Global survey investigating causes of treatment inertia in type 2 diabetes cardiorenal risk management.

AIM: To explore reasons behind treatment inertia in current approaches to early cardiorenal risk management in type 2 diabetes (T2D). METHODS: A global, web-based, quantitative panel survey of primary care physicians (PCPs) and primary care diabetes specialists treating people living with T2D. The questions covered current management of T2D, particularly the use of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors as second-/third-line therapies. RESULTS: Of 1677 respondents from 18 countries who completed the survey, 73.4% were responsible for second-/third-line therapy initiation. Two thirds had modified treatment decisions based on recent cardiovascular outcomes trials (CVOTs). Respondents cited restricted access to therapies and limits on regular appointments as the greatest barriers to second-/third-line therapy prescription. Although 81.6% agreed that early intensification to second-/third-line therapies is associated with clinical benefits, 46.1% of respondents still reserve these for later lines of therapy, and 23.8% would not consider changing therapeutic approach in patients with well-controlled T2D but increasing cardiovascular risk. CONCLUSIONS: Substantial barriers still prevent optimization of primary setting T2D patient care. Education programs which enable PCPs to translate CVOT evidence into clinical benefits for patients with T2D could address many of the remaining knowledge gaps identified.

Glucansucrase catalyzed synthesis and functional characterization of nordihydroguaiaretic acid glucosides.

Nordihydroguaiaretic acid (NDGA) is the major lignan of the creosote bush Larrea tridentata known for its antioxidative and pharmacological properties. Here we present the identification of glucansucrases for NDGA glucosylation and the physicochemical and biological characterization of the glucosides. Extracellular glucansucrase of L. pseudomesenteroides DSM 20193 was selected from 19 glucansucrase positive Leuconostoc and Weissella strains. Kinetic analysis of the PEG-fractionated enzyme revealed a KM of 6.6 mM and a kcat of 2.6 s-1 for NDGA. Full-factorial design methodology was used to optimize conversion resulting in 95.5% total NDGA glucosides. In total 7 glucosides were detected by LC-MS ranging from mono- to triglucoside. The 4-O-α-D-monoglucoside and the symmetrical 4,4'-O-α-D-diglucoside were the major products in all biotransformations. Water solubility and half-life stability at 45 °C increased significantly in the order diglucoside > monoglucoside > aglycon. Analysis of cellular antioxidative capacity exhibited a time-dependent activity increase pointing towards glucoside hydrolysis. Accordingly, NDGA-glucosides impaired metastasis of triple negative breast cancer cells to the same degree as the aglycon with 35% reduction of cell migration by the mono- and 34% reduction by the diglucoside after 20 h.

Novel characteristics of succinate coenzyme A (Succinate-CoA) ligases: conversion of malate to malyl-CoA and CoA-thioester formation of succinate analogues in vitro.

Three succinate coenzyme A (succinate-CoA) ligases (SucCD) from Escherichia coli, Advenella mimigardefordensis DPN7(T), and Alcanivorax borkumensis SK2 were characterized regarding their substrate specificity concerning succinate analogues. Previous studies had suggested that SucCD enzymes might be promiscuous toward succinate analogues, such as itaconate and 3-sulfinopropionate (3SP). The latter is an intermediate of the degradation pathway of 3,3'-dithiodipropionate (DTDP), a precursor for the biotechnical production of polythioesters (PTEs) in bacteria. The sucCD genes were expressed in E. coli BL21(DE3)/pLysS. The SucCD enzymes of E. coli and A. mimigardefordensis DPN7(T) were purified in the native state using stepwise purification protocols, while SucCD from A. borkumensis SK2 was equipped with a C-terminal hexahistidine tag at the SucD subunit. Besides the preference for the physiological substrates succinate, itaconate, ATP, and CoA, high enzyme activity was additionally determined for both enantiomeric forms of malate, amounting to 10 to 21% of the activity with succinate. Km values ranged from 2.5 to 3.6 mM for l-malate and from 3.6 to 4.2 mM for d-malate for the SucCD enzymes investigated in this study. As l-malate-CoA ligase is present in the serine cycle for assimilation of C1 compounds in methylotrophs, structural comparison of these two enzymes as members of the same subsubclass suggested a strong resemblance of SucCD to l-malate-CoA ligase and gave rise to the speculation that malate-CoA ligases and succinate-CoA ligases have the same evolutionary origin. Although enzyme activities were very low for the additional substrates investigated, liquid chromatography/electrospray ionization-mass spectrometry analyses proved the ability of SucCD enzymes to form CoA-thioesters of adipate, glutarate, and fumarate. Since all SucCD enzymes were able to activate 3SP to 3SP-CoA, we consequently demonstrated that the activation of 3SP is not a unique characteristic of the SucCD from A. mimigardefordensis DPN7(T). The essential role of sucCD in the activation of 3SP in vivo was proved by genetic complementation.

Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis.

OBJECTIVES: To assess the prevalence of the 19 neuropsychiatric (NP) syndromes in systemic lupus erythematosus (SLE) patients, as defined by the American College of Rheumatology (ACR) in 1999, and better understand the reasons for interstudy variability of prevalence estimates, by performing a meta-analysis of relevant publications. METHODS: A literature search from April 1999 to May 2008 was performed to identify studies investigating NP syndromes in patients with definite SLE, applying the 1999 ACR case definitions and having a sample size of at least 30 patients. Excluded were studies that did not relate to all 19 NPSLE syndromes, presented duplicate data, or were irrelevant. RESULTS: Seventeen of 112 identified studies matched the inclusion criteria, reporting on a total of 5057 SLE patients, including 1439 NPSLE patients, with 2709 NPSLE syndromes. In a subanalysis of the 10 higher quality prospective and elicited studies (2049 patients) using the random-effects model, the prevalence of NP syndromes in SLE patients was estimated to be 56.3% (95% CI 42.5%-74.7%), and the most frequent NP syndromes were headache 28.3% (18.2%-44.1%), mood disorders 20.7% (11.5%-37.4%), cognitive dysfunction 19.7% (10.7%-36%), seizures 9.9% (4.8%-20.5%), and cerebrovascular disease 8.0% (4.5%-14.3%), although significant between-study heterogeneity was present (P < 0.05). Autonomic disorder and Guillain-Barré syndrome carried a prevalence of less than 0.1%. No case of plexopathy was reported. CONCLUSIONS: NP syndromes were estimated to exist in more than half of SLE patients. The most prevalent manifestations were headache, mood disorders, and cognitive dysfunction. A major limitation of the study was the significant heterogeneity of prevalence estimates between studies.

Quantitation of the thickness of the non-enhanced myocardial rim predicts recovery of territorial myocardial function in chronic ischemic heart disease: a cardiac magnetic resonance imaging study.

OBJECTIVES: We sought to determine whether the thickness of the non-contrast-enhanced myocardial rim (RIM) predicts recovery of territorial myocardial function after revascularization in chronic ischemic cardiomyopathy (ICM). BACKGROUND: Non-contrast-enhanced dysfunctional myocardium at late gadolinium-enhanced CMR depicts the presence of viable myocardium. METHODS: In 29 patients (65 +/- 8 years) with ICM (EF 33 +/- 10), ceCMR and cine images were acquired 5 +/- 10 days before revascularization. Cine images were repeated after 6 months. Regional wall thickness, wall thickening and RIM were determined in each of 12 segments per short-axis slice (4-8/patient), which were assigned to the respective supplying coronary artery (LAD, LCX and RCA). A threshold for normal wall-thickening was derived from a control group (n = 14; 52 +/- 17 years). Functional improvement at follow-up was defined as wall thickening >2 mm. RESULTS: Of the 1,896 analyzed segments, 655 segments showed severe dysfunction. At follow-up, 307 segments demonstrated functional improvement. The RIM differed between segments with and without improvement (6.6 +/- 2.4 mm vs. 2.8 +/- 2.0 mm; p < 0.0001). The area under the receiver operator characteristic (ROC) for predicting overall functional recovery was 0.91 (95%, CI 0.88-0.93, p < 0.001). A RIM of 4.0 mm predicted functional recovery after revascularization of the supplying coronary artery with a sensitivity and a specificity of 88 and 82% for the LAD, 96 and 86% for the RCA and 88 and 83% for the LCX, respectively. CONCLUSION: RIM may be a useful marker for predicting territorial functional recovery after revascularization in patients with chronic ICM.