was 1.64 (1.06, 2.54) and major adverse cardiac event (MACE) (in tertile 3) was 1.36 (1.05, 1.95) for each SD increase in the TyG index. The subgroup analyses also confirmed the significant association of the TyG index and long-term prognosis. CONCLUSION: The TyG index is an independent predictor of long-term all-cause mortality and MACE in elderly ACS patients.

Evaluation of the prognostic ability of serum uric acid for elderly acute coronary syndrome patients with diabetes mellitus: a prospective cohort study.

OBJECTIVES: This study evaluated the prognostic power of serum uric acid (UA) in predicting adverse events in elderly acute coronary syndrome (ACS) patients with diabetes mellitus (DM). METHODS: The analysis involved 718 ACS patients |>80 years old whose general clinical data and baseline blood biochemical indicators were collected prospectively from January 2006 to December 2012. These patients were classified into two groups based on DM status, and then followed up after discharge. The Kaplan-Meier method was used for major adverse cardiac event (MACE) rates and all-cause mortality. Multivariate Cox regression was performed to analyze the relationship between UA level and long-term clinical prognosis. Receiver operating characteristic (ROC) curves were analyzed to predict the cutoff value of UA in elderly ACS patients with DM. There were 242 and 476 patients in the DM and non-DM (NDM) groups, respectively, and the follow-up time after discharge was 40‒120 months (median, 63 months; interquartile range, 51‒74 months). RESULTS: The all-cause mortality, cardiac mortality, and MACE rates in both DM and NDM patients were higher than those in the control group (P=0.001). All-cause mortalities, cardiac mortalities, and MACE rates in DM patients with moderate and high UA levels were significantly higher than those in the NDM group (P=0.001). Long-term survival rates decreased significantly with increased UA levels in the ACS groups (P=0.001). UA (odds ratio (OR)=2.106, 95% confidence interval (CI)=1.244‒3.568, P=0.006) was found to be an independent risk factor for all-cause mortality and MACE in elderly ACS patients with DM. The cutoff value of UA was 353.6 µmol/L (sensitivity, 67.4%; specificity, 65.7%). CONCLUSIONS: Serum UA level is a strong independent predictor of long-term all-cause death and MACE in elderly ACS patients with DM.

Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain.

Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.

Cardioprotective Role of Melatonin in Acute Myocardial Infarction.

Melatonin is a pleiotropic, indole secreted, and synthesized by the human pineal gland. Melatonin has biological effects including anti-apoptosis, protecting mitochondria, anti-oxidation, anti-inflammation, and stimulating target cells to secrete cytokines. Its protective effect on cardiomyocytes in acute myocardial infarction (AMI) has caused widespread interest in the actions of this molecule. The effects of melatonin against oxidative stress, promoting autophagic repair of cells, regulating immune and inflammatory responses, enhancing mitochondrial function, and relieving endoplasmic reticulum stress, play crucial roles in protecting cardiomyocytes from infarction. Mitochondrial apoptosis and dysfunction are common occurrence in cardiomyocyte injury after myocardial infarction. This review focuses on the targets of melatonin in protecting cardiomyocytes in AMI, the main molecular signaling pathways that melatonin influences in its endogenous protective role in myocardial infarction, and the developmental prospect of melatonin in myocardial infarction treatment.

Intracoronary arterial retrograde thrombolysis with percutaneous coronary intervention: a novel use of thrombolytic to treat acute ST-segment elevation myocardial infarction.

BACKGROUND: Clearance of coronary arterial thrombosis is necessary in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing urgent percutaneous coronary intervention (PCI). There is currently no highly-recommended method of thrombus removal during interventional procedures. We describe a new method for opening culprit vessels to treat STEMI: intracoronary arterial retrograde thrombolysis (ICART) with PCI. METHODS & RESULTS: Eight patients underwent ICART. The guidewire was advanced to the distal coronary artery through the occlusion lesion. Then, we inserted a microcatheter into the distal end of the occluded coronary artery over the guidewire. Urokinase (5-10 wu) mixed with contrast agents was slowly injected into the occluded section of the coronary artery through the microcatheter. The intracoronary thrombus gradually dissolved in 3-17 min, and the effect of thrombolysis was visible in real time. Stents were then implanted according to the characteristics of the recanalized culprit lesion to achieve full revascularization. One patient experienced premature ventricular contraction during vascular revascularization, and no malignant arrhythmias were seen in any patient. No reflow or slow flow was not observed post PCI. Thrombolysis in myocardial infarction flow grade and myocardial blush grade post-primary PCI was 3 in all eight patients. No patients experienced bleeding or stroke. CONCLUSIONS: ICART was accurate and effective for treating intracoronary thrombi in patients with STEMI in this preliminary study. ICART was an effective, feasible, and simple approach to the management of STEMI, and no intraprocedural complications occurred in any of the patients. ICART may be a breakthrough in the treatment of acute STEMI.

High-resolution temporally resolved chemiluminescence based on double-layered 3D microfluidic paper-based device for multiplexed analysis.

In this work, a double-layered three-dimensional (3D) microfluidic paper-based analytical device (µPAD) with high resolution temporally resolved chemiluminescence (CL) emissions were designed for multiplexed CL analysis. The temporally resolved CL emissions were obtained by virtue of the 3D branched microfluidic channel design, which create time delays for luminol transported from one detection zone to another. The peak intensity and peak shape of the temporally resolved CL emissions were quite stable and base-line separated with resolution as high as 21.2-24.4. Then, the fabricated µPAD was applied to multiplexed determination of glucose, lactate, cholesterol, and choline as model analytes. The sample was added to four detection zone modified with CL catalyst cobalt ion and different oxidase by virtue of chitosan. When luminol flowed to µPAD, four temporally resolved CL peaks were successively generated from the cobalt ion catalyzed CL reactions between luminol and generated H2O2 from the specific enzymatic reactions between the oxidase and the analytes. The generated four CL emission peaks in the CL kinetic curve increased in proportion to the concentrations of glucose, lactate, cholesterol, and choline, respectively. Finally, four linear calibration curves were obtained for the detection of glucose (0.01-1.0 mmol/L), lactate (0.02-5.0 mmol/L), cholesterol (0.01-0.4 mmol/L), and choline (0.001-1.0 mmol/L). The detection limits were as low as 8 µmol/L, 15 µmol/L, 6 µmol/L, and 0.07 µmol/L for glucose, lactate, choline, and cholesterol detection, respectively. The present work provides a new strategy for the fabrication of simple and sensitive 3D µPAD with high resolution temporally resolved CL emissions for multiplexed CL analysis, which holds great application potential for point-of-care diagnosis.

Computational probe of cavitation events in protein systems.

Previous all-atom simulations have identified several classes of proteins where hydrophobic de-wetting (cavitation) is at play. Here we develop and validate a computationally fast method that predicts in which protein systems water spontaneously cavitates. We implement a cubic lattice model, which incorporates the protein shape from crystallographic data and the protein-water interactions from thermodynamic data. Combining it with the previously developed coarse-grained model for water, we determine the extent of occupancy of water at protein-protein interfaces and in protein-ligand cavities. The model captures essential findings from all-atom molecular dynamics studies on the same systems by distinguishing protein cavities that dry from those that remain wet. We also interpret the origin of the cavitation inside the melittin tetramer on simple thermodynamic grounds, and show that part of the mellitin surface is sufficiently hydrophobic to trigger cavitation. Using Glauber/Kawasaki dynamics we obtain the time-scales for de-wetting events that are in agreement with those from all-atom simulations. The method can serve as an intermediate step between the necessary initial screening that identifies proteins with abundance of hydrophobic patches using bioinformatics tools (L. Hua, X. H. Huang, P. Liu, R. H. Zhou and B. J. Berne, J. Phys. Chem. B, 2007, 111, 9069), and computationally extensive studies that need to incorporate molecular details (e.g. single mutation studies of amino acid residues).

Probing surface tension additivity on chemically heterogeneous surfaces by a molecular approach.

Surface free energy of a chemically heterogeneous surface is often treated as an approximately additive quantity through the Cassie equation [Cassie ABD (1948) Discuss Faraday Soc 3:11-16]. However, deviations from additivity are common, and molecular interpretations are still lacking. We use molecular simulations to measure the microscopic analogue of contact angle, Θ(c), of aqueous nanodrops on heterogeneous synthetic and natural surfaces as a function of surface composition. The synthetic surfaces are layers of graphene functionalized with prototypical nonpolar and polar head group: methyl, amino, and nitrile. We demonstrate positive as well as negative deviations from the linear additivity. We show the deviations reflect the uneven exposure of mixture components to the solvent and the linear relation is recovered if fractions of solvent-accessible surface are used as the measure of composition. As the spatial variations in polarity become of larger amplitude, the linear relation can no longer be obtained. Protein surfaces represent such natural patterned surfaces, also characterized by larger patches and roughness. Our calculations reveal strong deviations from linear additivity on a prototypical surface comprising surface fragments of melittin dimer. The deviations reflect the disproportionately strong influence of isolated polar patches, preferential wetting, and changes in the position of the liquid interface above hydrophobic patches. Because solvent-induced contribution to the free energy of surface association grows as cos Θ(c), deviations of cos Θ(c) from the linear relation directly reflect nonadditive adhesive energies of biosurfaces.

The influence of molecular-scale roughness on the surface spreading of an aqueous nanodrop.

We examine the effect of nanoscale roughness on spreading and surface mobility of water nanodroplets. Using molecular dynamics, we consider model surfaces with sub-nanoscale asperities at varied surface coverage and with different distribution patterns. We test materials that are hydrophobic, and those that are hydrophilic in the absence of surface corrugations. Interestingly, on both types of surfaces, the introduction of surface asperities gives rise to a sharp increase in the apparent contact angle. The Cassie-Baxter equation is obeyed approximately on hydrophobic substrates, however, the increase in the contact angle on a hydrophilic surface differs qualitatively from the behavior on macroscopically rough surfaces described by the Wenzel equation. On the hydrophobic substrate, the superhydrophobic state with the maximal contact angle of 180 degrees is reached when the asperity coverage falls below 25%, suggesting that superhydrophobicity can also be achieved by the nanoscale roughness of a macroscopically smooth material. We further examine the effect of surface roughness on droplet mobility on the substrate. The apparent diffusion constant shows a dramatic slow down of the nanodroplet translation even for asperity coverage in the range of 1% for a hydrophilic surface, while droplets on corrugated hydrophobic surfaces retain the ability to flow around the asperities. In contrast, for smooth surfaces we find that the drop mobility on the hydrophilic surface exceeds that on the hydrophobic one.