Background: Fingolimod is the first oral immunomodulatory therapy approved for highly active relapsing remitting multiple sclerosis. Based on the distribution pattern of fingolimod interacting sphingosine-1-phosphat receptors in organism including immune system and cardiovascular system clinical monitoring of patients and evaluation of adverse events are recommended. Despite extensive data on cardiovascular safety, experience with fingolimod in patients with concomitant cardiological disease, especially within the pulmonary circulation, is rare. Case presentation: We report the case of a 46-year-old woman presented with relapsing remitting multiple sclerosis and severe idiopathic pulmonary arterial hypertension. Fingolimod was initiated because of disease activity of multiple sclerosis with two relapses and gadolinium-enhancing lesions in MRI. The patient demonstrated stable disease course of idiopathic pulmonary arterial hypertension when fingolimod was started. Fingolimod therapy did not alter or even worsen the pulmonary or cardiovascular conditions during first dose application as well as follow up of nine months. Conclusion: In this report, we present the first case of fingolimod treatment in a patient with highly active multiple sclerosis and severe idiopathic pulmonary arterial hypertension. We suggest an interdisciplinary approach with detailed cardiopulmonary monitoring for safety in such patients.

Background Migrants in many European countries including Germany tend to utilize preventive measures less frequently than the majority population. Little is known about the dental health of migrants as well as about their oral health behaviour, particularly in the adult population. The aim of this study was to examine differences in the uptake of annual dental check-ups in adult migrants and non-migrants in Germany. Methods We used data from the cross-sectional survey ‘German Health Update 2010’ conducted by the Robert Koch Institute (n = 22,050). Data from 21,741 German-speaking respondents with information on the use of dental check-ups was available, of which 3404 (15.7%) were migrants. Multiple logistic regression models were applied to adjust for demographic and socioeconomic confounders, including the place of residence as well as type of health insurance. Results Migrants were generally younger, had a lower socioeconomic status and showed a lower utilization of dental check-ups. The unadjusted odds ratio (OR) for utilization was 0.67 (95%-CI = 0.61–0.73). After adjusting for demographic and socioeconomic confounders the chance only increased slightly (adjusted OR = 0.71; 95%-CI = 0.65–0.77). Conclusions The analysis shows that migration status is associated with a reduced chance of attending dental check-ups, independently of demographic and socioeconomic factors. The influence of other factors, such as type of health insurance and place of residence had also no influence on the association. Migrants are exposed to different barriers in the health care system, comprising the patient, provider and system level. Further studies need to examine the relevant barriers for the uptake of preventive dental services in order to devise appropriate migrant- sensitive measures of dental prevention.

Alloying aluminum offers the possibility of creating low-density high-entropy alloys (HEAs). Several studies that focus on the system AlCoCrFeNiTi differ in their phase determination. The effect of aluminum on the phase composition and microstructure of the compositionally complex alloy (CCA) system AlxCoCrFeNiTi was studied with variation in aluminum content (molar ratios x = 0.2, 0.8, and 1.5). The chemical composition and elemental segregation was measured for the different domains in the microstructure. The crystal structure was determined using X-ray diffraction (XRD) analysis. To identify the spatial distribution of the phases found with XRD, phase mapping with associated orientation distribution was performed using electron backscatter diffraction. This made it possible to correlate the chemical and structural conditions of the phases. The phase formation strongly depends on the aluminum content. Two different body-centered cubic (bcc) phases were found. Texture analysis proved the presence of a face-centered cubic (fcc) phase for all aluminum amounts. The hard η-(Ni, Co)3Ti phase in the x = 0.2 alloy was detected via metallographic investigation and confirmed via electron backscatter diffraction. Additionally, a centered cluster (cc) with the A12 structure type was detected in the x = 0.2 and 0.8 alloys. The correlation of structural and chemical properties as well as microstructure formation contribute to a better understanding of the alloying effects concerning the aluminum content in CCAs. Especially in the context of current developments in lightweight high-entropy alloys (HEAs), the presented results provide an approach to the development of new alloy systems.

Goal-directed behavior is based on representations of contingencies between a certain situation (S), a certain (re)action (R) and a certain outcome (O). These S-R-O representations enable flexible response selection in different situations according to the currently pursued goal. Importantly however, the successful formation of such representations is a necessary but not sufficient precondition for goal-directed behavior which additionally requires the actual usage of the contingency information for action control. The present fMRI study aimed at identifying the neural basis of each of these two aspects: representing vs. explicitly using experienced S-R-O contingencies. To this end, we created three experimental conditions: S-R-O contingency present and used for outcome-based response selection, S-R-O contingency present but not used, and S-R-O contingency absent. The comparison between conditions with and without S-R-O contingency revealed that the angular gyrus is relevant for representing S-R-O contingencies. The explicit usage of learnt S-R-O representations in turn was associated with increased functional coupling between angular gyrus and several subcortical (hippocampus, caudate head), prefrontal (lateral orbitofrontal cortex (OFC), rostrolateral prefrontal cortex (RLPFC)) and cerebellar areas, which we suggest represent different explicit and implicit processes of goal-directed action control. Hence, we ascribe a central role to the angular gyrus in associating actions to their sensory outcomes which is used to guide behavior through coupling of the angular gyrus with multiple areas related to different aspects of action control.

Sulfated glycosaminoglycans (GAG) are components of the bone marrow stem cell niche and to a minor extent of mature bone tissue with important functions in regulating stem cell lineage commitment and differentiation. We anticipated that artificial extracellular matrices (aECM) composed of collagen I and synthetically oversulfated GAG derivatives affect preferentially the differentiation of osteoblast-precursor cells and early osteoblasts. A set of gradually sulfated chondroitin sulfate and hyaluronan derivatives was used for the preparation of aECM. All these matrices were analysed with human bone marrow stromal cells to identify the most potent aECM and to determine the influence of the degree and position of sulfate groups and the kind of disaccharide units on the osteogenic differentiation. Oversulfated GAG derivatives with a sulfate group at the C-6 position of the N-acetylglycosamine revealed the most pronounced proosteogenic effect as determined by tissue nonspecific alkaline phosphatase activity and calcium deposition. A subset of the aECM was further analysed with different primary osteoblasts and cell lines reflecting different maturation stages to test whether the effect of sulfated GAG derivatives depends on the maturation status of the cells. It was shown that the proosteogenic effect of aECMwasmost prominent in early osteoblasts. [ABSTRACT FROM AUTHOR]

The Saccharomyces cerevisiae kinase Sat4p has been originally identified as a protein involved in salt tolerance and stabilization of plasma membrane transporters, implicating a cytoplasmic localization. Our study revealed an additional mitochondrial (mt) localization, suggesting a dual function for Sat4p. While no mt related phenotype was observed in the absence of Sat4p, its overexpression resulted in significant changes of a specific mitochondrial subproteome. As shown by a comparative two dimensional difference gel electrophoresis (2D-DIGE) approach combined with mass spectrometry, particularly two groups of proteins were affected: the iron-sulfur containing aconitase-type proteins (Aco1p, Lys4p) and the lipoamide-containing subproteome (Lat1p, Kgd2p and Gcv3p). The lipoylation sites of all three proteins could be assigned by nanoLC-MS/MS to Lys75 (Lat1p), Lys114 (Kgd2p) and Lys102 (Gcv3p), respectively. Sat4p overexpression resulted in accumulation of the delipoylated protein variants and in reduced levels of aconitase-type proteins, accompanied by a decrease in the activities of the respective enzyme complexes. We propose a regulatory role of Sat4p in the late steps of the maturation of a specific subset of mitochondrial iron-sulfur cluster proteins, including Aco1p and lipoate synthase Lip5p. Impairment of the latter enzyme may account for the observed lipoylation defects.

It has been discovered during the past few years that demosponges of the order Verongida such as Aplysina cavernicola exhibit chitin-based skeletons. Verongida sponges are well known to produce bioactive brominated tyrosine derivatives. We could recently demonstrate that brominated compounds do not exclusively occur in the cellular matrix but also in the skeletons of the marine sponges Aplysina cavernicola and Ianthella basta. Our measurements imply that these yet unknown compounds are strongly, possibly covalently bound to the sponge skeletons. In the present work, we determined the skeletal amino acid composition of the demosponge A. cavernicola especially with respect to the presence of halogenated amino acids. The investigations of the skeletons before and after MeOH extraction confirmed that only a small amount of the brominated skeleton-bound compounds dissolves in MeOH. The main part of the brominated compounds is strongly attached to the skeletons but can be extracted for example by using Ba(OH)2. Various halogenated tyrosine derivatives were identified by GC-MS and LC-MS in these Ba(OH)2 extracts of the skeletons.

Significant associations between self-reported “whole units” of work and self-reported mental task requirements as well as personal outcomes are well known. Also of interest is, however, whether a significant association also exists between the underlying objective assignment of tasks, i.e. the division of labour, and self-reported mental requirements. Such an association would represent a concrete starting point for job design or redesign. We analyzed this question for retail sale jobs as an example of the numerous human service jobs, which usually consist of customer- and object-centred tasks. The study (N = 558 employees) evaluated the potential association between documented assignments of customer-centred and goods-centred activities and employees’ perceived mental requirements, skill utilisation, and learning on the job, as well as mental difficulties. A significant association of moderate effect size between the objective division of labour and self-reported mental job requirements was shown. Theoretical and practical consequences of this association are also discussed.

Danggui Buxue Tang (DBT), a herbal decoction containing Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), has been used in treating menopausal irregularity in women for more than 800 years in China. Pharmacological results showed that DBT exhibited significant estrogenic properties in vitro, which therefore suggested that DBT could activate the nuclear estrogen receptors. Here, we assessed the estrogenic properties of DBT in an ovariectomized in vivo rat model: DBT was applied to the ovariectomized rats for 3 days. The application of DBT did not alter the weight of uterus and liver, as well as the transcript expression of the proliferation markers including the estrogen receptors α and β. However, DBT stimulated the transcript expression of the estrogen responsive genes. In addition, the inductive role of DBT on the expression of members of the aryl hydrocarbon receptor family in uterus and liver of ovariectomized rats was confirmed. These responses of DBT however were clearly distinct from the response pattern detectable here for 17β-estradiol. Therefore, DBT exhibited weak, but significant, estrogenic properties in vivo; however, some of its activities were independent of the estrogen receptor. Thus, DBT could be an exciting Chinese herbal decoction for an alternative treatment of hormone replacement therapy for women in menopause without subsequent estrogenic side effects.

Purpose: To investigate species differences in the distribution and localization of alpha B-crystallin (ABC) in the normal retina and optic nerve head region, and to describe changes during outer and inner retina degeneration. Material and methods: Animals studied included mice, rats, cats, pigs, cows, and monkeys. Sections of the optic nerve and central retina were labeled with antibodies against ABC and glial fibrillary acidic protein (GFAP). Results: ABC was located in astrocytes and Muller cells with different intensities. During outer retina degeneration (dystrophic rat and Abyssinian cat), only late stages showed an increase in ABC in the retina and optic nerve head. Inner retina degeneration in the glaucoma mouse model showed no increase of ABC. In the monkey glaucoma model, only the innermost layer of the optic nerve head showed increased labeling for ABC. Conclusions: The distribution of ABC is species dependent and is (excluding the mouse) present in the nerve fiber layer of the retina and in the optic nerve head (localization of astrocytes). Chronic retinal degeneration does not necessarily lead to an over-expression of ABC. While in outer retinal degeneration induction was predominantly present in late stages, pressure-induced glaucoma led to a specific increase in ABC already in early stages indicating a local stress-response in this region.