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Gerrit Kann,1,* Junaid Owasil,1,* Karina Kuczka,2 Annette Haberl,1 Timo Wolf,1 Pavel Khaykin,1 Sebastian Harder,2 Christoph Stephan,1 Nils von Hentig1 1HIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany; 2Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany*These authors contributed equally to this workCorrespondence: Nils von HentigHIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, GermanyTel +49-69-63017680Fax +49-69-630183442Email Hentig@em.uni-frankfurt.deBackground: In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks.Methods: The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin α-IIb/Integrin β-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses.Results: CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation.Conclusion: CD62P expression, detecting the ɑ-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART.Clinical Trial Registration No.: DRKS00000288.Keywords: HIV protease inhibitors, platelets, leucocytes, PAC-1, GIIb/IIIa-receptor

A complex of a metal in its zero oxidation state can be considered a stabilized, but highly reactive, form of a single metal atom. Such complexes are common for the more noble transition metals. Although rare examples are known for electronegative late-main-group p-block metals or semimetals.sup.1-6, it is a challenge to isolate early-main-group s-block metals in their zero oxidation state.sup.7-11. This is directly related to their very low electronegativity and strong tendency to oxidize. Here we present examples of zero-oxidation-state magnesium (that is, magnesium(0)) complexes that are stabilized by superbulky, monoanionic, [beta]-diketiminate ligands. Whereas the reactivity of an organomagnesium compound is typically defined by the nucleophilicity of its organic groups and the electrophilicity of Mg.sup.2+ cations, the Mg.sup.0 complexes reported here feature electron-rich Mg centres that are nucleophilic and strongly reducing. The latter property is exemplified by the ability to reduce Na.sup.+ to Na.sup.0. We also present a complex with a linear Mg.sub.3 core that formally could be described as a Mg.sup.I-Mg.sup.0-Mg.sup.I unit. Such multinuclear mixed-valence Mg.sub.n clusters are discussed as fleeting intermediates during the early stages of Grignard reagent formation. Their remarkably strong reducing power implies a rich reactivity and application as specialized reducing agents. Strongly reducing [beta]-diketiminate complexes containing magnesium in its zero oxidation state are reported, among which is a compound with a linear triatomic Mg-Mg-Mg core., Author(s): B. Rösch [sup.1] , T. X. Gentner [sup.1] , J. Eyselein [sup.1] , J. Langer [sup.1] , H. Elsen [sup.1] , S. Harder [sup.1] Author Affiliations: (1) Department of [...]

A test stand for the next generation of the Silicon Vertex Detector (SVX-II) of the Collider Detector Facility (CDF) at Fermilab has been developed. It is capable of performing cosmic ray, beam, and laser pulsing tests on silicon strip detectors using the new generation of SVX chips. The test stand is composed of a SGI workstation, a VME CPU, the Silicon Test Acquisition and Readout (STAR) board, the Test Fiber Interface Board (TFIB), and the Test Port Card (TPC). The STAR mediates between external stimuli for the different tests and produces appropriate high level commands which are sent to the TFIB. The TFIB, in conjunction with the TPC, translates these commands into the correct logic levels to control the SVX chips. The four modes of operation of the SVX chips are configuration, data acquisition, digitization, and data readout. The data read out from the SVX chips is transferred to the STAR. The STAR can then be accessed by the VME CPU and the SGI workstation for future analyses. The detailed description of this test stand will be given.

PURPOSE: The purpose of this study was to evaluate and to compare the bone-cutting performance and intraosseous temperature development of three modern ultrasonic devices for bone surgery (UDBS). MATERIALS AND METHODS: The following UDBS and associated cutting tips (straight bone saws) were used in this study: (1) Piezosurgery II professional, tip OT 7 (Mectron); (2) Piezotome, tip BS 1 (Acteon); and (3) SurgySonic, tip ES007 (American Dental Systems/Gunther Jerney). In the experimental setup UDBS, handpieces were immobilized, and bone specimens from the middiaphysis of a bovine femur were moved in a longitudinal direction under the cutting tip to a standardized depth of 3.0 mm. Intraosseous temperature development was measured using a glass-fiber isolated thermocouple. The cutting performance was defined by the time required to reach the cutting depth of 3.0 mm. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: The median increase (25th through 75th percentiles) of the local intraosseous temperature was 3.0 degrees C (2.2 degrees C to 4.2 degrees C) for the SurgySonic, 2.2 degrees C (1.8 degrees C to 3.2 degrees C) for the Piezosurgery II, and 1.1 degrees C (0.7 degrees C to 1.6 degrees C) for the Piezotome. The median cutting performance was 0.31 mm/s (0.11 to 0.46 mm/s) for the Piezotome, 0.25 mm/s (0.23 to 0.27 mm/s) for the Piezosurgery II, and 0.04 mm/s (0.03 to 0.05 mm/s) for the SurgySonic. CONCLUSIONS: Among the three tested UDBS, the Piezotome and the Piezosurgery II showed a significantly higher cutting performance than the SurgySonic. The Piezotome produced the smallest increase in intraosseous temperature. [ABSTRACT FROM AUTHOR]

Objective: The home environment provided by the caregivers of a child is an influential single factor for development and well‐being. We aimed to compare the quality of the home environment of children at familial high risk of schizophrenia or bipolar disorder with population‐based controls. Methods: Danish nationwide registers were used to retrieve a cohort of 522 7‐year‐old children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) or none of these diagnoses (N = 200). The home environment was assessed using the Middle Childhood‐Home Observation for Measurement of the Environment Inventory (MC‐HOME Inventory). Results: The proportion of children living in home environments that were evaluated not to meet the needs of a 7‐year‐old child was significantly larger in the two familial high‐risk groups. This was true for 21% of the children with familial predisposition for schizophrenia and 7% of children with familial disposition for bipolar disorder. Conclusion: Children born to parents diagnosed with schizophrenia and to a lesser extent bipolar disorder are at an increased risk of growing up in a home environment with an insufficient level of stimulation and support. Identifying families with inadequate home environments is a necessary step towards specialized help and support to at‐risk families. [ABSTRACT FROM AUTHOR]

The Arctic is a sensitive region in terms of climate change and a rich natural resource for global economic activity. Arctic shipping is an important contributor to the region's anthropogenic air emissions, including black carbon - a short-lived climate forcing pollutant especially effective in accelerating the melting of ice and snow. These emissions are projected to increase as declining sea ice coverage due to climate change allows for increased shipping activity in the Arctic. To understand the impacts of these increased emissions, scientists and modelers require high-resolution, geospatial emissions inventories that can be used for regional assessment modeling. This paper presents 5 km×5 km Arctic emissions inventories of important greenhouse gases, black carbon and other pollutants under existing and future (2050) scenarios that account for growth of shipping in the region, potential diversion traffic through emerging routes, and possible emissions control measures. Short-lived forcing of ~4.5 gigagrams of black carbon from Arctic shipping may increase climate forcing; a first-order calculation of global warming potential due to 2030 emissions in the high-growth scenario suggests that short-lived forcing of ~4.5 gigagrams of black carbon from Arctic shipping may increase climate forcing due to Arctic ships by at least 17% compared to warming from these vessels' CO2 emissions (~42 000 gigagrams). The paper also presents maximum feasible reduction scenarios for black carbon in particular. These emissions reduction scenarios will enable scientists and policymakers to evaluate the efficacy and benefits of technological controls for black carbon, and other pollutants from ships. [ABSTRACT FROM AUTHOR]

Ice core records show atmospheric methane mixing ratio and interpolar gradient varying with climate. Changes in wetland sources have been implicated as the basis for this observed variation in the record, but more recently, modeling studies suggest that changes in the CH4 sink resulting from changes in sea surface temperature (SST) and emissions of other volatile organic carbon (VOC) compounds by vegetation must also be considered. We use the Goddard Institute for Space Studies (GISS) General Circulation Model (GCM) with the GISS Tropospheric Chemistry Model to study the response of the methane mixing ratio to source changes during the Holocene and also to a changing chemical sink during glacial-interglacial transitions. We combine model results with ice core data to demonstrate a method that provides constraints on changes in northern and tropical methane sources. Results show that within the Holocene, changes in the atmospheric methane mixing ratio and latitudinal gradient are not linear with respect to changing methane emissions. Tropical and northern emissions varied from preindustrial levels by as much as 38% and 15%, respectively, within the Holocene. At glacial-interglacial transitions the methane mixing ratio is sensitive to changes in both VOC and tropical methane emissions and the sensitivity also depends strongly on the assumed SST shift. Our findings suggest that changes in the ice core methane record are likely the result of changes in both the source and the sink. Changes in the sink become especially important when changes in methane mixing ratio and/or climate are large. [ABSTRACT FROM AUTHOR]

The Retention Index Test Homburg (RTH-II) is quoted to detect effects of shear stress on platelets, which involve ADP receptor signaling. RTH-II might be a tool for monitoring antiplatelet therapy for compounds that interfere with ADP induced platelet activation and secretion. In a series of investigations, we used an ADP (2  µM) triggered RTH-II in parallel with light-transmittance aggregometry and flow cytometry in subjects before and after clopidogrel. A loading dose of 225  mg clopidogrel leads to a significant reduction ( p    12 -inhibitors on platelet degranulation, perhaps in addition to aggregometry. [ABSTRACT FROM AUTHOR]

Introduction: Formation of platelet-leukocyte aggregates (PLA) via the CD62p-ligand PSGL-1 represents an important mechanism by which leukocytes contribute to thrombotic and inflammatory events. Deficient variants (namely the Thr715Pro- SNP for CD62p and a VNTR-polymorphism for PSGL-1) might affect PLA formation and probably the response to clopidogrel (which is known to reduce PLA-formation). Methods: CD62p-expression, PLA-formation and the up-regulation of CD11b before (V1) and 24 hours after (V2) a loading dose of clopidogrel 225 mg were investigated in ten wild-type controls, ten heterozygote carriers of the Thr715Pro-allele and five carriers of the rare PSGL-1 B-allele (2 A/B and 3 B/B). Results: CD62p-expression before application of clopidogrel and under clopidogrel treatment in Pro715-haplotype samples did not differ from that in wild-type subjects. The response to clopidogrel was similar in all subjects. Pro715-carriers exhibited a significantly lower percent age of monocytes with platelets attached prior to clopidogrel treatment (ADP: median 22 (1st – 3rd quartile 20 – 23), TRAP: 27 (25 – 38)) compared to the wild-type (ADP: 37 (31 – 44), TRAP: 55 (37 – 63)). These differences were not present under clopidogrel, and CD11b-expression was significantly reduced in both groups (controls: median 150 (quartile range 121 – 230) to 113 (121 – 230), Pro715-carriers: 147 (139 – 221) to 126 (109 – 170); all values refer to mean fluorescence intensity). Statistical analysis was not done in the case of PSGL-1 B-allele carriers, but PLA-formation be fore and under clopidogrel was always at the bottom end of the range seen in the control group and the Pro715-carriers or even below this range. Conclusion: Minor phenotypic differences in the CD62p-PSGL-1 axis could be demonstrated in this study. Carriers of these polymorphisms showed a full response to clopidogrel comparable to that in control subjects. [ABSTRACT FROM AUTHOR]

Although the administration of recombinant coagulation factor VIIa (rFVIIa) is a well established treatment in haemophilia with inhibitory antibodies, monitoring the therapeutic efficacy is still a problem. This is because the complete haemostatic effect in vivo depends on negatively charged surfaces provided by exposed lipids from activated platelets which are not present in standard clinical assays using plasma. The thrombin generation assay, however, measures the endogenous thrombin potential (ETP) in platelet-rich plasma (PRP) and this assay might be useful for monitoring the haemostatic response to rFVIIa. We characterized the in vitro concentration-response relationship of rFVIIa and the thrombin generation parameters ETP, PEAK and TIME TO PEAK using platelet-rich plasma (PRP) and rFVIIa at concentrations between one and five times the therapeutic dose. We also studied the effect of inhibiting tissue-factor and the intrinsic coagulation pathway using excess TF-neutralizing antibodies and corn trypsin inhibitor (CTI), respectively. There was a sigmoid relationship between ETP and PEAK and the dose of rFVIIa. Increasing rFVIIa concentrations between 100 and 500 U/ml resulted in a progressive increase in ETP, whereas supratherapeutical concentrations led to a plateau phase. The plateau phase differed between patients, suggesting a biological variation in the maximum ETP. Neutralization of plasma TF with TF-Ab partially decreased FVIIa efficacy. The inhibitory effect of CTI on rFVIIa-induced thrombin generation via the intrinsic pathway was negligible. The thrombin generation assay using PRP is a useful test for determining the sufficient efficacy of rFVIIa in blood. Once a plateau level is reached, higher doses of rFVIIa have no additional effect on haemostatic efficacy. The variation in plateau levels between subjects indicates that there are inter-individual differences in the level of thrombin activity that can be generated. High doses of rFVIIa are effective even in the absence of TF. [ABSTRACT FROM AUTHOR]