Phenomenology of Hybrid Scenarios of Neutrino Dark Energy

We study the phenomenology of hybrid scenarios of neutrino dark energy, where in addition to a so-called Mass Varying Neutrino (MaVaN) sector a cosmological constant (from a false vacuum) is driving the accelerated expansion of the universe today. For general power law potentials we calculate the effective equation of state parameter w_{eff}(z) in terms of the neutrino mass scale. Due to the interaction of the dark energy field (acceleron) with the neutrino sector, w_{eff}(z) is predicted to become smaller than -1 for z>0, which could be tested in future cosmological observations. For the considered scenarios, the neutrino mass scale additionally determines which fraction of the dark energy is dynamical, and which originates from the cosmological constant like vacuum energy of the false vacuum. On the other hand, the field value of the acceleron field today as well as the masses of the right-handed neutrinos, which appear in the seesaw-type mechanism for small neutrino masses, are not fixed. This, in principle, allows to realise hybrid scenarios of neutrino dark energy with a high-scale seesaw where the right-handed neutrino masses are close to the GUT scale. We also comment on how MaVaN Hybrid Scenarios with high-scale seesaw might help to resolve stability problems of dark energy models with non-relativistic neutrinos.Comment: 22 pages, 5 figures; references and comments added; version to be published in JCA

Differences in Niemann-Pick disease type C symptomatology observed in patients of different ages

BACKGROUND : Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression ismore pronounced in patientswith early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Here we describe the prevalence of signs and symptoms observed in patientswith NP-C and analyse the relationship between these symptoms in different age groups. METHODS : The combined patient cohort used in the analyses comprised NP-C cases (n=164) and controls (n= 135) aged 0 to 60 years from two previously published cohorts; a cohort of all ages fromwhich patients ≤4 years of agewere excluded and a cohortwith early-onset NP-C and age-matched controls. The analysis of relationships between different signs and symptoms was performed for both NP-C cases and controls in two sub-groups, ≤4 and N4 years of age, using cluster analyses. The threshold of 4 years of age was selected to reflect the minimum age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual signs and symptoms at age of diagnosis, patientswere categorised by age into 5-year sub-groups, and prevalence values estimated for each sign and symptom of NP-C. RESULTS : Twomain clusters of symptomswere clearly defined for NP-C cases in each age sub-group,whereas clusters were not as clearly defined for controls. For NP-C cases ≤4 years of age, one cluster comprised exclusively visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C cases N4 years of age, each cluster contained amixture of visceral, neurological and psychiatric items. Prevalence estimations showed that visceral symptoms (e.g. isolated unexplained splenomegaly)were most common inNPC cases ≤4 years of age. Neurological symptoms were generallymore common in NP-C cases N4 years of age than in younger patients, with the exception of hypotonia and delayed developmental milestones. CONCLUSIONS : These analyses provide a comprehensive overviewof symptomatology observed in a large combined cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations from clinical practice and support the importance of multi-disciplinary approaches for identification of patients with NP-C, taking into account age-specific manifestations and their possible correlations.Manuscript preparation for this publication was supported by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.EM,MP, CJH,MWand JVT have received consulting fees or honoraria from Actelion Pharmaceuticals Ltd.http://www.elsevier.com/locate/ymgmeam2017Paediatrics and Child Healt

Proneuropeptide Y and neuropeptide Y metabolites in healthy volunteers and patients with a pheochromocytoma or paraganglioma

Neuropeptide Y (NPY1-36) is a vasoconstrictor peptide co-secreted with catecholamines by sympathetic nerves, the adrenal medulla, and neoplasms such as pheochromocytomas and paragangliomas (PPGLs). It is produced by the intracellular cleavage of proNPY and metabolized into multiple fragments with distinct biological activities. NPY immunoassays for PPGL have a diagnostic sensitivity ranging from 33 to 100%, depending on the antibody used. We have validated a multiplex micro-UHPLC-MS/MS assay for the specific and sensitive quantification of proNPY, NPY1-39, NPY1-37, NPY1-36, NPY2-36, NPY3-36, NPY1-35, NPY3-35, and the C-flanking peptide of NPY (CPON) (collectively termed NPYs), and determined the NPYs reference intervals and concentrations in 32 PPGL patients before, during, and after surgery. Depending on the peptide measured, NPYs were above the upper reference limit (URL) in 20% to 67% of patients, whereas plasma free metanephrine and normetanephrine, the gold standard for PPGL, were above the URL in 40% and 87% of patients, respectively. Age, sex, tachycardia, and tumor localization were not correlated with NPYs. Plasma free metanephrines performed better than NPYs in the detection of PPGL, but NPYs may be a substitute for an early diagnosis of PPGL for patients that suffer from severe kidney impairment or receiving treatments that interfere with catecholamine reuptake

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.The authors thank Dominique Spirig and Andrew Smith of PHOCUS Services\ud Ltd, a member of the Fishawack Group of Companies, who provided\ud medical writing support funded by Actelion Pharmaceuticals Ltd.\ud The manuscript preparation was funded by a support grant from Actelion\ud Pharmaceuticals Ltd, Allschwil, Switzerland. All authors agreed to submit the\ud manuscript for publication and can confirm the content of the manuscript\ud has not been influenced by the funding body

A cross‐sectional, prospective ocular motor study in 72 patients with Niemann‐Pick disease type C

Objective: To characterize ocular motor function in patients with Niemann-Pick disease type C (NPC). Methods: In a multicontinental, cross-sectional study we characterized ocular-motor function in 72 patients from 12 countries by video-oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls (HC). Results: Some 98.2% of patients generated vertical saccades below the 95% CI of the controls' peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% CI of HC. The involvement in both downward and upward directions was similar (51°/s (68.9, [32.7-69.3]) downward versus 78.8°/s (65.9, [60.8-96.8]) upward). Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit correlated best to disease severity. Compensating strategies such as blinks to elicit saccades, and head and upper body movements to overcome the gaze palsy, were observed. Vertical reflexive saccades were more impaired and slower than self-paced ones. Gaze-holding was normal. Ocular-motor performance depended on the age of onset and disease duration. Conclusions: This is the largest cohort of NPC patients investigated for ocular-motor function. Vertical supranuclear saccade palsy is the hallmark of NPC. Vertical upward and downward saccades are equally impaired. Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials. Compensating strategies can contribute to establishing a diagnosis

Common Man, Society and Religion in the 16th century/Gemeiner Mann, Gesellschaft und Religion im 16. Jahrhundert

Der zweisprachige Sammelband vereinigt zum Teil bahnbrechende Ergebnisse einer interdisziplinären Forschungstagung, deren Beiträge sozial-, wirtschafts-, kultur- und kirchengeschichtliche Aspekte der Frühneuzeit im Karpatenbogen aufgreifen. Basierend auf vielfach erstmals ausgewerteten Quellen bearbeiten die Beiträge aktuelle Fragestellungen und Forschungshorizonte zur Interdependenz von sozialen, ökonomischen, kulturellen und religiösen Phänomenen im Karpatenbogen der Frühen Neuzeit, in dem die Osmanen der international dominante politische Faktor wurden. Transformationsprozesse wurden angestoßen durch Bevölkerungs- und Militärbewegungen, ökonomische, politische und religiös-mentale Umwälzungen, die zwischen opportunistischer Anpassung und rebellierendem Widerstand oszillierten und entsprechende politische Maßnahmen und Gegenreaktionen hervorriefen. Dabei wird die bislang geltende Forschungsmeinung zur Toleranzgeschichte Siebenbürgens in Frage gestellt und völlig neu bewertet

Cardiovascular Agents Affect the Tone of Pulmonary Arteries and Veins in Precision-Cut Lung Slices

Cardiovascular agents are pivotal in the therapy of heart failure. Apart from their action on ventricular contractility and systemic afterload, they affect pulmonary arteries and veins. Although these effects are crucial in heart failure with coexisting pulmonary hypertension or lung oedema, they are poorly defined, especially in pulmonary veins. Therefore, we investigated the pulmonary vascular effects of adrenoceptor agonists, vasopressin and angiotensin II in the model of precision-cut lung slices that allows simultaneous studies of pulmonary arteries and veins.Precision-cut lung slices were prepared from guinea pigs and imaged by videomicroscopy. Concentration-response curves of cardiovascular drugs were analysed in pulmonary arteries and veins.Pulmonary veins responded stronger than arteries to α(1)-agonists (contraction) and β(2)-agonists (relaxation). Notably, inhibition of β(2)-adrenoceptors unmasked the α(1)-mimetic effect of norepinephrine and epinephrine in pulmonary veins. Vasopressin and angiotensin II contracted pulmonary veins via V(1a) and AT(1) receptors, respectively, without affecting pulmonary arteries.Vasopressin and (nor)epinephrine in combination with β(2)-inhibition caused pulmonary venoconstriction. If applicable in humans, these treatments would enhance capillary hydrostatic pressures and lung oedema, suggesting their cautious use in left heart failure. Vice versa, the prevention of pulmonary venoconstriction by AT(1) receptor antagonists might contribute to their beneficial effects seen in left heart failure. Further, α(1)-mimetic agents might exacerbate pulmonary hypertension and right ventricular failure by contracting pulmonary arteries, whereas vasopressin might not

Common Man, Society and Religion in the 16th century/Gemeiner Mann, Gesellschaft und Religion im 16. Jahrhundert

Der zweisprachige Sammelband vereinigt zum Teil bahnbrechende Ergebnisse einer interdisziplinären Forschungstagung, deren Beiträge sozial-, wirtschafts-, kultur- und kirchengeschichtliche Aspekte der Frühneuzeit im Karpatenbogen aufgreifen. Basierend auf vielfach erstmals ausgewerteten Quellen bearbeiten die Beiträge aktuelle Fragestellungen und Forschungshorizonte zur Interdependenz von sozialen, ökonomischen, kulturellen und religiösen Phänomenen im Karpatenbogen der Frühen Neuzeit, in dem die Osmanen der international dominante politische Faktor wurden. Transformationsprozesse wurden angestoßen durch Bevölkerungs- und Militärbewegungen, ökonomische, politische und religiös-mentale Umwälzungen, die zwischen opportunistischer Anpassung und rebellierendem Widerstand oszillierten und entsprechende politische Maßnahmen und Gegenreaktionen hervorriefen. Dabei wird die bislang geltende Forschungsmeinung zur Toleranzgeschichte Siebenbürgens in Frage gestellt und völlig neu bewertet

Fluctuations around Bjorken Flow and the onset of turbulent phenomena

We study how fluctuations in fluid dynamic fields can be dissipated or amplified within the characteristic spatio-temporal structure of a heavy ion collision. The initial conditions for a fluid dynamic evolution of heavy ion collisions may contain significant fluctuations in all fluid dynamical fields, including the velocity field and its vorticity components. We formulate and analyze the theory of local fluctuations around average fluid fields described by Bjorken's model. For conditions of laminar flow, when a linearized treatment of the dynamic evolution applies, we discuss explicitly how fluctuations of large wave number get dissipated while modes of sufficiently long wave-length pass almost unattenuated or can even be amplified. In the opposite case of large Reynold's numbers (which is inverse to viscosity), we establish that (after suitable coordinate transformations) the dynamics is governed by an evolution equation of non-relativistic Navier-Stokes type that becomes essentially two-dimensional at late times. One can then use the theory of Kolmogorov and Kraichnan for an explicit characterization of turbulent phenomena in terms of the wave-mode dependence of correlations of fluid dynamic fields. We note in particular that fluid dynamic correlations introduce characteristic power-law dependences in two-particle correlation functions.Comment: 40 pages, 5 figures, published versio