Therapie mit CSE-Hemmern — mehr als Lipidsenkung?

An elevated plasma cholesterol concentration is an established risk factor for coronary heart disease. Dietary and drug interventions with fibrate, nicotinic acid and colestyramine have resulted in a decreased rate of major coronary events but failed to decrease mortality. Studies using the more potent lipid lowering statins have shown remarkable results in primary (WOSCOPS, AFCAPS, TexCAPS) and secondary prevention (4S, CARE, LIPID). The use of these drugs reduced the risk for coronary events as well as the need for interventions. Furthermore, improvement of angina has been shown in several studies. In high-risk patients coronary heart disease associated mortality and overall mortality was reduced. Lowering of cholesterol was shown to be effective in women, older people and diabetics. Lipid lowering improves prognosis after heart transplant and could be an alternative to PTCA. Furthermore it was also shown that cholesterol lowering reduces the incidence of stroke. New mechanisms are discussed to explain the rapid onset of clinical improvement. Among these are: influences on inflammatory processes in the plaque, on vascular smooth muscle activity, on coagulation and on endothelial dysfunction.     

Laparoscopic thrombendarterectomy of the infrarenal aorta

The aim was to perform a totally laparoscopic thrombendarterectomy (TEA) of the infrarenal aorta to reduce the trauma connected to the surgical approach. A 52-year-old man was referred to our institution with severe claudication. Angiography revealed a subtotal stenosis of the infrarenal aorta. Because the lesion was not suitable for an interventional procedure, a TEA was planned. The surgery was performed through six ports using a transperitoneal approach with pneumoperitoneum. The laparoscopic TEA was carried out according to the standards of open vascular surgery. The surgery time was 285 minutes, the crossclamping lasted 105 minutes, and the blood loss was 100 mL. The angiographic and functional results were excellent. The patient experienced a rapid recovery and was discharged after 6 days. This case report shows the feasibility of totally laparoscopic TEA of the infrarenal aorta. The well-known advantages of minimally invasive techniques in abdominal surgery with regard to the decrease of surgical trauma may also be valid in aortic surgery for occlusive disease.     

A survival tree method for the analysis of discrete event times in clinical and epidemiological studies

Survival trees are a popular alternative to parametric survival modeling when there are interactions between the predictor variables or when the aim is to stratify patients into prognostic subgroups. A limitation of classical survival tree methodology is that most algorithms for tree construction are designed for continuous outcome variables. Hence, classical methods might not be appropriate if failure time data are measured on a discrete time scale (as is often the case in longitudinal studies where data are collected, e.g., quarterly or yearly). To address this issue, we develop a method for discrete survival tree construction. The proposed technique is based on the result that the likelihood of a discrete survival model is equivalent to the likelihood of a regression model for binary outcome data. Hence, we modify tree construction methods for binary outcomes such that they result in optimized partitions for the estimation of discrete hazard functions. By applying the proposed method to data from a randomized trial in patients with filarial lymphedema, we demonstrate how discrete survival trees can be used to identify clinically relevant patient groups with similar survival behavior. Copyright © 2015 John Wiley & Sons, Ltd.     

In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.     

Molecular insights into human daily behavior

Human beings exhibit wide variation in their timing of daily behavior. We and others have suggested previously that such differences might arise because of alterations in the period length of the endogenous human circadian oscillator. Using dermal fibroblast cells from skin biopsies of 28 subjects of early and late chronotype (11 "larks" and 17 "owls"), we have studied the circadian period lengths of these two groups, as well as their ability to phase-shift and entrain to environmental and chemical signals. We find not only period length differences between the two classes, but also significant changes in the amplitude and phase-shifting properties of the circadian oscillator among individuals with identical "normal" period lengths. Mathematical modeling shows that these alterations could also account for the extreme behavioral phenotypes of these subjects. We conclude that human chronotype may be influenced not only by the period length of the circadian oscillator, but also by cellular components that affect its amplitude and phase. In many instances, these changes can be studied at the molecular level in primary dermal cells.     

Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei

Trypanosomatid RNA editing is a unique process and essential for these organisms. It therefore represents a drug target for a group of protozoa that includes the causative agents for African sleeping sickness and other devastating tropical and subtropical diseases. Here, we present drug-like inhibitors of a key enzyme in the editing machinery, RNA-editing ligase 1 (REL1). These inhibitors were identified through a strategy employing molecular dynamics to account for protein flexibility. A virtual screen of the REL1 crystal structure against the National Cancer Institute Diversity Set was performed by using AutoDock4. The top 30 compounds, predicted to interact with REL1's ATP-binding pocket, were further refined by using the relaxed complex scheme (RCS), which redocks the compounds to receptor structures extracted from an explicitly solvated molecular dynamics trajectory. The resulting reordering of the ligands and filtering based on drug-like properties resulted in an initial recommended set of 8 ligands, 2 of which exhibited micromolar activity against REL1. A subsequent hierarchical similarity search with the most active compound over the full National Cancer Institute database and RCS rescoring resulted in an additional set of 6 ligands, 2 of which were confirmed as REL1 inhibitors with IC₅₀ values of ≈1 μM. Tests of the 3 most promising compounds against the most closely related bacteriophage T4 RNA ligase 2, as well as against human DNA ligase IIIβ, indicated a considerable degree of selectivity for RNA ligases. These compounds are promising scaffolds for future drug design and discovery efforts against these important pathogens.     

The treadmill effect in a fixed budget system

We examine the interaction in the market for physician services when the total budget for reimbursement is fixed. Physicians obtain points for the services they render. At the end of the period the budget is divided by the sum of all points submitted, which determines the price per point. We show that this retrospective payment system involves -- compared to a fee-for-service remuneration system -- a severe coordination problem, which potentially leads to the "treadmill effect". We argue that when market entry is possible, a budget can be efficiency enhancing, if in addition a price floor is used.