Search

Modern conceptualizations suggest the independence of positive and negative mental health constructs. Research of positive constructs in psychotherapy is scarce. This study analyzed the development of patients' strengths during psychotherapy and whether pre-therapy strengths incrementally predict treatment outcome.Two hundred and two patients (56.44% female, mean age = 42.49) treated by 54 therapists underwent cognitive behavioral therapy. Patients' strengths in different contexts as well as psychopathology, interpersonal problems, and self-esteem were assessed at the beginning and end of therapy.Strengths increased in the contexts of everyday life (EvdayS; d = 0.44, p 0.001) and current problems (ProbS; d = 0.70, p 0.001). Strengths in the context of previous crises that were managed successfully (CrisesS) did not change. However, baseline scores of CrisesS were a significant incremental predictor of all outcomes.A differentiated assessment of positive constructs is useful for outcome prediction and the implementation of strength-based interventions.

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years’ follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was −0.29 mmol/L [95% CI −0.54; −0.04], P = 0.025. Liver fat (−1.34 percentage points [95% CI −2.17; −0.50], P = 0.002) and cardiovascular risk (−1.82 percentage points [95% CI −3.13; −0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype–based LI may be beneficial for the prevention of diabetes.

Although the cannabinoid receptor 2 (CB2R) is often thought to play a role mainly outside the brain several publications unequivocally showed the presence of CB2R on hippocampal principal neurons. Activation of CB2R produced a long-lasting membrane potential hyperpolarization, altered the input/output function of CA2/3 principal neurons and produced alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB2R signaling have not been studied in detail. Here we demonstrate that the deletion of CB2 leads to a highly significant increase in hippocampal synapsin-I expression levels and particle density, as well as increased vesicular GABA transporter (vGAT) levels. This phenotype was restricted to females and not observed in males. Furthermore, we demonstrate an impairment of social memory in CB2 deficient mice. Our results thus demonstrate that the lack of CB2R leads to changes in the hippocampal synaptic landscape and reveals an important sex-specific difference in endocannabinoid signaling. This study supports a significant role of the CB2R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a sex-specific role of CB2R in synaptic architecture.

BackgroundBoth obstructive sleep apnea (OSA) and (at least a fraction of) sudden infant death syndrome (SIDS) are associated with impaired respiration. For OSA, an association with several gene variants was identified. Therefore, our hypothesis is that these polymorphisms might be of relevance in SIDS as well.MethodsTwenty-four single nucleotide polymorphisms (SNPs) in 21 candidate genes connected to OSA, were genotyped in a total of 282 SIDS cases and 374 controls. Additionally, subgroups based on factors codetermining the SIDS risk (age, sex, season, and prone position) were established and compared as well.ResultsTwo of the analyzed SNPs showed nominally significant differences between SIDS and control groups: rs1042714 inADRB2(adrenoceptor beta 2) and rs1800541 inEDN1(endothelin 1). In the subgroup analyses, 10 further SNPs gave significant results. Nevertheless, these associations did not survive adjustment for multiple testing.ConclusionsOur results suggest that there might be a link between SIDS and OSA and its resulting respiratory and cardiovascular problems, albeit this predisposition might be dependent on the combination with other, hitherto unknown gene variants. These findings may encourage replication studies to get a better understanding of this connection.

Juliane Schürmann,1 Frank Noack,2,3 Steffi Bethge,4 Viktoria Heinze,4 Axel Schlitt4,5 1Department of Cardiology and Pulmonology AMEOS Clinic Bernburg, Bernburg, Germany; 2Department of Emergency Medicine, University Clinic Halle-Saale, Halle, Germany; 3Department of Medicine I, University Clinic Halle-Saale, Halle, Germany; 4Paracelsus-Harz-Clinic Bad Suderode, Quedlinburg, Germany; 5Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle, GermanyCorrespondence: Juliane SchürmannDepartment of Cardiology and Pulmonology AMEOS Clinic, Bernburg, 06406, GermanyTel +49 3471 341504Fax +49 3471 342053Email jsch.med@bernburg.ameos.deBackground: Heart failure is the third most fatal disease in Germany and generates considerable treatment costs. The multimodal program of inpatient rehabilitation can improve the symptoms and prognosis of these patients. At the present time, however, only few data are available on the effectiveness of rehabilitation for heart failure patients.Methods: After receiving study approval from the ethics committee of the Saxony–Anhalt Medical Association, 200 patients with a primary or secondary diagnosis of heart failure were prospectively included in the study at Paracelsus-Harz-Clinic Bad Suderode, Quedlinburg, Germany. Baseline parameters such as age, gender, and BMI were documented. Outcome variables included NYHA classifications, quality of life, and mortality. For follow-up, the patients were contacted again by mail or phone after three and 12 months and, data on symptoms and serious events were recorded.Results: The proportion of patients with a highly reduced ejection fraction (HFrEF) was 13.5%, with a midrange reduced ejection fraction (HFmrEF) 33%, and with preserved ejection fraction (HFpEF) 53.5%. The mean age was 64 ± 11.9 years, the proportion of women 24.1%. The effects of rehabilitation were documented by low overall mortality (no patient died during the stay, only 4% of the patients died in the 12-month follow-up) and an improvement in NYHA classification during and after the inpatient rehabilitation.Conclusion: This monocentric study showed effects both for symptoms (improvement in NYHA classifications) and prognosis (overall mortality) after rehabilitation. These data reflect the effectiveness of multimodal rehabilitation and underscore the need for rehabilitation in patients diagnosed with heart failure after an acute event and hospital stay or who present with chronic deterioration.Keywords: heart failure, cardiac rehabilitation, inpatient rehabilitation

A previous randomised controlled trial demonstrated the effects of a telephone-assisted self-help (TASH) intervention for parents of pharmacologically treated children with attention-deficit/hyperactivity disorder (ADHD) on ADHD symptoms, oppositional symptoms, functional impairment, and negative parenting behaviour (per-protocol analyses). In the current study, we examined whether changes in positive and negative parenting behaviour mediated the effects on symptoms and impairment. Parents in an enhancement group (n = 51) participated in a 12-month TASH intervention (eight booklets plus up to 14 telephone consultations) as an adjunct to routine clinical care, whereas parents in a waitlist control group (n = 52) received routine clinical care only. Parents completed measures of child symptoms, child functional impairment, and parenting behaviour at baseline, at 6 months, and at 12 months. The mediating effects of parenting behaviour were examined using regression analyses. Per-protocol analyses (n = 74) revealed a significant indirect intervention effect on functional impairment through negative parenting behaviour at 6 months as well as indirect intervention effects on oppositional symptoms and functional impairment through negative parenting behaviour at 12 months. The indirect effect on ADHD symptoms through negative parenting behaviour at 12 months just failed to reach significance. The analyses yielded no indirect intervention effects through positive parenting behaviour. The study provides some, albeit limited, support for the importance of changes in negative parenting behaviour to achieve changes in symptoms and functional impairment during parent training. In consideration of the inconsistent results of previous studies concerning the mediating role of positive and negative parenting behaviour, further research is required to better understand the mechanisms of change during parent training, also including other possible mediators like parenting stress and parental self-efficacy.

This observational study examined treatment satisfaction (TS) following routine outpatient cognitive-behavioral therapy (CBT) in a large sample of children (n = 795; aged 6 to 10 years). TS was investigated in parent and therapist rating. Means, standard deviations and inter-rater correlations were calculated to investigate TS. Regression analysis was conducted to examine potential correlates of TS (patient-related variables, mental disorder characteristics, socio-demographic factors and treatment variables). High TS in parent and therapist rating was found, with therapists showing a lower degree of TS than parents (completely or predominantly satisfied: parent rating 94.1%, therapist rating 69.5%). A statistically significant, moderate inter-rater correlation was found. Regression analysis explained 21.8% of the variance in parent rating and 57.2% in therapist rating. Most of the TS variance was explained by mental disorder characteristics (parent-rated symptoms and therapist-rated global impairment at treatment end) and by treatment variables (especially the therapist-rated cooperation of parents and patients), whereas socio-demographic and patient-related variables did not show any relevant associations with TS. Based on these results, to optimize TS, therapists should concentrate on establishing a sustainable cooperation of parents and children during therapy, and work to achieve a low global impairment at treatment end. Electronic supplementary material The online version of this article (10.1007/s00787-020-01528-1) contains supplementary material, which is available to authorized users.

Comment in Does HIV-1 virulence matter in the ART era? Lewitus E, Rolland M. Med (N Y). 2022 Apr 8;3(4):217-219. doi: 10.1016/j.medj.2022.03.003. PMID: 35590149; International audience; We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

Pancreatic steatosis associates with β-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.

BACKGROUND: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. METHODS: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html). RESULTS: We identified 6710 differentially methylated regions at a stringent false discovery rate

The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

Context/Objective Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D. Design/Patients Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging. Results T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P Conclusions Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

Aims The protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized; however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions. Methods and results Tamoxifen-induced Scrib-knockout mice were crossed with ApoE−/− knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes. Conclusions By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.

The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity., Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.

Bayesian cognitive modeling has become a prominent tool for the cognitive sciences aiming at a deeper understanding of the human mind and applications in cognitive systems, e.g., humanoid or wearable robotics. Such approaches can capture human behavior adequately with a focus on the crossmodal processing of sensory information. The rubber foot illusion is a paradigm in which such integration is relevant. After experimental stimulation, many participants perceive their real limb closer to an artificial replicate than it actually is. A measurable effect of this recalibration on localization is called the proprioceptive drift. We investigate whether the Bayesian causal inference model can estimate the proprioceptive drift observed in empirical studies. Moreover, we juxtapose two models employing informed prior distributions on limb location against an existing model assuming uniform prior distribution. The model involving empirically informed prior information yields better predictions of the proprioceptive drift regarding the rubber foot illusion when evaluated with separate experimental data. Contrary, the uniform model produces implausibly narrow position estimates that seem due to the precision ratio between the contributing sensory channels. We conclude that an informed prior on limb localization is a plausible and necessary modification to the Bayesian causal inference model when applied to limb illusions. Future research could overcome the remaining discrepancy between model predictions and empirical observation by investigating the changes in sensory precision as a function of distance between the eyes and respective limbs.

Summary: An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MIN6 beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk. : Kluth et al. identify a significant enrichment of cilia-annotated genes that are differentially expressed in pancreatic islets of obese mice. Many of the genes were also linked to human T2D, suggesting that dysregulation of cilia-associated genes may participate in T2D risk. Keywords: beta-cell proliferation, cilia genes, human pancreatic islets, islet transcriptomics, New Zealand Obese mouse, pathway enrichment analysis, primary cilia, type 2 diabetes

There is evidence that inflammation plays a role in the etiology of sudden infant death syndrome (SIDS). Immune system dysregulation seems to be the background of higher infection susceptibility in SIDS infants. This phenotype is possibly determined by genetic factors. Twenty-three single nucleotide polymorphisms (SNPs) in the following 13 candidate genes governing the immune system were successfully genotyped in 251 Caucasian SIDS cases and 336 controls from Germany: ADAR1, CSF2RB, DDX58, IFNA1, IFNA21, IFNA8, IFNAR2, IFNG, IL6, MX2, OAS1, OAS3, and TNFA. Associations between genotypes and SIDS were then statistically evaluated using logistic regression analyses. Overall analysis revealed statistically significant results for two variants in interferon gamma (IFNG) (rs2069705: OR 1.40 (1.07; 1.83), p = 0.01; and rs2069727: OR 0.75 (0.59; 0.96), p = 0.02) and for one variant in interferon alpha 8 (IFNA8) (rs1330321: OR 1.85 (1.06; 3.21), p = 0.03). Haplotype analyses identified a three-marker risk IFNG haplotype rs2069727-rs2069718-rs2069705 associated with SIDS (OR = 1.62, 95% CI 1.23–2.13; p = 0.0003). Subgroup associations were found for variants in adenosine deaminase acting on RNA1 (ADAR1), 2′,5′-oligoadenylate synthetase-1 (OAS1) and colony stimulating factor 2 receptor beta common subunit (CSF2RB). In summary, this large study of 251 SIDS cases for common variants in 13 candidate genes governing the immune system has provided first evidence for a role of IFNG in the etiology of SIDS and should stimulate further research into the clinicopathological relevance of immunomodulatory genes for this fatal syndrome.

Background: Hydrogen sulfide (H 2 S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions. Methods: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E–deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H 2 S bioavailability, and amino acid profiling were also performed with human material. Results: The endothelial cell–specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H 2 S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of H 2 S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R–target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l -cystathionine negatively correlated with vascular reactivity and H 2 S levels, indicating its potential use as a biomarker for vascular disease. Conclusions: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H 2 S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H 2 S are lost owing to the phosphorylation and inhibition of the enzyme.

Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance., Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe; 1235

Background Asthma treatment should be modified according to symptom control and future risk, but there are scarce data on what drives treatment adjustments in routine tertiary care. Objective We studied factors that drive asthma treatment adjustment in pediatric outpatient clinics. Methods We performed a cross-sectional analysis of the Swiss Paediatric Airway Cohort, a clinical cohort of 0- to 16-year-old children seen by pediatric pulmonologists. We collected information on diagnosis, treatment, lung function, and FeNO from hospital records; and on symptoms, sociodemographic, and environmental factors from a parental questionnaire. We used reported symptoms to classify asthma control and categorized treatment according to the 2020 Global Initiative for Asthma guidelines. We used multivariable logistic regression to study factors associated with treatment adjustment (step-up or down vs no change). Results We included 551 children diagnosed with asthma (mean age, 10 years; 37% female). At the clinical visit, most children were prescribed Global Initiative for Asthma step 3 (35%). Compared with previsit treatment, 252 children remained on the same step (47%), 227 were stepped up (42%), and 58 were stepped down (11%). Female sex (adjusted odds ratio [aOR] = 1.61; 95% confidence interval [CI], 1.05-2.47), poor asthma control (aOR = 3.08; 95% CI, 1.72-5.54), and lower FEV1 Z-score (aOR = 0.70; 95% CI, 0.56-0.86 per one Z-score increase) were independently associated with treatment step-up, and low FeNO (aOR = 2.34; 95% CI, 1.23-4.45) was associated with treatment step-down, with marked heterogeneity between clinics. Conclusions In this tertiary care real-life study, we identified main drivers for asthma treatment adjustment. These findings may help improve both asthma management guidelines and clinical practice.

BACKGROUND Early failure of osteosyntheses is common even with use of locking plates. In patients with comminuted fractures and epiphyseal osseous defects, we performed a series of osteosyntheses by locking plate in combination with an allograft bone augmentation. Because of encouraging short-term results in the literature, we assumed that the method could be a potential alternative to a reverse shoulder prosthesis. MATERIAL AND METHODS Twenty-six patients with a dislocated proximal humeral fracture (Neer IV/V/VI) were studied. A lyophilized allogeneic bone graft was used to reinforce the humeral head fragments before locking plate osteosynthesis. The outcomes of fractures were assessed with Disabilities of the Arm, Shoulder and Hand (DASH) and Constant-Murley (Constant) scores, range of motion, a visual analog scale, and with radiological testing. The Constant-Murley scores were the endpoint of our study. RESULTS The Neer classification of the fractures was type IV in 4 patients, type V in 20 patients, and type VI in 2 patients. The mean DASH score was 52.85 (range, 4.17-79.3) and the mean Constant score was 39.26 (range, 17-88). We observed late necrosis of the humeral head in 15 of 24 patients (62.5%), although early radiological follow-up showed that the humeral head had been anatomically reconstructed. CONCLUSIONS Long-term follow-up demonstrated inferior functional results, as displayed by poor Constant scores. There was a high incidence of necrosis, in spite of initial anatomical reconstruction. Biointegration of the allogeneic bone graft and revascularization of the humeral head fragments could be impaired in geriatric patients who have gross dislocation. Therefore, augmentation of the humeral head with allogeneic bone grafts cannot be recommended in these patients.

BACKGROUND: Cerebral vasospasm (CVS) is a frequent complication after subarachnoid hemorrhage (SAH), with no sufficient therapy and a complex pathophysiology. OBJECTIVE: To explore the vitamin D system as a potential treatment for CVS. METHODS: 25-vitamin D3 levels tested between 2007 and 2015 and data of SAH patients admitted during the months with a peak vs nadir of VitD3 values were analyzed, retrospectively. We prospectively correlated VitD3 and vasospasm/outcome data in SAH patients admitted in 2017. An experimental mice SAH model and cell culture model were used to investigate the effect of 1,25-dihydroxyvitamin D3 (1,25-VitD3). Additionally, the mediators acting in the VitD mechanism were researched and detected. RESULTS: Based on the retrospective analysis demonstrating an increased frequency of vasospasm in SAH patients during the low vitamin D period in winter, we started basic research experiments. Active 1,25-VitD3 hormone attenuated CVS, neurological deficit, and inflammation after intrathecal blood injection in mice. Deletion of the vitamin D receptor in the endothelium or in myeloid cells decreased the protective 1,25-VitD3 effect. Co-culture experiments of myeloid and endothelial cells with blood confirmed the anti-inflammatory 1,25-VitD3 effect but also revealed an induction of stroma-cell-derived factor 1α (SDF1α), vascular endothelial growth factor, and endothelial nitric oxide synthase by 1,25-VitD3. In mice, SDF1α mimicked the protective effect of 1,25-VitD3 against CVS. From bench to bedside, CVS severity was inversely correlated with vitamin D plasma level, prospectively. Patients with more severe CVS exhibited attenuated expression of SDF1α and 1,25-VitD3-responsive genes on circulating myeloid cells. CONCLUSION: 1,25-VitD3 attenuates CVS after SAH by inducing SDF1α. However, VitD administration should be tested as optional treatment to prevent CVS. ispartof: NEUROSURGERY vol:88 issue:3 pages:674-685 ispartof: location:United States status: published

Objectives Monitoring critical time intervals in acute ischemic stroke treatment delivers metrics for quality of performance – the door-to-needle time being well-established. To resolve the conflict of self-reporting bias a “StrokeWatch” was designed – an instrument for objective standardized real-time measurement of procedural times. Materials and methods An observational, monocentric analysis of patients receiving intravenous thrombolysis for acute ischemic stroke between January 2018 and September 2019 was performed based on an ongoing investigator-initiated, prospective, and blinded endpoint registry. Patient data and treatment intervals before and after introduction of "StrokeWatch" were compared. Results “StrokeWatch” was designed as a mobile board equipped with three digital stopwatches tracking door-to-needle, door-to-groin, and door-to-recanalization intervals as well as a form for standardized documentation. 118 patients before introduction of “StrokeWatch” (subgroup A) and 53 patients after introduction of “StrokeWatch” (subgroup B) were compared. There were no significant differences in baseline characteristics, procedural times, or clinical outcome. A non-significant increase in patients with door-to-needle intervals of 60 min or faster (93.2 vs 98.1%, p = 0.243) and good functional outcome (mRS d90 ≤ 2, 47.5 vs 58.5%, p = 0.218) as well as a significant increase in reports of delayed arrival of intra-hospital patient transport service (0.8 vs 13.2%, p = 0.001) were observed in subgroup B. Conclusions The implementation of StrokeWatch for objective standardized real-time measurement of door-to-needle times is feasible in a real-life setting without negative impact on procedural times or outcome. It helped to reassure a high-quality treatment standard and reveal factors associated with procedural delays.

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19., New-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients, however, the underlying mechanisms are not fully understood. Here, the authors show that SARS-CoV-2 is detectable in both endocrine and exocrine cells of the pancreata of patients with COVID-19.

Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan-Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59-66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39-0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011-2017), being on a multi-tablet regimen (MTR).Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.

Introduction: The aim of the study is to compare length of hospital stay, transfusion rates, and re-intervention rates during hospitalization for transurethral resection of the prostate (TUR-P), open prostatectomy (OP), and laser therapy (LT) for surgical treatment of benign prostatic obstruction (BPO). Methods: URO-Cert is an organization, in which clinical data of prostatic diseases from 2 university, 19 public, and 3 private hospitals and 270 office-based urologists are collected in order to document treatment quality. Data on diagnostics, therapy, and course of disease are recorded web based. The analysis includes datasets from 2005 to 2017. Results: Of 10,420 patients, 8,389 were treated with TUR-P, 1,334 with OP, and 697 with LT. Median length of hospital stay was 6 days (IQR: 4–7) for TUR-P, 9 days (IQR: 7–11) for OP, and 5 days (IQR: 4–6) for LT (p < 0.001). Risk for a hospital stay ≥7 days was higher for OP versus TUR-P (OR: 7.25; 95% CI = 6.27–8.36; p < 0.001) and LT (OR: 17.89; 95% CI = 14.12–22.65; p < 0.001) and higher for TUR-P versus LT (OR: 2.47; 95% CI = 2.03–3.01; p < 0.001). OP had a significantly higher risk for transfusions than TUR-P (OR: 2.44; 95% CI = 1.74–3.41; p < 0.001) and LT (OR: 3.32; 95% CI = 1.56–7.01; p < 0.001). Transfusion rates were not significantly different between TUR-P and LT (OR: 1.36; 95% CI = 0.66–2.79; p = 0.51). Risk of re-intervention was not different between all 3 approaches. Conclusion: OP was associated with higher transfusion rates and longer hospital stay than TUR-P and LT. Risk of transfusion was not different between TUR-P and LT, but TUR-P was inferior to LT concerning length of hospital stay. Re-intervention rates during hospitalization did not differ between the groups.

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival., Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA Sarrah, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.

Thorough preclinical evaluation reveals a negligible role of lipocalin 13 in systemic glucose and lipid metabolism., Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.

Background: The prognosis of patients with acute ischemic stroke (AIS) essentially depends on both prompt diagnosis and appropriate treatment. Endovascular stroke therapy (EST) proved to be highly efficient in the treatment of emergent large vessel occluding (ELVO) strokes in the anterior circulation. To achieve a timely diagnosis, a robust combination of few and simple signs to identify ELVOs in AIS patients applicable by paramedics in the prehospital triage is worthwhile. Methods: This retrospective single-center study included 904 AIS patients (324 ELVO, 580 non-ELVO) admitted between 2010 and 2015 in a tertiary stroke center. We re-evaluated two symptoms based on NIHSS items, gaze deviation and hemiparesis of the limbs (“Gaze deviation and Paresis Score, GPS”) for the pre-hospital prediction of ELVO. Results: A positive GPS AIS in patients predicted ELVO with a sensitivity of 0.89, specificity = 0.97, positive predictive value (PPV) = 0.95, negative predictive value (NPV) = 0.94 and diagnostic odds ratio (DOR) = 34.25 (CI: 20.75 - 56.53). The positive Likelihood-ratio (LR + ) was 29.67, the negative Likelihood ratio (LR - ) 0.11. NIHSS of patients with positive GPS (gaze palsy NIHSS ≥ 0, Motor arm NIHSS ≥2 and Motor leg NIHSS ≥2) was markedly higher compared to negative GPS patients (pConclusions: The GPS proved to be similarly accurate in detecting ELVO in the anterior circulation of AIS patients and even more specific than other published clinical scores. Its simplicity and clarity might enable non-neurological medical staff to identify ELVO AIS patients with high certainty in a preclinical setting.

We report a case of a probable HIV-1 transmission by human bite. The analyzed data from ten previously reported suspected or allegedly confirmed HIV transmissions revealed a deep bleeding bite wound as the primary risk factor. A high HIV plasma viral load and bleeding oral lesions are present most of the time during HIV transmission by bite. HIV post-exposure prophylaxis (PEP) should be recommended in case of a bleeding wound resulting from a bite of an HIV-infected person. PEP was missed in this presented case.

Gestational diabetes mellitus (GDM) is a complex metabolic disease involving genetic and environmental factors. Recent studies have underlined its heterogeneity, so it is reasonable to divide patients into subpopulations depending on whether an insulin secretion or sensitivity defect is predominant. Since testing for GDM is usually performed in the second trimester, misinterpretation of prediabetes as gestational diabetes may occur. As with type 2 diabetes (T2DM), rodent models are needed for both GDM and prediabetes, but few do exist. Here, we compared the metabolic changes in pregnant normal NMRI mice with those in New Zealand obese (NZO) mice. Male animals of this strain are an established model of T2DM, whereas female mice of this strain are protected from hyperglycemia and β‐cell death. We demonstrate that female NZO mice exhibited impaired glucose tolerance, preconceptional hyperinsulinemia, and hyperglucagonemia without any signs of manifest diabetes. The NZO model showed, compared with the NMRI control strain, a reduced proliferative response of the Langerhans islets during pregnancy (3.7 ± 0.4 vs. 7.2 ± 0.8% Ki‐67‐positive nuclei, p = .004). However, oral glucose tolerance tests revealed improved stimulation of insulin secretion in both strains. But this adaption was not sufficient to prevent impaired glucose tolerance in NZO mice compared with the NMRI control (p = .0002). Interestingly, glucose‐stimulated insulin secretion was blunted in isolated primary NZO islets in perifusion experiments. In summary, the NZO mouse reflects important characteristics of human GDM and prediabetes in pregnancy and serves as a model for subpopulations with early alterations in glucose metabolism and primary insulin secretion defect., The aim of this work was to evaluate metabolic changes during pregnancy within the polygenic NZO mouse model and if it is a suitable one for the human disease. NZO mice showed early alterations in glucose homeostasis and insulin secretion, but no overt diabetes. Interestingly, the preconceptionally impaired glucose tolerance did not deteriorate during gestation despite a proliferation defect of Langerhans islets.

Due to the high incidence and demographic development, there is an urgent need for healthcare research data on lower urinary tract symptoms due to benign prostatic hyperplasia (LTUS/BPH). Since 2005 the Governing Body of German Prostate Centers (DVPZ) has been collecting data from 22 prostate centers in order to determine the quality and type of cross-sectoral care in particular for LUTS/BPH patients.Presentation of the DVPZ database in general, as well as an investigation of treatment patterns for medical and instrumental therapies.The analysis is based on UroCloud data sets from 30 November 2017. In the UroCloud data on diagnostics, therapy and course of disease are recorded in a web-based manner.A total of 29,555 therapies were documented for 18,299 patients (1.6/patient), divided into 48.5% instrumental, 29.2% medical treatment, and 18.0% "wait and see" (in 4.3% no assignment was possible). Patients treated with an instrumental therapy were oldest (median: 72 years, interquartile range: 66-77), had the largest prostate volumes (50 ml, 35-75 ml), and were mostly bothered by symptoms (International Prostate Symptom Score = 19/4). The majority of patients under medical treatment received alphablockers (56%); phytotherapeutics were used least frequently (3%). Instrumental therapies are dominated by transurethral resection (TUR) of the prostate (60.0%), open prostatectomy (9.4%) and laser therapy (5.0%), with laser therapy having the shortest hospital stay (5 days) and the lowest transfusion and re-intervention rates (1.0% and 4.6%, respectively).The DVPZ certificate covers the complete spectrum of cross-sectoral care for LUTS/BPH patients and documents the use of the various therapies as well as their application and effectiveness in the daily routine setting.HINTERGRUND: Aufgrund der hohen Inzidenz und der demografischen Entwicklung besteht großer Bedarf an Versorgungsdaten zum benignen Prostatasyndrom (BPS). Der Dachverband der Prostatazentren Deutschlands e. V. (DVPZ) erhebt seit 2005 strukturiert Daten in derzeit 22 Prostatazentren, um Qualität und Art der sektorübergreifenden Versorgung u. a. von BPS-Patienten abzubilden.Dieser Artikel stellt die Datenerhebung in den Prostatazentren des DVPZ i. Allg. dar und untersucht die verschiedenen Behandlungsmuster medikamentöser und instrumenteller Therapien.Die Analyse basiert auf UroCloud-Datensätzen vom 30.11.2017. Diese bildet webbasiert chronologische Krankheitsverläufe und Qualitätsparameter ab.Von 18.299 Patienten wurden insgesamt 29.555 Therapien dokumentiert (1,6/Patient). Diese verteilen sich auf 48,5 % instrumentelle, 29,2 % medikamentöse und 18,0 % Wait-and-see-Verfahren (4,3 % keine Zuordnung). Instrumentell behandelte Patienten waren am ältesten (im Median: 72, IQR: 66–77 Jahre), hatten die größten Prostatavolumina (50; 35–75 ml) bzw. die ausgeprägtesten Symptome (IPSS = 19/4). Die Mehrheit der medikamentös behandelten Patienten erhielt Alpha-Blocker (56 %), am seltensten wurden Phytotherapeutika eingesetzt (3 %). Bei den instrumentellen Therapien dominieren TUR-Prostata (60,0 %), offene Adenomenukleation (9,4 %) und Lasertherapie (LT, 5,0 %), wobei LT durch den kürzesten stationären Aufenthalt (5 Tage) sowie die niedrigsten Transfusions- und Reinterventionsraten (1,0 bzw. 4,6 %) gekennzeichnet war.Das DVPZ-Zertifikat bildet die gesamte Bandbreite der sektorübergreifenden Versorgung von BPS-Patienten ab und dokumentiert den Einsatz der verschiedenen Therapien sowie deren Anwendungs- und Wirksamkeitsunterschiede in der Versorgungsrealität.

Between 1966 to 1969, Bernhard Grzimek (Frankfurt Zoological Society, FZS) introduced chimpanzees (Pan troglodytes) previously held in European institutions to Rubondo Island in Lake Victoria in Tanzania. Earlier publications report various numbers of released animals and that all founders originated from West Africa. We revise these assumptions through consultation of archived FZS records and genetic analyses of surviving descendants. Accordingly, 17 chimpanzees were transported to Africa in four waves, with male-female ratios of 3:8, 1:0, 1:0 and 2:2; one female died in transit. Thus, 16 chimpanzees were released in total. FZS and studbook records allocate a West African provenance to only 19% of the founders and a generic "Africa" origin to 56%. Still, studbook records render it unlikely that any of the founders were captive-born. In addition, our genetic analyses based on biological samples from the current descendants trace the geographical origin of their ancestors back to West Africa (P. t. verus) and Central Africa (P. t. troglodytes). Based on counts of individuals and night nests, we estimate that the population, since 1969, grew to around 35 individuals in 2014 (annual increase 3.3%). Thus, chimpanzees released onto a large forested island free from predators or hunting pressure, habitat destruction and conspecific competition can form a self-sustaining island population without human support.

Objective Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic β-cells. Methods A β-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. Results The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co-localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from β-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from β-cell-specific Arfrp1 knockout mice. Conclusion Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting., Highlights • β-cell specific deletion of the trans-Golgi residing small GTPase ARFRP1 leads to elevated blood glucose levels in mice. • GOPC is a newly identified ARFRP1 dependent scaffolding protein. • ARFRP1 and GOPC are required for glucose-stimulated insulin secretion from pancreatic β-cells.

Significance Caveolae are small plasma membrane invaginations that are particularly abundant in adipocytes. Caveolae are implicated in lipid uptake, but the exact mechanism is not clear. Here, we characterized the physiological function of EHD2, a protein that is found at the neck of caveolae. We established a link between higher caveolar mobility induced by EHD2 loss and increased cellular fatty acid uptake. Concurrently, lipid droplets were enlarged in various tissues of EHD2-lacking mice. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway. Notably, obese patients express only low levels of EHD2, implicating a role of EHD2-controlled caveolar dynamics in obesity., Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation of EHD2 in mice leads to increased lipid droplet size in fat tissue. This organismic phenotype was paralleled at the cellular level by increased fatty acid uptake via a caveolae- and CD36-dependent pathway that also involves dynamin. Concomitantly, elevated numbers of detached caveolae were found in brown and white adipose tissue lacking EHD2, and increased caveolar mobility in mouse embryonic fibroblasts. EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway and imply that low EHD2 expression levels are linked to obesity.

BACKGROUND & AIMS: Currently, only a few genetic variants explain the heritability of fatty liver disease. Quantitative trait loci (QTL) analysis of mouse strains has identified the susceptibility locus Ltg/NZO (liver triglycerides from New Zealand obese [NZO] alleles) on chromosome 18 as associating with increased hepatic triglycerides. Herein, we aimed to identify genomic variants responsible for this association.; METHODS: Recombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and characterized for liver fat. Bioinformatic analysis, mRNA profiles and electrophoretic mobility shift assays were performed to identify genes responsible for the Ltg/NZO phenotype. Candidate genes were manipulated invivo by injecting specific microRNAs into C57BL/6 mice. Pulldown coupled with mass spectrometry-based proteomics and immunoprecipitation were performed to identify interaction partners of IFGGA2.; RESULTS: Through positional cloning, we identified 2 immunity-related GTPases (Ifgga2, Ifgga4) that prevent hepatic lipid storage. Expression of both murine genes and the human orthologue IRGM was significantly lower in fatty livers. Accordingly, liver-specific suppression of either Ifgga2 or Ifgga4 led to a 3-4-fold greater increase in hepatic fat content. In the liver of low-fat diet-fed mice, IFGGA2 localized to endosomes/lysosomes, while on a high-fat diet it associated with lipid droplets. Pulldown experiments and proteomics identified the lipase ATGL as a binding partner of IFGGA2 which was confirmed by co-immunoprecipitation. Both proteins partially co-localized with the autophagic marker LC3B. Ifgga2 suppression in hepatocytes reduced the amount of LC3B-II, whereas overexpression of Ifgga2 increased the association of LC3B with lipid droplets and decreased triglyceride storage.; CONCLUSION: IFGGA2 interacts with ATGL and protects against hepatic steatosis, most likely by enhancing the binding of LC3B to lipid droplets.; LAY SUMMARY: The genetic basis of non-alcoholic fatty liver disease remains incompletely defined. Herein, we identified members of the immunity-related GTPase family in mice and humans that act as regulators of hepatic fat accumulation, with links to autophagy. Overexpression of the gene Ifgga2 was shown to reduce hepatic lipid storage and could be a therapeutic target for the treatment of fatty liver disease. Copyright © 2020 European Association for the Study of the Liver. All rights reserved.

IntroductionEven well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy and adequate treatment, and its impact on the long-term health of both mother and child.MethodsThe multicentre PREG study, a prospective cohort study, is designed to metabolically and phenotypically characterise women with a 75-g five-point oral glucose tolerance test (OGTT) during, and repeatedly after pregnancy. Outcome measures are maternal glycaemia during OGTTs, birth outcome and the health and growth development of the offspring. The children of the study participants are followed up until adulthood with developmental tests and metabolic and epigenetic phenotyping in the PREG Offspring study. A total of 800 women (600 with GDM, 200 controls) will be recruited.Ethics and disseminationThe study protocol has been approved by all local ethics committees. Results will be disseminated via conference presentations and peer-reviewed publications.Trial registration numberThe PREG study and the PREG Offspring study are registered with Clinical Trials (ClinicalTrials.gov identifiers: NCT04270578, NCT04722900).

Recent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk.

Besides liver, IGF-I is expressed in adipose tissue. However, the effects of this local IGF-I on adipose tissue and metabolism are unclear. We generated adipocyte-specific knock-out mice on the background of the Berlin Fat Mouse Inbred (BFMI) line to evaluate the contribution of adipocyte-IGF-I on glucose metabolism and adipose tissue development. BFMI mice are obese, non-diabetic with elevated plasma insulin and IGF-I concentration. The knock-out in adipocytes led to a total white adipose tissue expression of 50-60% due to unaltered Igf-1 expression in stromavascular cells. The lack of IGF-I from adipocytes did not alter plasma IGF-I concentration. BFMI

The majority of patients undergoing endovascular stroke treatment (EST) in randomized controlled trials received additional systemic thrombolysis ("combination or bridging therapy (C/BT)"). Nevertheless, its usefulness in this subtype of acute ischemic stroke (AIS) is discussed controversially. Of all consecutive AIS patients, who received any kind of reperfusion therapy in a tertiary university stroke center between January 2015 and March 2016, those with large vessel occlusions (LVO) and EST with or without additional C/BT, were compared primarily regarding procedural aspects. Data were extracted from an investigator-initiated, single-center, prospective and blinded end-point study. 70 AIS patients with EST alone and 118 with C/BT were identified. Significant baseline differences existed in pre-existing cardiovascular disease (52.9% (EST alone) vs. 35.6% (C/BT), p = 0.023), use of anticoagulation (30.6% vs. 5.9%, p

Objective Intracellular vesicle trafficking maintains cellular structures and functions. The assembly of cargo-laden vesicles at the trans-Golgi network is initiated by the ARF family of small GTPases. Here, we demonstrate the role of the trans-Golgi localized monomeric GTPase ARFRP1 in endosomal-mediated vesicle trafficking of mature adipocytes. Methods Control (Arfrp1flox/flox) and inducible fat-specific Arfrp1 knockout (Arfrp1iAT−/−) mice were metabolically characterized. In vitro experiments on mature 3T3-L1 cells and primary mouse adipocytes were conducted to validate the impact of ARFRP1 on localization of adiponectin and the insulin receptor. Finally, secretion and transferrin-based uptake and recycling assays were performed with HeLa and HeLa M-C1 cells. Results We identified the ARFRP1-based sorting machinery to be involved in vesicle trafficking relying on the endosomal compartment for cell surface delivery. Secretion of adiponectin from fat depots was selectively reduced in Arfrp1iAT−/− mice, and Arfrp1-depleted 3T3-L1 adipocytes revealed an accumulation of adiponectin in Rab11-positive endosomes. Plasma adiponectin deficiency of Arfrp1iAT−/− mice resulted in deteriorated hepatic insulin sensitivity, increased gluconeogenesis and elevated fasting blood glucose levels. Additionally, the insulin receptor, undergoing endocytic recycling after ligand binding, was less abundant at the plasma membrane of adipocytes lacking Arfrp1. This had detrimental effects on adipose insulin signaling, followed by insufficient suppression of basal lipolytic activity and impaired adipose tissue expansion. Conclusions Our findings suggest that adiponectin secretion and insulin receptor surface targeting utilize the same post-Golgi trafficking pathways that are essential for an appropriate systemic insulin sensitivity and glucose homeostasis., Highlights • Trans-Golgi localized GTPase ARFRP1 regulates endosomal-mediated trafficking. • ARFRP1 maintains proper adiponectin secretion and insulin receptor surface targeting. • Adipocyte-specific loss of Arfrp1 impairs adipose and hepatic insulin sensitivity. • ARFRP1-based trafficking preserves adipose tissue mass and glucose homeostasis.

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.

Due to their extraordinarily broad differentiation potential and persistence during adulthood, adult neural crest-derived stem cells (NCSCs) are highly promising candidates for clinical applications, particularly when facing the challenging treatment of neurodegenerative diseases or complex craniofacial injuries. Successful application of human NCSCs in regenerative medicine and pharmaceutical research mainly relies on the availability of sufficient amounts of tissue for cell isolation procedures. Facing this challenge, we here describe for the first time a novel population of NCSCs within the middle turbinate of the human nasal cavity. From a surgical point of view, high amounts of tissue are routinely and easily removed during nasal biopsies. Investigating the presence of putative stem cells in obtained middle turbinate tissue by immunohistochemistry, we observed Nestin+/p75NTR+/S100+/α smooth muscle actin (αSMA)- cells, which we successfully isolated and cultivated in vitro. Cultivated middle turbinate stem cells (MTSCs) kept their expression of neural crest and stemness markers Nestin, p75 NTR and S100 and showed the capability of sphere formation and clonal growth, indicating their stem cell character. Application of directed in vitro differentiation assays resulted in successful differentiation of MTSCs into osteogenic and neuronal cell types. Regarding the high amount of tissue obtained during surgery as well as their broad differentiation capability, MTSCs seem to be a highly promising novel neural crest stem cell population for applications in cell replacement therapy and pharmacological research.

Hands, much like faces, convey social information, instructions and intentions to an observer. While the neural processes of face perception have been widely studied, it was only recently that fMRI identified occipito-temporal areas sensitive to static images of hands as body parts. To complement these studies with fine-grained timing information, we measured event-related EEG potentials (ERPs) from 33 subjects who were presented with static images of hands versus faces, whole bodies, and inanimate objects as controls. Already at N1 latency, ~ 170 ms, hand-related ERP patterns were manifest in two results: (1) significant differences in amplitudes for images of hands versus bodies in occipito-temporal N1 responses; (2) left lateralization of responses to images of hands, and also of the difference waveforms (hands minus bodies), quantifying hand-related responses. In line with fMRI studies of hand-sensitive areas distinct from extrastriate body area (EBA), the current findings provide electrophysiological evidence for hand-sensitive brain activation, occurring at a similarly early latency as N1 responses to faces.

Objective Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. Methods Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. Results Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. Conclusions Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling., Graphical abstract Image 1, Highlights • NAFLD patients have augmented plasma DPP4 activity. • Hepatocyte-specific DPP4 overexpression in mice.(1)promotes fatty liver disease.(2)induces hepatic insulin resistance.(3)reduces systemic levels of active GLP-1.(4)enhances adipose tissue expansion and inflammation.

Aims/hypothesis Fibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes. Methods Male NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints. Results FGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression. Conclusions/interpretation FGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4389-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.