Inhibition of Aminoglycoside 6′-N-Acetyltransferase Type Ib-Mediated Amikacin Resistance in Klebsiella pneumoniae by Zinc and Copper Pyrithione

The in vitro activity of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] was inhibited by CuCl₂ with a 50% inhibitory concentration (IC₅₀) of 2.8 μM. The growth of an amikacin-resistant Klebsiella pneumoniae strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by the addition of Zn²⁺ or Cu²⁺ in complex with the ionophore pyrithione. Coordination complexes between cations and ionophores could be developed for their use, in combination with aminoglycosides, to treat resistant infections.     

Infantile pyknocytosis,a rare cause of hemolytic anemia in newborns: report of two cases in twin girls and literature overview

Infantile pyknocytosis is a rare cause of neonatal jaundice and hemolytic anemia. We report on two cases in twin girls that were diagnosed on peripheral blood smear reading. Pyknocytosis should be considered in cases of early unexplained severe hemolytic anemia, and systematic peripheral smear review performed. Its management consists of phototherapy and RBC transfusion.     

Quantifying the atomic-level mechanics of single long physisorbed molecular chains

Individual in situ polymerized fluorene chains 10–100 nm long linked by C–C bonds are pulled vertically from an Au(111) substrate by the tip of a low-temperature atomic force microscope. The conformation of the selected chains is imaged before and after manipulation using scanning tunneling microscopy. The measured force gradient shows strong and periodic variations that correspond to the step-by-step detachment of individual fluorene repeat units. These variations persist at constant intensity until the entire polymer is completely removed from the surface. Calculations based on an extended Frenkel–Kontorova model reproduce the periodicity and magnitude of these features and allow us to relate them to the detachment force and desorption energy of the repeat units. The adsorbed part of the polymer slides easily along the surface during the pulling process, leading to only small oscillations as a result of the high stiffness of the fluorenes and of their length mismatch with respect to the substrate surface structure. A significant lateral force also is caused by the sequential detachment of individual units. The gained insight into the molecule–surface interactions during sliding and pulling should aid the design of mechanoresponsive nanosystems and devices.Ever since the invention of the atomic force microscope (AFM) (1) and the first imaging applications, force spectroscopy has been applied to study the mechanical behavior of polymers (2); more complex chain-like biomolecules, e.g., DNA complementary strands (3); and proteins, subject to controlled extension (2) or applied force (4), mostly in solution and at room temperature. Reactive groups are chemically inserted at the ends and/or along each molecule to firmly bind some of them to suitably functionalized tips and sample surfaces. Irreversible jumps in curves of force vs. vertical separation may be associated in this way with the rupture of bonds or the unfolding of coiled subunits. If reproducible, the lowest peak in the histogram of the forces attained just before each jump is attributed to such an event in a single molecular chain or complementary pair. In the case of homogeneous polymers or protein segments, simulations based on two-state rate theory combined with a standard model of polymer nonlinear elasticity can reproduce such events, whereas reversible plateaus or continuous rises in the force may be associated with fast binding–rebinding processes or with large thermal fluctuations (2). Attention thus has focused on conformational changes strongly influenced by pulling speed or imposed force jumps (4) and also by external stimuli, e.g., optical excitation of inserted chromophores (5) or specific reactants or enzymes (6). Furthermore, mechanical forces recently were discovered by chemists as a unique stimulus to induce specific chemical reactions. In this so-called mechanochemistry, sonication typically is applied to polymer systems and is believed to result in a strong force acting on the weakest link in the chain, where the reaction takes place (7, 8). Regardless of the direct or indirect exposure to force, it is clear that the mechanics of polymer chains constrained in their surrounding environment is of utmost importance for a variety of biophysical and chemical processes as well as self-healing materials applications (9, 10).A few pulling studies have been conducted on polyelectrolytes unspecifically adsorbed on self-assembled monolayers via tunable electrostatic interactions (11), including DNA (12). They merely revealed noisy force plateaus, interpreted as continuous partial desorption of single chains, terminated by a drop to zero upon complete detachment from the surface. Despite the undisputed merit of these studies, little is known about the mechanical behavior of single molecular chains pulled off a surface, both defined and characterized on the atomic scale, in the absence of significant thermal fluctuations and drifts. Measurements at low temperature reduce the diffusion of adsorbates and provide an opportunity to determine the energetic landscape of specific molecules interacting with a surface under controlled conditions. As demonstrated here, the sliding and detachment mechanisms of individual polymer repeat units can then be inferred from the analysis of pulling experiments. A detailed interpretation of our results, based on a modified Frenkel–Kontorova (FK) model (13), also is presented.     

Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second-line treatment after metformin and are often ranked at the same level as newer glucose-lowering medications. Strong evidence now shows that sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT-2is and GLP-1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT-2is and/or GLP-1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second-line agents continues to be acceptable in resource-constrained settings.