Polymorphismen im Interleukin-6-Signaltransduktionsweg bei Patienten mit Koronarer Herzerkrankung

Als potentielle genetische Risikofaktoren der koronaren Herzerkrankung wurden in dieser Arbeit auf Basis einer populationsbasierten Fall-Kontroll-Assoziationsstudie 73 Single Nucleotide Polymorphisms (SNPs) aus zwölf Kandidatengenen des IL-6 Signaltransduktionsweges in einer explorativen Studie mit 1096 Fällen und 636 Kontrollen untersucht. Dabei wurden Assoziationen von drei SNPs innerhalb des Gens MAPK1 (Mitogen activated protein kinase 1) identifiziert, mit SNP rs6928 als am stärksten assoziiert (p=0,0026 OR=1,41 95% CI 1,13-1,77). Dieses SNP wurde in einer Replikationsstudie mit unabhängigen Kohorten überprüft. Die Genotypisierung erfolgte mittels der SNPlex und TaqMan Technologie. Beide Ansätze wurden soweit möglich auf die KHK relevanten klassischen Risikofaktoren mittels logistischer Regression adjustiert und auf multiples Testen korrigiert. In der Replikationsstudie konnte die Assoziation der explorativen Studie nicht bestätigt werden

Shared autonomic pathways connect bone marrow and peripheral adipose tissues across the central neuraxis

Bone marrow adipose tissue (BMAT) is increased in both obesity and anorexia. This is unique relative to white adipose tissue (WAT), which is generally more attuned to metabolic demand. It suggests that there may be regulatory pathways that are common to both BMAT and WAT and also those that are specific to BMAT alone. The central nervous system (CNS) is a key mediator of adipose tissue function through sympathetic adrenergic neurons. Thus, we hypothesized that central autonomic pathways may be involved in BMAT regulation. To test this, we first quantified the innervation of BMAT by tyrosine hydroxylase (TH) positive nerves within the metaphysis and diaphysis of the tibia of B6 and C3H mice. We found that many of the TH+ axons were concentrated around central blood vessels in the bone marrow. However, there were also areas of free nerve endings which terminated in regions of BMAT adipocytes. Overall, the proportion of nerve-associated BMAT adipocytes increased from proximal to distal along the length of the tibia (from ~3-5 to ~14-24%), regardless of mouse strain. To identify the central pathways involved in BMAT innervation and compare to peripheral WAT, we then performed retrograde viral tract tracing with an attenuated pseudorabies virus (PRV) to infect efferent nerves from the tibial metaphysis (inclusive of BMAT) and inguinal WAT (iWAT) of C3H mice. PRV positive neurons were identified consistently from both injection sites in the intermediolateral horn of the spinal cord, reticular formation, rostroventral medulla, solitary tract, periaqueductal gray, locus coeruleus, subcoeruleus, Barrington\u27s nucleus, and hypothalamus. We also observed dual-PRV infected neurons within the majority of these regions. Similar tracings were observed in pons, midbrain, and hypothalamic regions from B6 femur and tibia, demonstrating that these results persist across mouse strains and between skeletal sites. Altogether, this is the first quantitative report of BMAT autonomic innervation and reveals common central neuroanatomic pathways, including putative command neurons, involved in coordinating multiple aspects of sympathetic output and facilitation of parallel processing between bone marrow/BMAT and peripheral adipose tissue

Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss

The prevalence of obesity has continued to rise over the past three decades leading to significant increases in obesity-related medical care costs from metabolic and non-metabolic sequelae. It is now clear that expansion of body fat leads to an increase in inflammation with systemic effects on metabolism. In mouse models of diet-induced obesity there is also an expansion of bone marrow adipocytes. However, the persistence of these changes after weight-loss has not been well described. The objective of this study was to investigate the impact of high-fat diet (HFD) and subsequent weight-loss on skeletal parameters in C57Bl6/J mice. Male mice were given a normal chow diet (ND) or 60% HFD at 6-weeks of age for 12-, 16-, or 20-weeks. A third group of mice was put on HFD for 12-weeks and then on ND for 8-weeks to mimic weight-loss. After these dietary challenges the tibia and femur were removed and analyzed by microCT for bone morphology. Decalcification followed by osmium staining was used to assess bone marrow adiposity and mechanical testing was performed to assess bone strength. After 12-, 16-, or 20-weeks of HFD, mice had significant weight gain relative to controls. Body mass returned to normal after weight-loss. Marrow adipose tissue (MAT) volume in the tibia increased after 16-weeks of HFD and persisted in the 20-week HFD group. Weight loss prevented HFD-induced MAT expansion. Trabecular bone volume fraction, mineral content, and number were decreased after 12-, 16-, or 20-weeks of HFD, relative to ND controls, with only partial recovery after weight-loss. Mechanical testing demonstrated decreased fracture resistance after 20-weeks of HFD. Loss of mechanical integrity did not recover after weight-loss. Our study demonstrates that HFD causes long-term, persistent changes in bone quality, despite prevention of marrow adipose tissue accumulation, as demonstrated through changes in bone morphology and mechanical strength in a mouse model of diet-induced obesity and weight-loss

Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

Patients with diabetes have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild-type mice also developed diabetic bone disease but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockout rescued bone health through sustained osteoblast function with abrogation of local oxidative stress responses. This was independent of the neural actions of SARM1, as beneficial effects on bone were lost with neural conditional Sarm1 knockout. This study demonstrates that the onset of skeletal disease occurs rapidly in both male and female mice with T1D completely independently of DPN. In addition, this reveals that clinical SARM1 inhibitors, currently being developed for treatment of neuropathy, may also have benefits for diabetic bone through actions outside of the nervous system

Frequency of actionable molecular drivers in lung cancer patients with precocious brain metastases

Brain metastases frequently occur during the course of disease in patients suffering from lung cancer. Occasionally, neurological symptoms caused by brain metastases (BM) might represent the first sign of systemic tumor disease (so called precocious metastases), leading to the detection of the primary lung tumor. The biological basis of precocious BM is largely unknown, and treatment options are not well established for this subgroup of patients. Therefore, we retrospectively analyzed 33 patients (24 non-small cell lung cancer (NSCLC)), 9 small cell lung cancer (SCLC)) presenting with precocious BM focusing on molecular alterations potentially relevant for the tumor's biology and treatment. We found five FGFR1 amplifications (4 adenocarcinoma, 1 SCLC) among 31 analyzed patients (16.1%), eight MET amplifications among 30 analyzed tumors (7 NSCLC, 1 SCLC; 26.7%), three EGFR mutations within 33 patients (all adenocarcinomas, 9.1%), and five KRAS mutations among 32 patients (all adenocarcinomas; 15.6%). No ALK, ROS1 or RET gene rearrangements were detected. Our findings suggest that patients with precocious BM of lung cancer harbor EGFR mutations, MET amplifications or FGFR1 amplifications as potential targeted treatment options

A convolutional neural network trained with dermoscopic images performed on par with 145 dermatologists in a clinical melanoma image classification task

Background: Recent studies have demonstrated the use of convolutional neural networks (CNNs) to classify images of melanoma with accuracies comparable to those achieved by board-certified dermatologists. However, the performance of a CNN exclusively trained with dermoscopic images in a clinical image classification task in direct competition with a large number of dermatologists has not been measured to date. This study compares the performance of a convolutional neuronal network trained with dermoscopic images exclusively for identifying melanoma in clinical photographs with the manual grading of the same images by dermatologists. Methods: We compared automatic digital melanoma classification with the performance of 145 dermatologists of 12 German university hospitals. We used methods from enhanced deep learning to train a CNN with 12,378 open-source dermoscopic images. We used 100 clinical images to compare the performance of the CNN to that of the dermatologists. Dermatologists were compared with the deep neural network in terms of sensitivity, specificity and receiver operating characteristics. Findings: The mean sensitivity and specificity achieved by the dermatologists with clinical images was 89.4% (range: 55.0%-100%) and 64.4% (range: 22.5%-92.5%). At the same sensitivity, the CNN exhibited a mean specificity of 68.2% (range 47.5%-86.25%). Among the dermatologists, the attendings showed the highest mean sensitivity of 92.8% at a mean specificity of 57.7%. With the same high sensitivity of 92.8%, the CNN had a mean specificity of 61.1%. Interpretation: For the first time, dermatologist-level image classification was achieved on a clinical image classification task without training on clinical images. The CNN had a smaller variance of results indicating a higher robustness of computer vision compared with human assessment for dermatologic image classification tasks. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)