Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus?

The objective of this study was to investigate whether reduction in hypertriglyceridaemia is associated with a slower rate of progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus (NIDDM). Fifteen normotensive NIDDM patients with hypertriglyceridaemia (> 2.5 mmol L-1) and microalbuminuria were randomly selected to receive either placebo (eight patients) or gemfibrozil 600 mg b.i.d. (seven patients). Progression of microalbuminuria was assessed during a 12-month follow-up period with measurements, consisting of blood tests and triplicate 24-h urine collections, at 1, 3, 6, 9 and 12 months. All but one patient in the treatment group showed a favourable response (> or = 20% reduction) of hypertriglyceridaemia to gemfibrozil. One patient in the placebo group showed a spontaneous reduction in triglyceride levels. Progression of microalbuminuria was lower, although not statistically significantly so, in the treatment group (36%) than in the placebo group (65%). In the group with > or = 20% reduction in triglyceride levels, progression of MA was significantly lower than in the group with stable or increasing triglyceride levels (+1%, range -56% to +49% vs. +97%, range -35% to +202% respectively) (P = 0.03). Continued follow-up data of patients switching from placebo to gemfibrozil after the trial further support the role of serum triglyceride reduction in stabilizing albumin excretion. In conclusion, the results indicate that, in microalbuminuric NIDDM patients, effective treatment of dyslipidaemia could be associated with stabilization of urinary albumin excretion.     

Characterization of Fluorescent Proteins with Intramolecular Photostabilization**

Genetically encodable fluorescent proteins have revolutionized biological imaging in vivo and in vitro. Despite their importance, their photophysical properties, i. e., brightness, count-rate and photostability, are relatively poor compared to synthetic organic fluorophores or quantum dots. Intramolecular photostabilizers were recently rediscovered as an effective approach to improve photophysical properties of organic fluorophores. Here, direct conjugation of triplet-state quenchers or redox-active substances creates high local concentrations of photostabilizer around the fluorophore. In this paper, we screen for effects of covalently linked photostabilizers on fluorescent proteins. We produced a double cysteine mutant (A206C/L221C) of α-GFP for attachment of photostabilizer-maleimides on the β-barrel near the chromophore. Whereas labelling with photostabilizers such as trolox, a nitrophenyl group, and cyclooctatetraene, which are often used for organic fluorophores, had no effect on α-GFP-photostability, a substantial increase of photostability was found upon conjugation to azobenzene. Although the mechanism of the photostabilizing effects remains to be elucidated, we speculate that the higher triplet-energy of azobenzene might be crucial for triplet-quenching of fluorophores in the blue spectral range. Our study paves the way for the development of fluorescent proteins with photostabilizers in the protein barrel by methods such as unnatural amino acid incorporation.     

DisCoveR: accurate and efficient discovery of declarative process models

International Journal on Software Tools for Technology Transfer - Declarative process modeling formalisms—which capture high-level process constraints—have seen growing interest,...     

Contracts for cross-organizational workflows as timed Dynamic Condition Response Graphs

We conservatively extend the declarative Dynamic Condition Response (DCR) Graph process model, introduced in the PhD thesis of the second author, to allow for discrete time deadlines. We prove that safety and liveness properties can be verified by mapping finite timed DCR Graphs to finite state transition systems. We exemplify how deadlines can introduce time-locks and deadlocks and violate liveness. We then prove that the general technique for safe distribution of DCR Graphs provided in previous work can be extended to timed DCR Graphs. We exemplify the use of timed DCR Graphs and the distribution technique in praxis on a timed extension of a cross-organizational case management process arising from a previous case study. The example shows how a timed DCR Graph can be used to describe the global contract for a timed workflow process involving several organizations, which can then be distributed as a network of communicating timed DCR Graphs describing the local contract for each organization.     

The effects of levonorgestrel, desogestrel and gestodene on the pulsatile release of luteinizing hormone in oral contraceptive users

The dynamics of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release were investigated in 60 long-term oral contraceptive (OC) users. Five different types of OC, all containing the same amount of estrogens were studied: three monophasic preparations containing levonorgestrel, desogestrel and gestodene, respectively, and two triphasic formulations, containing levonorgestrel or gestodene. Thirteen healthy, normally cycling volunteers served as controls. Blood sampling was performed at 10-min intervals during a 6-h period to determine the pulsatile release of LH. LH and FSH were measured using a sensitive immunoradiometric assay. Pulse patterns were classified on the basis of the overall LH level, as well as on the character of the LH pulses, according to both frequency and amplitude characteristics. Pulsatile LH release was maintained during OC use. After the 7-day pill-free interval, FSH levels as well as the LH pulse patterns were comparable to those of early follicular-phase controls. FSH levels and FSH release in response to a gonadotropin releasing hormone (GnRH) challenge were profoundly suppressed in all OC users, as early as day 8 of the pill cycle. LH release during the pill cycle was characterized by either a low frequency (median 1 pulse/6 h), high amplitude (median 2.5 IU/l) pulse pattern or by a pattern of low-amplitude pulses (median 0.2 IU/l) and low basal LH levels (median 0.2 IU/l). The distribution of these pulse patterns showed marked differences between different OC preparations and depended on both the type and dose regimen of the gestagenic component of the OC.     

Small BODIPY Probes for Combined Dual 19F MRI and Fluorescence Imaging

The combination of the two complementary imaging modalities ¹⁹F magnetic resonance imaging (MRI) and fluorescence imaging (FLI) possesses high potential for biological and medical applications. Herein we report the first design, synthesis, dual detection validation, and cytotoxic testing of four promising BODIPY dyes for dual ¹⁹F MRI–fluorescence detection. Using straightforward Steglich reactions, small fluorinated alcohols were easily covalently tethered to a BODIPY dye in high yields, leaving its fluorescence properties unaffected. The synthesized compounds were analyzed with various techniques to demonstrate their potential utility in dual imaging. As expected, the chemically and magnetically equivalent trifluoromethyl groups of the agents exhibited a single NMR signal. The determined longitudinal relaxation times T₁ and the transverse relaxation times T₂, both in the lower second range, enabled the imaging of four compounds in vitro. The most auspicious dual ¹⁹F MRI–fluorescence agent was also successfully imaged in a mouse post‐mortem within a 9.4 T small‐animal tomograph. Toxicological assays with human cells (primary HUVEC and HepG2 cell line) also indicated the possibility for animal testing.     

Exploring how users engage with hybrid process artifacts based on declarative process models: a behavioral analysis based on eye-tracking and think-aloud

Process design artifacts have been increasingly used to guide the modeling of business processes. To support users in designing and understanding process models, different process artifacts have been combined in several ways leading to the emergence of the so-called “hybrid process artifacts”. While many hybrid artifacts have been proposed in the literature, little is known about how they can actually support users in practice. To address this gap, this work investigates the way users engage with hybrid process artifacts during comprehension tasks. In particular, we focus on a hybrid representation of DCR Graphs (DCR-HR) combining a process model, textual annotations and an interactive simulation. Following a qualitative approach, we conduct a multi-granular analysis exploiting process mining, eye-tracking techniques, and verbal data analysis to scrutinize the reading patterns and the strategies adopted by users when being confronted with DCR-HR. The findings of the coarse-grained analysis provide important insights about the behavior of domain experts and IT specialists and show how user’s background and task type change the use of hybrid process artifacts. As for the fine-grained analysis, user’s behavior was classified into goal-directed and exploratory and different strategies of using the interactive simulation were identified. In addition, a progressive switch from an exploratory behavior to a goal-directed behavior was observed. These insights pave the way for an improved development of hybrid process artifacts and delineate several directions for future work.

     

Model reduction tools for nonlinear structural dynamics

Three mode types are proposed for reducing nonlinear dynamical system equations, resulting from finite element discretizations: tangent modes, modal derivatives, and newly added static modes. Tangent modes are obtained from an eigenvalue problem with a momentary tangent stiffness matrix. Their derivatives with respect to modal coordinates contain much beneficial reduction information. Three approaches to obtain modal derivatives are presented, including a newly introduced numerical way. Direct and reduced integration results of truss examples show that tangent modes do not describe the nonlinear system sufficiently well, whereas combining tangent modes with modal derivatives and/or static modes provides much better reduction results.