Natalizumab: targeting alpha4-integrins in multiple sclerosis

In 1992, it was shown that monoclonal antibodies blocking alpha(4)-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As alpha(4)beta(1)-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-alpha(4)-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn's disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.

Gender differences in patients referred for atrial fibrillation management to a tertiary center

BACKGROUND: Atrial fibrillation (AF) ablation is less frequently performed in women than in men. Although the prevalence of AF is slightly higher in men, this does not fully account for the lower number of AF ablations performed in women. This study sought to examine the effect of gender on referral for AF and subsequent AF management. METHODS: Consecutive patients referred to our tertiary arrhythmia outpatient clinic for AF management were retrospectively analyzed. RESULTS: Of 264 patients referred, only 27% were women. Women were older than men (63 +/- 9 vs 58 +/- 11 years, P = 0.002), more often had paroxysmal AF (78% vs 63% in men, P = 0.022), and women more frequently complained about palpitations (71% vs 49%, P = 0.002). In addition, they had more often experienced amiodarone side effects than men (56% vs 36%, P = 0.046). In this referred population, there was no difference in the proportion of women and men undergoing AF ablation immediately following the initial evaluation (21% vs 25%, P = ns), at any time during the follow-up (38% vs 44%, P = ns), and there was no difference in the proportion of patients undergoing atrioventricular node ablation in both sexes (6% of women vs 3% of men, P = ns). CONCLUSIONS: There is an important difference in the proportion of men and women referred for management of AF in a specialized outpatient arrhythmia clinic, with women being referred three times less often than men. However, there is no gender-related difference in the subsequent treatment decisions. These findings emphasize the importance of focusing on management of symptomatic AF in women.

Erythropoietin enhances oxygenation in critically perfused tissue through modulation of nitric oxide synthase

The aim of this study was to investigate the effect of human recombinant erythropoietin (EPO) on the microcirculation and oxygenation of critically ischemic tissue and to elucidate the role of endothelial NO synthase in EPO-mediated tissue protection. Island flaps were dissected from the back skin of anesthetized male Syrian golden hamsters including a critically ischemic, hypoxic area that was perfused via a collateralized vasculature. Before ischemia, animals received an injection of epoetin beta at a dose of 5,000 U/kg body weight with (n = 7) or without (n = 7) blocking NO synthase by 30 mg/kg body weight L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride). Saline-treated animals served as control (n = 7). Ischemic tissue damage was characterized by severe hypoperfusion and inflammation, hypoxia, and accumulation of apoptotic cell nuclei after 5 h of collateralization. Erythropoietin pretreatment increased arteriolar and venular blood flow by 33% and 37%, respectively (P < 0.05), and attenuated leukocytic inflammation by approximately 75% (P < 0.05). Furthermore, partial tissue oxygen tension in the ischemic tissue increased from 8.2 to 15.8 mmHg (P < 0.05), which was paralleled by a 21% increased density of patent capillaries (P < 0.05) and a 50% reduced apoptotic cell count (P < 0.05). The improved microcirculation and oxygenation were associated with a 2.2-fold (P < 0.05) increase of endothelial NO synthase protein expression. Of interest, L-NAME completely abolished all the beneficial effects of EPO pretreatment. Our study demonstrates that, in critically ischemic and hypoxic collateralized tissue, EPO pretreatment improves tissue perfusion and oxygenation in vivo. This effect may be attributed to NO-dependent vasodilative effects and anti-inflammatory actions on the altered vascular endothelium.

Electroanatomic mapping of the endocardium. Implication for catheter ablation of ventricular tachycardia.

The electroanatomic mapping system Carto((R)) with its combination of anatomic and electrophysiologic information has substantially improved our understanding of arrhythmia mechanisms and substrates in patients with ventricular tachycardia (VT) and structural heart disease. Identification of the individual arrhythmogenic substrate and successful ablation guided by the combination of sinus rhythm voltage mapping and conventional electrophysiologic techniques like pace and activation/entrainment mapping are best described for patients with recurrent VT in remote myocardial infarction. In about 75-90% of the patients, the target VT can be ablated with acute success and the patients remain free of any VT recurrence in up to 75%. First results of electroanatomically guided ablation in patients with arrhythmogenic right ventricular dysplasia are promising. Data on ablation of VT in other structural heart diseases are very limited, since the arrhythmogenic substrate is very diffuse, e. g., in dilated cardiomyopathy, or there are only small patient numbers, e. g., for cardiac sarcoidosis or monomorphic VT after repair of congenital heart disease. In this article, the current status of electroanatomically guided endocardial mapping and ablation of VT in patients with structural heart disease is described.

The Effect of Open-Irrigated Radiofrequency Catheter Ablation of Atrial Fibrillation on Left Atrial Pressure and B-Type Natriuretic Peptide

Background Open-irrigated radiofrequency catheter ablation (oiRFA) of atrial fibrillation (AF) imposes a volume load and risk of pulmonary edema. We sought to assess the effect of volume administration during ablation on left atrial (LA) pressure and B-type natriuretic peptide (BNP). Methods LA pressure was measured via transseptal sheath at the beginning and end of 44 LA ablation procedures in 42 patients. BNP plasma levels were measured before and after 10 procedures. Results A median of 3,255 (interquartile range [IQR], 2,014)-mL saline was administered during the procedure. During LA ablation, the median fluid balance was +1,438 (IQR, 1,109) mL and LA pressure increased by median 3.7 (IQR, 5.9) mm Hg (P < 0.001). LA pressure did not change in the 19 procedures with furosemide administration (median ΔP = −0.3 [IQR, 7.1] mm Hg, P = 0.334). The correlation of LA pressure and fluid balance was weak (rs = 0.383, P = 0.021). BNP decreased in all four procedures starting in AF or atrial tachycardia and then converting to sinus rhythm (P = 0.068), and increased in all six procedures starting and finishing in sinus rhythm (P = 0.028). After ablation, symptomatic volume overload responding to diuresis occurred in three patients. Conclusions A substantial intravascular volume load during oiRFA can be absorbed with little change in LA pressure, such that LA pressure is not a reliable indicator of the fluid balance. Subsequent redistribution of the volume load imposes a risk after the procedure. Conversion to sinus rhythm may improve ability to acutely accommodate the volume load.

The evolution of host associations in the parasitic wasp genus Ichneumon (Hymenoptera: Ichneumonidae): convergent adaptations to host pupation sites

Background: The diversification of organisms with a parasitic lifestyle is often tightly linked to the evolution of their host associations. If a tight host association exists, closely related species tend to attack closely related hosts; host associations are less stable if associations are determined by more plastic traits like parasitoid searching and oviposition behaviour. The pupal-parasitoids of the genus Ichneumon attack a variety of macrolepidopteran hosts.They are either monophagous or polyphagous, and therefore offer a promissing system to investigate the evolution of host associations. Ichneumon was previously divided into two groups based on general body shape; however, a stout shape has been suggested as an adaptation to buried host pupation sites, and might thus not represent a reliable phylogenetic character. Results: We here reconstruct the first molecular phylogeny of the genus Ichneumon using two mitochondrial (CO1 and NADH1) and one nuclear marker (28S). The resulting phylogeny only supports monophyly of Ichneumon when Ichneumon lugens Gravenhorst, 1829 (formerly in Chasmias, stat. rev.) and Ichneumon deliratorius Linnaeus, 1758 (formerly Coelichneumon) are included. Neither parasitoid species that attack hosts belonging to one family nor those attacking butterflies (Rhopalocera) form monophyletic clades. Ancestral state reconstructions suggest multiple transitions between searching for hosts above versus below ground and between a stout versus elongated body shape. A model assuming correlated evolution between the two characters was preferred over independent evolution of host-searching niche and body shape. Conclusions: Host relations, both in terms of phylogeny and ecology, evolved at a high pace in the genus Ichneumon. Numerous switches between hosts of different lepidopteran families have occurred, a pattern that seems to be the rule among idiobiont parasitoids. A stout body and antennal shape in the parasitoid female is confirmed as an ecological adaptation to host pupation sites below ground and has evolved convergently several times. Morphological characters that might be involved in adaptation to hosts should be avoided as diagnostic characters for phylogeny and classification, as they can be expected to show high levels of homoplasy.

Impact of cardiac computed tomography of the interatrial septum before pulmonary vein isolation

BACKGROUND Multidetector computed tomography (MDCT) may be useful to identify patients with patent foramen ovale (PFO). The aim of this study was to analyze whether a MDCT performed before pulmonary vein isolation reliably detects a PFO that may be used for access to the left atrium. METHODS AND RESULTS In 79 consecutive patients, who were referred for catheter ablation of symptomatic paroxysmal or persistent atrial fibrillation (AF), the presence of a PFO was explored by MDCT and transesophageal echocardiography (TEE). TEE was considered as the gold standard, and quality of TEE was good in all patients. In 16 patients (20.3%), MDCT could not be used for analysis because of artifacts, mainly because of AF. On TEE, a PFO was found in 15 (23.8%) of the 63 patients with usable MDCT. MDCT detected six PFO of which four were present on TEE. This corresponded to a sensitivity of 26.7%, a specificity of 95.8%, a negative predictive value of 80.7%, and a positive predictive value of 66.7%. The receiver operating characteristics curve of MDCT for the detection of PFO was 0.613 (95% confidence interval 0.493-0.732). CONCLUSIONS MDCT may detect a PFO before pulmonary isolation. However, presence of AF may lead to artifacts on MDCT impeding a meaningful analysis. Furthermore, in this study sensitivity and positive predictive value of MDCT were low and therefore MDCT was not a reliable screening tool for detection of PFO.

River loads and modern denudation of the Alps — A review

This paper presents the first comprehensive analysis of sediment and dissolved load across an entire mountain range. We investigate patterns and rates of modern denudation of the European Alps based on a compilation of data about river loads and reservoir sedimentation from 202 drainage basins that are between ca. 1 to 10,000 km2 large. The study basins cover about 50% of the total area of the Alps. Modern glaciated basins have the highest sediment yields of up to 7000 t km− 2 a− 1, which are on average 5 to 10 times higher than in non-glaciated basins. Likewise sediment yield and glacial cover are positively correlated. Instead, relief is a relatively weak predictor of sediment yield. The strong glacial impact in the correlations is due to glacier recession since the 19th century as well as due to glacial conditioning during repeated Quaternary glaciations which have produced the strong transient state of the Alpine landscape. We suggest that this is the major cause for ca. 3 fold enhanced denudation of the western compared to the eastern Alps. Chemical denudation rates are highest in the external Alps dominated by carbonate sedimentary rocks, where they make up about one third of total denudation. The high rates cannot be explained without anhydrite dissolution. We estimated that only 45% of the sediments mobilized in headwaters are exported out off the Alps, most sediments being trapped in artificial reservoirs. The total amount of sediment annually trapped within the Alps equates to 43 Mt. When corrected for sediment storage, we obtain an area-weighted mean total denudation rate for the Alps of about 0.32 mm a− 1. The pre-dam rate might be as high as 0.42 mm a− 1. In total, ca. 35 plus 23 Mt of mass are exported each year out of the Alps as solids and solutes, respectively. These rates are not enough to out pace modern rock uplift. Nevertheless, pattern of sediment yield across the Alps coincides roughly with the intensity of glacial conditioning and modern rock uplift, supporting the hypothesis of an erosion-driven uplift of the Alps.

Neuroprotective effect of cathodal transcranial direct current stimulation in a rat stroke model

Experimental focal brain ischemia generates in the penumbra recurrent depolarizations which spread across the injured cortex inducing infarct growth. Transcranial direct current stimulation can induce a lasting, polarity-specific, modulation of cortical excitability. To verify whether cathodal transcranial direct current stimulation could reduce the infarct size and the number of depolarizations, focal ischemia was induced in the rat by the 3 vessels occlusion technique. In the first experiment 12 ischemic rats received cathodal stimulation (alternating 15min on and 15min off) starting 45min after middle cerebral artery occlusion and lasting 4h. In the second experiment 12 ischemic rats received cathodal transcranial direct current stimulation with the same protocol but starting soon after middle cerebral artery occlusion and lasting 6h. In both experiments controls were 12 ischemic rats not receiving stimulation. Cathodal stimulation reduced the infarct volume in the first experiment by 20% (p=0.002) and in the second by 30% (p=0.003). The area of cerebral infarction was smaller in animals receiving cathodal stimulation in both experiments (p=0.005). Cathodal stimulation reduced the number of depolarizations (p=0.023) and infarct volume correlated with the number of depolarizations (p=0.048). Our findings indicate that cathodal transcranial direct current stimulation exert a neuroprotective effect in the acute phase of stroke possibly decreasing the number of spreading depolarizations. These findings may have translational relevance and open a new avenue in neuroprotection of stroke in humans.

Timely Tenses: Considering Present Tense Narration

When the jury of the Man Booker Prize 2010 chose three novels for their short-list that were written in present tense they earned some harsh criticism. To some, like Philipp Pullman, present tense narration seemed to be no more than an annoying fad, “a silly affectation,” which he criticises as a limitation to narrative possibility.1 Nevertheless, present tense narration is spreading fast, not only among Booker Prize nominees and winners. Indeed, it has become so common that it hardly seems to draw much attention anymore. But what is the appeal of present tense narration to contemporary authors? What effect does the choice of present tense narration have on the ways stories are told and read? This paper will address and compare the use of present tense narration in recent British novels by authors such as Hilary Mantel (Wolf Hall, Bring up the Bodies), Ali Smith (Hotel World, The Accidental ), Tom McCarthy (C) and others, looking for similarities and differences in their respective narrative rationale. In view of the heterogeneous and complex use of present tense in contemporary fiction, I would like to suggest, merely pointing to the pace of contemporary life and the simultaneity of new communication media does not suffice to adequately address a phenomenon that has become a characteristic feature of 21st century narration. 1 Laura Roberts. “Philip Pullman and Philip Hensher criticise Booker Prize for including present tense novels.” The Telegraph. 11. Sept. 2010.

EChO

A dedicated mission to investigate exoplanetary atmospheres represents a major milestone in our quest to understand our place in the universe by placing our Solar System in context and by addressing the suitability of planets for the presence of life. EChO—the Exoplanet Characterisation Observatory—is a mission concept specifically geared for this purpose. EChO will provide simultaneous, multi-wavelength spectroscopic observations on a stable platform that will allow very long exposures. The use of passive cooling, few moving parts and well established technology gives a low-risk and potentially long-lived mission. EChO will build on observations by Hubble, Spitzer and ground-based telescopes, which discovered the first molecules and atoms in exoplanetary atmospheres. However, EChO’s configuration and specifications are designed to study a number of systems in a consistent manner that will eliminate the ambiguities affecting prior observations. EChO will simultaneously observe a broad enough spectral region—from the visible to the mid-infrared—to constrain from one single spectrum the temperature structure of the atmosphere, the abundances of the major carbon and oxygen bearing species, the expected photochemically-produced species and magnetospheric signatures. The spectral range and resolution are tailored to separate bands belonging to up to 30 molecules and retrieve the composition and temperature structure of planetary atmospheres. The target list for EChO includes planets ranging from Jupiter-sized with equilibrium temperatures T eq up to 2,000 K, to those of a few Earth masses, with T eq \u223c 300 K. The list will include planets with no Solar System analog, such as the recently discovered planets GJ1214b, whose density lies between that of terrestrial and gaseous planets, or the rocky-iron planet 55 Cnc e, with day-side temperature close to 3,000 K. As the number of detected exoplanets is growing rapidly each year, and the mass and radius of those detected steadily decreases, the target list will be constantly adjusted to include the most interesting systems. We have baselined a dispersive spectrograph design covering continuously the 0.4–16 μm spectral range in 6 channels (1 in the visible, 5 in the InfraRed), which allows the spectral resolution to be adapted from several tens to several hundreds, depending on the target brightness. The instrument will be mounted behind a 1.5 m class telescope, passively cooled to 50 K, with the instrument structure and optics passively cooled to \u223c45 K. EChO will be placed in a grand halo orbit around L2. This orbit, in combination with an optimised thermal shield design, provides a highly stable thermal environment and a high degree of visibility of the sky to observe repeatedly several tens of targets over the year. Both the baseline and alternative designs have been evaluated and no critical items with Technology Readiness Level (TRL) less than 4–5 have been identified. We have also undertaken a first-order cost and development plan analysis and find that EChO is easily compatible with the ESA M-class mission framework.

The development of self-esteem

In this article, we review new insights gained from recent longitudinal studies examining the development of self-esteem and its influence on important life outcomes. The evidence supports the following three conclusions. First, self-esteem increases from adolescence to middle adulthood, peaks at about age 50 to 60 years, and then decreases at an accelerating pace into old age; moreover, there are no cohort differences in the self-esteem trajectory from adolescence to old age. Second, self-esteem is a relatively stable, but by no means immutable, trait; individuals with relatively high (or low) self-esteem at one stage of life are likely to have relatively high (or low) self-esteem decades later. Third, high self-esteem prospectively predicts success and well-being in life domains such as relationships, work, and health. Given the increasing evidence that self-esteem has important real-world consequences, the topic of self-esteem development is of considerable societal significance.

Interhemispheric cerebral blood flow balance during recovery of motor hand function after ischemic stroke - a longitudinal MRI study using arterial spin labeling perfusion

BACKGROUND Unilateral ischemic stroke disrupts the well balanced interactions within bilateral cortical networks. Restitution of interhemispheric balance is thought to contribute to post-stroke recovery. Longitudinal measurements of cerebral blood flow (CBF) changes might act as surrogate marker for this process. OBJECTIVE To quantify longitudinal CBF changes using arterial spin labeling MRI (ASL) and interhemispheric balance within the cortical sensorimotor network and to assess their relationship with motor hand function recovery. METHODS Longitudinal CBF data were acquired in 23 patients at 3 and 9 months after cortical sensorimotor stroke and in 20 healthy controls using pulsed ASL. Recovery of grip force and manual dexterity was assessed with tasks requiring power and precision grips. Voxel-based analysis was performed to identify areas of significant CBF change. Region-of-interest analyses were used to quantify the interhemispheric balance across nodes of the cortical sensorimotor network. RESULTS Dexterity was more affected, and recovered at a slower pace than grip force. In patients with successful recovery of dexterous hand function, CBF decreased over time in the contralesional supplementary motor area, paralimbic anterior cingulate cortex and superior precuneus, and interhemispheric balance returned to healthy control levels. In contrast, patients with poor recovery presented with sustained hypoperfusion in the sensorimotor cortices encompassing the ischemic tissue, and CBF remained lateralized to the contralesional hemisphere. CONCLUSIONS Sustained perfusion imbalance within the cortical sensorimotor network, as measured with task-unrelated ASL, is associated with poor recovery of dexterous hand function after stroke. CBF at rest might be used to monitor recovery and gain prognostic information.

Die katholische Kirche und Moralpolitik in Österreich: Reformdynamiken in der Regulierung von Schwangerschaftsabbrüchen und der Anerkennung gleichgeschlechtlicher Partnerschaften

Eine vergleichende Analyse der Regulierung von Schwangerschaftsabbrüchen und gleichgeschlechtlichen Partnerschaften in Westeuropa im Zeitraum von 1960 bis 2010 zeigt, dass katholisch geprägte Staaten diese Bereiche grundsätzlich nicht weniger stark liberalisiert haben als andere Länder. Allerdings drosselt der Katholizismus offensichtlich die Geschwindigkeit von Reformprozessen. Auf Basis einer detaillierten explorativen Analyse der Politikentwicklungen in Österreich, das sehr früh die Gesetzgebung zum Schwangerschaftsabbruch lockerte, jedoch bei der Einführung registrierter homosexueller Partnerschaften lange zögerte, leiten wir induktiv theoretische Implikationen ab: Die katholische Kirche kann permissive Reformen so lange verhindern, wie institutionelle und kulturelle Gelegenheitsstrukturen nicht der säkular-liberalen Opposition behilflich sind, erfolgreiches Agenda-Setting zu betreiben und Mehrheiten für einen Politikwechsel zu gewinnen.