Real-life long-term effectiveness of fingolimod in Swiss patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naïve prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naïve and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

[Historical development of drug testing in Swiss equestrian sports]. / Geschichtliche Entwicklung und Analyse der Medikationskontrollen im Schweizer Pferdesport.

INTRODUCTION: The goal of this study was to describe the development of equine drug testing in horses in Switzerland. This was achieved through evaluation of a film made by the Institute of Forensic Medicine at the University of Basel entitled 'Doping von Rennpferden' [Doping of Race Horses], toxicological detection, 1962', the analysis of doping test results of the Swiss Equestrian Federation and by interviewing individuals of various professions who were involved in equine drug testing at the time. The study compares early and modern methods of drug testing and highlights the changes in the attitude of equestrian athletes, horse owners and the general public toward doping in equestrian sports. The high sensitivity of modern analytical methods allows the detection of drugs at levels considerably below therapeutic concentrations. This has resulted in a shift from zero tolerance for Controlled Medication Substances to the establishment of sub-therapeutic threshold concentrations. The lists of performance-enhancing drugs used in doping are updated continually. It became clear from this work that in the early 1960s, Switzerland played a leadership role in anti-doping in equestrian sports, and that the efforts to keep the sport free of performance-enhancing drugs remain exemplary.

INTRODUCTION: Le but du présent travail était d'étudier les débuts des contrôles de médication dans le sport équestre suisse. Il comprend l'analyse du film "Dopage de chevaux de course, mise en évidence toxicologique", un film de 1962 de l'Institut médico-légal de Bâle, une enquête auprès de témoins de l'époque provenant de divers milieux et l'exploitation des résultats des analyses de dopage de la Fédération Suisse des Sports Equestres (FSSE). Ces recherchent montrent comment les contrôles antidopage étaient effectués à l'époque en comparaison à aujourd'hui et comment le positionnement des cavaliers, des propriétaires et de la population en général sur cette question s'est modifiée au cours des années. Vu la très haute sensibilité des méthodes d'analyse utilisées actuellement, de nombreuses substances peuvent être aujourd'hui détectées dans des concentrations sans effet pharmacologique. Cela a conduit pour les médicaments contrôlés (Controlled Medication Substances) a une tendance à l'abandon de la "tolérance zéro" et à l'utilisation de valeurs-limites sans effet thérapeutique. Les listes des substances dopantes sont continuellement mises à jour. Les résultats de cette étude montrent que la Suisse, au début des années soixante, a joué un rôle de précurseur dans le contrôle de médication dans les sports équestres et que ses efforts pour le maintien d'un sport équestre propre restent exemplaires aujourd'hui.

Vertical perturbations of human gait: organisation and adaptation of leg muscle responses.

During the last several years, evidence has arisen that the neuronal control of human locomotion depends on feedback from load receptors. The aim of the present study was to determine the effects and the course of sudden and unexpected changes in body load (vertical perturbations) on leg muscle activity patterns during walking on a treadmill. Twenty-two healthy subjects walking with 25% body weight support (BWS) were repetitively and randomly loaded to 5% or unloaded to 45% BWS during left mid-stance. At the new level of BWS, the subjects performed 3-11 steps before returning to 25% BWS (base level). EMG activity of upper and lower leg muscles was recorded from both sides. The bilateral leg muscle activity pattern changed following perturbations in the lower leg muscles and the net effect of the vertical perturbations showed onset latencies with a range of 90-105 ms. Body loading enhanced while unloading diminished the magnitude of ipsilateral extensor EMG amplitude, compared to walking at base level. Contralateral leg flexor burst activity was shortened following loading and prolonged following unloading perturbation while flexor EMG amplitude was unchanged. A general decrease in EMG amplitudes occurred during the course of the experiment. This is assumed to be due to adaptation. Only the muscles directly activated by the perturbations did not significantly change EMG amplitude. This is assumed to be due to the required compensation of the perturbations by polysynaptic spinal reflexes released following the perturbations. The findings underline the importance of load receptor input for the control of locomotion.

praja2 regulates KSR1 stability and mitogenic signaling.

The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency.

Sleep ability mediates individual differences in the vulnerability to sleep loss: evidence from a PER3 polymorphism.

Sleep deprivation is highly prevalent in our 24/7 society with harmful consequences on daytime functioning on the individual level. Genetically determined, trait-like vulnerability contributes to prominent inter-individual variability in the behavioral responses to sleep loss and adverse circadian phase. We aimed at investigating the effects of differential sleep pressure levels (high vs low) on the circadian modulation of neurobehavioral performance, sleepiness correlates, and nap sleep in individuals genotyped for a polymorphism in the clock gene PERIOD3. Fourteen homozygous long (PER3(5/5)) and 15 homozygous short (PER3(4/4)) allele carriers underwent both a 40-h sleep deprivation and multiple nap protocol under controlled laboratory conditions. We compared genotypes regarding subjective and ocular correlates of sleepiness, unintentional sleep episodes as well as psychomotor vigilance during both protocols. Nap sleep was monitored by polysomnography and visually scored according to standard criteria. The detrimental effects of high sleep pressure on sleepiness correlates and psychomotor vigilance were more pronounced in PER3(5/5) than PER3(4/4) carriers. Under low sleep pressure, both groups showed similar circadian time courses. Concomitantly, nap sleep efficiency and subjective sleep quality across all naps tended to be higher in the more vulnerable PER3(5/5) carriers. In addition, PER3-dependent sleep-loss-related attentional lapses were mediated by sleep efficiency across the circadian cycle. Our data corroborate a greater detrimental impact of sleep deprivation in PER3(5/5) compared to PER3(4/4) carriers. They further suggest that the group with greater attentional performance impairment due to sleep deprivation (PER3(5/5) carriers) is superior at initiating sleep over the 24-h cycle. This higher sleep ability may mirror a faster sleep pressure build-up between the multiple sleep opportunities and thus a greater flexibility in sleep initiation. Finally, our data show that this higher nap sleep efficiency is positively related to attentional failures under sleep loss conditions and might thus be used as a marker for inter-individual vulnerability to elevated sleep pressure.

Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation.

BACKGROUND AND PURPOSE: Prolonged wakefulness impairs sustained vigilant attention, measured with the psychomotor vigilance task (PVT), and induces a compensatory increase in sleep intensity in recovery sleep, quantified by slow-wave activity (SWA) in the sleep electroencephalogram (EEG). These effects of sleep deprivation are counteracted by the adenosine receptor antagonist caffeine, implying involvement of the adenosine neuromodulator/receptor system. To examine a role for adenosine A(2A) receptors, we investigated whether variation of the A(2A) receptor gene (ADORA2A) modified effects of caffeine on PVT and SWA after sleep deprivation. EXPERIMENTAL APPROACH: A haplotype analysis of eight single-nucleotide polymorphisms of ADORA2A was performed in 82 volunteers. In 45 young men carrying five different allele combinations, we investigated the effects of prolonged waking and 2 × 200 mg caffeine or 2 × 100 mg modafinil on psychomotor vigilance, sleepiness, and the waking and sleep EEG. KEY RESULTS: Throughout extended wakefulness, the carriers of haplotype HT4 performed faster on the PVT than carriers of non-HT4 haplotype alleles. In haplotype HT4, caffeine failed to counteract the waking-induced impairment of PVT performance and the rebound of SWA in recovery sleep. However, caffeine was effective in non-HT4 allele carriers, and modafinil reduced the consequences of prolonged waking, independently of ADORA2A haplotype. CONCLUSIONS AND IMPLICATIONS: Common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in rested and sleep-deprived state. It also modulates individual responses to caffeine after sleep deprivation. These findings demonstrate a role for adenosine A(2A) receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.

Signal transmission in exocrine cells is associated with rapid activity changes of acyltransferases and diacylglycerol kinase due to reversible protein phosphorylation.

Stimulation of secretion in guinea pig parotid gland lobules by either isoproterenol or carbachol is associated with a removal of acyl groups from the acyl-CoA pool and their incorporation into diacylglycerols and triglycerides (Söling, H. D., Machado-De Domenech, E., Kleineke, J., and Fest, W. (1987) J. Biol. Chem. 262, 16786-16792). This is associated with an increased incorporation of glycerol into diacylglycerol. These changes occur during the first 20-30 s of stimulation. We can show now that these changes are associated with a significant increase in the activities of lysophosphatidate acyltransferase, diacylglycerol kinase, and diacylglycerol acyltransferase which reaches a maximum during the first 60 s after stimulation. In vitro experiments with isolated parotid microsomes, the catalytic subunit of cAMP-dependent or Ca2+/calmodulin-dependent protein kinase, and with purified protein phosphatases indicate that the activation of enzyme activities in intact parotid gland cells results from protein phosphorylation. The two protein kinases seem to activate the three enzymes by phosphorylating the same site(s). Protein kinase C was almost ineffective. Glycerol kinase, glycerolphosphate acyltransferase, phosphatidate phosphohydrolase, CTP:phosphatidate cytidylyltransferase, and phosphatidylinositol synthase remained unchanged in the intact cell as well as during incubation with protein kinases in vitro. Lysophosphatidate acyltransferase, diacylglycerol kinase, and diacylglycerol acyltransferase can be activated by the two protein kinases also in microsomes from guinea pig cerebellum. It seems, therefore, that the regulation leading to rapid changes of enzyme activities during signal transmission in parotid acinar cells could be operative also in other cell types.

Morphological and molecular differentiation of invasive freshwater species of the genus Corbicula (Bivalvia, corbiculidea) suggest the presence of three taxa in French rivers.

Asiatic Clams are common in brackish and fresh water in Asia, and they were introduced into North America in 1924 and have now spread throughout the continent. During the last two decades they have been reported in Europe, but the number of species here is uncertain. Populations of Corbicula from France and the Netherlands were analysed morphologically and genetically to quantify the degree of species and/or population differentiation. The morphological and genetic data, based on allozymes and mitochondrial sequences, were in full agreement. They indicate that there are two distinct species, identified as C. fluminalis and C. fluminea, in the two countries. Analyses of the mitochondrial COI gene revealed an unexpected divergent population of Corbicula in the Rhône. All these individuals were morphologically identified as C. fluminea, but had a COI sequence different from the two previous species. This population may, therefore, be a more ancient population, or a distinct species introduced via a different colonization route.