Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide

Background: The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial KATP channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic KATP channels less than does Glib. We examined the effects of Glim on IP and on the protection afforded by diazoxide (Diaz), an opener of mitochondrial KATP channels. Methods and results: Rat hearts were Langendorff-perfused, subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion, and assigned to 1 of the following treatment groups: (1) control; (2) IP of 2x 5 minutes each of global ischemia before lethal ischemia; or pretreatment with (3) 30 µmol/L Diaz, (4) 10 µmol/L Glim, (5) 10 µmol/L Glib, (6) IP+Glim, (7) IP+Glib, (8) Diaz+Glim, or (9) Diaz+Glib. IP limited infarct size (18.5±1% vs 43.7±3% in control, P<0.01) as did Diaz (22.2±4.7%, P<0.01). The protective actions of IP or Diaz were not abolished by Glim (18.5±3% in IP+Glim, 22.3±3% in Diaz+Glim; P<0.01 vs control). However, Glib abolished the infarct-limiting effects of IP and Diaz. Patch-clamp studies in isolated rat ventricular myocytes confirmed that both Glim and Glib (each at 1 µmol/L) blocked sarcolemmal KATP currents. However, in isolated cardiac mitochondria, Glim (10 µmol/L) failed to block the effects of KATP opening by GTP, in contrast to the blockade caused by Glib. Conclusions: Although it blocks sarcolemmal currents in rat cardiac myocytes, Glim does not block the beneficial effects of mitochondrial KATP channel opening in the isolated rat heart. These data may have significant implications for the treatment of type 2 diabetes in patients with ongoing ischemic heart disease

Partial and Interaction Spline Models for the Semiparametric Estimation of Functions of Several Variables

A partial spline model is a model for a response as a function of several variables, which is the sum of a smooth function of several variables and a parametric function of the same plus possibly some other variables. Partial spline models in one and several variables, with direct and indirect data, with Gaussian errors and as an extension of GLIM to partially penalized GLIM models are described. Application to the modeling of change of regime in several variables is described. Interaction splines are introduced and described and their potential use for modeling non-linear interactions between variables by semiparametric methods is noted. Reference is made to recent work in efficient computational methods

Transverse beam polarization and limits on leptoquark couplings in e+e- --> t tbar

It is shown that if electron and positron beams at a linear collider are transversely polarized, azimuthal asymmetries of the final-state top quark in e+e- --> t tbar can be used to probe a combination of couplings of left and right chiralities in a scalar leptoquark model. The CP-conserving azimuthal asymmetry would be a sensitive test of the chirality violating couplings. A linear collider operating at sqrt{s}=500 GeV and having transverse polarizations of 80% and 60% respectively for the e- and e+ beams, can put a limit of the order of 0.025 on the product of the left and right chirality leptoquark couplings (in units of the electromagnetic coupling constant), with a leptoquark mass of 1 TeV and for an integrated luminosity of 500 inverse fb. The CP-violating azimuthal asymmetry, which would provide a direct test of CP-violating phases in leptoquark couplings, can be constrained to the same level of accuracy. However, this limit is uninteresting in view of the much better indirect limit from the electric dipole moment of the electron.Comment: 13 pages latex, with 6 figures included. Revised version corrects minor error. Latest version corrects minor errors, to appear in Phys. Lett.

An instrument for assessing primary students' knowledge of information graphics in mathematics

Information graphics have become increasingly important in representing, organising and analysing information in a technological age. In classroom contexts, information graphics are typically associated with graphs, maps and number lines. However, all students need to become competent with the broad range of graphics that they will encounter in mathematical situations. This paper provides a rationale for creating a test to measure students’ knowledge of graphics. This instrument can be used in mass testing and individual (in-depth) situations. Our analysis of the utility of this instrument informs policy and practice. The results provide an appreciation of the relative difficulty of different information graphics; and provide the capacity to benchmark information about students’ knowledge of graphics. The implications for practice include the need to support the development of students’ knowledge of graphics, the existence of gender differences, the role of cross-curriculum applications in learning about graphics, and the need to explicate the links among graphics

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the β-cell sulfonylurea receptor. Scatchard plot analysis of [3H]sulfonylurea binding to membranes isolated from rat β-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells demonstrated that glimepiride has a 2.5–3-fold lower affinity than glibenclamide. This corresponded well to the 8–9-fold higher koff and 2.5–3-fold higher kon rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [3H]sulfonylurea binding and the Kd values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [3H]sulfonylurea bound to β-cell membranes were significantly higher for glimepiride compared to glibenclamide. However, the binding affinity of glimepiride measured by both equilibrium binding and kinetic binding studies upon solubilization of β-cell tumor membranes and RINm5F cell membranes increased up to the value for glibenclamide. This was primarily based on a drastic decrease of the dissociation rate constant of glimepiride whereas the kinetics of glibenclamide binding remained largely unaffected upon solubilization. These data suggest that the Kd value alone is not sufficient for characterization of a sulfonylurea drug, since the kinetic binding parameters may also determine its acute blood sugar lowering efficacy

Mimicry or meltdown? On the greening of local new politics parties

By scrutinizing a specific type of local lists - interpreted as a local variant of ‘New Politics Parties’ - this paper aims to give an initial impetus to understanding the internal variations concealed by the all-purpose denominator of local lists. Local New Politics Parties are identified as local policy-seeking parties based on a grassroots democratic and post-material values. Based on a qualitative analysis of three local New Politics Parties their common characteristics, developments and strategies are analysed and clarified. These small parties’ quest for political relevance urges them to adopt office-seeking objectives, also implying a moderation of their profile and a move towards mainstream parties. In response to the increasing organizational costs of public office, as well as to societal changes local New Politics Parties are compelled to look for cooperation formulas with other political actors in the form of local cartels or by affiliating with a national (green) party