Resistance of the failing dystrophic hamster heart to the cardioprotective effects of diltiazem and clentiazem: evidence of coronary vascular dysfunctions

Although hypothermia and cardioplegic cardiac arrest provide effective protection during cardiac surgery, ischemia of long duration, poor preoperative myocardial function, and ventricular hypertrophy may lead to heterogeneous delivery of cardioplegic solutions, incomplete protection, and impaired postischemic recovery. Calcium antagonists are potent cardioprotective agents, but their efficacy in the presence of cold cardioplegia is still controversial, especially in heart failure, since it is often believed that failing hearts are more sensitive to their negative inotropic and chronotropic actions. However, recent data have demonstrated that the benzothiazepine-like calcium antagonists diltiazem and clentiazem, in selected dose ranges, elicit significant cardioprotection independently of intrinsic cardiodepression, thus lending support to their use in cardioprotective maneuvers involving the failing heart. We therefore evaluated the cardioprotective interaction of diltiazem, clentiazem, and cold cardioplegia in both normal and failing ischemic hearts. Hearts were excised from 200- to 225-day-old cardiomyopathic hamsters (CMHs) of the UM-X7.1 line and age-matched normal healthy controls. Ex vivo perfusion was performed at a constant pressure (140 cmH2O; 1 cmH2O = 98.1 Pa) according to the method of Langendorff. Heart rate, left ventricular developed pressure (LVDP), and coronary flow were monitored throughout the study. Global ischemia was produced for 90 min by shutting down the perfusate flow, followed by reperfusion for 30 min. Normal and failing CMH hearts were either untreated (control) or perfused at the onset of global ischemia with one of the following combinations: cold cardioplegia alone (St. Thomas' Hospital cardioplegic solution, 4 degrees C, infused for 2 min), cold cardioplegia + 10 nM diltiazem, or cold cardioplegia + 10 nM clentiazem. The cardiac and coronary dilator properties of 10 nM diltiazem and 10 nM clentiazem alone were investigated in separate groups of isolated preparations. Failing CMH hearts had lower basal LVDP (42 +/- 2 vs. 77 +/- 2 mmHg (1 mmHg = 133.3 Pa) for normal hearts, p < 0.05), while coronary flow was only slightly reduced (5.6 +/- 0.2 vs. 6.2 +/- 0.2 mL/min for normal hearts). Following 90 min global ischemia, coronary flow was increased in both groups, but the peak hyperemic response declined only in failing CMH hearts (+50 +/- 17 vs. +82 +/- 17% in normal hearts). In normal hearts, LVDP virtually recovered within 5 min of reperfusion but steadily decreased thereafter (-37 +/- 4% at 30 min). In contrast, in failing CMH hearts, LVDP significantly decreased early during reperfusion but improved over time (-19 +/- 7% at 30 min). In normal hearts, the addition of diltiazem or clentiazem to cold cardioplegic solutions resulted in improved postischemic contractile function for the duration of reperfusion (85 +/- 4% vs. only 71 +/- 6% for cardioplegia, p < 0.05). The post-ischemic increase in coronary flow was similar in all groups. In failing CMH hearts, the addition of diltiazem or clentiazem afforded no significant contractile benefit at reperfusion. In nonischemic normal hearts, infusion of diltiazem or clentiazem (10 nM) alone increased coronary flow (+6 +/- 1% for diltiazem and +24 +/- 3% for clentiazem) without significant negative inotropic or chronotropic effects. In nonischemic failing CMH hearts, infusion of diltiazem or clentiazem did not elicit cardiodepression. In contrast their coronary dilator actions reverted to vasoconstriction (diltiazem) or were significantly attenuated (clentiazem). From these experiments we can conclude that, compared with the normal heart, the failing CMH heart adapted differently to global ischemia.     

Natural description of large inelastic deformations for shells of arbitrary shape-application of trump element

The paper presents an extension of the range of application of the simple triangular shell element evolved in [1] to the domain of large inelastic deformations. The element is partly based on ideas of physical lumping which contain a simple mechanical interpretation. None of the virtual work or variational principles are applicable to the present model of a finite element thus implying its approximate character. Nevertheless it is hoped that the proposed element, denoted as in [1] by TRUMP, will prove useful for the study of geometrically complicated and materially nonlinear problems of shell systems in which transverse shear may have to be included. In such cases the application of the high order “formal” displacement elements may prove difficult and expensive. Some examples illustrate the technique.     

Monotonicity Inference for Higher-Order Formulas

Formulas are often monotonic in the sense that satisfiability for a given domain of discourse entails satisfiability for all larger domains. Monotonicity is undecidable in general, but we devised three calculi that infer it in many cases for higher-order logic. The third calculus has been implemented in Isabelle’s model finder Nitpick, where it is used both to prune the search space and to soundly interpret infinite types with finite sets, leading to dramatic speed and precision improvements.     

Impaired coronary sensitivity to diltiazem in experimental heart failure: involvement of the cyclooxygenase but not the nitric oxide-synthase pathway

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.     

Extending Sledgehammer with SMT Solvers

Sledgehammer is a component of Isabelle/HOL that employs resolution-based first-order automatic theorem provers (ATPs) to discharge goals arising in interactive proofs. It heuristically selects relevant facts and, if an ATP is successful, produces a snippet that replays the proof in Isabelle. We extended Sledgehammer to invoke satisfiability modulo theories (SMT) solvers as well, exploiting its relevance filter and parallel architecture. The ATPs and SMT solvers nicely complement each other, and Isabelle users are now pleasantly surprised by SMT proofs for problems beyond the ATPs’ reach.     

THE ROLE OF HIERARCHY LEVELS IN VOCAL IMITATIONS OF SONGBIRDS

The singing of adult birds shows a clear hierarchical organization and, due to its development through vocal imitation of sound patterns, makes an excellent biological model to examine the variables that influence the imitation of patterns on different hierarchy levels, e.g., songs and elements composing the songs. We studied such variables in the nightingale (Luscinia megarhynchos), i.e., a species that in the wild uses a large repertoire of songs. Subjects were raised in the lab and tutored by presenting them with a serial learning task, here a sequence of differently patterned songs. Analyses of singing, which the trained subjects performed at the end of their vocal ontogeny, allowed us to uncover hierarchy-related accomplishments and also specific constraints in learning by imitation. Our results showed that an imitation of elements and element sequences reflected a kind of "gestalt" learning, which finally became visible in the form of specific song patterns. An imitation of song sequences, on the other hand, reflected a kind of "list" learning, which finally emerged into the formation of specific subrepertoires of song types. The structure of such subrepertoires mirrored the serial order of imitated songs but allowed, nevertheless, a serially flexible retrieval of single types of songs. These findings contribute to a better understanding of relationships between signal imitation and signal use during vocal interactions among songbirds.     

Stabilization and Control of Delayed Recycling High Order Systems with one Unstable Pole at the Direct Path

In this work the stabilization and control of delayed recycling systems is addressed. Recycling systems are characterized by possessing two main paths, named the direct (feedforward) and the recycling (feedback) paths. Such class of systems reuse the energy and/or the partially processed matter increasing the efficiency of the overall process. A control methodology is proposed for the stabilization and control of this kind of system. The particular class of systems addressed here contains one unstable pole, m stable poles, a delay term and possible p left half plane (LHP) zeros in the direct path and a delayed stable subsystem in the recycling path. The strategy is based on an asymptotic observer‐predictor to estimate the required internal signals. Necessary and sufficient conditions are stated in order to guarantee the stabilization of the proposed scheme, achieving step tracking and rejection.     

β-Actin Peptide-Based Inhibitors of Histidine Methyltransferase SETD3

SETD3 was recently identified as the histidine methyltransferase responsible for N³-methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin peptide was found to be the most potent SETD3 inhibitor (IC₅₀=161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for β-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3.