Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

Fashion as a form of Communication

Die vorliegende Bachelorarbeit beschäftigt sich mit der Mode als eine Form der visuellen Kommunikation. Dabei steht die Kleidung, unsere zweite Haut, im Fokus. Ziel dieser Ar-beit ist es, durch die Analyse geschichtlicher Daten und anhand ausgewählter Szenen zu zeigen, wie Mode als Kommunikationsform seit der Französischen Revolution bis ins 20. Jahrhundert funktionierte und auch heute noch funktioniert. Außerdem wurde diese Arbeit zum Anlass genommen, mithilfe der wichtigsten Modetheorien zu zeigen, dass sich nicht nur die Ausbreitung und Entwicklung der Mode verändert hat sondern vor allem, in Bezug auf die Kommunikation, ihre Bedeutungsvielfalt, also das, was man mit Mode ausdrücken kann. In diesem Zusammenhang soll ein Ausblick darüber gegeben werden, wie sich das Thema zukünftig entwickeln könnte. Das Thema wird auf Grundlage der Auswertung vergangener und aktueller Fachliteratur veranschaulicht, diskutiert und kritisch reflektiert. Im Ergebnis wird deutlich, dass sich die Mode in ihrer Funktion als Kommunikationsform stark verändert hat aber auch heute noch mithilfe der Mode Botschaften an die soziale Umwelt gesendet werden können

Synthesis of Chiral Pentadienyl-Ligands Based on the Natural Product (–)-Myrtenal and their Application in Coordination Chemistry

Im Gegensatz zu der eingehend untersuchten Chemie der Metallocene waren die analogen offenen und halboffenen Metallocene lange Zeit unerforscht. Pioniere auf diesem Themen-gebiet sind Ernst et al., deren Arbeiten sich auf achirale Pentadienyl-Liganden beschränkte. In dieser Dissertation wird die Synthese, Charakterisierung und Koordinationschemie von enantiomerenreinen Pentadienyl-Liganden beschrieben und diskutiert. Das Strukturmotiv dieser Liganden basiert exklusiv auf dem Naturstoff (–)-Myrtenal (1), welcher kostengünstig aus dem chiral pool erhältlich ist. Dieses Startmaterial kann durch Wittig Olefinierungen in chirale Pentadiene 2 umgewandelt werden. Nach anschließender Deprotonierung zu den entsprechenden Kalium-Pentadieniden 3 und durch deren Umsetzungen mit Erdalkali-metallen, Seltenerdmetallen und Übergangsmetallen konnten eine Vielzahl an enantio-merenreinen, homoleptische und heteroleptische Pentadienyl-Komplexe erhalten werden. Die Charakterisierung dieser Organometallverbindungen erfolgte durch NMR Spektroskopie und Röntgenstrukturanalyse. Zudem konnten für die Erdalkalimetall-Metallocene erste katalytische Untersuchungen (Ringöffnungspolymerisation von rac-Lactid) durchgeführt werden. Der zweite Teil der Dissertation fokussiert sich auf die Herstellung von enantiomerenreinen offenen Constrained Geometry Komplexen, die auf Amino- und Amidosilylpentadienide als Liganden basieren. Die Liganden werden durch Reaktionen der Kalium-Pentadienide 3 mit Dimethylaminodimethylsilyl-, Diethylaminodimethylsilyl- and tert-Butylaminodimethylchlorosilan sowie der anschließenden Deprotonierung mit der Schlosser-Base erhalten. Für die Aminosilylpentadienide können offene Übergangsmetall-Metallocene und halboffene Trozircene hergestellt und vollständig charakterisiert werden. Im Gegensatz dazu sind bei den Umsetzungen der Amidosilylpentadienide mit Seltenerdmetallen eine neue Klasse an Constrained Geometry Komplexen erhalten worden.In contrast to the developed metallocene chemistry the related open and half-open metallocenes remained unexplored for a long time. However, pioneering work in this area was done by Ernst and co-workers using achiral pentadienyl ligands. In this dissertation the syntheses, characterization and coordination chemistry of enantiomerically pure pentadienyl-ligands are described and discussed. The ligand structure is exclusively based on the natural product (–)-myrtenal (1) which is inexpensive and readily available from the chiral pool. This starting material can be converted into chiral pentadienes 2 via Wittig olefination. After deprotonation with the Schlosser base to the corresponding potassium-pentadienides 3 and treatment of them with alkaline earth metals, rare earth metals and transition metals a diversity of enantiomerically pure homoleptic and heteroleptic pentadienyl-complexes could be obtained. These organometallic compounds were evaluated by NMR-spectroscopy and X-ray analysis. Furthermore the first catalytic studies on the open alkaline earth metal metallocenes in ring-opening polymerization of rac-lactide were undertaken. The second part of this dissertation focuses on the preparation of enantiomerically pure open constrained geometry complexes. Therefore amino- and amidosilylpentadienides 4 have been synthesized by the reaction of dimethylaminodimethylsilyl-, diethylaminodimethylsilyl- and tert-butylaminodimethylchlorosilane with the potassium-pentadienides 3, followed by deprotonation with the Schlosser base. Based on the aminosilylpentadienides open transition metal metallocenes and half open trozircenes could be prepared and fully characterized. In contrast, treatment of the amidosilylpentadienides with rare earth metals resulted in the formation of a new class of constrained geometry complexes

Probabilistic modeling reveals coordinated social interaction states and their multisensory bases

Social behavior across animal species ranges from simple pairwise interactions to thousands of individuals coordinating goal-directed movements. Regardless of the scale, these interactions are governed by the interplay between multimodal sensory information and the internal state of each animal. Here, we investigate how animals use multiple sensory modalities to guide social behavior in the highly social zebrafish (Danio rerio) and uncover the complex features of pairwise interactions early in development. To identify distinct behaviors and understand how they vary over time, we developed a new hidden Markov model with constrained linear-model emissions to automatically classify states of coordinated interaction, using the movements of one animal to predict those of another. We discovered that social behaviors alternate between two interaction states within a single experimental session, distinguished by unique movements and timescales. Long-range interactions, akin to shoaling, rely on vision, while mechanosensation underlies rapid synchronized movements and parallel swimming, precursors of schooling. Altogether, we observe spontaneous interactions in pairs of fish, develop novel hidden Markov modeling to reveal two fundamental interaction modes, and identify the sensory systems involved in each. Our modeling approach to pairwise social interactions has broad applicability to a wide variety of naturalistic behaviors and species and solves the challenge of detecting transient couplings between quasi-periodic time series.Comment: 29 pages, 6 figures, 3 supplementary figures. *Joint first author, +Joint last autho

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

Epidemiological characteristics of hemophilia in the pre-primary prophylaxis era: a historical cohort

Introduction: Epidemiological studies on hemophilia in the Brazilian population are historically scarce. Despite the continuous effort made by the National Program of Inherited Bleeding Disorders to map this condition, little information is available, especially on the period prior to program conception. Therefore, the present study aims to assess the epidemiological, serological, and clinical characteristics of patients with hemophilia in the state of Rio Grande do Sul, Brazil. Methods: A total of 455 patients had their medical records reviewed from January 1, 2003 to December 31, 2007. Results: We observed a remarkable prevalence of hepatitis C virus (HCV) infection in patients with both hemophilia A and B, and this prevalence significantly increased along with age (p < 0.001). No positive anti-HCV results were observed among children younger than 5 years old. There was a significant correlation between the severity of hemophilia and the number of arthropathies in all age categories. Considering the presence of inhibitors, a significant difference was observed between age groups, as older patients had higher inhibitor titers. There was a significant correlation between mean coagulation factor consumption and the number of arthropathies in patients over 5 years old. Conclusions: This profile analysis of patients with hemophilia reflects a gradual improvement in treatment safety and efficiency, as well as the need for continued investment in this population

Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia

Many biologic markers are associated with poor prognosis in chronic lymphocytic leukemia (CLL), but their mechanistic role remains unclear. Bax is an essential proapoptotic protein and decreased levels in malignant cells lead to resistance to apoptosis. Using a Bax degradation activity (BDA) assay, CLL cells were found to show variable Bax instability. However, BDA did not correlate with Bax protein levels: BDA positive and negative cases had high and low baseline Bax levels. BDA positive cases showed a marked accumulation of poor prognostic markers-unmutated immunoglobulin heavy chain variable genes, ZAP-70/CD38 positivity, 11q22/17p13 deletion, and short lymphocyte doubling time. Patients with BDA positive cells had a shorter median overall survival (OS; 126 months vs not reached, P = .011) and time to first treatment (16 vs 156 months, P = .029) than BDA negative cases. Dual BDA and ZAP-70 positivity had a median OS of 84 months (P = .012). The BDA assay measures the intrinsic ubiquitin/proteasome activity of CLL cells and dynamic changes in Bax protein levels over time. Mechanistically, Bax instability may represent a final common pathway for disparate prognostic markers, as well as being itself an indicator of poor prognosis.</p