Warum reagiert mein Patient anders auf dieses Medikament? : Pharmakogenomik und personalisierte Medizin in der Praxis

Inter- und intraindividuelle Variabilität in der Arzneimittelwirkung ist häufig. Die Ursachen dieser Unterschiede sind vielseitig und bei jedem Patienten in verschiedener Kombination vorhanden. Hauptursachen sind genetische Diversität und wechselnde Umweltfaktoren wie Ernährung,andere Arzneimittel und "Lifestyle". Variabilität kann die Pharmakokinetik, z.B. den Arzneimittelabbau, oder die Pharmakodynamik, d.h. den Wirkungsmechanismus eines Medikamentes betreffen. Diese individuellen Unterschiede im Ansprechen auf ein Medikament sind ein wichtiger Teil des Konzeptes der "Personalisierten Medizin" mit dem Anspruch, für jeden Patienten eine massgeschneiderte Therapie anzuwenden, d.h. das für seine persönliche Problematik richtige Medikament in der richtigen Dosierung. Durchbrüche in den Technologien der Genomik haben dazu geführt, dass vor allem die genetische Variation der Arzneimittelwirkung besser untersucht werden kann. Diese Studien haben zu molekulargenetischen Tests geführt, die die Wirksamkeit oder das Risiko unerwünschter Nebenwirkungen besser voraussagen können. Am häufigsten wird die "Personalisierte Medizin" heute in der Krebstherapie oder bei HIV Infektionen angewandt, zunehmend aber auch in anderen therapeutischen Gebieten. Die heute bekannten Situationen, die auch für die Praxis von Bedeutung sein können, werden hier zusammengefasst. Patienten der Internet-Generation sind besser informiert über ihre Krankheit und über die Therapie, die sie erhalten. Zunehmend werden auch Patienten in der Praxis mit bereits vorhandenen Informationen zu ihrer Gensequenz oder gewissen Gentests erscheinen

The molecular athlete: exercise physiology from mechanisms to medals

Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels of endurance and strength, to elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the signal integration, interpretation and output coordination of the cellular and molecular mechanisms that govern muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite athletes largely rely on a "trial and error" approach with the experience and practices of successful coaches and athletes often providing the bases for "post hoc" scientific enquiry and research. This review provides a synopsis of the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to endurance- and resistance-based training. These traits are placed in the context of innate genetic and inter-individual differences in exercise capacity and performance, with special considerations given to the ageing athletes. Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise, and how such adaptations translate from "molecules to medals"

Low molecular weight heparin-induced skin necrosis—a systematic review

Background: Low molecular weight heparins (LMWHs) are currently used as a standard for anti-thrombotic therapy. Skin necrosis caused by LMWH is a rare and probably under-reported complication. The aim of our systematic review is to analyse the present literature for cases of LMWH-induced skin necrosis, emphasising the pathogenesis, clinical pattern, and management of this rare side effect. Methods: We performed a Medline literature search (PubMed database) and manual cross-referencing to identify all articles related to LMWH-induced skin necrosis. Data were analysed for type of LMWH used, time until skin necrosis occurred, localisation, size, laboratory findings, switch anticoagulant, complications, and outcome. Additionally, the case of a patient from our hospital is presented. Results: We included a total of 20 articles (21 cases) reporting on LMWH-induced skin necrosis. Skin necrosis occurred locally and distant from the injection site. Heparin-induced antibodies were frequently observed (positive 9/11 articles, negative 2/11). However, severe thrombocytopenia (platelet count <100,000cells/ml) occurred in only four cases, while platelet count remained normal in 50% of the cases. After patients had been switched to other anti-thrombotic drugs, the clinical course was usually benign; however, reconstructive surgery was necessary in two cases. Conclusion: LMWH-induced skin necrosis may occur as part of the heparin-induced thrombocytopenia (HIT) syndrome, but other pathomechanisms, including allergic reactions and local trauma, may also be involved. When HIT is excluded, unfractionated heparin is a safe switch anticoagulant. Otherwise, non-heparin preparations such as hirudin or fondaparinux should be preferre

Surgical Management of Gynecomastia—a 10-year Analysis

Background: Gynecomastia is defined as the benign enlargement of the male breast. Most studies on surgical treatment of gynecomastia show only small series and lack histopathology results. The aim of this study was to analyze the surgical approach in the treatment of gynecomastia and the related outcome over a 10-year period. Patients and methods: All patients undergoing surgical gynecomastia corrections in our department between 1996 and 2006 were included for retrospective evaluation. The data were analyzed for etiology, stage of gynecomastia, surgical technique, complications, risk factors, and histological results. Results: A total of 100 patients with 160 operations were included. Techniques included subcutaneous mastectomy alone or with additional hand-assisted liposuction, isolated liposuction, and formal breast reduction. Atypical histological findings were found in 3% of the patients (spindle-cell hemangioendothelioma, papilloma). The surgical revision rate among all patients was 7%. Body mass index and a weight of the resected specimen higher than 40 g were identified as significant risk factors for complications (p < 0.05). Conclusions: The treatment of gynecomastia requires an individualized approach. Caution must be taken in performing large resections, which are associated with increased complication rates. Histological tissue analysis should be routinely performed in all true gynecomastia corrections, because histological results may reveal atypical cellular patholog

Interleukin-6 potentiates endurance training adaptation and improves functional capacity in old mice

Interventions to preserve functional capacities at advanced age are becoming increasingly important. So far, exercise provides the only means to counteract age-related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin-6 (IL-6), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.; Sedentary old male mice (Sed+Saline, n = 15) were compared with animals that received recombinant IL-6 (rIL-6) in an exercise-mimicking pulsatile manner (Sed+IL-6, n = 16), were trained with a moderate-intensity, low-volume endurance exercise regimen (Ex+Saline, n = 13), or were exposed to a combination of these two interventions (Ex+IL-6, n = 16) for 12 weeks. Before and at the end of the intervention, mice underwent a battery of tests to quantify endurance performance, muscle contractility in situ, motor coordination, and gait and metabolic parameters.; Mice exposed to enhanced levels of IL-6 during endurance exercise bouts showed superior improvements in endurance performance (33% more work and 12% greater peak power compared with baseline), fatigue resistance in situ (P = 0.0014 vs. Sed+Saline; P = 0.0199 vs. Sed+IL-6; and P = 0.0342 vs. Ex+Saline), motor coordination (rotarod performance, P = 0.0428), and gait (gait speed, P = 0.0053) following training. Pulsatile rIL-6 treatment in sedentary mice had only marginal effects on glucose tolerance and some gait parameters. No increase in adverse events or mortality related to rIL-6 treatment was observed.; Administration of rIL-6 paired with treadmill running bouts potentiates the adaptive response to a moderate-intensity low-volume endurance exercise regimen in old mice, while being safe and well tolerated

The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals

BACKGROUND: Drugs and other xenobiotics alter gene expression of cytochromes P450 (CYP) by activating the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in mammals. In non-mammalian species, only one xenosensor gene has been found. Using chicken as a model organism, the aim of our study was to elucidate whether non-mammalian species only have one or two xenosensors like mammals. RESULTS: To explore the evolutionary aspect of this divergence, we tried to identify additional xenobiotic sensing nuclear receptors in chicken using various experimental approaches. However, none of those revealed novel candidates. Ablation of chicken xenobiotic receptor (CXR) function by RNAi or dominant-negative alleles drastically reduced drug-induction in a chicken hepatoma cell line. Subsequently, we functionally and structurally characterized CXR and compared our results to PXR and CAR. Despite the high similarity in their amino acid sequence, PXR and CAR have very distinct modes of activation. Some aspects of CXR function, e.g. direct ligand activation and high promiscuity are very reminiscent of PXR. On the other hand, cellular localization studies revealed common characteristics of CXR and CAR in terms of cytoplasmic-nuclear distribution. Finally, CXR has unique properties regarding its regulation in comparison to PXR and CAR. CONCLUSION: Our finding thus strongly suggest that CXR constitutes an ancestral gene which has evolved into PXR and CAR in mammals. Future studies should elucidate the reason for this divergence in mammalian versus non-mammalian species

Remodeling of metabolism and inflammation by exercise ameliorates tumor-associated anemia

A considerable number of patients with cancer suffer from anemia, which has detrimental effects on quality of life and survival. The mechanisms underlying tumor-associated anemia are multifactorial and poorly understood. Therefore, we aimed at systematically assessing the patho-etiology of tumor-associated anemia in mice. We demonstrate that reduced red blood cell (RBC) survival rather than altered erythropoiesis is driving the development of anemia. The tumor-induced inflammatory and metabolic remodeling affect RBC integrity and augment splenic phagocyte activity promoting erythrophagocytosis. Exercise training normalizes these tumor-associated abnormal metabolic profiles and inflammation and thereby ameliorates anemia, in part, by promoting RBC survival. Fatigue was prevented in exercising tumor-bearing mice. Thus, exercise has the unique potential to substantially modulate metabolism and inflammation and thereby counteracts pathological remodeling of these parameters by the tumor microenvironment. Translation of this finding to patients with cancer could have a major impact on quality of life and potentially survival

Molecular control of endurance training adaptation in male mouse skeletal muscle

Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases

Population Monte Carlo algorithms

We give a cross-disciplinary survey on ``population'' Monte Carlo algorithms. In these algorithms, a set of ``walkers'' or ``particles'' is used as a representation of a high-dimensional vector. The computation is carried out by a random walk and split/deletion of these objects. The algorithms are developed in various fields in physics and statistical sciences and called by lots of different terms -- ``quantum Monte Carlo'', ``transfer-matrix Monte Carlo'', ``Monte Carlo filter (particle filter)'',``sequential Monte Carlo'' and ``PERM'' etc. Here we discuss them in a coherent framework. We also touch on related algorithms -- genetic algorithms and annealed importance sampling.Comment: Title is changed (Population-based Monte Carlo -> Population Monte Carlo). A number of small but important corrections and additions. References are also added. Original Version is read at 2000 Workshop on Information-Based Induction Sciences (July 17-18, 2000, Syuzenji, Shizuoka, Japan). No figure