Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia

Evaluierung der Auswirkungen von klein- und großflächigen Leuchten auf die Melatoninsuppression als Maß für nicht-visuelle Wirkungen von Licht

Seit der Entdeckung des ipRGC Rezeptors gilt dem Forschungsgebiet nicht-visuelle (eng. non-imageforming, NIF) Wirkung von Licht neue Aufmerksamkeit. “Nicht-visuell” bedeutet, dass ein Fehlen des ipRGC (engl. intrinsically photosensitive retinal ganglion cells) Rezeptors keine Auswirkung auf das Sehen des Menschen hätte, jedoch wären Auswirkungen auf den circadianen Rhythmus des Menschen zu beobachten. Der ipRGC Rezeptor ist eine fotosensitive Ganglienzelle und mit nur weniger als 5% aller Ganglienzellen auf der Netzhaut des Auges verteilt. Der Rezeptor enthält das Photopigment Melanopsin. Wird der Rezeptor angeregt, so kann nachts die Ausschüttung des Hormons Melatonin durch die Zirbeldrüse gehemmt werden. Melatonin wird zunehmend im Laufe der Abendstunden und während der Nacht ausgeschüttet. Mit einer angepassten Beleuchtung könnte der circadiane Rhythmus eines Menschen unterstützt werden. Zur Untersuchung des Einflusses der Größe der Lichtquelle auf die Melatoninunterdrückung wurde im Jahr 2013 von Philipp Novotny et al. eine Probandenstudie mit 30 Versuchsteilnehmern durchgeführt. Diese wurden mit zwei unterschiedlich großen Flächen beleuchtet, um zu erforschen ob die Melatoninunterdrückung flächenabhängig ist. Der Melatoninspiegel wurde mittels Salivaproben untersucht. Bereits 2010 führte Philipp Novotny et al. dieselbe Probandenstudie mit 6 Versuchsteilnehmern durch. Die Auswertung der Studiendaten ergaben einen Trend, dass eine große Fläche die Melatoninausschüttung unter den verwendeten Versuchsbedingungen mehr unterdrücken könnte. Mittels einer größeren Teilnehmerzahl sollte dies 2013 wiederholt überprüft werden, jedoch wurden die Ergebnisse bisher noch nicht veröffentlicht. Dieser Beitrag stellt die ermittelten Ergebnisse von Novotny et al.s zweiter Studie vor, analysiert diese und berücksichtigt zusätzliche Faktoren wie z.B. den Einfallswinkel des Lichts in die Augen des Betrachters. Zur Charakterisierung der Lichtbedingungen und Beschreibung des Stimulus für nichtvisuelle Effekte wurde der Aufbau von Novotny et al.s Studie in einem LED Testraum am Fachgebiet Lichttechnik der Technischen Universität Berlin rekonstruiert. Hierbei soll eine fundierte Aussage über die Wirkung unterschiedlich großer Flächen getroffen werden

Valve hemodynamic performance and myocardial strain after implantation of a third-generation, balloon-expandable, transcatheter aortic valve

Background: Left ventricular (LV) mechanics are impaired in patients with severe aortic stenosis (AS); however, transcatheter aortic valve implantation (TAVI) may positively affect LV mechanics. Assessed herein is the performance of the SAPIEN 3 transcatheter heart valve (THV) and the effect of TAVI on LV function recovery, as assessed by global longitudinal strain (GLS). Methods: A subset of patients from the SOURCE 3 registry (n = 276) from 16 European centers received SAPIEN 3 balloon-expandable THV. Echocardiography was performed at baseline, postprocedure, and at 1 year, including assessment of GLS using standard two-dimensional images, and was analyzed in a core laboratory. Paired analyses between baseline and discharge, baseline and at 1 year were conducted. Results: Hemodynamic parameters were improved after TAVI and sustained to 1 year. At 1 year, the rate of moderate to severe paravalvular leaks (PVL), and moderate to severe mitral and tricuspid regurgitations were 1.8%, 1.7%, and 8.0%, respectively. The discharge GLS (–15.6 ± 5.1; p = 0.004; n = 149) improved significantly from baseline (–15.1 ± 4.8) following TAVI. This improvement was sustained at 1 year compared with baseline (–17.0 ± 4.6, p < 0.001; n = 100). Conversely, LV ejection fraction (LVEF) did not significantly change following TAVI (p = 0.47). Conclusions: Following TAVI with a third-generation THV, valve performances were good at 1 year with low PVL rate. The LV mechanics improved immediately after the procedure and were maintained at 1 year. These findings demonstrate the benefit of TAVI on LV mechanics, and suggests that GLS may be superior to LVEF in assessing this benefit. Clinicaltrial.gov number: NCT0269895

Brain connectivity alterations in early psychosis: from clinical to neuroimaging staging.

Early in the course of psychosis, alterations in brain connectivity accompany the emergence of psychiatric symptoms and cognitive impairments, including processing speed. The clinical-staging model is a refined form of diagnosis that places the patient along a continuum of illness conditions, which allows stage-specific interventions with the potential of improving patient care and outcome. This cross-sectional study investigates brain connectivity features that characterize the clinical stages following a first psychotic episode. Structural brain networks were derived from diffusion-weighted MRI for 71 early-psychosis patients and 76 healthy controls. Patients were classified into stage II (first-episode), IIIa (incomplete remission), IIIb (one relapse), and IIIc (two or more relapses), according to the course of the illness until the time of scanning. Brain connectivity measures and diffusion parameters (fractional anisotropy, apparent diffusion coefficient) were investigated using general linear models and sparse linear discriminant analysis (sLDA), studying distinct subgroups of patients who were at specific stages of early psychosis. We found that brain connectivity impairments were more severe in clinical stages following the first-psychosis episode (stages IIIa, IIIb, IIIc) than in first-episode psychosis (stage II) patients. These alterations were spatially diffuse but converged on a set of vulnerable regions, whose inter-connectivity selectively correlated with processing speed in patients and controls. The sLDA suggested that relapsing-remitting (stages IIIb, IIIc) and non-remitting (stage IIIa) patients are characterized by distinct dysconnectivity profiles. Our results indicate that neuroimaging markers of brain dysconnectivity in early psychosis may reflect the heterogeneity of the illness and provide a connectomics signature of the clinical-staging model

Intermittent Surface Oxygenation Results in Similar Mitochondrial Protection and Maintenance of Aerobic Metabolism as Compared to Continuous Oxygenation during Hypothermic Machine Kidney Machine Perfusion

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation ( = 12); (2) 22-h HMP + continuous membrane oxygenation ( = 6); and (3) 22-h HMP + continuous surface oxygenation ( = 7). Brief perfusate O uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport

Surveillance of high-risk early postsurgical patients for real-time detection of complications using wireless monitoring (SHEPHERD study):results of a randomized multicenter stepped wedge cluster trial

Background: Vital signs measurements on the ward are performed intermittently. This could lead to failure to rapidly detect patients with deteriorating vital signs and worsens long-term outcome. The aim of this study was to test the hypothesis that continuous wireless monitoring of vital signs on the postsurgical ward improves patient outcome. Methods: In this prospective, multicenter, stepped-wedge cluster randomized study, patients in the control group received standard monitoring. The intervention group received continuous wireless monitoring of heart rate, respiratory rate and temperature on top of standard care. Automated alerts indicating vital signs deviation from baseline were sent to ward nurses, triggering the calculation of a full early warning score followed. The primary outcome was the occurrence of new disability three months after surgery. Results: The study was terminated early (at 57% inclusion) due to COVID-19 restrictions. Therefore, only descriptive statistics are presented. A total of 747 patients were enrolled in this study and eligible for statistical analyses, 517 patients in the control group and 230 patients in the intervention group, the latter only from one hospital. New disability at three months after surgery occurred in 43.7% in the control group and in 39.1% in the intervention group (absolute difference 4.6%). Conclusion: This is the largest randomized controlled trial investigating continuous wireless monitoring in postoperative patients. While patients in the intervention group seemed to experience less (new) disability than patients in the control group, results remain inconclusive with regard to postoperative patient outcome due to premature study termination. Clinical trial registration: ClinicalTrials.gov, ID: NCT02957825.</p

N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial

Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSHmPFC) as measured by (1)H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group x time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSHmPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients

Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

Recent studies have shown that cannabis may disrupt glutamate (Glu) signaling depressing Glu tone in frequent users. Current evidence have also consistently reported lower Glu-levels in various brain regions, particularly in the medial prefrontal cortex (mPFC) of chronic schizophrenia patients, while findings in early psychosis (EP) are not conclusive. Since cannabis may alter Glu synaptic plasticity and its use is a known risk factor for psychosis, studies focusing on Glu signaling in EP with or without a concomitant cannabis-usage seem crucial

Effect of ABCG2, OCT1, and ABCB1(MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial

Introduction Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R