Myelination in the absence of UDP-galactose:ceramide galactosyl-transferase and fatty acid 2 -hydroxylase

<p>Abstract</p> <p>Background</p> <p>The sphingolipids galactosylceramide (GalCer) and sulfatide are major myelin components and are thought to play important roles in myelin function. The importance of GalCer and sulfatide has been validated using UDP-galactose:ceramide galactosyltransferase-deficient (<it>Cgt</it>^-/-) mice, which are impaired in myelin maintenance. These mice, however, are still able to form compact myelin. Loss of GalCer and sulfatide in these mice is accompanied by up-regulation of 2-hydroxylated fatty acid containing (HFA)-glucosylceramide in myelin. This was interpreted as a partial compensation of the loss of HFA-GalCer, which may prevent a more severe myelin phenotype. In order to test this hypothesis, we have generated <it>Cgt</it>^-/-mice with an additional deletion of the fatty acid 2-hydroxylase (<it>Fa2h</it>) gene.</p> <p>Results</p> <p><it>Fa2h</it>^-/-/Cgt^-/-double-deficient mice lack sulfatide, GalCer, and in addition HFA-GlcCer and sphingomyelin. Interestingly, compared to <it>Cgt</it>^-/-mice the amount of GlcCer in CNS myelin was strongly reduced in <it>Fa2h</it>^-/-/<it>Cgt</it>^-/-mice by more than 80%. This was accompanied by a significant increase in sphingomyelin, which was the predominant sphingolipid in <it>Fa2h</it>^-/-/<it>Cgt</it>^-/-mice. Despite these significant changes in myelin sphingolipids, compact myelin was formed in <it>Fa2h</it>^-/-/<it>Cgt</it>^-/-mice, and g-ratios of myelinated axons in the spinal cord of 4-week-old <it>Fa2h</it>^-/-/<it>Cgt</it>^-/-mice did not differ significantly from that of <it>Cgt</it>^-/-mice, and there was no obvious phenotypic difference between <it>Fa2h</it>^-/-/<it>Cgt</it>^-/-and <it>Cgt</it>^-/-mice</p> <p>Conclusions</p> <p>These data show that compact myelin can be formed with non-hydroxylated sphingomyelin as the predominant sphingolipid and suggest that the presence of HFA-GlcCer and HFA-sphingomyelin in <it>Cgt</it>^-/-mice does not functionally compensate the loss of HFA-GalCer.</p

Estimating errors reliably in Monte Carlo simulations of the Ehrenfest model

Using the Ehrenfest urn model we illustrate the subtleties of error estimation in Monte Carlo simulations. We discuss how the smooth results of correlated sampling in Markov chains can fool one's perception of the accuracy of the data, and show (via numerical and analytical methods) how to obtain reliable error estimates from correlated samples

Self-consistent ladder DΓ\GammaA approach

We present and implement a self-consistent D$\Gamma$A approach for multi-orbital models and ab initio materials calculations. It is applied to the one-band Hubbard model at various interaction strengths with and without doping, to the two-band Hubbard model with two largely different bandwidths, and to SrVO$_3$. The self-energy feedback reduces critical temperatures compared to dynamical mean-field theory, even to zero temperature in two-dimensions. Compared to a one-shot, non-self-consistent calculation the non-local correlations are significantly reduced when they are strong. In case non-local correlations are weak to moderate as for SrVO$_3$, one-shot calculations are sufficient.Comment: 21 Pages, 20 Figure

Murine Whole-Organ Immune Cell Populations Revealed by Multi-epitope-Ligand Cartography

Multi-epitope-ligand cartography (MELC) is an innovative high-throughput fluorescence microscopy–based method. A tissue section is analyzed through a repeated cycling of (1) incubation with a fluorophore-labeled antibody, (2) fluorescence imaging, and (3) soft bleaching. This method allows staining of the same tissue section with up to 100 fluorescent markers and to analyze their toponomic expression using further image processing and pixel-precise overlay of the corresponding images. In this study, we adapted this method to identify a large panel of murine leukocyte subpopulations in a whole frozen section of a peripheral lymph node. Using the resulting antibody library, we examined non-inflamed versus inflamed tissues of brain and spinal cord in the experimental autoimmune encephalomyelitis (EAE) model. The presence and activity of specific leukocyte subpopulations (different T cell subpopulations, dendritic cells, macrophages, etc.) could be assessed and the cellular localizations and the corresponding activation status in situ were investigated. The results were then correlated with quantitative RT-PCR

HiatoGast 1: an exploring, semiblinded trial establishing a new endoscopical categorisation of axial hiatal hernias

Introduction Axial hiatal hernias are a common incidental finding in endoscopical examinations, but reflux symptoms do not necessarily correspond to the presence of hiatal hernias. Diagnosing a reflux disease is difficult due to a leak of existing distinct criteria, especially in order to evaluate a surgical indication. Also a preoperative measurement of the hernia is necessary to choose between surgical options. Methods and analysis We planned a semiblinded trial including a questionnaire and an oesophagogastroduodenoscopy afterwards. While the endoscopy is done, the hiatus oesophagi should be measured in inversion technique under maximum insufflation including length, width and herniated volume. A sample of 210 participants until December 2020 is determined to evaluate the primary endpoint: we look forward to evaluate the anatomical parameters of reflux and non-reflux participants. Ethics and Dissemination The study has been approved by the local ethics committee on 12th February 2019, the data will bei published after closure of inclusion. Trial registration number German Clinical Trials Register (DRKS00016863)

Effect of pitchfork bifurcations on the spectral statistics of Hamiltonian systems

We present a quantitative semiclassical treatment of the effects of bifurcations on the spectral rigidity and the spectral form factor of a Hamiltonian quantum system defined by two coupled quartic oscillators, which on the classical level exhibits mixed phase space dynamics. We show that the signature of a pitchfork bifurcation is two-fold: Beside the known effect of an enhanced periodic orbit contribution due to its peculiar $\hbar$-dependence at the bifurcation, we demonstrate that the orbit pair born {\em at} the bifurcation gives rise to distinct deviations from universality slightly {\em above} the bifurcation. This requires a semiclassical treatment beyond the so-called diagonal approximation. Our semiclassical predictions for both the coarse-grained density of states and the spectral rigidity, are in excellent agreement with corresponding quantum-mechanical results.Comment: LaTex, 25 pp., 14 Figures (26 *.eps files); final version 3, to be published in Journal of Physics

Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study):An Open, Interventional, Investigator-Initiated, International Multicenter Study

Objectives: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. Materials and Methods: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. Results: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. Conclusions: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03386058.</p

Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study):An Open, Interventional, Investigator-Initiated, International Multicenter Study

Objectives: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. Materials and Methods: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. Results: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. Conclusions: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03386058.</p

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation – Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study

Purpose Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients. Methods In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire). Results The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership. Conclusions Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments