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1.  Comparison of three different methods for the quantification of equine insulin 
BMC Veterinary Research  2016;12(1):196.
Exact analysis of equine insulin in blood samples is the key element for assessing insulin resistance or insulin dysregulation in horses. However, previous studies indicated marked differences in insulin concentrations obtained from sample analyses with different immunoassays. Most assays used in veterinary medicine are originally designed for use in human diagnostics and are based on antibodies directed against human insulin, although amino acid sequences between equine and human insulin differ. Species-specific assays are being used more frequently and seem to provide advantages compared to human-specific assays. The aim of this study was to compare three immunoassays, one porcine-specific insulin enzyme-linked immunosorbent assay (ELISA), advertised to be specific for equine insulin, one porcine-specific insulin radioimmunoassay (RIA) and one human-specific insulin chemiluminescence immunoassay (CLIA), all three widely used in veterinary laboratories for the analysis of equine insulin. Furthermore, we tested their clinical applicability in assessing insulin resistance and dysregulation by analysis of basal blood and blood samples obtained during a dynamic diagnostic stimulation test (OGT) with elevated insulin concentrations.
Insulin values obtained from the ELISA, RIA and CLIA, investigated for analyses of basal blood samples differed significantly between all three assays. Analyses of samples obtained during dynamic diagnostic stimulation testing with consecutively higher insulin concentrations revealed significantly (p < 0.001) lower insulin concentrations supplied by the CLIA compared to the ELISA. However, values measured by ELISA were intermediate and not different to those measured by RIA. Calculated recovery upon dilution, as a marker for assay accuracy in diluted samples, was 98 ± 4 % for ELISA, 160 ± 41 % for RIA and 101 ± 11 % for CLIA.
Our results indicate that insulin concentrations of one sample measured by different methods vary greatly and should be interpreted carefully. Consideration of the immunoassay method and reliable assay-specific reference ranges are of particular importance especially in clinical cases where small changes in insulin levels can cause false classification in terms of insulin sensitivity of horses and ponies.
PMCID: PMC5016943  PMID: 27613127
Horse; Equine; Insulin; Quantification; ELISA; RIA; CLIA; EMS
2.  Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans 
Scientific Reports  2016;6:30162.
Human monocytes are a heterogeneous cell population, which can be divided into a classical (CD14++CD16−), a non-classical (CD14+CD16+), and an intermediate (CD14++CD16+) subset. We hypothesized that low-grade inflammation may differentially affect monocyte subsets. We used a human lipopolysaccharide (LPS) infusion model to mimic low-grade inflammation to identify, which monocyte subsets are preferentially activated under these conditions. Monocyte subsets were identified by staining for CD14 and CD16, activation status of monocytes was analyzed by staining for CD11b and a novel in situ mRNA hybridization approach to detect IL-6 and IL-8 specific mRNA at the single-cell level by flow cytometry. After LPS challenge, cell numbers of monocyte subsets dropped after 2 h with cell numbers recovering after 6 h. Distribution of monocyte subsets was skewed dramatically towards the intermediate subset after 24 h. Furthermore, intermediate monocytes displayed the largest increase of CD11b expression after 2 h. Finally, IL-6 and IL-8 mRNA levels increased in intermediate and non-classical monocytes after 6 h whereas these mRNA levels in classical monocytes changed only marginally. In conclusion, our data indicates that the main responding subset of monocytes to standardized low-grade inflammation induced by LPS in humans is the CD14++CD16+ intermediate subset followed by the CD14+CD16+ non-classical monocyte subset. Circulating classical monocytes showed comparably less reaction to LPS challenge in vivo.
PMCID: PMC4957086  PMID: 27444882
3.  Metabotypes with properly functioning mitochondria and anti-inflammation predict extended productive life span in dairy cows 
Scientific Reports  2016;6:24642.
The failure to adapt metabolism to the homeorhetic demands of lactation is considered as a main factor in reducing the productive life span of dairy cows. The so far defined markers of production performance and metabolic health in dairy cows do not predict the length of productive life span satisfyingly. This study aimed to identify novel pathways and biomarkers related to productive life in dairy cows by means of (targeted) metabolomics. In a longitudinal study from 42 days before up to 100 days after parturition, we identified metabolites such as long-chain acylcarnitines and biogenic amines associated with extended productive life spans. These metabolites are mainly secreted by the liver and depend on the functionality of hepatic mitochondria. The concentrations of biogenic amines and some acylcarnitines differed already before the onset of lactation thus indicating their predictive potential for continuation or early ending of productive life.
PMCID: PMC4835701  PMID: 27089826
4.  N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes 
Scientific Reports  2016;6:23723.
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16, and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-CoA and lipid metabolism. Concordantly, cytoplasmic acetyl-CoA levels and global histone H3 acetylation were decreased. Further, activating histone marks (H3K27ac and H3K9ac) in promoters/enhancers of brown marker genes showed reduced acetylation status. Taken together, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. Thereby, we mechanistically connect the NAA pathway to the epigenomic regulation of gene expression, modulating the phenotype of brown adipocytes.
PMCID: PMC4820693  PMID: 27045997
5.  Cause of Death and Predictors of All‐Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF  
Pokorney, Sean D. | Piccini, Jonathan P. | Stevens, Susanna R. | Patel, Manesh R. | Pieper, Karen S. | Halperin, Jonathan L. | Breithardt, Günter | Singer, Daniel E. | Hankey, Graeme J. | Hacke, Werner | Becker, Richard C. | Berkowitz, Scott D. | Nessel, Christopher C. | Mahaffey, Kenneth W. | Fox, Keith A. A. | Califf, Robert M. | Anderson, J. | Bedwell, N. | Bilsker, M. | Bruce, G. | Agah, R. | DeSantis, M. | Eisenberg, S. | Flores, A. | Herzog, W. | Klein, S. | Snyder, H. | Krueger, S. | Almaguer, E. | Lavie, E. | Lee, C. | Mallis, G. | Modi, M. | Woodworth, G. | Niazi, I. | Peart, B. | Sundaram, S. | Snoddy, B. | Sotolongo, R. | Moloney, J. | Vijayaraghavan, K. | Whittier, F. | Yellen, L. | Banerjee, S. | Lustgarten, D. | Suresh, D. | Gelernt, M. | Levinson, L. | Ghanekar, R. | Kneller, G. | Hall, C. | Fadl, Y. | Pirwitz, M. | French, W. | Mayer, N. | Pugeda, J. | Steel, K. | Mody, F. | Malik, A. | Chandna, H. | Go, A. | Emlein, G. | Bowden, W. | Moscoso, R. | Hodson, R. | Berk, M. | Pan, D. | Pappas, J. | Orchard, R. | Lynchard, G. | Vijay, N. | Khan, W. | El Khadra, M | Antonishen, M. | Cucher, F. | Staab, M. | Zebrack, J. | Borromeo, S | Heilman, J. | Chaturvedi, S. | Makam, S. | Turk, S. | Hyers, T. | Williams, G. | Labroo, A. | Gill, S. | Myears, D. | Weinstein, J. | Shanes, 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R. | Storozhakov, G. | Tankhilevich, B. | Tereschenko, S. | Khokhlov, A. | Khrustalev, O. | Chernov, S. | Shvarts, Y. | Shubik, Y. | Shulman, V. | Yakushin, S. | Bugrova, O. | Ivleva, A. | Libis, R. | Khozyainova, N. | Maslov, S. | Baranova, E. | Sherenkov, A. | Libov, I. | Lusov, V. | Chumakova, G. | Kuznetsov, V. | Ryamzina, I. | Reshetko, O. | Boldueva, S. | Alekseeva, N. | Novikova, T. | Dvornikov, V. | Idrisova, E. | Shostak, N. | Yarokhno, N. | Tebloev, K. | Treshkur, T. | Mazurov, V. | Loktin, E. | Sedavnyh, I. | Alexeeva, O. | Yakhontova, P. | Repin, A. | Izmozherova, N. | Kostenko, V. | Fokin, A. | Ketova, G. | Kouz, S. | Leader, R. | Ayala‐Paredes, F. | Luton, R. | Ma, P. | Pandey, S. | Pesant, Y. | Senior, R. | Vertes, G. | Bell, A. | Crowley, D. | Vizel, S. | Lasko, B. | Landry, D. | Berger, L. | Heath, J. | Bessoudo, R. | Ling, M. | Tellier, G. | Berlingieri, J. | Kafka, H. | Hill, L. | Mazza, G. | O'Mahony, W. | Chilvers, M. | O'Mahony, M. | Newman, D. | Silagy, 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A. | Lorga Filho, A. | Pimentel Filho, P. | Moura Jorge, J. | Maia, L. | Manenti, E. | D'Aurea Mora, R | de Souza Neto, J | Precoma, D. | Rabelo, A. | Rocha, J. | Rossi, P. | Kerr Saraiva, J. | Zimerman, L. | Bodanese, L. | Figueiredo, E. | de Souza, W. Sebba Barroso | Braga, J. | Alessi, S. | Gomes, M. | Silva, R. | Teixeira, M. | Costa, F. | Motta, M. | Sobral Filho, D. | Reis, G. | Garbelini, B | Zimmermann, S. | Pereira Barretto, A. | Dohmann, H. | Barreto Filho, J. | Ghorayeb, N. | Borelli, F. | Rossi dos Santos, F. | Lopes Prudente, M. | Vejar, M. | Lanas, F. | Del Pino, R. | Potthoff, S. | Charme, G. | Aguirre, A. | Saldana, A. | Garces, E. | Bunster, L. | Figueroa, H. | Olivares, C. | Raffo, C. | Vergara, E. | Sepulveda, P. | Jano, G. | Morales Alvarado, J. | Suarez, R. | Urina, M. | Perez, G. | Quintero, A. | Pava, L. | Botero Lopez, R. | Luengas, C. | Hernandez, E. | Sanchez, D. | Poveda, C. | Coronel, J. | Beltran, R. | Jaramillo, C. | Pardo, J. | Ponte Negretti, C. | Isea, J. | Vergara, G. | Morr, I. | Sim, K. | Wan Ahmad, W. | Yusof, Z. | Rosman, A. | Basri, H | Thompson, P. | Jeffery, I. | Purnell, P. | Roberts‐Thomson, P. | Heddle, W. | Waites, J. | Walters, D. | Amerena, J. | Challa, P. | Karrasch, J. | Lowy, A. | Fitzpatrick, D. | Parsons, M. | Phan, T. | Bladin, C. | Donnan, G. | Aroney, G. | Gerraty, R. | Anderson, C. | Blombery, P. | Martin, P. | Tissa Wijeratne, K. | Cross, D. | Crimmins, D. | Packham, D. | Jackson, D. | Chua, W. | Merino, R. | Magno, M. | Tirador, L. | Batalla, E. | Manalo, C. | Uy, N. | Ebo, G. | Reyes, E. | Bernan, A. | Richards, M. | Hart, H. | Mann, S. | Fisher, R. | Stewart, R. | Wilkins, G. | Barber, A. | Tan, R. | Ong, H. | Singh, R. | Sukonthasarn, A. | Tanomsup, S. | Krittayaphong, R. | Piamsomboon, C. | Piyayotai, D. | Sunsaneewitayakul, B. | Baek, S. | Seo, H. | Rim, S. | Kim, C. | Kim, K. | Ryu, K. | Jo, S. | Tahk, S. | Lee, H. | Kim, Y. | Shin, D. | Choi, Y. | Chung, N. | Namgung, J. | Hong, T. | Shin, W. | Jin, S. | Yan, X. | Fu, G. | Lu, G. | Yang, K. | Xu, D. | Chen, J. | Liu, J. | Wu, S. | Song, J.
Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.
Methods and Results
In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).
In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.
Clinical Trial Registration
URL: Unique identifier: NCT00403767.
PMCID: PMC4943233  PMID: 26955859
atrial fibrillation; mortality; rivaroxaban; stroke; warfarin; Atrial Fibrillation; Sudden Cardiac Death; Heart Failure; Ischemic Stroke; Intracranial Hemorrhage
6.  Inflammation and Cardiac Outcome 
Purpose of Review
Inflammation is a key component in cardiovascular disease. Controlling inflammatory events and their subsequent processes hold the potential for novel therapeutic options. Cytokines are the propagators of inflammation. In this review we will discuss important cytokines, including IL-6, TNF-alpha, MCP-1, M-CSF and GDF-15 and their effect on cardiac outcome.
Recent findings
IL-6 is a useful biomarker in patients with coronary artery disease.
PMCID: PMC4497511  PMID: 21378564
7.  Synthetic Long Peptide Influenza Vaccine Containing Conserved T and B Cell Epitopes Reduces Viral Load in Lungs of Mice and Ferrets 
PLoS ONE  2015;10(6):e0127969.
Currently licensed influenza vaccines mainly induce antibodies against highly variable epitopes. Due to antigenic drift, protection is subtype or strain-specific and regular vaccine updates are required. In case of antigenic shifts, which have caused several pandemics in the past, completely new vaccines need to be developed. We set out to develop a vaccine that provides protection against a broad range of influenza viruses. Therefore, highly conserved parts of the influenza A virus (IAV) were selected of which we constructed antibody and T cell inducing peptide-based vaccines. The B epitope vaccine consists of the highly conserved HA2 fusion peptide and M2e peptide coupled to a CD4 helper epitope. The T epitope vaccine comprises 25 overlapping synthetic long peptides of 26-34 amino acids, thereby avoiding restriction for a certain MHC haplotype. These peptides are derived from nucleoprotein (NP), polymerase basic protein 1 (PB1) and matrix protein 1 (M1). C57BL/6 mice, BALB/c mice, and ferrets were vaccinated with the B epitopes, 25 SLP or a combination of both. Vaccine-specific antibodies were detected in sera of mice and ferrets and vaccine-specific cellular responses were measured in mice. Following challenge, both mice and ferrets showed a reduction of virus titers in the lungs in response to vaccination. Summarizing, a peptide-based vaccine directed against conserved parts of influenza virus containing B and T cell epitopes shows promising results for further development. Such a vaccine may reduce disease burden and virus transmission during pandemic outbreaks.
PMCID: PMC4457525  PMID: 26046664
8.  A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis 
Cell Death & Disease  2015;6(5):e1767-.
Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3. Necroptotic cell death contributes to the pathophysiology of several disorders involving tissue damage, including myocardial infarction, stroke and ischemia-reperfusion injury. However, no inhibitors of necroptosis are currently in clinical use. Here we performed a phenotypic screen for small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α)-induced necroptosis in Fas-associated protein with death domain (FADD)-deficient Jurkat cells using a representative panel of Food and Drug Administration (FDA)-approved drugs. We identified two anti-cancer agents, ponatinib and pazopanib, as submicromolar inhibitors of necroptosis. Both compounds inhibited necroptotic cell death induced by various cell death receptor ligands in human cells, while not protecting from apoptosis. Ponatinib and pazopanib abrogated phosphorylation of mixed lineage kinase domain-like protein (MLKL) upon TNF-α-induced necroptosis, indicating that both agents target a component upstream of MLKL. An unbiased chemical proteomic approach determined the cellular target spectrum of ponatinib, revealing key members of the necroptosis signaling pathway. We validated RIPK1, RIPK3 and transforming growth factor-β-activated kinase 1 (TAK1) as novel, direct targets of ponatinib by using competitive binding, cellular thermal shift and recombinant kinase assays. Ponatinib inhibited both RIPK1 and RIPK3, while pazopanib preferentially targeted RIPK1. The identification of the FDA-approved drugs ponatinib and pazopanib as cellular inhibitors of necroptosis highlights them as potentially interesting for the treatment of pathologies caused or aggravated by necroptotic cell death.
PMCID: PMC4669708  PMID: 25996294
9.  Gene expression profiles induced by growth factors in in vitro cultured osteoblasts 
Bone & Joint Research  2014;3(7):236-240.
Effects of insulin-like growth factor 1 (IGF1), fibroblast growth factor 2 (FGF2) and bone morphogenetic protein 2 (BMP2) on the expression of genes involved in the proliferation and differentiation of osteoblasts in culture were analysed. The best sequence of growth factor addition that induces expansion of cells before their differentiation was sought.
Primary human osteoblasts in in vitro culture were treated with IGF1, BMP2 or FGF2 (10 ng/ml) for 24 hours (IGF1) or 48 hours (BMP2 and FGF2). Experiments were performed during the exponential growth phase with approximately 1e7 cells per 75 cm2 flask. mRNA was reverse transcribed directly and analysed using RT-PCR Taqman assays. Expression levels of key genes involved in cell growth and differentiation (CDH11, TNFRSF11B, RUNX2, POSTN, ALP, WNT5A, LEF1, HSPA5, FOS, p21) were monitored using RT-PCR with gene-specific Taqman probes.
Autocrine expression of BMP2 is stimulated by FGF2 and BMP2 itself. BMP2 and FGF2 act as proliferative factors as indicated by reduced expression of ALP and POSTN, whereas IGF1 exhibits a more subtle picture: the Wingless und Int-1 (Wnt) signalling pathway and the Smad pathway, but not p38 mitogen-activated protein (MAP) kinase signalling, were shown to be activated by IGF1, leading to proliferation and differentiation of the cells.
For future use of autologous bone cells in the management of bony defects, new treatment options take advantage of growth factors and differentiation factors. Thus, our results might help to guide the timely application of these factors for the expansion and subsequent differentiation of osteoblastic cells in culture.
Cite this article: Bone Joint Res 2014;3:236–40.
PMCID: PMC4112778  PMID: 25057185
Osteoblasts; Tissue engineering; SMAD; Wnt; Alkaline phosphatase
10.  Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities 
British Journal of Pharmacology  2012;167(6):1177-1194.
Since the first discovery of an inverse correlation between high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL-C levels have been major research topics. The Framingham study and others that followed could show that HDL-C is an independent cardiovascular risk factor and that the increase of HDL-C of only 10 mg·L−1 leads to a risk reduction of 2–3%. While statin therapy and therefore low-density lipoprotein-cholesterol (LDL-C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL-C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL-C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL-C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL-C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given.
PMCID: PMC3504986  PMID: 22725625
High-density lipoprotein; function/dysfunction; coronary artery disease; pharmacology; niacin; fibrate; statin; cholesterol ester transfer protein (CETP); PPAR agonist; liver X-receptor agonist
11.  The inflammatory mediator oncostatin M induces angiopoietin 2 expression in endothelial cells in vitro and in vivo 
Members of the glycoprotein 130 (gp130) receptor–gp130 ligand family play a role in angiogenesis in different tissues. We tested the effect of this cytokine family on the angiopoietin (Ang)–Tie system, which is involved in blood vessel maturation, stabilization, and regression.
Oncostatin M (OSM) increased Ang2 expression in human umbilical vein endothelial cells via Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase activation. Furthermore, OSM induced Ang2 expression in macrovascular endothelial cells isolated from the human aorta and in microvascular endothelial cells isolated from human heart. Our in vivo experiments revealed that mRNA expression of Ang2 in hearts of mice injected with OSM increased significantly, and levels of OSM mRNA significantly correlated with mRNA levels of Ang2 in human hearts. In addition, OSM increased the expression of its own receptors, gp130 and OSM receptor, in endothelial cells in vitro and in mice in vivo, and levels of OSM mRNA significantly correlated with mRNA levels of gp130 and OSM receptor in human hearts.
Our data, showing the effects of OSM on the Ang–Tie system in endothelial cells, in hearts of mice, and in human heart tissue, provide yet another link between inflammation and angiogenesis.
PMCID: PMC2857505  PMID: 20088942
angiogenesis; angiopoietin; cytokine; oncostatin M
14.  No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis 
Journal of Clinical Pathology  2006;59(11):1186-1190.
That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence.
To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae.
Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H pylori and M pneumoniae. IgG antibody titres against H pylori and M pneumoniae and plasma levels of soluble E‐selectin, soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 were determined.
M pneumoniae‐specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M pneumoniae‐specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti‐M pneumoniae antibodies was not observed. H pylori‐specific DNA could not be detected in the specimens tested.
The absence of H pylori and the random distribution of M pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.
PMCID: PMC1860507  PMID: 16644879
15.  Early glycoprotein IIb–IIIa inhibitors in primary angioplasty (EGYPT) cooperation: an individual patient data meta-analysis 
Heart  2008;94(12):1548-1558.
Even though time-to-treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits from early pharmacological reperfusion by glycoprotein (Gp) IIb–IIIa inhibitors are still unclear. The aim of this meta-analysis was to combine individual data from all randomised trials conducted on facilitated primary angioplasty by the use of early Gp IIb–IIIa inhibitors.
Methods and results:
The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) from January 1990 to October 2007. All randomised trials on facilitation by the early administration of Gp IIb–IIIa inhibitors in ST-segment elevation myocardial infarction (STEMI) were examined. No language restrictions were enforced. Individual patient data were obtained from 11 out of 13 trials, including 1662 patients (840 patients (50.5%) randomly assigned to early and 822 patients (49.5%) to late Gp IIb–IIIa inhibitor administration). Preprocedural Thrombolysis in Myocardial Infarction Study (TIMI) grade 3 flow was more frequent with early Gp IIb–IIIa inhibitors. Postprocedural TIMI 3 flow and myocardial blush grade 3 were higher with early Gp IIb–IIIa inhibitors but did not reach statistical significance except for abciximab, whereas the rate of complete ST-segment resolution was significantly higher with early Gp IIb–IIIa inhibitors. Mortality was not significantly different between groups, although early abciximab demonstrated improved survival compared with late administration, even after adjustment for clinical and angiographic confounding factors.
This meta-analysis shows that pharmacological facilitation with the early administration of Gp IIb–IIIa inhibitors in patients undergoing primary angioplasty for STEMI is associated with significant benefits in terms of preprocedural epicardial recanalisation and ST-segment resolution, which translated into non-significant mortality benefits except for abciximab.
PMCID: PMC2582788  PMID: 18474534
16.  A cellular and molecular investigation of the action of PMX464, a putative thioredoxin inhibitor, in normal and colorectal cancer cell lines 
British Journal of Pharmacology  2007;151(8):1167-1175.
Background and Purpose:
PMX464 is a novel benzothiazole substituted cyclohexadienone reportedly targeting the thioredoxin (Trx1)/thioredoxin reductase (TrxR1) system. We have previously shown that PMX464 has enhanced hypoxic anti-proliferative effects in colorectal tumour cells, with some non-tumour cells (quiescent endothelium and fibroblasts) being relatively resistant. The current study aimed to validate the Trx1 system as a molecular target of PMX464 in tumour cells and to investigate the differential sensitivities of normal cells at the molecular level.
Experimental Approach:
Proliferation, clonogenic survival, protein expression and function, cell cycle and apoptosis assays were conducted using colorectal tumour (HT29), endothelial (HUVEC) and fibroblast (MRCV) cells treated with PMX464 under normoxic and hypoxic (1% O2) conditions.
Key Results:
Protein and enzyme assays showed that PMX464, in HT29, inhibited Trx1 function without altering expression and that inhibition correlated with decreased proliferation and survival, and was more marked under hypoxia. In contrast, although hypoxic HUVEC were sensitive, in terms of proliferation and survival, inhibition of Trx1 function was not observed. Quiescent HUVEC and MRCVs (that have undetectable Trx1 protein) were relatively resistant. The effect on HT29 cells was essentially due to cell cycle inhibition, as apoptosis was modest. Anti-proliferative effects were lost after a lag period, suggesting a reversible phenomenon.
Conclusions and Implications:
The Trx1 system is an important target in tumour cells and can be inhibited by PMX464. Quiescent HUVEC and fibroblasts are relatively resistant conferring a therapeutic benefit when targeting Trx1.
PMCID: PMC2189840  PMID: 17572693
thioredoxin; colorectal cancer; chemotherapy; angiogenesis
17.  Effect of retrobulbar versus subconjunctival anaesthesia on retrobulbar haemodynamics 
Aim: To investigate the effect of retrobulbar and subconjunctival anaesthesia on retrobulbar haemodynamics by colour Doppler imaging.
Method: 39 patients (mean age 71 (SD 9) years; 19 females, 20 males) undergoing planned cataract surgery were included in the prospective study. Colour Doppler imaging (Siemens Sonoline Sienna, Germany) was performed before, directly after either subconjunctival (16 patients) or retrobulbar (23 patients) anaesthesia, and after cataract surgery to measure the peak systolic (PSV) and end diastolic velocities (EDV) in the ophthalmic artery (OA), central retinal artery (CRA), and central retinal vein (CRV).
Results: After retrobulbar anaesthesia there was a significant reduction of the PSV and of the EDV in all investigated vessels. After surgery the flow velocities increased again. Subconjunctival anaesthesia had no significant effects on retrobulbar haemodynamics.
Conclusion: Retrobulbar anaesthesia induces a high reduction of velocity in the retrobulbar vessels in contrast with subconjunctival anaesthesia. Therefore subconjunctival anaesthesia should be preferred particularly in patients with problems of the ocular perfusion (for example, glaucoma).
PMCID: PMC1772696  PMID: 15923508
colour Doppler imaging; cataract surgery; retrobulbar anaesthesia; subconjunctival anaesthesia; retrobulbar haemodynamics; blood flow
18.  Comparison of EDTA and acid-citrate-dextrose collection tubes for detection of cytomegalovirus antigenemia and infectivity in leukocytes before and after storage. 
Journal of Clinical Microbiology  1997;35(1):305-306.
Duplicate blood samples collected in EDTA and acid-citrate-dextrose (ACD) were compared by cytomegalovirus (CMV) pp65 antigenemia and CMV infectivity on the day of sample collection and after 1 and 2 days of storage at 4 degrees C. No significant difference was detected between EDTA and ACD. However, CMV antigenemia was more sensitive than culture at all time points tested.
PMCID: PMC229565  PMID: 8968934
19.  Purification and structural characterization of a flavoprotein induced by iron limitation in Methanobacterium thermoautotrophicum Marburg. 
Journal of Bacteriology  1995;177(9):2436-2441.
Cells of Methanobacterium thermoautotrophicum (strain Marburg) grown under iron-limiting conditions were found to synthesize a soluble polypeptide as one of the major cell proteins. This polypeptide purified as a homotetramer (170 kDa [subunit molecular mass, 43 kDa]) had a UV-visible spectrum typical of flavoproteins and contained 0.7 mol of flavin mononucleotide per mol of monomer. Quantitative analysis by immunoblotting with polyclonal antibodies indicated that the flavoprotein, which amounts to about 0.6% of soluble cell protein under iron-sufficient conditions (> or = 50 microM Fe2+), was induced fivefold by iron limitation (< 12 microM Fe2+). The flavoprotein-encoding gene, fprA, was cloned and sequenced. Sequence analysis revealed a well-conserved archaebacterial consensus promoter upstream of fprA, a flavodoxin signature within fprA, and 28% amino acid identity with a putative flavin mononucleotide-containing protein of Rhodobacter capsulatus which is found within an operon involved in nitrogen fixation. A possible physiological function for the flavoprotein is discussed.
PMCID: PMC176902  PMID: 7730275
20.  Effect of delayed specimen processing on cytomegalovirus antigenemia test results. 
Journal of Clinical Microbiology  1995;33(1):257-259.
Blood samples held at either 4 degrees C or room temperature for 1 day had similar mean decreases in number of cytomegalovirus antigenemia-positive cells (52 to 55%) and similar false-negative test results (13 to 14%). After 2 days, samples held at 4 degrees C showed no further decline, whereas samples held at room temperature had a mean 81% decrease in positive cells, a 32% false-negative rate, and a more marked deterioration in cell morphology.
PMCID: PMC227925  PMID: 7699056
21.  Effect of verapamil on cell cycle transit and c-myc gene expression in normal and malignant murine cells. 
British Journal of Cancer  1989;59(5):714-718.
Verapamil, the prototype calcium channel blocker, reversibly inhibits cell proliferation in many normal and tumour cell lines (Schmidt et al., Cancer Res., 48, 3617, 1988). We have found that two closely related cell lines - B16 murine melanoma cells and B10.BR normal murine melanocytes growing in culture - behave differently in the presence of verapamil, and we are now utilising these two related cell lines to help elucidate the molecular basis of verapamil's antiproliferative effect. In this study, we studied cell cycle phase distribution and c-myc gene expression in both cell lines in the absence of verapamil, during incubation with verapamil and after the cells were washed free of verapamil. Our studies show that 100 microM verapamil rapidly blocks DNA synthesis in melanocytes but not in B16 cells. Similarly, incubation with verapamil for 6-24 h results in a decreased c-myc signal in melanocytes, but a transient increase in c-myc expression in B16 cells. After verapamil is washed from the cells following a 24-h incubation with drug, c-myc expression increases in melanocytes as they begin again to proliferate, but decreases in B16 cells as they begin to die. Our disparate results with these cell lines suggest that c-myc gene expression, regardless of its known involvement in growth control, is not the immediate target for verapamil's inhibitory action.
PMCID: PMC2247239  PMID: 2736205
23.  Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation 
Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug–drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.
PMCID: PMC3712459  PMID: 23557519

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