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The common practice of using alkalotic cardioplegic solutions is not supported by experimental evidence. The present study was conducted (1) to assess the effects of varying the pH (7.00,7.40, and 7.70 at 20° C) of a glutamate-containing cardioplegic solution on intracellular pH, high-energy phosphate content, and postarrest functional recovery and (2) to compare the effects of various buffers (glutamate, bicarbonate, TRIS, and histidine) at a given pH (7.00 and 7.40). Isolated perfused rat hearts were subjected to 2 hours of cardioplegic arrest at 15° C followed by 30 minutes of reperfusion. Intracellular pH and high-energy phosphate content were measured at 4 minute intervals by phosphorus 31 nuclear magnetic resonance spectroscopy. These data were correlated with postischemic recovery of function. There was no significant difference between the intracellular pH values recorded at the end of arrest in the three glutamate-containing groups. However, the acidotic solution (pH 7.00) resulted in better preservation than the alkalotic solution (pH 7.70), as evidenced by (1) a higher creatine phosphate content at the end of arrest (61% ± 9% of control values versus 30% ± 9% [mean ± standard error of the mean], p < 0.05), (2) a higher adenosine triphosphate content at the end of reperfusion (102% ±5% versus 82% ± 6%, p < 0.05), and (3) a faster recovery of aortic flow (at 3 minutes of reperfusion, 91% ± 11% versus 51% ± 11%, p < 0.05). Subsequent comparison of buffers showed that bicarbonate, TRIS, and histidine were equally effective in maintaining intracellular pH close to control values during arrest. Conversely, the use of glutamate resulted in a more pronounced fall in intracellular pH, which correlated with a better preservation of adenosine triphosphate and a better functional recovery than in the other groups. Overall, the greatest extent of preservation was provided by the pH 7.00 glutamate-containing cardioplegic solution. We conclude that additional protection can be conferred to the cold, chemically arrested heart by combining (1) mild intracellular acidosis, which lowers metabolic needs during arrest, most likely through a limitation of calcium overload, and (2) provision of glutamate, which may act as a substrate for anaerobic energy production while allowing intracellular pH to be kept within the appropriate range.

Objective: Ischemic preconditioning is now established as an effective means of reducing infarct size. However, it remains uncertain whether preconditioning can improve the myocardial protection afforded by cardioplegia. The present study was designed to address this issue. Methods: After the institution of cardiopulmonary bypass, 10 patients were preconditioned with 3 minutes of aortic crossclamping followed by 2 minutes of reperfusion before the onset of retrograde continuous warm cardioplegic arrest. Ten case-matched patients served as controls. Three blood samples were drawn simultaneously from the radial artery and the coronary sinus before bypass, at the end of the 5-minute preconditioning protocol or after 5 minutes of bypass in control patients, and at the end of cardioplegic arrest. These samples were assayed for creatine kinase MB isoenzyme and lactate. Right atrial biopsy specimens taken at the same time points were processed by Northern blotting for the expression of messenger ribonucleic acid of both c-fos and heat shock protein 70. Results: At the end of arrest, the release of creatine kinase MB from the myocardium was markedly greater in preconditioned patients than in the controls. The transmyocardial lactate gradient was shifted toward production in the preconditioned group (+0.22 +/- 0.13 mmol/L) and toward extraction in the control group (-0.06 +/- 0.21 mmol/L). Molecular biology data did not suggest a protective effect of preconditioning. There were no clinical adverse events related to preconditioning. Conclusions: Preconditioning does not enhance cardioplegic protection and might even be deleterious. These results do not dismiss its use in cardiac operations. They rather emphasize the need for identifying pharmacologic mediators that could safely and effectively duplicate the cardioprotective effects of ischemic preconditioning. (J THORAC CARDIOVASC SURG 1996;112:1378-86)

Ischemic preconditioning defines an adaptive endogenous mechanism in which a brief episode of reversible ischemia renders the heart more resistant to a subsequent period of sustained ischemia. Because the cardioprotective effects of ischemic preconditioning might be mediated by an activation of adenosine triphosphate-sensitive potassium channels, this study was designed to assess whether these effects could be duplicated by the preischemic administration of a potassium channel opener. Fifty isolated isovolumic buffer-perfused rat hearts underwent 45 minutes of normothermic potassium arrest followed by 1 hour of reperfusion. They were divided into five equal groups that differed with regard to the preconditioning regimen: Group 1 hearts were left untreated and served as controls; in group 2, preconditioning was achieved with 5 minutes of total global ischemia followed by 5 minutes of buffer reperfusion before cardioplegic arrest; in group 3, the preconditioning stimulus consisted of a 5-minute infusion of the potassium channel opener nicorandil (10 @mmol/L) followed by 5 minutes of drug-free buffer perfusion before arrest; group 4 hearts underwent a similar protocol except that the infusion of nicorandil was preceded by that of the potassium channel blocker glibenclamide (10 @mmol/L); group 5 hearts were ischemically preconditioned like those of group 2 except that the no-flow preconditioning period was also preceded by a 5-minute infusion of glibenclamide (50 @mmol/L). The results demonstrate that ischemic preconditioning significantly improved contractility and reduced contracture during reperfusion, as compared with results in control hearts. These protective effects were duplicated by pretreatment with nicorandil but were abolished when the drug was antagonized by a prior infusion of glibenclamide. Likewise, the glibenclamide-induced blockade of potassium channels largely blunted the beneficial effects of ischemic preconditioning. These data suggest that opening of adenosine triphosphate-sensitive potassium channels substantially contributes to preconditioning-induced cardiac protection in a surgically relevant model of global ischemia and, consequently, that the use of potassium channel openers like nicorandil could be an effective means of enhancing cardioplegic protection. (J THORAC CARDIOVASC SURG 1995;110:1606-14)

The effect of acadesine, an adenosine-regulating agent, on the incidence of myocardial infarction, all adverse cardiovascular outcomes (myocardial infarction, cardiac death, left ventricular dysfunction, life-threatening arrhythmia, or cerebrovascular accident) and mortality was assessed in 821 patients undergoing coronary artery bypass grafting. Patients were prospectively stratified to a high-risk group (age >70 years, unstable angina, previous coronary bypass, unsuccessful angioplasty, or ejection fraction <30%) or a non-high-risk group. They were randomized in a double-blind manner to placebo (n = 418) or acadesine (n = 403) by intravenous infusion over 7 hours (0.1 mg/kg per minute) and in the cardioplegic solution (placebo or acadesine; 5 @mg/ml). Acadesine did not significantly affect the incidence of myocardial infarction in the overall study population, but it significantly reduced the incidence of Q-wave myocardial infarction in high-risk patients (placebo, 19.7% acadesine, 10.0% p = 0.032). The incidences of all adverse cardiovascular outcomes (placebo, 19.4%; acadesine, 18.4%) and overall mortality (placebo, 3.4%; acadesine, 2.7%) were similar between the two treatment groups. However, acadesine reduced the incidence of cardiac related events that contributed to deaths occurring during the first 3 postoperative days so that the incidence of death in this period was lower (placebo, 1.9%; acadesine, 0.2%; p = 0.038). No adverse events were related to acadesine treatment. Although overall there were no statistically significant between-group differences for the primary study end points, a secondary analysis in a prospectively defined high-risk subgroup suggests that acadesine may be beneficial in some patients.

• An argon fluoride excimer laser (193 nm) with a moving slit delivery system was used to perform anterior myopic keratomileusis in both eyes of 24 New Zealand white rabbits. Rabbits were killed immediately after ablation and at intervals up to 100 days. By slit-lamp microscopy, four rabbits at day 100 exhibited four clear corneas and four corneas had central, spotty, subepithelial haze. Light and electron microscopy documented corneal healing. In the early stages a transient acellular zone in the anterior stroma appeared over a period of three weeks, followed by an increased number of fibrocytes. In the corneas with opacification, focal areas of 20-μm-thick subepithelial scarring were present. An unexpected finding was transient damage to posterior stromal keratocytes and endothelial cells. The endothelium produced a layer of granular material that migrated anteriorly across Descemet's membrane. Immunochemistry at day 6 showed a marked staining for collagen IV, proteoglycans, fibronectin, and laminin.

Oxygen-derived free radicals play an important role in the myocardial injury associated with ischemia and reperfusion. This study was designed to assess whether the protection afforded by a K+rich, Mg2+rich cardioplegic solution could be enhanced by the addition of free radical scavengers acting at different levels of the radical generating pathway. Forty isolated isovolumic rat hearts were divided into five groups (n = 8). Four groups of hearts were subjected to 90 minutes of normothermic cardioplegic arrest followed by 45 minutes of reperfusion. Hearts were given an initial bolus of either unmodified cardioplegic solution or cardioplegic solution enriched with superoxide dismutase (200,000 U/L) reduced glutathione (0.1 mmol/L), or peroxidase (6,000 U/L). One group of hearts was aerobically perfused throughout the experimental protocol and served as nonischemic controls. Based on comparisons of postreperfusion ventricular pressure development, maximal ventricular dP/dt, left ventricular compliance and coronary flow, peroxidase-containing cardioplegic solution afforded the best myocardial protection, with values of these indicators not significantly different from those of nonischemic perfused control hearts. Glutathione afforded protection slightly inferior to that of peroxidase but still markedly better than in groups receiving superoxide dismutase or unmodified cardioplegic solution. This study confirms that cardioplegic protection can be enhanced by the addition of free radical scavengers, in particular peroxidase.

Facebook News Feed personalization algorithm has a significant impact, on a daily basis, on the lifestyle, mood and opinion of millions of Internet users. Nonetheless, the behavior of such algorithm lacks transparency, motivating measurements, modeling and analysis in order to understand and improve its properties. In this paper, we propose a reproducible methodology encompassing measurements, an analytical model and a fairness-based News Feed design. The model leverages the versatility and analytical tractability of time-to-live (TTL) counters to capture the visibility and occupancy of publishers over a News Feed. Measurements are used to parameterize and to validate the expressive power of the proposed model. Then, we conduct a what-if analysis to assess the visibility and occupancy bias incurred by users against a baseline derived from the model. Our results indicate that a significant bias exists and it is more prominent at the top position of the News Feed. In addition, we find that the bias is non-negligible even for users that are deliberately set as neutral with respect to their political views, motivating the proposal of a novel and more transparent fairness-based News Feed design.

The biosynthesis of type I, type V and type VI collagens was studied by incubation of calf corneas in vitro with [3H]proline as a marker. Pepsin-solubilized collagen types were isolated by salt fractionation and quantified by SDS/PAGE. Expressed as proportions of the total hydroxyproline solubilized, corneal stroma comprised 75% type I, 8% type V and 17% type VI collagen. The rates of [3H]proline incorporation, linear up to 24 h for each collagen type, were highest for type VI collagen and lowest for type I collagen. From pulse-chase experiments, the calculated apparent half-lives for types I, V and VI collagens were 36 h, 10 h and 6 h respectively.

Introduction:Activation the cell cycle of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) via genetic modification enhances their remuscularization capacity after direct intramyocardial injection to infarcted mouse hearts. In this study, we aimed to identify chemicals which activate cardiomyocyte proliferation in the human cardiac muscle patch and test their therapeutic potency.Materials and methods:CHIR99021 (a Wnt1 activator) and FGF1 were encapsulated into poly lactic-co-glycolic acid nanoparticles (C+F-NPs). hiPSC-CMs patches were generated and treated with C+F-NPs (hCMPNP-C+F) or empty nanoparticles (hCMPNP-E). MI was surgically induced in NOD/SCID Gamma mice by ligation of the left anterior descending coronary. The mice were randomly divided into 4 groups (n=10 each group): MI hearts treated with hCMPNP-C+F, with hCMPNP-E, or with neither experimental patch (MI only); a fourth group of animals underwent sham surgery (Sham). Cardiac function was evaluated by Echocardiography 4 week after surgery and the engraftment rate by both in-vivo bioluminesce imaging (BLI) and histological assessments of cells that expressed the human variant of cardiac troponin T and human nuclear antigen. Cell proliferation was assessed via immunostaining in transplanted patches and in cultivated hiPSC-CMs using the following markers: Ki67, Brdu, PH3, and Aurora B.Results:The proportion of cells that expressed cell cycle markers (Ki67; BrdU; Aurora B and PH3) was ~4-6 folds greater in cultured hiPSC-CMs with C+F than without C+F treatment. In the mouse MI model, the number of engrafted cells was about 4 folds in hCMPNP-C+Fgroup than in hCMPNP-Egroup at 4 weeks after the transplantation. The iCM-C+F NP-Patch transplantation was associated with significant improvement in left ventricular (LV) function, infarct size, LV anterior wall thickness, myocardial hypertrophy, and reduced apoptosis in the peri-scar boarder zone myocardium.Conclusions:CHIR99021 and FGF1 synergistically activate cell cycle of hiPSC-CMs and significantly enhance the potency for cardiac patch repair of injured myocardium in MI mice, which is accompanied by a significant improvement of cardiac function.

About one‐third of cellular proteins in eukaryotic cells are localized to membrane‐enclosed organelles in the endomembrane system. Trafficking of these membrane proteins (including soluble lumenal proteins) among the organelles is mediated by small sac‐like vesicles. Vesicle‐mediated membrane trafficking regulates a broad range of biological processes, many of which are still poorly understood at the molecular level. A powerful approach to dissect a vesicle‐mediated membrane trafficking pathway is unbiased genome‐wide genetic screening, which only recently became possible in mammalian cells with the isolation of haploid human cell lines and the development of CRISPR‐Cas9 genome editing. Here, we describe a FACS‐based method to select populations of live mutant cells based on the surface levels of endogenous proteins or engineered reporters. Collection of these mutant populations enables subsequent deep sequencing and bioinformatics analysis to identify genes that regulate the trafficking pathway. This method can be readily adapted to genetically dissect a broad range of mammalian membrane trafficking processes using haploid genetics or CRISPR‐Cas9 screens. © 2018 by John Wiley & Sons, Inc.

Discusses guidelines when producing a music video. Importance of planning in advance; Collaboration with a music video director; Creation of a storyboard; Preparation of the band. INSETS: Budgets;Online Resources.

Discusses how open mic, a forum where musicians can gather and perform an unscheduled set, can help musicians polish their performance skills and make valuable contacts. Tips when performing at an open mic; Opportunities for bands and instrumentalists; Experience that open mic provides. INSET: Be a host.

Presents tips and advice from professional musicians on how to make rehearsals as productive as possible. Necessity of coming into the rehearsal prepared; Importance of having flexibility and an understanding of short- and long-term goals; Benefits of initially working out the vocal harmonies a cappella before blending in the instruments; Need to have a well-equipped rehearsal space. INSET: Rules to Rehearse By.

Discusses how progressive-metal rock band Dream Theater prepares for a concert tour. Development of a composition into an arrangement; Biggest challenges facing the task of translating the album into a live performance; Maintenance of a disciplined work ethic; Band's recording of a double-CD 'Six Degrees of Inner Turbulence'; Strategies for dealing with technical problems. INSETS: Dream Gear;A Nightmare Uncovered.

PKCδ-dependent phosphorylation of the SNARE inhibitor tomosyn reduces mast cell degranulation.

A VARIETY of mechanisms underlie the pharmacological blockade of membrane excitability. Some drugs seem to reduce the frequency at which ion channels open; a good example is the effect of curare on acetylcholine receptor channels at normal resting potentials. Another sort of mechanism may account for the action of many local anaesthetics and related drugs containing charged ammonium groups. It is postulated that such molecules block transmembrane currents as they bind to sites within open ion channels, much like a plug in a drain, with the important difference that the events occur on a millisecond time scale. This model, which we shall call ‘open-channel blockade’, was first applied to the effect of internal tetraethylammonium ions on K+channels in squid axon1and more recently to similar actions of local anaesthetics on acetylcholine receptor channels2–4and on electrically excitable Na+channels5. (Curare seems to exert an additional open-channel blockade at high negative potentials6,7.) The concept of open-channel blockade would receive direct experimental support from the demonstration that the blockade is exerted even if the blocking molecule is not bound to the channel (or indeed is not present at all) until after the channel opens. Such a demonstration is made possible by a drug that (1) blocks acetylcholine receptor channels in Electrophoruselectroplaque, and (2) is created, in less than a millisecond, by a flash of light.

The management of a patient with lung metastatic choriocarcinoma appearing one year after a hydatiform mole, is presented and discussed. After an initial response to chemotherapy, resistance developed; subsequently a lobectomy was performed with good results.

Purpose: With the advent of percutaneous transcatheter device closures in congenital heart defects and the emergence of percutaneous left atrial appendage closure, there is an increasingly important role for echocardiographic guidance and control of device position and function. Disc occluder devices frequently present as an unexplained ‘figure-of-8’ on echocardiography. The aim of this study was to clarify this ‘figure-of-8’ display and to relate its morphology to transducer position and device type. Methods: A mathematical model was developed to resemble disc occluder geometry and to allow a numerical simulation of the echocardiographic appearance. In addition, we developed an in vitro set-up for echocardiographic analysis of various disc occluders and various transducer positions. Results: In the mathematical model of an epitrochoid curve (closely resembling disc occluder geometry) a ‘figure-of-8’ display is obtained when emphasizing points with tangent vector perpendicular to the direction of ultrasound waves. Decreasing imaging depth results in a more asymmetric ‘figure-of-8’, with small upper part and wide lower part. Clinical and in vitro data are in close agreement with these results (Figure 1). Furthermore a ‘figure-of-8’ display is only obtained in a coronal imaging position, and is similar for different commercially available disc occluder types. Conclusions: The ‘figure-of-8’ display in the ultrasound image of a disc occluder is an imaging artifact due to the specific ‘epitrochoidal’ geometry of a deployed device and its interaction with ultrasound waves. The morphology of the ‘figure-of-8’ depends on transducer position, i.e. imaging depth, and is similar for different device types. Figure 1 Impact of imaging depth

Focuses on the taxation of private foundations in the United States. Administrative complications in establishing a private foundation; Simplicity of the estate tax rules and complexity of the income tax rules for charitable giving; Benefits of a well-funded private foundation for family members.

Presents advice on the use of marketed proprietary tax plans or tax shelters in the United States. Provision of the buyer a chance at avoiding the 20 percent penalties assessed on negligent or substantial tax underpayments; Concerns about audit risk which is left to the buyer; Factors need to be considered by shelter buyers.