Niemann-Pick disease type C symptomatology: an expert-based clinical description

Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months–6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca®), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.

Eisströme und Schelfeise an der Küste der Amundsen See (West-Antarktis), beobachtet mit ERS-SAR /// Es stehen 2 Dateien zur Auswahl: pdf-Datei Abbildungen nur schwarz-weiss, zip-Datei Abbildungen farbig

In der vorliegenden Diplomarbeit erfolgte die Beobachtung von Eisströmen und Schelfeisen an der Küste der Amundsen See in der West-Antarktis, unter Verwendung von ERS-SAR-Amplitudenbildprodukten. Bestandteile dieser Beobachtung waren die Erstellung eines Gletscherinventares, die Erstellung von Multitemporalbildern, die Auswertung von Veränderungen der Eisfronpositionen und - schwerpunktmäßig - die Bestimmung von Eisfließgeschwindigkeiten und deren räumlicher und zeitlicher Vergleich.

Eye movement and diffusion tensor imaging analysis of treatment effects in a Niemann-Pick Type C patient

New treatment options for Niemann-Pick Type C (NPC) have recently become available. To assess the efficiency and efficacy of these new treatment markers for disease status and progression are needed. Both the diagnosis and the monitoring of disease progression are challenging and mostly rely on clinical impression and functional testing of horizontal eye movements. Diffusion tensor imaging (DTI) provides information about the microintegrity especially of white matter. We show here in a case report how DTI and measures derived from this imaging method can serve as adjunct quantitative markers for disease management in Niemann-Pick Type C. Two approaches are taken--first, we compare the fractional anisotropy (FA) in the white matter globally between a 29-year-old NPC patient and 18 healthy age-matched controls and show the remarkable difference in FA relatively early in the course of the disease. Second, a voxelwise comparison of FA values reveals where white matter integrity is compromised locally and demonstrate an individualized analysis of FA changes before and after 1year of treatment with Miglustat. This method might be useful in future treatment trials for NPC to assess treatment effects.

Editor's Pick

In this new column, which from now on shall appear at regular intervals, the editors of JIPITEC would like to present to their readers monographs that in their mind are either outstanding or are worth being mentioned and recommended to the interested reader. Each individual editor is responsible for his or her own choice and each text reflects personal interests and preferences rather than an editorial policy.

Exact Solutions to the Symmetric and Asymmetric Vehicle Routing Problem with Simultaneous Delivery and Pick-Up

In reverse logistics networks, products (e.g., bottles or containers) have to be transported from a depot to customer locations and, after use, from customer locations back to the depot. In order to operate economically beneficial, companies prefer a simultaneous delivery and pick-up service. The resulting Vehicle Routing Problem with Simultaneous Delivery and Pick-up (VRPSDP) is an operational problem, which has to be solved daily by many companies. We present two mixed-integer linear model formulations for the VRPSDP, namely a vehicle-flow and a commodity-flow model. In order to strengthen the models, domain-reducing preprocessing techniques, and effective cutting planes are outlined. Symmetric benchmark instances known from the literature as well as new asymmetric instances derived from real-world problems are solved to optimality using CPLEX 12.1.

rund und schwarz: Fotografien von Mike Niederhauser

Fotobuch anlässlich des Firmenjubiläums von Pneu Fahrni und der Ausstellung der Fotografien in der Zone Contemporaine, Niederwangen bei Bern

Scheduling the factory pick-up of new cars

Car manufacturers increasingly offer delivery programs for the factory pick-up of new cars. Such a program consists of a broad range of event-marketing activities. In this paper we investigate the problem of scheduling the delivery program activities of one day such that the sum of the customers’ waiting times is minimized. We show how to model this problem as a resource-constrained project scheduling problem with nonregular objective function, and we present a relaxation-based beam-search solution heuristic. The relaxations are solved by exploiting a duality relationship between temporal scheduling and min-cost network flow problems. This approach has been developed in cooperation with a German automaker. The performance of the heuristic has been evaluated based on practical and randomly generated test instances.

Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study.

STUDY QUESTION Does intrauterine application of diluted seminal plasma (SP) at the time of ovum pick-up improve the pregnancy rate by ≥14% in IVF treatment? SUMMARY ANSWER Intrauterine instillation of diluted SP at the time of ovum pick-up is unlikely to increase the pregnancy rate by ≥14% in IVF. WHAT IS KNOWN ALREADY SP modulates endometrial function, and sexual intercourse around the time of embryo transfer has been suggested to increase the likelihood of pregnancy. A previous randomized double-blind pilot study demonstrated a strong trend towards increased pregnancy rates following the intracervical application of undiluted SP. As this study was not conclusive and as the finding could have been confounded by sexual intercourse, the intrauterine application of diluted SP was investigated in the present trial. STUDY DESIGN, SIZE, DURATION A single-centre, prospective, double-blind, placebo-controlled, randomized, superiority trial on women undergoing IVF was conducted from April 2007 until February 2012 at the University Department of Gynaecological Endocrinology and Reproductive Medicine, Heidelberg, Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was powered to detect an 14% increase in the clinical pregnancy rate and two sequential tests were planned using the Pocock spending function. At the first interim analysis, 279 women had been randomly assigned to intrauterine diluted SP (20% SP in saline from the patients' partner) (n = 138) or placebo (n = 141) at the time of ovum pick-up. MAIN RESULTS AND THE ROLE OF CHANCE The clinical pregnancy rate per randomized patient was 37/138 (26.8%) in the SP group and 41/141 (29.1%) in the placebo group (difference: -2.3%, 95% confidence interval of the difference: -12.7 to +8.2%; P = 0.69). The live birth rate per randomized patient was 28/138 (20.3%) in the SP group and 33/141 (23.4%) in the placebo group (difference: -3.1%, 95% confidence interval of the difference: -12.7 to +6.6%; P = 0.56). It was decided to terminate the trial due to futility at the first interim analysis, at a conditional power of 62%. LIMITATIONS, REASONS FOR CAUTION The confidence interval of the difference remains wide, thus clinically relevant differences cannot reliably be excluded based on this single study. WIDER IMPLICATIONS OF THE FINDINGS The results of this study cast doubt on the validity of the concept that SP increases endometrial receptivity and thus implantation in humans. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the department's own research facilities. TRIAL REGISTRATION NUMBER DRKS00004615.

Festschrift Adolf Schwarz zum siebzigsten Geburtstage 15. Juli 1916 gewidmet von Freunden und Schülern

hrsg. von Samuel Krauss

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study

BackgroundNiemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort.MethodsClinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and period prevalence rates for neurological, psychiatric and visceral symptoms associated with NP-C disease. The NP-C suspicion index was calculated for the time of neurological disease onset and the time of diagnosis.ResultsThe shortest median diagnostic delay was noted for vertical supranuclear gaze palsy (2y). Ataxia, dysarthria, dysphagia, spasticity, cataplexy, seizures and cognitive decline displayed similar median diagnostic delays (4¿5y). The longest median diagnostic delay was associated with hepatosplenomegaly (15y). Highest period prevalence rates were noted for ataxia, dysarthria, vertical supranuclear gaze palsy and cognitive decline. The NP-C suspicion index revealed a median score of 81 points in nine patients at the time of neurological disease onset which is highly suspicious for NP-C disease. At the time of diagnosis, the score increased to 206 points.ConclusionA neurologic-psychiatric disease pattern represents the most characteristic clinical manifestation of NP-C and occurs early in the disease course. Visceral manifestation such as isolated hepatosplenomegaly often fails recognition and thus highlights the importance of a work-up for lysosomal storage disorders. The NP-C suspicion index emphasizes the importance of a multisystem evaluation, but seems to be weak in monosymptomatic and infantile NP-C patients.