Optical pumping of quantum dot micropillar lasers.

Arrays of quantum dot micropillar lasers are an attractive technology platform for various applications in the wider field of nanophotonics. Of particular interest is the potential efficiency enhancement as a consequence of cavity quantum electrodynamics effects, which makes them prime candidates for next generation photonic neurons in neural network hardware. However, particularly for optical pumping, their power-conversion efficiency can be very low. Here we perform an in-depth experimental analysis of quantum dot microlasers and investigate their input-output relationship over a wide range of optical pumping conditions. We find that the current energy efficiency limitation is caused by disadvantageous optical pumping concepts and by a low exciton conversion efficiency. Our results indicate that for non-resonant pumping into the GaAs matrix (wetting layer), 3.4% (0.6%) of the optical pump is converted into lasing-relevant excitons, and of those only 2% (0.75%) provide gain to the lasing transition. Based on our findings, we propose to improve the pumping efficiency by orders of magnitude by increasing the aluminium content of the AlGaAs/GaAs mirror pairs in the upper Bragg reflector.

Artificial urine and FBS supplemented media in cytocompatibility assays for PLGA-PEG-based intravesical devices using the urothelium cell line UROtsa.

European and German directives for approval of new medical devices require tests for cytotoxicity in relevant media, since urine can influence cytotoxicity of biodegradable devices. The aim of this study was to determine the long-term cytotoxicity of PLGA-b-mPEG (PLGA-PEG) polymer carriers and artificial urine (AU) to human UROtsa cells. Benign urothelial UROtsa cells were incubated in fetal bovine serum-containing RPMI 1640 medium supplemented with a range of concentrations of AU for 24 h and 7 days. Cell viability was determined by the XTT assay and by live/dead staining. The cytotoxicity of medium containing degradation products from PLGA-PEG carriers was also tested on the UROtsa cells in AU-containing and control medium. PLGA-PEG carriers exhibited no cytotoxicity to UROtsa cells after 24 h of incubation. However, after 7 days, cytotoxicity was observed, but this was largely attributable to the effects of 30% AU on the cells. Compared to phosphate buffer saline (PBS) and normalized to RPMI 1640 medium, significant cytotoxicity was observed by 24 h in medium containing 50% AU and by 7 days in medium containing 30% AU. Live/Dead staining confirmed proliferation results and no pH-changes could be observed. Here we demonstrate for the first time the impact of AU on standard cytotoxicity tests related to biomaterials for urinary-tract applications. Our study showed cytotoxic effects of high concentrations of 50% AU by 24 h and by physiological concentrations of AU (i.e., 30%) by 7 days. We have also demonstrated that PLGA-PEG has no cytotoxic effects in the appropriate AU-containing test environment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2140-2147, 2018.

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors.

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

Potential in two types of collagen scaffolds for urological tissue engineering applications - Are there differences in growth behaviour of juvenile and adult vesical cells?

The aging society has a deep impact on patient care in urology. The number of patients in need of partial or whole bladder wall replacement is increasing simultaneously with the number of cancer incidents. Therefore, urological research requires a model of bladder wall replacement in adult and elderly people. Two types of porcine collagen I/III scaffolds were used in vitro for comparison of cell growth of two different pig breeds at different growth stages. Scaffolds were characterised with scanning electron and laser scanning microscopy. Urothelial and detrusor smooth muscle cells were isolated from 15 adult Göttingen minipigs and 15 juvenile German Landrace pigs. Growth behaviour was examined in cell culture and seeded onto the collagen scaffolds via immunohistochemistry, two-photon laser scanning microscopy and a viability assay. The collagen scaffolds showed different structured surfaces which are appropriate for seeding of the two different cell types. Moisturisation of the scaffolds resulted in a change of the structure. Cell growth of German Landrace urothelial cells and smooth muscle cells was significantly higher than cell growth of the Göttingen minipig cells. Seeding of scaffolds with both cell types from both pig races was possible which could be shown by immunohistochemistry and two-photon laser scanning microscopy. Growth behaviour on the scaffolds was significantly increased for the German Landrace compared to Göttingen minipig. Nevertheless, seeding with the adult Göttingen minipig cells resulted in a closed layer on the surface and urothelial cells and smooth muscle cells showed increasing growth until day 14. The results show that these collagen scaffolds are adequate for the seeding with vesical cells. Moreover, they seem appropriate for the use as an in vitro model for the adult or elderly as the cells of the adult Göttingen minipig too, show good growth behaviour.

The effects of stress during early postnatal periods on behavior and hippocampal neuroplasticity markers in adult male mice.

Infancy is a critical period for brain development. Emerging evidence indicates that stress experienced during that period can have long-term programming effects on the brain and behavior. However, whether different time periods represent different vulnerabilities to the programming of different neurobehavioral domains is not yet known. Disrupted maternal care is known to interfere with neurodevelopmental processes and may lead to the manifestation of behavioral abnormalities in adulthood. Mouse dams confronted with insufficient bedding/nesting material have been shown to provide fragmented maternal care to their offspring. Here, we compared the impact of this model of early-life stress (ELS) during different developmental periods comprising either postnatal days (PNDs) 2-9 (ELS-early) or PND 10-17 (ELS-late) on behavior and hippocampal cell adhesion molecules in male mice in adulthood. ELS-early treatment caused a permanent reduction in bodyweight, whereas this reduction only occurred transiently during juvenility in ELS-late mice. Anxiety was only affected in ELS-late mice, while cognition and sociability were equally impaired in both ELS-treated groups. We analyzed hippocampal gene expression of the γ2 subunit of the GABAa receptor (Gabrg2) and of genes encoding cell adhesion molecules. Gabrg2 expression was increased in the ventral hippocampus in ELS-late-treated animals and was correlated with anxiety-like behavior in the open-field (OF) test. ELS-early-treated animals exhibited an increase in nectin-1 expression in the dorsal hippocampus, and this increase was associated with the social deficits seen in these animals. Our findings highlight the relevance of developmental age on stress-induced long-term behavioral alterations. They also suggest potential links between early stress-induced alterations in hippocampal Gabrg2 expression and the developmental programming of anxiety and between changes in hippocampal nectin-1 expression and stress-induced social impairments.

[Positron emission tomography 2013 in Germany. Results of the query and current status]. / Positronenemissionstomographie 2013 in Deutschland. Ergebnisse der Erhebung und Standortbestimmung.

AIM: Five years after the first survey the positron emission tomography (PET) council of the German Society of Nuclear Medicine (DGN) repeated a survey to re-evaluate the status of PET diagnostics in Germany based on the data of the year 2013. METHODS: A web-based questionnaire was used for gathering information retrospectively. Details regarding the physicians involved in PET operations, PET systems, and radiopharmaceuticals were also part of the survey as well as indications and number of studies. Furthermore, the role of PET and PET/CT within the diagnostic process was evaluated. In addition, official statistical hospital reports were analysed. RESULTS: Responses from 52 sites were analysed. They reported a total of 38,350 PET studies in 2013. In the majority of cases PET was used in oncologic indications (87%). Further main applications were: neurology 6%, cardiology 1%, and inflammation 5%. University or other hospitals performed 85% of the studies. The portion of in-patients was 26%. Hybrid systems (56 PET/CT, 5 PET/MRT, and 2 stand-alone PET) were most frequently used for imaging. The radiotracers were labelled with F-18 in 90% of the studies, whereas Ga-68 was used in 9% and C-11 in 1%. Lung tumours were the most investigated tumour entity (40%), followed by malignant lymphoma (8%), tumours of the gastrointestinal tract (5%), and NET (5%). 20% of the 333 physicians hold a PET certificate awarded by the DGN. More than 50% of the facilities were certified according ISO9001, KTQ or QEP standard. The findings of nearly 60% of the oncological studies were discussed interdisciplinary in a tumour board. In federal statistical reports a 56% increase of in-patient PET operations during 5 years was found. CONCLUSION: In Germany, a moderate increase (9% per year) of PET studies is observed, but compared with other industrialised countries PET is still less established.

Micturition in Göttingen minipigs: first reference in vivo data for urological research and review of literature.

One possible symptom of overactive bladder (OAB) is urinary incontinence, which is generally considered to be an age-associated disease and which is rapidly increasing with demographic changes. Rodent models are commonly used for the investigation of lower urinary tract functions, although the use of these species has limitations in several translational aspects. In biomedical research and preclinical toxicology, Göttingen minipigs are used increasingly. But in urological research, only few data are available for Göttingen minipigs. To the best of our knowledge, this study is one of the first to provide reference data of micturition in female Göttingen minipigs. Micturition frequency and volumes were monitored and analyzed in five female Göttingen minipigs. Voided volume was 520 ± 383 mL (mean ± standard deviation of mean [SD]) and micturition frequency 6.17 ± 3.68 (mean ± SD). We also performed a review of the literature to compare our data with data from different species (humans, pigs, rats and mice). Our findings revealed that micturition volume and frequency of Göttingen minipigs are more comparable with that of humans, leading to the conclusion that Göttingen minipigs may be the better choice for translational research in different research fields, such as urology, neurology and nephrology, etc. The provision of in vivo reference values meets with the 3R concept of 'reduction, refinement and replacement' of laboratory animals, because they allow comprehensive statistical power calculations (reduction), planning of telemetric approaches (refinement), and generation of computer-based modulation for the development of intravesical drug delivery systems (replacement).

[Sustainable Strategies for Health Promotion in Urban Districts]. / Nachhaltige Strategien für die stadtteilbezogene Gesundheitsförderung.

In a city district striving to sustainably develop into a healthy living environment for its residents, cooperation with locally active players as well as network management and the inclusion of citizens and local businesses as non-professional multipliers are particularly promising strategies for developing effective ways of promoting health and integrating them into existing structures in order to reach the target group.

Urinary concentrations of ethyl glucuronide and ethyl sulfate as thresholds to determine potential ethanol-induced alteration of steroid profiles.

The suppression of steroid biotransformation resulting in a decrease of the major urinary metabolites--androsterone and etiocholanolone--and the elevation of testosterone/epitestosterone (T/E) ratios following ethanol administration is well described. At least the latter parameter T/E represents an important indicator for endogenous steroid abuse in doping control. The quantitative correlation between ethanol consumption markers and steroid profile alteration was evaluated, aiming to differentiate between permitted ethanol administration and potential steroid abuse. Steroid profiles, ethanol, ethyl glucuronide (EtG), and sulfate (EtS) were quantified after administration of ethanol (intended maximum ethanol concentration in blood was 1 mg/g) to 21 male and 15 female volunteers. EtG concentrations in urine (corrected by either specific gravity or creatinine concentration) were found to be most suitable for quantitative evaluations. Gender specific urinary EtG concentrations of 48 ug/ml (men) and 15.5 ug/ml (women) may be considered as useful thresholds for a potential ethanol-induced suppression of steroids biotransformation.

S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system.

Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefässchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed. The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).

Tigeciclina versus vancomycin más aztreonam en el tratamiento de infecciones complicadas de piel y tejidos blandos: Experiencia en Latinoamérica / Tigecycline as effective as vancomycin plus aztreonam in the treatment of complicated skin and skin structure infections: Experience in Latin America

BACKGROUND: Treating complicated skin and skin structure infections (cSSSIs) can be challenging. Tigecycline was compared to vancomycin/aztreonam in patients with cSSSIs in a multinational trial; this article reports on the Latin American (LA) population. METHODS: Patients were randomly assigned to receive tigecycline or vancomycin/ aztreonam. Primary endpoint was clinical cure rate at test-of-cure (TOC). Several secondary endpoints and safety were also assessed. RESULTS: A subtotal of 167 LA patients from the multinational trial (N = 573) received ≥ 1 dose of study drug. At TOC, cure rates were similar between tigecycline and vancomycin/aztreonam in the clinically evaluable population.) Noninferiority of tigecycline could not be demonstrated (insufficient sample sizes). Tigecycline-treated patients had higher incidences of nausea, vomiting, anorexia; vancomycin/aztreonam-treated patients had higher incidences of pruritus and rash. CONCLUSIONS: Efficacy results in the LA population were consistent with the multinational study suggesting that tigecycline is noninferior to vancomycin/aztreonam in treating patients with cSSSI.

INTRODUCCIÓN: El tratamiento de infecciones complicadas de piel y tejidos blandos (ICPTB) puede representar un desafío. Se comparó la eficacia de tigeciclina versus vancomicina/aztreonam en pacientes con ICPTB en un estudio multicéntrico; este artículo se refiere a la experiencia en Latinoamérica (LA). MÉTODO: Se asignaron, en forma randomizada, los pacientes a dos grupos de tratamiento: tigeciclina o vancomicina/aztreonam. La meta a evaluar (outcome) primaria fue la curación clínica, denominada test de curación (TC). Se establecieron, además, metas secundarias y la evaluación de seguridad del fármaco. RESULTADOS: Un subtotal de 167 pacientes procedentes de LA, de un estudio multinacional que incluyó 573 pacientes, recibieron ≥ 1 dosis del fármaco en estudio. Al TC, los porcentajes de curación fueron similares entre tigeciclina y vanco-micina/aztreonam en los pacientes clínicamente evaluables). La no inferioridad de tigeciclina no pudo ser demostrada (tamaño de muestra insuficiente). Los pacientes tratados con tigeciclina tuvieron mayor incidencia de náuseas, vómitos y anorexia; los pacientes que recibieron vancomicina/aztreonam tuvieron mayor incidencia de prurito y rash. CONCLUSIONES: Los resultados de eficacia en LA fueron consistentes con el estudio multinacional sugiriendo que tigeciclina no es inferior a vancomicina/aztreonam en el tratamiento de pacientes con ICPTB.

[Urothelial carcinoma in situ of the seminal vesicles--an indicator of tumour multifocality]. / Urotheliales Carcinoma in situ der Samenblasen--Ausdruck von Tumormultifokalität.

We report a case of multifocal urothelial carcinoma in situ of the left ureter with early stromal invasion and concomitant in situ lesions in bladder, prostate and seminal vesicle. After complete topographical mapping of the cystoprostatovesiculectomy specimen the unusual manifestation of urothelial carcinoma in situ in a seminal vesicle turned out to be a tumour spread via the ductus ejaculatorius into the seminal vesicle. DNA sequencing of the tumour suppressor gene TP53 of different tumour lesions revealed identical wild-type sequences.

Inhibition of a pacemaker during nerve stimulation for regional anaesthesia.

Electromagnetic interference is an important cause of pacemaker malfunction. We describe a case in which the use of a peripheral nerve stimulator at a pulse duration of 1 ms and a current of 1.4 mA led to complete but transient inhibition of a permanent pacemaker in a 73-year-old female who had undergone a total shoulder replacement.

[Central induction area. Reduction of non-operative time without additional costs]. / Zentrale Einleitung. Personalneutrale Reduktion der Wechselzeiten.

BACKGROUND: Induction areas (IA) can lead to more efficient operating sessions through shortening the changeover time between patients. To date IAs have always required additional staff members, whose cost was only partly covered by improvements in productivity. The objective of this project was to demonstrate that a reduction in non-operative time through a newly introduced induction area can be achieved without a need for extra personnel. METHODS: Non-operative time in 5,963 ENT, orthopedic and cardiac surgical patients from 8 operating theatres were studied for 1 year before and 1 year after the introduction of an induction area. The non-operative time was defined as the time between the end of surgical procedures in one operation and the start of surgical procedures in the next, within regular working hours. Through reallocation of anesthetic nursing and medical staff it was possible to introduce the induction area without increasing staff numbers. RESULTS: Non-operative time was significantly reduced from 20 min (range 10-30 min) to 14 min (5-25 min). Subgroup analysis showed significant reductions in all specialities: from 10 min (2.5-20 min) to 5 min (0-20 min) in 1,240 cardiac surgical patients, 25 min (20-35 min) to 15 min (5-25 min) in 2,433 ENT patients and 20 min (10-30 min) to 10 min (0-20 min) in 2,290 orthopedic patients. There were no critical incidents attributable to patient handover. DISCUSSION AND CONCLUSIONS: An induction area can be established and can reduce non-operative time and improve operation theatre throughput without the need for extra personnel. The efficiency of these measures will be increased when the relevant surgical organizational measures are taken to adjust to the faster anesthesiology workflow. The induction area does not lead to a higher rate of critical incidents. To what extent the induction area can be used for structured training of doctors and nurses, remains to be investigated.

[Guidelines for intensive care in cardiac surgery patients: haemodynamic monitoring and cardio-circulatory treatment guidelines of the German Society for Thoracic and Cardiovascular Surgery and the German Society of Anaesthesiology and Intensive Care Medicine]. / Die intensivmedizinische Versorgung herzchirurgischer Patienten: Hämodynamisches Monitoring und Herz-Kreislauf-Therapie S3-Leitlinie der Deutschen Gesellschaft für Thorax-, Herz- und Gefässchirurgie (DGTHG) und der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI).

Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors, are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery and the German Society for Anaesthesiology and Intensive Care Medicine made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess available monitoring methods and their risks as well as the differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilators, inodilators and calcium-sensitizers and the use of intra-aortic balloon pumps. The guideline has been developed according to the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).

Current practice of hemodynamic monitoring and vasopressor and inotropic therapy in post-operative cardiac surgery patients in Germany: results from a postal survey.

BACKGROUND: In Germany, more than 100,000 patients are monitored and treated in 80 intensive care units (ICUs) following cardiac surgery each year. The controversies concerning the different methods of hemodynamic monitoring and the appropriate agents for volume therapy and inotropic support are well known. However, little is known about how monitoring and treatment are currently performed. METHODS: A questionnaire with 39 questions was sent to the leading physicians of 80 ICUs in Germany, treating patients after cardiac surgery. The questions to be answered covered the current practice of hemodynamic monitoring, volume replacement, inotropic/vasopressor support and transfusions in patients after cardiac surgery. RESULTS: Sixty-nine per cent of the questionnaires were completed and returned. All ICUs used basic monitoring as recommended by the societies. The use of advanced hemodynamic monitoring included the pulmonary artery catheter (58.2%), transesophageal echocardiography (38.1%) and transpulmonary dilution techniques (13%). Crystalloids (21.2%) and colloids (73%) were used for volume replacement. Epinephrine (41.8%) and dobutamine (30.9%) were the first-choice inotropic drugs for the treatment of low cardiac output syndrome, followed by phosphodiesterase inhibitors (14.5%). Second-choice drugs for the treatment of low cardiac output syndrome were enoximone (29%), milrinone (25%) and dobutamine (25%). A written transfusion protocol and a transfusion threshold for red blood cells existed in 59% and 79% of ICUs, respectively. CONCLUSION: Hemodynamic monitoring and the variability in clinical practice with regard to volume replacement, transfusion triggers and the use of vasopressors/inotropes in cardiac surgery patients tend to follow the results of traditional experience rather than current scientific knowledge. Guidelines are therefore necessary to help to improve the standards of intensive care after cardiac surgery and thus the outcome of patients.

Differential distribution of voltage-gated potassium channels Kv 1.1-Kv1.6 in the rat retina during development.

The discharge behavior of neurons depends on a variable expression and sorting pattern of voltage-dependent potassium (Kv) channels that changes during development. The rodent retina represents a neuronal network whose main functions develop after birth. To obtain information about neuronal maturation we analyzed the expression of subunits of the Kv1 subfamily in the rat retina during postnatal development using immunocytochemistry and immunoelectron microscopy. At postnatal day 5 (P5) all the alpha-subunits of Kv1.1-Kv1.6 channels were found to be expressed in the ganglion cell layer (GCL), most of them already at P1 or P3. Their expression upregulates postnatally and the pattern and distribution change in an isoform-specific manner. Additionally Kv1 channels are found in the outer and inner plexiform layer (OPL, IPL) and in the inner nuclear layer (INL) at different postnatal stages. In adult retina the Kv 1.3 channel localizes to the inner and outer segments of cones. In contrast, Kv1.4 is highly expressed in the outer retina at P8. In adult retina Kv1.4 occurs in rod inner segments (RIS) near the connecting cilium where it colocalizes with synapse associated protein SAP 97. By using confocal laser scanning microscopy we showed a differential localization of Kv1.1-1.6 to cholinergic amacrine and rod bipolar cells of the INL of the adult retina.

Mouse genetics in drug target discovery and validation: no simple answers to complex problems.

In a typical target-driven drug discovery project, the mechanism of action of the prospective therapeutic has to be validated experimentally at an early stage when pharmacological data are not yet available. This necessity has given genetic analysis of potential drug targets in model organisms a central role in the early discovery phase. The potential and the common pitfalls of mouse genetics in this context are discussed here. Using examples from recent studies in obesity and diabetes research, the role of endophenotypes, functional challenges and developmental compensation is discussed. Although unexpected results are sometimes perceived as limitations or technical problems of the mouse as a model organism, this review argues that these findings provide key information about medically relevant aspects of biology and are essential to improve oversimplistic models of pathophysiology.