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.
To explore reasons behind treatment inertia in current approaches to early cardiorenal risk management in type 2 diabetes (T2D).
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.
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.
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.
•Recent guidelines recommend glucose-lowering therapies with cardiorenal benefits.•Most primary care physicians (PCPs) are aware of recent cardiovascular outcomes trials.•Some PCPs remain unsure of the clinical implications of these trials.•PCPs may resist adjusting therapies even as patient cardiovascular risk increases.•Healthcare/insurer restrictions are a key barrier contributing to treatment inertia.
Catechins are the major group of bioactive flavanols in green tea and cacao. 17 glucansucrase-active strains were identified from a set of 41 lactic acid bacteria, which were able to glucosylate ...(+)-catechin in a non-natural acceptor reaction. In total cell free extracts of 12 Leuconostoc and 5 Weissella strains were active on catechin and also 8 cell fractions exhibited catechin glucosylation activity. Six enzymes were selected for further evaluation and enriched up to 37 fold in yields of at least 40%. Glucansucrase of L. citreum DSM 5577 was the most efficient biocatalyst for (+)-catechin transformation with conversions of >40% after 24 h. NMR analysis of the major reaction product confirmed the (+)-catechin-4′-O-α-d-glucoside. Only L. kimchi B-65337 produced a second catechin monoglucoside. Four out of six glucansucrases glucosylated esculetin and all enzymes were active on haematoxylin. Glucansucrases of L. citreum DSM 5577, L. kimchi B-65337 and W. beninensis DSM 22752 were the best suited biocatalysts with conversions of >30% for esculetin and >60% for haematoxylin. W. beninensis DSM 22752 glucansucrase produced 89% haematoxylin glucosides without process optimization. L. kimchi B-65337 and W. beninensis DSM 22752 synthesized >40% diglucosides with the bifunctional haematoxylin. NMR analysis of the purified esculetin products confirmed formation of the 6-O-α-d- and 7-O-α-d-glucosides. Also two haematoxylin monoglucosides were identified as the 9-O-α-d- and 3-O-α-d-glucosides.
Background: Despite recent recommendations for the use of glucose-lowering therapies with additional cardiovascular (CV) and renal benefits, as demonstrated through CV outcomes trials (CVOTs), many ...patients (pts) with type 2 diabetes mellitus (T2D) managed in primary care remain on therapeutic regimens now considered suboptimal. This global survey of primary care physicians (PCPs) investigated current approaches to early CV and renal risk management of pts with T2D.
Methods: This web-based, global, quantitative panel survey of PCPs and primary care diabetes specialists (PCDSs) constituted 20 demographic, Likert scale, and multiple-choice questions covering the current management of pts with T2D, particularly the use of second/third line therapies (sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors).
Results: Globally, 1558 PCPs and 119 PCDSs from 18 countries completed the survey. Respondents saw a mean 132 pts with T2D per month and had treated pts with T2D for 17 years. Overall, 73% of PCPs and 72% of PCDSs were responsible for second/third line treatment initiation. The biggest barrier to second/third line treatment initiation identified by respondents was local healthcare systems/insurance companies restricting access to these therapies. Concerns over safety, pt disinterest, and difficulties in maintaining regular appointments were also identified as significant contributors to treatment inertia. Only 68% of PCPs and 52% of PCDSs were aware of data published from recent CVOTs, while 68% and 58%, respectively, stated they had changed their treatment decisions based on these trials.
Conclusions: Significant barriers still prevent optimization of T2D pt care in the primary setting, including limited familiarity of PCPs and PCDSs with new CVOT data, treatment inertia, and access restrictions for second/third line treatments.
Disclosure
S. Brunton: Advisory Panel; Self; Abbott, Bayer U.S., Merck & Co., Inc., Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. F. Cos: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk A/S, Sanofi. G.F. Deed: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Sanofi-Aventis. N. Kanumilli: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Novartis AG, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis. Speaker’s Bureau; Self; Napp Pharmaceuticals. P.R. Kushner: Advisory Panel; Self; Abbott, AstraZeneca, Bayer U.S., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. P.J. Lin: Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch + Lomb, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Mead Johnson Nutrition, Merck & Co., Inc., Novo Nordisk Inc., Sun Pharmaceutical Industries Ltd. Other Relationship; Self; Elsevier. J. Nolte: Advisory Panel; Self; AstraZeneca.
Funding
AstraZeneca
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•Four nordihydroguaiaretic acid glucosylating lactic acid bacteria were identified.•NDGA glucosylation with DSM 20,193 glucansucrase was optimized to 95.5% yield.•Major products were ...the mono- and the symmetrical diglucoside with 4,4`-O-α-D-structure.•Stability of the glucosides increased > 8 fold and water solubility up to 76 fold.•Antioxidant and anticanceractivities of the glucosides were maintained.
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.
Twelve Leuconostoc and seven Weissella strains with extracellular glucansucrase activity were obtained from an analysis of 41 lactic acid bacteria. Culture supernatants of all glucansucrase positive ...strains catalyzed the glycosylation of caffeic acid with sucrose as donor substrate. Eighteen enzymes produced one major peak, which was identified as caffeic acid-4′-O-α-D-monoglucoside by LC-MS and NMR spectroscopy. Only W. beninensis DSM 22752 formed significant amounts of the corresponding 3´-O-α-D-monoglucoside. The Weissella strain and five Leuconostoc strains with high glycosylation activity were selected for further studies. All glucansucrases catalyzed the glycosylation of the catechol protocatechuic acid, a side-chain truncated analogue of caffeic acid. The Leuconostoc enzymes displayed a preference for the 4′-O-α-D isomer, while the DSM 22752 glucansucrase also produced the protocatechuic acid-3′-O-α-D-monoglucoside. Lower activities with non-catecholic caffeic acid derivatives and no activity with mono-methylated caffeic acid were observed with all glucansucrases. Time-course analyses confirmed that glucansucrase from L. citreum DSM 5577 was the most efficient biocatalyst for catechol glucosylation with yields of up to 74% caffeic acid glucosides after 24 h. The enzyme displayed a high regio-preference for the 4′-O-α-d-isomer and formed less than 10% oligoglucosides. Gel electrophoretic analysis and activity staining of the PEG-enriched enzyme showed a single protein band with a molecular mass of 171 kDa. The DSM 5577 glucansucrase was tolerant against the co-solvents dimethyl sulfoxide and ethanol. Kinetic analysis revealed a KM of 27.6 mM for caffeic acid and 31 mM for sucrose with kcat values of 131 s−1 and 438 s−1.
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•Nineteen glucansucrase positive Leuconostoc and Weissella strains accepted caffeic acid.•Caffeic acid-4′-O-α-D-monoglucoside was the main product.•Novel glucosides of structural analogues umbellic and protocatechuic acid were discovered.•Purified glucansucrase of L. citreum DSM 5577 produced caffeic acid glucosides in 74% yield.•The solvent tolerant enzyme possessed a KM of 27.6 mM and a kcat of 131 s−1.
Der Vortrag beleuchtet neben der Geschichte der VOB und des Deutschen Vergabe‐ und Vertragsausschuss für Bauleistungen (DVA) auch dessen Organisation und seine satzungsgemäßen Aufgaben sowie das ...Verfahren der Erstellung oder Überarbeitung einer ATV.
Zentrales Thema ist die aktuelle Überarbeitung der Allgemeinen Technischen Vertragsbedingungen (ATV) des Hochbaus im Abschnitt 5 “Abrechnung“. Im Auftrag des DVA wurde im Hauptausschuss Hochbau eine neue Struktur für diesen Abschnitt erarbeitet, durch die mehr Klarheit und Transparenz bei den Aufmaßregelungen und der Abrechnung erzielt werden soll.
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.
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