Identification of the first synthetic steroidogenic factor 1 inverse agonists: pharmacological modulation of steroidogenic enzymes

Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.     

Chronische Sportverletzungen des Kniegelenks

Chronic sports injuries of the knee joint are common and mainly caused by repetitive (micro) trauma and exertion. Chronic insertion tendinopathies and avulsion fractures and symptoms related to entrapment, friction and impingement can be pathophysiologically distinguished in athletes. In this review, we depict the characteristic magnetic resonance imaging (MRI) findings of the most commonly occurring pathologies.     

Flooded Lung Generates a Suitable Acoustic Pathway for Transthoracic Application of High Intensity Focused Ultrasound in Liver

Background: In recent years, high intensity focused ultrasound (HIFU) has gained increasing clinical interest as a non-invasive method for local therapy of liver malignancies. HIFU treatment of tumours and metastases in the liver dome is limited due to the adjacent ultrasound blocking lung. One-lung flooding (OLF) enables complete sonography of lung and adjoining organs including liver. HIFU liver ablation passing through the flooded lung could enable a direct intercostal beam path and thus improve dose deposition in liver. In this study, we evaluate the feasibility of an ultrasound guided transthoracic, transpulmonary HIFU ablation of liver using OLF.Methods: After right-side lung flooding, ultrasound guided HIFU was applied transthoracic- transpulmonary into liver to create thermal lesions in three pigs. The HIFU beam was targeted five times into liver, two times at the liver surface and three times deeper into the tissue. During autopsy examinations of lung, diaphragm and liver located in the HIFU path were performed. The focal liver lesions and lung tissue out of the beam path were examined histologically.Results: Fifteen thermal liver lesions were generated by transpulmonary HIFU sonication in all targeted regions. The lesions appeared well-demarcated in grey color with a cigar-shaped configuration. The mean length and width of the superficial and deeper lesions were 15.8 mm (range: 13-18 mm) and 5.8 mm (range: 5-7 mm), and 10.9 mm (range: 9-13 mm) and 3.3 mm (range: 2-5 mm), respectively. Histopathological, all liver lesions revealed a homogeneous thermal necrosis lacking vitality. There were no signs of damage of the overlying diaphragm and lung tissue.Conclusions: Flooded lung is a suitable pathway for applying HIFU to the liver, thus enabling a transthoracic, transpulmonary approach. The enlarged acoustic window could enhance the ablation speed for targets in the hepatic dome.     

Collection,Cryostorage, Transplantation,and Disposal of Hematopoietic Stem Cell Products

Many transplantation centers routinely collect 1 or more autologous peripheral blood stem cell (PBSC) grafts in patients with hemato-oncologic and autoimmune disorders. However, subsequent high-dose chemotherapy and autologous blood stem cell transplantation (ABSCT) are often not performed, for various reasons. Currently, little is known about the actual utilization rate of stored PBSCs. We retrospectively analyzed the collection, storage, and disposal practices of PBSC products from a large cohort of patients (n?=?1020) with hematologic, oncologic, and autoimmune disorders at our institution over a 12-year period. Patients with multiple myeloma were excluded. Based on our institution-specific charges, we estimated the costs for PBSC collection/processing and storage. The median number of sufficient PBSC collections per patient in the whole cohort was 2 (range, 1 to 6). We could demonstrate that only 67% of all patients who had collected sufficient PBSCs for transplantation actually underwent ABSCT, and only a small minority of all patients (4%) underwent multiple ABSCTs. The actual use of the stored PBSC grafts varied among disease entities from >80% to 0%. From a retrospective standpoint, the collected and discarded (definitively not used) or stored (potentially not used) cryostored PBSCs were associated with considerable costs of collection, cryopreservation, and long-term cryostorage. Although keeping open the therapeutic option for future transplantations may be important, there is currently a huge discrepancy between collection/storage practices and actual utilization of the cryopreserved PBSCs, at a considerable cost and strain on patients. Our study provides a rationale for reevaluating the present standards.     

Prioritizing research challenges and funding for allergy and asthma and the need for translational research—The European Strategic Forum on Allergic Diseases

The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision‐makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy's output with the perspective offered by EAACI's partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real‐world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients’ organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.