Publications by authors named "Marc Weimer"

Objective: To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes.

Research Design And Methods: Patients with HbA1c levels of ≥7% to ≤ 10% (≥53 to ≤86 mmol/mol) while receiving metformin (≥1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10 mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA1c level from baseline at week 24.

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Objective: To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes.

Research Design And Methods: Patients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change from baseline in HbA1c at week 24.

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To assess the impact of a mixture containing dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs), male mice were initiated with N-nitroso-diethylamine and subsequently treated with PCB126, an Ah-Receptor agonist, and PCB153, acting via activation of the constitutive androstane receptor. The two congeners were given at two dose levels: the low dose was adjusted to induce ~150-fold increases in cytochrome P450 (Cyp)1a1 (PCB126) and Cyp2b10 mRNAs (PCB153), and the high dose was chosen as twice the low dose. To keep the liver PCB levels constant, mice were given initial loading doses followed by weekly maintenance doses calculated on the basis of the PCBs' half-lives.

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High-throughput screening approaches are carried out for the toxicity assessment of a large number of chemical compounds. In such large-scale in vitro toxicity studies several hundred or thousand concentration-response experiments are conducted. The automated evaluation of concentration-response data using statistical analysis scripts saves time and yields more consistent results in comparison to data analysis performed by the use of menu-driven statistical software.

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Concentration-response studies are performed to investigate the potency of the substance under investigation. Data are typically evaluated using non-linear regression. A common model is the log-logistic model which includes parameters for lower and upper boundary of mean response, EC50 and Hill slope.

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Background: Successful surgical repair of a regurgitant mitral valve (MV) is dependent on a comprehensive assessment of its complex anatomy. Although there is limited evidence of the feasibility and accuracy of intraoperative real-time 3-dimensional transesophageal echocardiography (RT3DTEE) in MV surgery, its use is increasing worldwide. We designed this prospective observational study of patients with mitral regurgitation to test initial findings on the accuracy of RT3DTEE images in the diagnosis of MV prolapse and chordal rupture relative to 2D imaging and to assess the potential of RT3DTEE for visualizing leaflet clefts.

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Adeno-associated virus type 2 (AAV2) has gained much interest as a gene delivery vector. A hallmark of AAV2-mediated gene transfer is an intracellular conformational change of the virus capsid, leading to the exposure of infection-relevant protein domains. These protein domains, which are located on the N-terminal portion of the structural proteins VP1 and VP2, include a catalytic phospholipase A(2) domain and three clusters of basic amino acids.

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Objective: To evaluate whether dynamic susceptibility-weighted contrast-enhanced (DSC), dynamic contrast-enhanced (DCE), and proton spectroscopic imaging ((1)H-MRSI) can identify progression and predict treatment failure during follow-up before tumor size changes, contrast agent uptake, or when new lesions become obvious. The aim was also to find out which of the aforementioned techniques had the best diagnostic performance compared with each other and standard magnetic resonance imaging (MRI).

Materials And Methods: Thirty-seven patients with gliomas (21 women, 16 men; mean age at inclusion, 48 ± 14 years [standard deviation]) were assessed prospectively by (1)H-MRSI (point-resolved spectroscopy), DCE, and DSC perfusion MRI, each after a single dose of gadobenate dimeglumine during follow-up.

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The human endometrium is unique among adult tissues. Its functions are modulated by numerous hormones and mediators. The aim of this study was to evaluate the suitability of human endometrial explants for studying functional effects of chemicals and drugs on gene expression biomarkers.

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ReProTect is a project within the 6th European Framework Program which has developed alternative methods aimed to reduce or replace animal experimentation in the field of reproductive toxicology. In its final year, a ring trial, named the "Feasibility Study", was conducted, in which 10 blinded chemicals with toxicologically well-documented profiles were analyzed by employing a test battery of 14 in vitro assays. EC(50) (half maximal effective concentration) or equivalent endpoints were determined and the test compounds were ranked relative to chemicals previously assayed in the tests of the battery.

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To date there are no validated methods available to test androgenicity or antiandrogenicity in vitro. A problem with testing androgenicity using reporter genes is the possibility by other steroid receptors than androgen receptors to activate the same reporter gene, thereby lowering selectivity. To avoid this we have established a robust and very selective method, the AR CALUX reporter gene assay, to test androgenic and antiandrogenic activity of compounds in vitro.

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Estrogenicity of chemicals has received significant attention and is linked to endocrine-disrupting activities. However, there is a paucity of validated methods to assess estrogenicity in vitro. We have established a robust method to test estrogenic and antiestrogenic activity of compounds in vitro, as an alternative to using animal models such as the uterotrophic assay.

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As a part of EU-project ReProTect, a comparison of the dual re-circulating human placental perfusion system was carried out, by two independent research groups. The detailed placental transfer data of model compounds [antipyrine, benzo(a)pyrene, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and IQ (2-amino-3-methylimidazo(4,5-f)quinoline] has been/will be published separately. For this project, a comparative re-analysis was done, by curve fitting the data and calculating two endpoints: AUC(120), defined as the area under the curve between time 0 and time 120 min and as t(0.

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The new European chemicals policy for the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) will most probably impose a dramatic increase in the number of animals required for reproductive toxicity testing. For this purpose, the development and validation of alternative methods is urgently needed in order to reduce the use of laboratory animals. The present study describes the inter-laboratory variability and the transferability assessment of an in vitro test able to identify chemical effects during the process of oocyte maturation in a bovine model.

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Despite about two decades of research in the field of endocrine active compounds, still no validated human recombinant (hr) estrogen receptor-alpha (ERalpha) binding assay is available, although hr-ERalpha is available from several sources. In a joint effort, US EPA and Bayer Schering Pharma with funding from the EU-sponsored 6th framework project, ReProTect, developed a model protocol for such a binding assay. Important features of this assay are the use of a full length hr-ERalpha and performance in a 96-well plate format.

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A stem cell-based reporter assay was developed to detect drug-induced alterations in the canonical Wnt/beta-catenin signaling pathway, which is involved in the regulation of early embryonic development. The so-called ReProGlo assay allows simultaneous determination of cell viability and luciferase reporter activity in a high throughput 96-well microtiter format. A clone of mouse embryonic stem (mES) cells stably expressing the SuperTopFlash reporter was established.

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The final stages of male gametogenesis are sensitive targets of DNA-reactive chemicals, most of which form adducts. Comet assay is a widely applied genotoxicity test that reveals DNA adducts through breaks formed during repair processes. However, sperm cells are essentially devoid of repair enzymes and comet assay is poorly sensitive in detecting chemically induced DNA lesions in sperm.

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Short-term dynamic culture of rat testicular fragments was evaluated as a model to assess effects on steroidogenesis. A total of 11 compounds differentially affecting testosterone synthesis (aminoglutethimide, ketoconazole, danazol, flutamide, diethylstilbestrol, genistein, butylparaben, nonoxynol-9, dimethoate, RU 486, and cadmium chloride) were used to explore the performance of the assay. Testosterone secretion into the medium and testosterone retained in tissue fragments was determined as a measure of steroidogenesis.

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Despite more than a decade of research in the field of endocrine active compounds with affinity for the androgen receptor (AR), still no validated recombinant AR binding assay is available, although recombinant AR can be obtained from several sources. With funding from the European Union (EU)-sponsored 6th framework project, ReProTect, we developed a model protocol for such an assay based on a simple AR binding assay recently developed at our institution. Important features of the protocol were the use of a rat recombinant fusion protein to thioredoxin containing both the hinge region and ligand binding domain (LBD) of the rat AR (which is identical to the human AR-LBD) and performance in a 96-well plate format.

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Spreading depression (SD) is a pronounced but transient disturbance of cellular homeostasis in the neuropil of the central nervous system which spreads in a wave-like manner across the tissue. At the wavefront the cells depolarize and a distinct ion redistribution between intra- and extracellular space is observed. In the aftermath of SD the recovering tissue is refractory: during an early absolute refractory period no further SD can be triggered, during the subsequent relative refractory period SD waves spread at lower velocity than usual.

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Spreading depression (SD) is a neurophysiological phenomenon which occurs in the grey substance of the central nervous system. SD is characterised by a wave-like spread of depressed neuronal activity, by large ion shifts between intra- and extracellular space, by cellular depolarization, and by altered optical properties of the tissue giving rise to an intrinsic optical signal (IOS). In the shadow of SD further waves are difficult to trigger and such waves spread at lower velocity than usual.

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