Identification and characterization of a new ensemble of cometary organic molecules.

In-situ study of comet 1P/Halley during its 1986 apparition revealed a surprising abundance of organic coma species. It remained unclear, whether or not these species originated from polymeric matter. Now, high-resolution mass-spectrometric data collected at comet 67P/Churyumov-Gerasimenko by ESA's Rosetta mission unveil the chemical structure of complex cometary organics. Here, we identify an ensemble of individual molecules with masses up to 140 Da while demonstrating inconsistency of the data with relevant amounts of polymeric matter. The ensemble has an average composition of C1H1.56O0.134N0.046S0.017, identical to meteoritic soluble organic matter, and includes a plethora of chain-based, cyclic, and aromatic hydrocarbons at an approximate ratio of 6:3:1. Its compositional and structural properties, except for the H/C ratio, resemble those of other Solar System reservoirs of organics-from organic material in the Saturnian ring rain to meteoritic soluble and insoluble organic matter -, which is compatible with a shared prestellar history.

Perceived neuropsychological impairment inversely related to self-reported health and employment in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients frequently report cognitive difficulties which impact daily functioning. The objective was to investigate the relationship between patient-reported cognitive impairment and depression, demographic and MS-related variables, and to clarify its impact on self-reported health measures and employment. METHOD: A large two-centre survey included the MS Neuropsychological Screening Questionnaire (MSNQ), the two-question screening tool for depression, vitality, health-related quality of life, the Health-Promoting Lifestyle Profile II and questions assessing social network satisfaction and employment status. RESULTS: Of the 751 respondents (median age 54 years, median Expanded Disability Status Scale 5, 66.2% female), two-thirds reported perceived neuropsychological impairment or depressive symptoms. Whilst depressive symptoms were related to higher MSNQ scores, the MSNQ poorly predicted depression. After correcting for confounders, higher MSNQ scores and depressive symptoms decreased vitality, health-related quality of life and health-promoting behaviours and increased the probability of being socially dissatisfied. In participants below retirement age, higher MSNQ and Expanded Disability Status Scale scores increased the probability of unemployment, whilst depression did not. CONCLUSION: The contribution of the MSNQ to self-reported health measures and its unique explanatory power regarding unemployment suggest that subjective cognitive complaints are connected to subtle, yet meaningful, neuropsychological dysfunction.

European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre­hospital management of stroke

Background and purpose The reduction of delay between onset and hospital arrival and adequate pre­hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence­based practices for the management of patients with suspected stroke in the pre­hospital setting. Methods The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations. Results Despite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre­hospital 'code stroke' including highest priority dispatch, pre­hospital notification and rapid transfer to the closest 'stroke­ready' centre. Insufficient evidence was found to recommend a pre­hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre­hospital telemedicine during ambulance transport. Conclusions These guidelines inform on the contemporary approach to patients with suspected stroke in the pre­hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.

European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre-hospital management of stroke.

BACKGROUND AND PURPOSE: The reduction of delay between onset and hospital arrival and adequate pre-hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence-based practices for the management of patients with suspected stroke in the pre-hospital setting. METHODS: The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations. RESULTS: Despite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre-hospital 'code stroke' including highest priority dispatch, pre-hospital notification and rapid transfer to the closest 'stroke-ready' centre. Insufficient evidence was found to recommend a pre-hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre-hospital telemedicine during ambulance transport. CONCLUSIONS: These guidelines inform on the contemporary approach to patients with suspected stroke in the pre-hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.

Xenon isotopes in 67P/Churyumov-Gerasimenko show that comets contributed to Earth's atmosphere.

The origin of cometary matter and the potential contribution of comets to inner-planet atmospheres are long-standing problems. During a series of dedicated low-altitude orbits, the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) on the Rosetta spacecraft analyzed the isotopes of xenon in the coma of comet 67P/Churyumov-Gerasimenko. The xenon isotopic composition shows deficits in heavy xenon isotopes and matches that of a primordial atmospheric component. The present-day Earth atmosphere contains 22 ± 5% cometary xenon, in addition to chondritic (or solar) xenon.

D2O and HDS in the coma of 67P/Churyumov-Gerasimenko.

The European Rosetta mission has been following comet 67P/Churyumov-Gerasimenko for 2 years, studying the nucleus and coma in great detail. For most of these 2 years the Rosetta Orbiter Sensor for Ion and Neutral Analysis (ROSINA) has analysed the volatile part of the coma. With its high mass resolution and sensitivity it was able to not only detect deuterated water HDO, but also doubly deuterated water, D2O and deuterated hydrogen sulfide HDS. The ratios for [HDO]/[H2O], [D2O]/[HDO] and [HDS]/[H2S] derived from our measurements are (1.05 ± 0.14) × 10-3, (1.80 ± 0.9) × 10-2 and (1.2 ± 0.3) × 10-3, respectively. These results yield a very high ratio of 17 for [D2O]/[HDO] relative to [HDO]/[H2O]. Statistically one would expect just 1/4. Such a high value can be explained by cometary water coming unprocessed from the presolar cloud, where water is formed on grains, leading to high deuterium fractionation. The high [HDS]/[H2S] ratio is compatible with upper limits determined in low-mass star-forming regions and also points to a direct correlation of cometary H2S with presolar grain surface chemistry.This article is part of the themed issue 'Cometary science after Rosetta'.

Self-reported levels of education and disability progression in multiple sclerosis.

OBJECTIVES: The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). MATERIALS AND METHODS: We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. RESULTS: Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. CONCLUSIONS: Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS.

PLANET TOPERS: Planets, Tracing the Transfer, Origin, Preservation, and Evolution of their ReservoirS.

The Interuniversity Attraction Pole (IAP) 'PLANET TOPERS' (Planets: Tracing the Transfer, Origin, Preservation, and Evolution of their Reservoirs) addresses the fundamental understanding of the thermal and compositional evolution of the different reservoirs of planetary bodies (core, mantle, crust, atmosphere, hydrosphere, cryosphere, and space) considering interactions and feedback mechanisms. Here we present the first results after 2 years of project work.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Abundant molecular oxygen in the coma of comet 67P/Churyumov-Gerasimenko.

The composition of the neutral gas comas of most comets is dominated by H2O, CO and CO2, typically comprising as much as 95 per cent of the total gas density. In addition, cometary comas have been found to contain a rich array of other molecules, including sulfuric compounds and complex hydrocarbons. Molecular oxygen (O2), however, despite its detection on other icy bodies such as the moons of Jupiter and Saturn, has remained undetected in cometary comas. Here we report in situ measurement of O2 in the coma of comet 67P/Churyumov-Gerasimenko, with local abundances ranging from one per cent to ten per cent relative to H2O and with a mean value of 3.80 ± 0.85 per cent. Our observations indicate that the O2/H2O ratio is isotropic in the coma and does not change systematically with heliocentric distance. This suggests that primordial O2 was incorporated into the nucleus during the comet's formation, which is unexpected given the low upper limits from remote sensing observations. Current Solar System formation models do not predict conditions that would allow this to occur.

Molecular nitrogen in comet 67P/Churyumov-Gerasimenko indicates a low formation temperature.

Molecular nitrogen (N2) is thought to have been the most abundant form of nitrogen in the protosolar nebula. It is the main N-bearing molecule in the atmospheres of Pluto and Triton and probably the main nitrogen reservoir from which the giant planets formed. Yet in comets, often considered the most primitive bodies in the solar system, N2 has not been detected. Here we report the direct in situ measurement of N2 in the Jupiter family comet 67P/Churyumov-Gerasimenko, made by the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis mass spectrometer aboard the Rosetta spacecraft. A N2/CO ratio of (5.70 ± 0.66) × 10(-3) (2σ standard deviation of the sampled mean) corresponds to depletion by a factor of ~25.4 ± 8.9 as compared to the protosolar value. This depletion suggests that cometary grains formed at low-temperature conditions below ~30 kelvin.

Cometary science. Time variability and heterogeneity in the coma of 67P/Churyumov-Gerasimenko.

Comets contain the best-preserved material from the beginning of our planetary system. Their nuclei and comae composition reveal clues about physical and chemical conditions during the early solar system when comets formed. ROSINA (Rosetta Orbiter Spectrometer for Ion and Neutral Analysis) onboard the Rosetta spacecraft has measured the coma composition of comet 67P/Churyumov-Gerasimenko with well-sampled time resolution per rotation. Measurements were made over many comet rotation periods and a wide range of latitudes. These measurements show large fluctuations in composition in a heterogeneous coma that has diurnal and possibly seasonal variations in the major outgassing species: water, carbon monoxide, and carbon dioxide. These results indicate a complex coma-nucleus relationship where seasonal variations may be driven by temperature differences just below the comet surface.

Cometary science. 67P/Churyumov-Gerasimenko, a Jupiter family comet with a high D/H ratio.

The provenance of water and organic compounds on Earth and other terrestrial planets has been discussed for a long time without reaching a consensus. One of the best means to distinguish between different scenarios is by determining the deuterium-to-hydrogen (D/H) ratios in the reservoirs for comets and Earth's oceans. Here, we report the direct in situ measurement of the D/H ratio in the Jupiter family comet 67P/Churyumov-Gerasimenko by the ROSINA mass spectrometer aboard the European Space Agency's Rosetta spacecraft, which is found to be (5.3 ± 0.7) × 10(-4)­that is, approximately three times the terrestrial value. Previous cometary measurements and our new finding suggest a wide range of D/H ratios in the water within Jupiter family objects and preclude the idea that this reservoir is solely composed of Earth ocean-like water.

RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)-a kinase at the crossroad between life and death downstream of various receptors-as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

ß2-adrenergic receptors protect axons during energetic stress but do not influence basal glio-axonal lactate shuttling in mouse white matter.

In vitro studies have demonstrated that ß2-adrenergic receptor activation stimulates glycogen degradation in astrocytes, generating lactate as a potential energy source for neurons. Using in vivo microdialysis in mouse cerebellar white matter we demonstrate continuous axonal lactate uptake and glial-axonal metabolic coupling of glutamate/lactate exchange. However, this physiological lactate production was not influenced by activation (clenbuterol) or blocking (ICI 118551) of ß2-adrenergic receptors. In two-photon imaging experiments on ex vivo mouse corpus callosum subjected to aglycemia, ß2-adrenergic activation rescued axons, whereas inhibition of axonal lactate uptake by α-cyano-4-hydroxycinnamic acid (4-CIN) was associated with severe axonal loss. Our results suggest that axonal protective effects of glial ß2-adrenergic receptor activation are not mediated by enhanced lactate production.

The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is found in about half of the multiple sclerosis (MS) population and is an important contributor to employment status and social functioning. CI is encountered in all disease stages and correlates only moderately with disease duration or Expanded Disability Status Scale scores. Most present neuropsychological test batteries are time-demanding and expensive. The Symbol Digit Modalities Test (SDMT) has been suggested as a screening tool for CI in MS. In this paper, we aim to assess the performance of the SDMT in predicting the outcome of an extensive battery. METHODS: Neuropsychological test results from 359 patients were assessed in a multidisciplinary MS center (National MS Center Melsbroek, Belgium). Using receiver operating characteristic curves, the performance of the SDMT in predicting the general cognitive outcome of the extensive Neuropsychological Screening Battery for MS (NSBMS) could be assessed. The performance of the SDMT was assessed for different levels of CI and compared with other cognitive tests. Finally, useful covariates were included in a logistic regression model. RESULTS: At a specificity of 0.60 a high sensitivity (0.91) was obtained indicating the potential of the SDMT as a sentinel test for CI in MS. The SDMT outperformed the individual tests included in the NSBMS, used as benchmark. As the logistic regression model did not result in a relevant improvement, it is concluded that most clinical variables influence both the SDMT and the NSBMS in a similar way. Excluding patients with possible practice effects, an optimal cutoff of 40 was found for the SDMT. CONCLUSION: As the SDMT is an easy, low-cost and fast test, this result may help to detect CI in everyday clinical practice.

Intracranial artery dissection.

The aim of this narrative review is to evaluate the pathogenesis, clinical features, diagnosis, treatment and prognosis of intracranial artery dissection (IAD). IAD is a rare and often unrecognized cause of stroke or subarachnoid haemorrhage (SAH), especially in young adults. Two types of IAD can be identified: a subintimal or subadventitial dissection. It is suggested that a subintimal dissection results in luminal stenosis, thromboembolism and subsequently cerebral ischaemia, whilst a subadventitial IAD could result in the formation of a pseudo-aneurysm and compression on brainstem or cranial nerves. Rupture of such a dissecting aneurysm causes SAH. The exact cause of IAD remains unknown but several factors are associated with its development. Diagnosis is based on clinical presentation and specific features seen on multimodal neuroimaging. The management of IAD depends on the clinical presentation. In the case of cerebral ischaemia, anticoagulants or antiplatelet agents are used, whilst in the case of SAH endovascular treatment is primarily advocated. Prognosis depends on clinical presentation. Presentation with SAH has a worse prognosis.

Neuroprotective efficacy of subcutaneous insulin-like growth factor-I administration in normotensive and hypertensive rats with an ischemic stroke.

The aim of this study was to test the insulin-like growth factor-I (IGF-I) as a neuroprotective agent in a rat model for ischemic stroke and to compare its neuroprotective effects in conscious normotensive and spontaneously hypertensive rats. The effects of subcutaneous IGF-I injection were investigated in both rat strains using the endothelin-1 rat model for ischemic stroke. Motor-sensory functions were measured using the Neurological Deficit Score. Infarct size was assessed by Cresyl Violet staining. Subcutaneous administration of IGF-I resulted in significantly reduced infarct volumes and an increase in motor-sensory functions in normotensive rats. In these rats, IGF-I did not modulate blood flow in the striatum and had no effect on the activation of astrocytes as assessed by GFAP staining. In hypertensive rats, the protective effects of IGF-I were smaller and not always significant. Furthermore, IGF-I significantly reduced microglial activation in the cortex of hypertensive rats, but not in normotensive rats. More detailed studies are required to find out whether the reduction by IGF-I of microglial activation contributes to an impairment IGF-I treatment efficacy. Indeed, we have shown before that microglia in hypertensive rats have different properties compared to those in control rats, as they exhibit a reduced responsiveness to ischemic stroke and lipopolysaccharide.