Altered sphingoid base profiles in type 1 compared to type 2 diabetes

Background: Sphingolipids are increasingly recognized to play a role in insulin resistance and diabetes. Recently we reported significant elevations of 1-deoxysphingolipids (1-deoxySL) - an atypical class of sphingolipids in patients with metabolic syndrome (MetS) and diabetes type 2 (T2DM). It is unknown whether 1-deoxySL in patients with diabetes type 1 (T1DM) are similarly elevated. Findings: We analyzed the long chain base profile by LC-MS after hydrolyzing the N-acyl and O-linked headgroups in plasma from individuals with T1DM (N = 27), T2DM (N = 30) and healthy controls (N = 23). 1-deoxySLs were significantly higher in the groups with T2DM but not different between T1DM and controls. In contrast to patients with T2DM, 1-deoxSL levels are not elevated in T1DM. Conclusions: Our study indicates that the 1-deoxySL formation is not per-se caused by hyperglycemia but rather specifically associated with metabolic changes in T2DM, such as elevated triglyceride levels. Electronic supplementary material The online version of this article (doi:10.1186/1476-511X-13-161) contains supplementary material, which is available to authorized users

Metachromatic Leukodystrophy: A Case of Triplets With the Late Infantile Variant and a Systematic Review of the Literature

Metachromatic Leukodystrophy is a rare disorder with great clinical variability. We report the first case of triplets with the late infantile form of the disease and their systematic progression of symptoms. We reviewed the literature and identified all human studies that reported new cases since 1921. We analyzed survival by decade to assess the impact of historical changes in management of care. Mean age at death and 5-year survival from onset of symptoms for late infantile, juvenile and adult phenotype were 4.2 years and 24.9%, 17.4 years and 70.3%, and 43.1 years and 88.6% respectively. 5-year survival of cases reported after 1990 was significantly better than cases reported before 1970 in all subtypes of metachromatic leukodystrophy (late infantile: 52% vs. 14%, juvenile: 100% vs. 46%, adult: 95% vs. 67%). Survival in the late infantile subtype was worse than in other subtypes. Survival significantly improved over time in all subtypes

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints

CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

Mutations in the colony stimulating factor 1 receptor

Approach for Predicting Production Scenarios Focused on Cross Impact Analysis

AbstractOne of the most consistent challenges in business is anticipating what the future holds and what impact it may have on current production systems. The scenario technique is a well-established method for developing and forecasting multiple future development paths for companies. However, this method is mostly employed to develop and to support strategic long-term decisions. The core idea of the approach introduced in this paper is to convey the future impact of today's decisions on production systems to employees involved in production planning processes. With the help of immersive visualization, performed in virtual reality (VR) systems, planning participants can perceive how the factory must adapt to fit future demands.In this paper, the focus is on the fourth phase of the scenario technique – so called scenario development – and, in particular, the cross impact analysis. With this methodology, the interrelations, or cross impacts of the different basic elements are determined. The cross impact analysis results serve as a basis for the development of a standardized tool that can be used to create probable production scenarios out of given production systems. This standardized tool will facilitate the usage of the scenario technique for factory planning projects, as it focuses the immense diversity of future uncertainties companies are faced with on the factory level

Ser/Thr/Tyr Protein Phosphorylation in the Archaeon Halobacterium salinarum—A Representative of the Third Domain of Life

In the quest for the origin and evolution of protein phosphorylation, the major regulatory post-translational modification in eukaryotes, the members of archaea, the “third domain of life”, play a protagonistic role. A plethora of studies have demonstrated that archaeal proteins are subject to post-translational modification by covalent phosphorylation, but little is known concerning the identities of the proteins affected, the impact on their functionality, the physiological roles of archaeal protein phosphorylation/dephosphorylation, and the protein kinases/phosphatases involved. These limited studies led to the initial hypothesis that archaea, similarly to other prokaryotes, use mainly histidine/aspartate phosphorylation, in their two-component systems representing a paradigm of prokaryotic signal transduction, while eukaryotes mostly use Ser/Thr/Tyr phosphorylation for creating highly sophisticated regulatory networks. In antithesis to the above hypothesis, several studies showed that Ser/Thr/Tyr phosphorylation is also common in the bacterial cell, and here we present the first genome-wide phosphoproteomic analysis of the model organism of archaea, Halobacterium salinarum, proving the existence/conservation of Ser/Thr/Tyr phosphorylation in the “third domain” of life, allowing a better understanding of the origin and evolution of the so-called “Nature's premier” mechanism for regulating the functional properties of proteins

Inelastic Photoproduction of J/Psi Mesons at HERA

An analysis of inelastic photoproduction of J/Psi mesons is presented using data collected at the ep collider HERA corresponding to an integrated luminosity of above 80pb-1. Differential and double differential cross sections are measured in a wide kinematic region: 60<W_gammap<260 GeV, 1<p_t^2< 60 GeV^2 and 0.05<z<0.9, where z is the fraction of the energy of the exchanged photon transferred to the J/Psi meson in the rest frame of the target proton. Cross sections at z<0.3 are presented for the first time. Theoretical calculations within the Colour Singlet Model at NLO for direct photon processes are shown to give a good description of the data in the medium z region (0.3<z<0.9) up to the highest p_t^2 values. A calculation using a k_t factorisation approach in LO in the Colour Singlet Model is also able to describe these data. The data in the full z range are also compared to LO calculations within a non-relativistic QCD framework including color octet and colour singlet contributions for direct and resolved photons. It seems possible to reconcile data and theory with modest contributions from colour octet processes. The polarisation of the J/Psi meson is measured as a function of z and p_t,psi and is reasonably described by the theoretical predictions.Comment: 30 pages, 11 figures, 11 table

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs

Clinical and radiographic course of arrested cerebral adrenoleukodystrophy

OBJECTIVE: To gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing. METHODS: We retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7-17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)- subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed. RESULTS: Cerebral lesions were first detected at a median age of 23.3 years (8.0-67.6 years) with an initial LS of 4 (0.5-9). NFS was 0.5 (0-6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE- converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression (rs = 0.559, p < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%. CONCLUSION: Arrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD