Reproducibility of global electrical heterogeneity measurements on 12-lead ECG: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: Vectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics. METHODS: GEH was measured on two 10-s 12­lead ECGs recorded on the same day in 4316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4 ± 9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradient's (SVG's) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi). RESULTS: Two N ECGs with heart rate (HR) bias of -0.64 (95% limits of agreement [LOA] -5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of -0.12 (95%LOA -14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA -15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA -33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA -3.0 to 3.5) showed aQRST bias of -1.03 (95%LOA -11.9 to 9.9). After excluding premature atrial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA -0.092 to 0.092). CONCLUSION: GEH measurements on N, S, and VP median beats are reproducible. SVG's scalar can be measured as either SAIQRST or VMQTi. SIGNIFICANCE: Satisfactory reproducibility of GEH metrics supports their implementation.

Electrophysiological ventricular substrate of stroke: a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVES: The goal of the study was to determine an association of cardiac ventricular substrate with thrombotic stroke (TS), cardioembolic stroke (ES) and intracerebral haemorrhage (ICH). DESIGN: Prospective cohort study. SETTING: The Atherosclerosis Risk in Communities (ARIC) study in 1987-1989 enrolled adults (45-64 years), selected as a probability sample from four US communities (Minneapolis, Minnesota; Washington, Maryland; Forsyth, North Carolina; Jackson, Mississippi). Visit 2 was in 1990-1992, visit 3 in 1993-1995, visit 4 in 1996-1998 and visit 5 in 2011-2013. PARTICIPANTS: ARIC participants with analysable ECGs and no history of stroke were included (n=14 479; age 54±6 y; 55% female; 24% black). Ventricular substrate was characterised by cardiac memory, spatial QRS-T angle (QRS-Ta), sum absolute QRST integral (SAIQRST), spatial ventricular gradient magnitude (SVGmag), premature ventricular contractions (PVCs) and tachycardia-dependent intermittent bundle branch block (TD-IBBB) on 12-lead ECG at visits 1-5. OUTCOME: Adjudicated TS included a first definite or probable thrombotic cerebral infarction, ES-a first definite or probable non-carotid cardioembolic brain infarction. Definite ICH was included if it was the only stroke event. RESULTS: Over a median 24.5 years follow-up, there were 899 TS, 400 ES and 120 ICH events. Cox proportional hazard risk models were adjusted for demographics, cardiovascular disease, risk factors, atrial fibrillation, atrial substrate and left ventricular hypertrophy. After adjustment, PVCs (HR 1.72; 95% CI 1.02 to 2.92), QRS-Ta (HR 1.15; 95% CI 1.03 to 1.28), SAIQRST (HR 1.20; 95% CI 1.07 to 1.34) and time-updated SVGmag (HR 1.19; 95% CI 1.08 to 1.32) associated with ES. Similarly, PVCs (HR 1.53; 95% CI 1.03 to 2.26), QRS-Ta (HR 1.08; 95% CI 1.01 to 1.16), SAIQRST (HR 1.07; 95% CI 1.01 to 1.14) and time-updated SVGmag (HR 1.11; 95% CI 1.04 to 1.19) associated with TS. TD-IBBB (HR 3.28; 95% CI 1.03 to 10.46) and time-updated SVGmag (HR 1.23; 95% CI 1.03 to 1.47) were associated with ICH. CONCLUSIONS: PVC burden (reflected by cardiac memory) is associated with ischaemic stroke. Transient cardiac memory (likely through TD-IBBB) precedes ICH.

Cooperative Self-Assembly of Helical Exciton-Coupled Biosurfactant-Functionalized Porphyrin Chromophores.

Biobased, self-organizing molecules are of considerable interest as functional materials due to their structural versatility, sophisticated nanoarchitectures, and sustainable biosynthesis. Here, we study the self-assembly of a systematic series of bioconjugate sophorolipid-functionalized zinc porphyrin complexes with potential applications in optoelectronic devices. Our results provide insight into the molecular features that control the polymerization pathway, in particular the influence of carbohydrate chirality and noncovalent hydrogen-bonding on biosurfactant-driven self-organization of sophisticated light-absorbing supramolecular polymers. The self-assembly process is driven by a combination of hydrogen-bond, steric, and π-π interactions. Compounds under investigation were synthesized to examine the influence of peripheral chiral carbohydrate hydrogen bonding on chromophore aggregation and physicochemical properties through selective acetylation of the sophorose moiety. In dilute methanol/water solution, we found that excitonically coupled helical structures form by strong carbohydrate hydrogen-bonding interactions, in contrast to weakly coupled J-type aggregate formation with acetyl-group substitution of sugar hydroxyl moieties. Temperature-dependent UV/vis absorption and circular dichroism revealed that supramolecular polymerization proceeds through a cooperative mechanism of self-assembly for compounds bearing free OH groups capable of forming hydrogen-bond interactions. In contrast, per-acetylation of the sophorolipid's sugar group leads to micellar aggregation that is governed by a sterically driven isodesmic (noncooperative) assembly mechanism.

Biosurfactant-functionalized porphyrin chromophore that forms J-aggregates.

Structurally complex biosynthesized building blocks whose structures can be systematically varied are of great interest for the synthesis of manipulable self-organizing supramolecular systems. Sophorolipids (SLs) are an important class of glycolipid biosurfactants that consists of a sophorose (glucose disaccharide) polar head group that allows structural diversification by full or selective acetylation at the 6'- and 6''-positions. Porphyrins are a group of naturally-occurring heterocyclic macromolecular organic compounds that have efficient charge transfer properties. Herein we describe the synthesis of SL-porphyrin conjugates where the number of sophorolipid arms, availability of hydrogen bonding sophorose hydroxyl groups and rigidity of the lipid chain were systematically varied. SLs differing in 'sophorose acetylation' and 'lipid unsaturation' were conjugated to zinc-porphyrin dyes by copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) 'click' chemistry. Mono-, di-, and tetra-conjugation of SL-arms to the zinc-porphyrin core provided variation in SL-arm steric effects. UV-vis spectra in methanol/water reveal features indicative of supramolecular J-type aggregates. The synthesized compounds were designed to provide a library of unique bio-based molecules with built-in variation in non-covalent interactions, hydrogen-bonding, π-π stacking, metal-ligand coordination, dipole-dipole, van der Waals, and hydrophobic interactions for future interrogation of supramolecular self-assembly into functional materials for electro-optical applications.

The chemical biology of Cu(II) complexes with imidazole or thiazole containing ligands: Synthesis, crystal structures and comparative biological activity.

The synthesis and characterization of two copper(II) complexes containing 2-(2-pyridyl)benzimidazole (PyBIm) are reported with the biological activity of these two complexes and a third Cu(II) complex containing 2-(2-pyridyl)benzothiazole (PyBTh). Complex 1, [Cu(PyBIm)(NO3)(H2O)](NO3), is a four coordinate, distorted square planar species with one ligand (N,N), nitrate and water bound to Cu(II). The [Cu(PyBIm)3](BF4)2 complex (2) has distorted octahedral geometry with a 3:1 Py(BIm) ligand to metal ratio. The distorted trigonal bi-pyramidal geometry of compound 3, [Cu(PyBTh)2(H2O)](BF4)2, is comprised of two PyBTh ligands and one water. Biological activity of 1-3 has been assessed by analyzing DNA interaction, nuclease ability, cytotoxic activity and antibacterial properties. Complex 3 exhibits potent concentration dependent SC-DNA cleavage forming single- and double-nicked DNA in contrast to the weak activity of complexes 1 and 2. Mechanistic studies indicate that all complexes utilize an oxidative mechanism however 1 and 2 employ O2(-) as the principal reactive oxygen species while the highly active 3 utilizes (1)O2. The interaction between 1-3 and DNA was investigated using fluorescence emission spectroscopy and revealed all complexes strongly intercalate DNA with Kapp values of 2.65 × 10(6), 1.85 × 10(6) and 2.72 × 10(6)M(-1), respectively. Cytotoxic effects of 1-3 were examined using HeLa and K562 cells and show cell death in the micromolar range with the activity of 1 ≈ 2 and were slightly higher than 3. Similar reactivity was observed in the antibacterial studies with E. coli and S. aureus. A detailed comparative analysis of the three complexes is presented.

Liraglutide for the treatment of type 2 diabetes: a clinical update.

This review updates the pharmacology, efficacy, safety, and tolerability of liraglutide, a glucagon-like peptide 1 (GLP-1) analog approved for the treatment of type 2 diabetes (T2DM) in January 2010. MEDLINE was searched (May 2009-January 1, 2011) for articles in English, using the terms liraglutide, NN2211, incretin mimetic, glucagon-like peptide (GLP)-1, and GLP-1 receptor agonist. Abstracts from key meetings (ADA 2009 and 2010, AACE 2010, EASD 2009, and EASD 2010) were also searched for relevant data. A GLP-1 analog with pharmacokinetic properties allowing once-daily administration via subcutaneous injection, liraglutide has shown clinical benefits when used as monotherapy or in combination. Liraglutide monotherapy has demonstrated efficacy in reducing hemoglobin A1c (A1C) and body weight, with low risk for hypoglycemic events. Liraglutide has also been studied in combination with metformin, glimepiride, and rosiglitazone for the treatment of T2DM. Extension studies within the Liraglutide Effects and Action in Diabetes clinical program have demonstrated the efficacy of liraglutide over 2 years of treatment. Overall, liraglutide has been shown to be well tolerated, with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials. Extended dosing periods have demonstrated the durability of response of liraglutide with respect to glycemic control, lack of weight gain, and blood pressure benefits. Compared with exenatide and sitagliptin, liraglutide seems to offer greater improvements in A1C, fasting plasma glucose, and body weight. Adverse events commonly associated with liraglutide in clinical trials included nausea and hypoglycemia. Emerging data suggest that liraglutide may be a useful option for patients with T2DM.

Intensifying treatment of type 2 diabetes mellitus: adding insulin.

Treatment for patients with type 2 diabetes mellitus is typically initiated with a combination of lifestyle modification and oral drugs. This treatment provides sustained glycemic control in some patients, but many others require administration of insulin as their disease progresses and pancreatic ß cells are lost. One of the most important points in long-term care for patients with type 2 diabetes is the transition to insulin therapy. Health care professionals must choose the most appropriate insulin preparations for management of patients with type 2 diabetes who cannot achieve treatment goals by using other therapies. These include basal, premixed, and basal-bolus insulin regimens. In addition, there are multiple approaches to initiation of insulin treatment, including addition of basal insulin to oral drugs, switching patients to a premixed insulin formulation, or basal-bolus treatment. The pharmacist can play a key role in the transition to insulin therapy by providing education and assisting in day-to-day management of patients with type 2 diabetes who require insulin for intensification of treatment.