Perimenopause and Postmenopause - Diagnosis and Interventions. Guideline of the DGGG and OEGGG (S3-Level, AWMF Registry Number 015-062, September 2020).

Aim The aim of the interdisciplinary S3-guideline Perimenopause and Postmenopause - Diagnosis and Interventions is to provide help to physicians as they inform women about the physiological changes which occur at this stage of life and the treatment options. The guideline should serve as a basis for decisions taken during routine medical care. This short version lists the statements and recommendations given in the long version of the guideline together with the evidence levels, the level of recommendation, and the strength of consensus. Methods The statements and recommendations are largely based on methodologically high-quality publications. The literature was evaluated by experts and mandate holders using evidence-based medicine (EbM) criteria. The search for evidence was carried out by the Essen Research Institute for Medical Management (EsFoMed). To some extent, this guideline also draws on an evaluation of the evidence used in the NICE guideline on Menopause and the S3-guidelines of the AWMF and has adapted parts of these guidelines. Recommendations Recommendations are given for the following subjects: diagnosis and therapeutic interventions for perimenopausal and postmenopausal women, urogynecology, cardiovascular disease, osteoporosis, dementia, depression, mood swings, hormone therapy and cancer risk, as well as primary ovarian insufficiency.

Metabolic reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis.

Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.

PPARδ-mediated mitochondrial rewiring of osteoblasts determines bone mass.

Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover.

JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function.

Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of ß-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

[Practical Ultrasound Skills in Medical School]. / Universitäre Ultraschall- ausbildung in Deutschland.

Practical Ultrasound Skills in Medical School Abstract. A more competency-based medical education is addressed in the German National Competence Based Catalogue of Learning Objectives (NKLM) for Undergraduate Medical Education. This catalogue defines a wide range of competencies in communication, knowledge and skills that enable a medical professional to act effectively and responsibly for the benefit of individual patients and the community. Currently, the cataloque has the status of recommendations for restructuring medical curricula. Medical faculties are called upon to gain practical experience over the next years. Ultrasound is implemented in the preclinical and clinical parts of the NKLM. However, the acquisition of practical ultrasound skills for students is not addressed.

Effects of rule uncertainty on cognitive flexibility in a card-sorting paradigm.

Cognitive flexibility has been studied in two separate research traditions. Neuropsychologists typically rely on rather complex assessment tools such as the Wisconsin Card Sorting Test (WCST). In contrast, task-switching paradigms are used in experimental psychology to obtain more specific measures of cognitive flexibility. We aim to contribute to the integration of these research traditions by examining the role of the key factor that differs between the WCST and experimental task-switching paradigms: rule uncertainty. In two experimental studies, we manipulated the degree of rule uncertainty after rule switches in a computerized version of the WCST. Across a variety of task parameters, reducing rule uncertainty consistently impaired the speed and accuracy of responses when the rule designated to be more likely turned out to be incorrect. Other performance measures such as the number of perseverative errors were not significantly affected by rule uncertainty. We conclude that a fine-grained analysis of WCST performance can dissociate behavioural indicators that are affected vs. unaffected by rule uncertainty. By this means, it is possible to integrate WCST results and findings obtained from task-switching paradigms that do not involve rule uncertainty.

Cognitive caching promotes flexibility in task switching: evidence from event-related potentials.

Time-consuming processes of task-set reconfiguration have been shown to contribute to the costs of switching between cognitive tasks. We describe and probe a novel mechanism serving to reduce the costs of task-set reconfiguration. We propose that when individuals are uncertain about the currently valid task, one task set is activated for execution while other task sets are maintained at a pre-active state in cognitive cache. We tested this idea by assessing an event-related potential (ERP) index of task-set reconfiguration in a three-rule task-switching paradigm involving varying degrees of task uncertainty. In high-uncertainty conditions, two viable tasks were equally likely to be correct whereas in low-uncertainty conditions, one task was more likely than the other. ERP and performance measures indicated substantial costs of task-set reconfiguration when participants were required to switch away from a task that had been likely to be correct. In contrast, task-set-reconfiguration costs were markedly reduced when the previous task set was chosen under high task uncertainty. These results suggest that cognitive caching of alternative task sets adds to human cognitive flexibility under high task uncertainty.

The functional right ventricle and tricuspid regurgitation in Ebstein's anomaly.

BACKGROUND: The size of the functional right ventricle of patients with Ebstein's anomaly is, according to contemporary opinion, small. However, the in vivo size of the functional right ventricle in patients with Ebstein's anomaly is unknown. Furthermore, it is unknown how the apical displacement and regurgitant fraction of the tricuspid valve in Ebstein's anomaly affects the size of the functional right ventricle. Therefore the primary aim of this study was to determine the volume of the functional right ventricle in patients with Ebstein's anomaly. The secondary aim of this study was to assess correlation of the volume of the functional right ventricle to the apical displacement and regurgitant fraction of the tricuspid valve. METHODS: Thirty-two consecutive patients with Ebstein's anomaly without previous cardiac surgery or shunts were studied prospectively by cardiovascular magnetic resonance. Functional right ventricle, left ventricle, and atrialized right ventricle volumes and tricuspid valve regurgitation were measured. RESULTS: Functional right ventricle end diastolic volumes were median 127 ml/m² (range: 76-339 ml/m²) and were median 2.5 (range: 1.3-8.8) times larger than the left ventricle volumes. Furthermore, functional right ventricle volumes correlated in a strong positive fashion with tricuspid valve regurgitation (p<0.001, R(2)=0.65) and modestly with the atrialized right ventricle volumes (p=0.027, R(2)=0.16). CONCLUSION: Patients with untreated Ebstein's anomaly have large functional right ventricles. The size of the enlarged functional right ventricle seems to depend on the degree of tricuspid valve regurgitation and not on the size of the atrialized right ventricle or the age of the patient.

Insulin-resistant brain state (IRBS) changes membrane composition of fatty acids in temporal and entorhinal brain cortices of rats: relevance to sporadic Alzheimer's disease?

An insulin-resistant brain state (IRBS) was induced by intracerebroventricular application of the diabetogenic substance streptozotocin (STZ) to investigate changes in cerebral fatty acids. Six weeks after the first STZ injection, increases were found in the concentrations of palmitic and stearic acid in temporal cortex; and of palmitic acid in entorhinal cortex indicative of membrane phospholipid breakdown, and damage of the membrane structure. The relevance of these changes is discussed in relation to sporadic Alzheimer's disease.