Mechanical thrombectomy for acute ischemic stroke: thrombus-device interaction, efficiency, and complications in vivo

BACKGROUND AND PURPOSE: Mechanical thrombectomy is a promising new modality of interventional stroke treatment. The various devices differ with regard to where they apply force on the thrombus, taking a proximal approach such as aspiration devices or a distal approach such as basket-like devices. The study compares the in vivo effectiveness and thrombus-device interaction of these 2 approaches. METHODS: Angiography and embolization with a radioopaque whole blood thrombus was performed in 10 swine. Mechanical thrombectomy was performed in 20 cranial vessels using a proximal aspiration device (Vasco35) and a distal basket-like device (Catch) with and without proximal balloon occlusion. Fifty-six retrieval attempts were made. RESULTS: The proximal device allowed fast repeated application with a low risk of thromboembolic events (3%) and vasospasm, but it had a significantly lower success rate (39.4%) in retrieving thrombotic material than the distal device (DD) (82.6%; odds ratio, 7.3; 95% CI, 2.0 to 26.4). The compaction of the thrombus during retrieval with DD increased the risk of vessel wall irritation significantly (P<0.01) and complicated retrieval into the guiding catheter. The number of embolic events was significantly higher with DD (26%; odds ratio, 11.3; 95% CI, 1.35 to 101.6) unless proximal balloon occlusion was used. CONCLUSIONS: The proximal and the distal approaches to mechanical thrombectomy proved to be effective at achieving recanalization of cranial vessels. The proximal device is faster in application and allowed repeated attempts with a low complication rate. The DD is more successful at removing thrombotic material, but its method of application and attendant thrombus compaction increase the risk of thromboembolic events and vasospasms.

Human TRPV5 and TRPV6: key players in cadmium and zinc toxicity

TRPV5 and TRPV6 are two major calcium transport pathways in the human body maintaining calcium homeostasis. TRPV5 is mainly expressed in the distal convoluted and connecting tubule where it is the major, regulated pathway for calcium reabsorption. TRPV6 serves as an important calcium entry pathway in the duodenum and the placenta. Previously, we showed that human TRPV6 (hTRPV6) transports several heavy metals. In this study we tested whether human TRPV5 (hTRPV5) also transports cadmium and zinc, and whether hTRPV5 together with hTRPV6 are involved in cadmium and zinc toxicity. The hTRPV5 mRNA and protein were expressed in HEK293 cells transiently transfected with pTagRFP-C1-hTRPV5. The overexpression of the hTRPV5 protein at the plasma membrane was revealed by cell surface biotinylation and immunofluorescence techniques. We observed that both cadmium and zinc permeate hTRPV5 in ion imaging experiments using Fura-2 or Newport Green DCF. Our results were further confirmed using whole-cell patch clamp technique. Transient overexpression of hTRPV5 or hTRPV6 sensitized cells to cadmium and zinc. Toxicity curves of cadmium and zinc were also shifted in hTRPV6 expressing HEK293 cells clones. Our results suggest that TRPV5 and TRPV6 are crucial gates controlling cadmium and zinc levels in the human body especially under low calcium dietary conditions, when these channels are maximally upregulated.

Nickel(II)-, cobalt(II)-, copper(II)-, and zinc(II)-phthalate and 1-methylimidazole coordination compounds: synthesis, crystal structures and magnetic properties

Three new coordination polymers [M(Pht)(1-MeIm)2]n (where M=Cu (1), Zn (2), Co (3); Pht2−=dianion of o-phthalic acid; 1-MeIm=1-methylimidazole) and two compounds [M(1-MeIm)6](HPht)2 · 2H2O (M=Co (4), Ni (5)) have been synthesized and characterized by X-ray crystallography. The structures of 1–3 (2 is isostructural to 3) consist of [M(1-MeIm)2] building units connected by 1,6-bridging phthalate ions to form infinite chains. In complex 1, each copper(II) center adopts a square coordination mode of N2O2 type by two O atoms from different phthalate ions and two N atoms of 1-MeIm, whereas in 3 two independent metal atoms are tetrahedrally (N2O2) coordinated to a pair of Pht ligands and a pair of 1-MeIm molecules. There are only van der Waals interactions between the chains in 1, while the three-dimensional network in 3 is assembled by C–H⋯O contacts. In contrast to polymers 1–3 the structures of 4 and 5 (complexes are also isostructural) are made up of the [M(1-MeIm)6]2+ cation, two hydrogen phthalate anions (HPht−) and two H2O solvate molecules. The coordination around each metal(II) atom is octahedral with six nitrogen atoms of 1-MeIm. Extended hydrogen bonding networks embracing the solvate water molecules and a phthalate residue as well as the weak C–H⋯O interactions stabilize the three-dimensional structures. Magnetic studies clearly show that the magnetic ions do not interact with each other. Furthermore, in compound 4 we have another example of a highly anisotropic Co2+ ion with a rhombic g-tensor and large zero-field-splitting. The complexes were also characterized by IR and 1H NMR spectroscopy, thermogravimetric analysis, and all data are discussed in the terms of known structures.

Comparison of the receptor FGFRL1 from sea urchins and humans illustrates evolution of a zinc binding motif in the intracellular domain

BACKGROUND: FGFRL1, the gene for the fifth member of the fibroblast growth factor receptor (FGFR) family, is found in all vertebrates from fish to man and in the cephalochordate amphioxus. Since it does not occur in more distantly related invertebrates such as insects and nematodes, we have speculated that FGFRL1 might have evolved just before branching of the vertebrate lineage from the other invertebrates (Beyeler and Trueb, 2006). RESULTS: We identified the gene for FGFRL1 also in the sea urchin Strongylocentrotus purpuratus and cloned its mRNA. The deduced amino acid sequence shares 62% sequence similarity with the human protein and shows conservation of all disulfides and N-linked carbohydrate attachment sites. Similar to the human protein, the S. purpuratus protein contains a histidine-rich motif at the C-terminus, but this motif is much shorter than the human counterpart. To analyze the function of the novel motif, recombinant fusion proteins were prepared in a bacterial expression system. The human fusion protein bound to nickel and zinc affinity columns, whereas the sea urchin protein barely interacted with such columns. Direct determination of metal ions by atomic absorption revealed 2.6 mole zinc/mole protein for human FGFRL1 and 1.7 mole zinc/mole protein for sea urchin FGFRL1. CONCLUSION: The FGFRL1 gene has evolved much earlier than previously assumed. A comparison of the intracellular domain between sea urchin and human FGFRL1 provides interesting insights into the shaping of a novel zinc binding domain.

Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases

Meprin and , zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1 , interleukin 18, or tumor growth factor . Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin and a K(i) of 1.1 × 10(-6) M meprin . This correlated with data obtained for a fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin and inhibition (residual activities of 27 and 22%, respectively) at a carp fetuin concentration of 1.5 × 10(-6) M. Human fetuin-A is a negative acute phase protein involved in inflammatory diseases, thus being a potential physiological regulator of meprin activity. We report kinetic studies of fetuin-A with the proteolytic enzymes astacin, LAST, LAST_MAM, trypsin, and chymotrypsin, indeed demonstrating that fetuin-A is a broad-range protease inhibitor. Fetuin-A inhibition of meprin activity was 40 times weaker than that of meprin activity. Therefore, we tested cystatin C, a protein structurally closely related to fetuin-A. Indeed, cystatin C was an inhibitor for human meprin (K(i) = 8.5 × 10(-6) M) but, interestingly, not for meprin . Thus, the identification of fetuin-A and cystatin C as endogenous proteolytic regulators of meprin activity broadens our understanding of the proteolytic network in plasma.

Capitals and capabilities: linking structure and agency to reduce health inequalities

While empirical evidence continues to show that low socio-economic position is associated with less likely chances of being in good health, our understanding of why this is so remains less than clear. In this paper we examine the theoretical foundations for a structure-agency approach to the reduction of social inequalities in health. We use Max Weber's work on lifestyles to provide the explanation for the dualism between life chances (structure) and choice-based life conduct (agency). For explaining how the unequal distribution of material and non-material resources leads to the reproduction of unequal life chances and limitations of choice in contemporary societies, we apply Pierre Bourdieu's theory on capital interaction and habitus. We find, however, that Bourdieu's habitus concept is insufficient with regard to the role of agency for structural change and therefore does not readily provide for a theoretically supported move from sociological explanation to public health action. We therefore suggest Amartya Sen's capability approach as a useful link between capital interaction theory and action to reduce social inequalities in health. This link allows for the consideration of structural conditions as well as an active role for individuals as agents in reducing these inequalities. We suggest that people's capabilities to be active for their health be considered as a key concept in public health practice to reduce health inequalities. Examples provided from an ongoing health promotion project in Germany link our theoretical perspective to a practical experience.

Pharmacotherapy, vaccines and malaria advice for HIV-infected travellers

Since the introduction of effective antiretroviral therapy (ART), HIV-infected individuals are travelling more frequently and international travel has become much safer. Specific concerns include the safety of ART during travel, drug adherence and interaction considerations, and effects of immunosuppression. This review describes potentially important infections, vaccine effectiveness, safety and special approaches for their use, and HIV-related issues regarding predeparture counselling. With advanced immunosuppression (CD4+ T-cell count < 200/microl or < 14%), the immunogenicity of several vaccines is reduced, complications could occur after live attenuated vaccines and certain infections acquired during travel may be more frequent or severe. Challenges include the best options for malaria chemoprophylaxis, standby treatment and medical follow-up of the increasing number of HIV-infected long-term travellers.

Patient satisfaction of primary care for musculoskeletal diseases: A comparison between Neural Therapy and conventional medicine

Background The main objective of this study was to assess and compare patient satisfaction with Neural Therapy (NT) and conventional medicine (COM) in primary care for musculoskeletal diseases. Methods A cross-sectional study in primary care for musculoskeletal disorders covering 77 conventional primary care providers and 18 physicians certified in NT with 241 and 164 patients respectively. Patients and physicians documented consultations and patients completed questionnaires at a one-month follow-up. Physicians documented duration and severity of symptoms, diagnosis, and procedures. The main outcomes in the evaluation of patients were: fulfillment of expectations, perceived treatment effects, and patient satisfaction. Results The most frequent diagnoses belonged to the group of dorsopathies (39% in COM, 46% in NT). We found significant differences between NT and COM with regard to patient evaluations. NT patients documented better fulfilment of treatment expectations and higher overall treatment satisfaction. More patients in NT reported positive side effects and less frequent negative effects than patients in COM. Also, significant differences between NT and COM patients were seen in the quality of the patient-physician interaction (relation and communication, medical care, information and support, continuity and cooperation, facilities availability, and accessibility), where NT patients showed higher satisfaction. Differences were also found with regard to the physicians' management of disease, with fewer work incapacity attestations issued and longer consultation times in NT. Conclusion Our findings show a significantly higher treatment and care-related patient satisfaction with primary care for musculoskeletal diseases provided by physicians practising Neural Therapy.

PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature

The transmembrane ligand ephrinB2 and its cognate Eph receptor tyrosine kinases are important regulators of embryonic blood vascular morphogenesis. However, the molecular mechanisms required for ephrinB2 transduced cellular signaling in vivo have not been characterized. To address this question, we generated two sets of knock-in mice: ephrinB2DeltaV mice expressed ephrinB2 lacking the C-terminal PDZ interaction site, and ephrinB2(5F) mice expressed ephrinB2 in which the five conserved tyrosine residues were replaced by phenylalanine to disrupt phosphotyrosine-dependent signaling events. Our analysis revealed that the homozygous mutant mice survived the requirement of ephrinB2 in embryonic blood vascular remodeling. However, ephrinB2DeltaV/DeltaV mice exhibited major lymphatic defects, including a failure to remodel their primary lymphatic capillary plexus into a hierarchical vessel network, hyperplasia, and lack of luminal valve formation. Unexpectedly, ephrinB2(5F/5F) mice displayed only a mild lymphatic phenotype. Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.

Recent environmental change and trace metal pollution in World Heritage Bathurst Harbour, southwest Tasmania, Australia

Bathurst Harbour in World Heritage southwest Tasmania, Australia, is one of the world’s most pristine estuarine systems. At present there is a lack of data on pollution impacts or long-term natural variability in the harbor. A ca. 350-year-old 210Pb-dated sediment core was analysed for trace metals to track pollution impacts from local and long-range sources. Lead and antimony increased from AD 1870 onwards, which likely reflects remote (i.e. mainland Australian and global) atmospheric pollution sources. Variability in the concentrations of copper and zinc closely followed the history of mining activities in western Tasmania, which began in the AD 1880s. Tin was generally low throughout the core, except for a large peak in AD 1989 ± 0.5 years, which may be a consequence of input from a local small-scale alluvial tin mine. Changes in diatom assemblages were also investigated. The diatom flora was composed mostly of planktonic freshwater and benthic brackish-marine species, consistent with stratified estuarine conditions. Since mining began, however, an overall decrease in the proportion of planktonic to benthic taxa occurred, with the exception of two distinct peaks in the twentieth century that coincided with periods of high rainfall. Despite the region’s remoteness, trace metal analyses revealed evidence of atmospheric pollution from Tasmanian and possibly longer-range mining activities. This, together with recent low rainfall, appears to have contributed to altering the diatom assemblages in one of the most pristine temperate estuaries in the world.

Environmental justice and health practices: understanding how health inequities arise at the local level

While empirical evidence continues to show that people living in low socio-economic status neighbourhoods are less likely to engage in health-enhancing behaviour, our understanding of why this is so remains less than clear. We suggest that two changes could take place to move from description to understanding in this field; (i) a move away from the established concept of individual health behaviour to a contextualised understanding of health practices; and (ii) a switch from focusing on health inequalities in outcomes to health inequities in conditions. We apply Pierre Bourdieu's theory on capital interaction but find it insufficient with regard to the role of agency for structural change. We therefore introduce Amartya Sen's capability approach as a useful link between capital interaction theory and action to reduce social inequities in health-related practices. Sen's capability theory also elucidates the importance of discussing unequal chances in terms of inequity, rather than inequality, in order to underscore the moral nature of inequalities. We draw on the discussion in social geography on environmental injustice, which also underscores the moral nature of the spatial distribution of opportunities. The article ends by applying this approach to the 'Interdisciplinary study of inequalities in smoking' framework.

Modern charge density studies: the entanglement of experiment and theory

This tutorial review article is intended to provide a general guidance to a reader interested to learn about the methodologies to obtain accurate electron density mapping in molecules and crystalline solids, from theory or from experiment, and to carry out a sensible interpretation of the results, for chemical, biochemical or materials science applications. The review mainly focuses on X-ray diffraction techniques and refinement of experimental models, in particular multipolar models. Neutron diffraction, which was widely used in the past to fix accurate positions of atoms, is now used for more specific purposes. The review illustrates three principal analyses of the experimental or theoretical electron density, based on quantum chemical, semi-empirical or empirical interpretation schemes, such as the quantum theory of atoms in molecules, the semi-classical evaluation of interaction energies and the Hirshfeld analysis. In particular, it is shown that a simple topological analysis based on a partition of the electron density cannot alone reveal the whole nature of chemical bonding. More information based on the pair density is necessary. A connection between quantum mechanics and observable quantities is given in order to provide the physical grounds to explain the observations and to justify the interpretations.

The Science of Exoplanets and Their Systems

A scientific forum on “The Future Science of Exoplanets and Their Systems,” sponsored by Europlanet* and the International Space Science Institute (ISSI)† and co-organized by the Center for Space and Habitability (CSH)‡ of the University of Bern, was held during December 5 and 6, 2012, in Bern, Switzerland. It gathered 24 well-known specialists in exoplanetary, Solar System, and stellar science to discuss the future of the fast-expanding field of exoplanetary research, which now has nearly 1000 objects to analyze and compare and will develop even more quickly over the coming years. The forum discussions included a review of current observational knowledge, efforts for exoplanetary atmosphere characterization and their formation, water formation, atmospheric evolution, habitability aspects, and our understanding of how exoplanets interact with their stellar and galactic environment throughout their history. Several important and timely research areas of focus for further research efforts in the field were identified by the forum participants. These scientific topics are related to the origin and formation of water and its delivery to planetary bodies and the role of the disk in relation to planet formation, including constraints from observations as well as star-planet interaction processes and their consequences for atmosphere-magnetosphere environments, evolution, and habitability. The relevance of these research areas is outlined in this report, and possible themes for future ISSI workshops are identified that may be proposed by the international research community over the coming 2–3 years.

Development of the First Fluorescence Screening Assay for the SLC39A2 Zinc Transporter.

Zinc is an essential micronutrient that is crucial for many vital cellular functions such as DNA and protein synthesis, metabolism, and intracellular signaling. Therefore, the intracellular zinc concentration is tightly regulated by zinc transporters and zinc-binding proteins. The members of the SCL39 transporter family transport zinc into the cytosol. The SLC39A2 (hZIP2) protein is highly expressed in prostate epithelial cells and was found to be involved in prostate cancer development. Thus far, there is no specific modulator available for the SLC39 transporters. The aim of this study was to develop a screening assay for compound screening targeting hZIP2. Employing the pIRES2-DsRed Express 2 bicistronic vector, we detected human ZIP2 expression at the plasma membrane in transiently transfected HEK293 cells. Using the FLIPR Tetra fluorescence plate reader, we demonstrated that ZIP2 transports Cd(2+) with an apparent Km value of 53.96 nM at an extracellular pH of 6.5. The cadmium influx via hZIP2 was inhibited by zinc in a competitive manner. We found that hZIP2 activity can be measured using cadmium in the range of 0.1 to 10 µM with our assay. In summary, for the first time we developed an assay for human ZIP2 that can be adapted to other zinc transporters.