New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop ...in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.
We found, in 1994, that the epitope for anticardiolipin antibodies (aCL) developed when β2-glycoprotein I (β2GPI) was adsorbed on polyoxygenated polystyrene plates. We also found, in 2009, that the ...cleaved form of β2GPI (nicked β2GPI) was bound to angiostatin 4.5 and attenuated its antiangiogenic property. We described in 2000 that antiprothrombin antibodies were bound to prothrombin exposed to immobilized phosphatidylserine (aPS/PT) and more than 95% of antiphospholipid syndrome patients who were positive for aPS/PT had lupus anticoagulant. We demonstrated that in the cells stimulated by human monoclonal anti-β2GPI antibodies, p38 mitogen-activated protein kinase phosphorylation was observed in the presence of β2GPI. Furthermore, we found that complement activation was essential for thrombus formation in patients with the antiphospholipid syndrome in vivo.
ABSTRACT Verticillium dahliae is responsible for Verticillium wilt on a wide range of hosts, including strawberry, on which low soil inoculum densities can cause significant crop loss. Determination ...of inoculum density is currently done by soil plating but this can take 6 to 8 weeks to complete and delay the grower's ability to make planting decisions. To provide a faster means for estimating pathogen populations in the soil, a multiplexed TaqMan real-time polymerase chain reaction (PCR) assay based on the ribosomal DNA (rDNA) intergenic spacer (IGS) was developed for V. dahliae. The assay was specific for V. dahliae and included an internal control for evaluation of inhibition due to the presence of PCR inhibitors in DNA extracted from soil samples. An excellent correlation was observed in regression analysis (R(2) = 0.96) between real-time PCR results and inoculum densities determined by soil plating in a range of field soils with pathogen densities as low as 1 to 2 microsclerotia/g of soil. Variation in copy number of the rDNA was also evaluated among isolates by SYBR Green real-time PCR amplification of the V. dahliae-specific amplicon compared with amplification of several single-copy genes and was estimated to range from ≈24 to 73 copies per haploid genome, which translated into possible differences in results among isolates of ≈1.8 cycle thresholds. Analysis of the variation in results of V. dahliae quantification among extractions of the same soil sample indicated that assaying four replicate DNA extractions for each field sample would provide accurate results. A TaqMan assay also was developed to help identify colonies of V. tricorpus on soil plates.
We present a novel method for simulating liquid with asynchronous time steps on Eulerian grids. Previous approaches focus on Smoothed Particle Hydrodynamics (SPH), Material Point Method (MPM) or ...tetrahedral Finite Element Method (FEM) but the method for simulating liquid purely on Eulerian grids have not yet been investigated. We address several challenges specifically arising from the Eulerian asynchronous time integrator such as regional pressure solve, asynchronous advection, interpolation, regional volume preservation, and dedicated segregation of the simulation domain according to the liquid velocity. We demonstrate our method on top of staggered grids combined with the level set method and the semi‐Lagrangian scheme. We run several examples and show that our method considerably outperforms the global adaptive time step method with respect to the computational runtime on scenes where a large variance of velocity is present.
Anticardiolipin antibodies (aCL) in the sera of patients with antiphospholipid syndrome (APS) recognize an altered structure of β2‐glycoprotein I (β2‐GPI) interacting with solid‐phase negatively ...charged phospholipids. β2‐GPI bound to Cu2+‐oxidized plasma lipoproteins, i.e. oxidized very low‐density lipoprotein (oxVLDL), oxidized low‐density lipoprotein (oxLDL), or oxidized high‐density lipoprotein (oxHDL). β2‐GPI inhibited in vitro uptake, i.e. cell surface binding, cellular association, and proteolytic degradation of oxLDL by murine macrophage J774A.1 cells. The binding of oxLDL to the macrophages was inhibited by the addition of polyinosinic acid (poly (I)), a competitor of the scavenger receptor, but not by another polyanionic acid, polycytidylic acid (poly (C)). Conversely, the binding of oxLDL was significantly increased by the simultaneous addition of human β2‐GPI and monoclonal aCL derived from NZW × BXSB F1 (WB F1) mice, an animal model of APS, or anti‐β‐GPI antibodies from BALB/c mice immunized with human β2‐GPI. These findings indicate that β2‐GPI may be an anti‐atherogenic protein and that the autoimmune response against β2‐GPI may have a role in the development of atherosclerosis in APS.
Abstract It has been shown that Wallerian degeneration, an anterograde degeneration of transected axons, is markedly delayed in a mutant mouse called slow Wallerian degeneration ( Wld S ). These mice ...also show resistance to axonal degeneration caused by microtubule depolymerizing drugs, suggesting that axonal microtubules are stabilized. Here, we have focused on tubulin acetylation, a post-translational modification associated with microtubule stability. We found that the basal level of microtubule acetylation was increased in cultured cerebellar granule cells from Wld S mice. Nicotinamide but not 3-aminobenzamide, an inhibitor for poly(ADP)ribose polymerase, enhanced tubulin acetylation and resistance to axonal degeneration in cultured cerebellar granule cells from wild-type (WT) mice, suggesting that mammalian Sir2-related protein (SIRT) 2, a nicotinamide adenine dinucleotide (NAD)–dependent tubulin deacetylase, could modulate resistance to axonal degeneration. Indeed, the levels of NAD and SIRT2 were decreased in the cytoplasm from Wld S granule cells. Moreover, SIRT2 overexpression abrogated microtubule hyperacetylation and resistance to axonal degeneration in these cells. Conversely, SIRT2 knockdown by using a lentiviral vector expressing small interfering RNA, enhanced microtubule acetylation and resistance to axonal degeneration in WT granule cells. Taken together, these results suggest that SIRT2-mediated tubulin deacetylation is involved in both microtubule hyperacetylation and resistance to axonal degeneration in Wld S granule cells.
Background Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low ...disease activity (LDA) is important for safety and economic reasons. Objective To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. Methods 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. Results The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated ΔmTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. Conclusion After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.
It has been revealed that spontaneous coherent brain activity during rest, measured by functional magnetic resonance imaging (fMRI), self-organizes a “small-world” network by which the human brain ...could sustain higher communication efficiency across global brain regions with lower energy consumption. However, the state-dependent dynamics of the network, especially the dependency on the conscious state, remain poorly understood. In this study, we conducted simultaneous electroencephalographic recording with resting-state fMRI to explore whether functional network organization reflects differences in the conscious state between an awake state and stage 1 sleep. We then evaluated whole-brain functional network properties with fine spatial resolution (3781 regions of interest) using graph theoretical analysis. We found that the efficiency of the functional network evaluated by path length decreased not only at the global level, but also in several specific regions depending on the conscious state. Furthermore, almost two-thirds of nodes that showed a significant decrease in nodal efficiency during stage 1 sleep were categorized as the default-mode network. These results suggest that brain functional network organizations are dynamically optimized for a higher level of information integration in the fully conscious awake state, and that the default-mode network plays a pivotal role in information integration for maintaining conscious awareness.
In 2006 and 2007, severely diseased strawberry (Fragaria × ananassa) plants were observed in five commercial fields in southern California (Orange County). Disease generally occurred in discrete ...patches. Within such patches, disease incidence ranged from 10 to 75%. Symptoms consisted of wilting of foliage, drying and death of older leaves, plant stunting, and eventual collapse and death of plants. When plant crowns were dissected, internal vascular and cortex tissues were dark brown to orange brown. Fruiting bodies or other fungal structures were not observed. A fungus was consistently isolated from symptomatic crown tissue that had been surface sterilized and placed on acidified corn meal agar (LA-CMA). All isolates produced numerous, dark, irregularly shaped sclerotia that were 67 to 170 μm long and 44 to 133 μm wide. When isolates were grown on 1.5% water agar with dried and sterilized wheat straw, dark, ostiolate pycnidia and hyaline, single-celled, cylindrical conidia were produced. On the basis of these characters, all isolates were identified as Macrophomina phaseolina (1). The symptomatic plants tested negative for Colletotrichum spp., Phytophthora spp., Verticillium dahliae, and other pathogens. Inoculum for pathogenicity tests was produced by growing six isolates on CMA on which sterilized wood toothpicks were placed on the agar surface. After 1 week, toothpicks were removed and inserted 4 to 5 mm deep into the basal crown tissue of potted strawberry plants (cv. Camarosa) grown in soilless, peatmoss-based rooting medium. Ten plants were inoculated per isolate and one toothpick was inserted per plant. Ten control strawberry plants were treated by inserting one sterile toothpick into each crown. All plants were then grown in a shadehouse. After 2 weeks, all inoculated plants began to show wilting and decline of foliage. By 4 weeks, all inoculated plants had collapsed. Internal crown tissue was discolored and similar in appearance to the original field plants. M. phaseolina was isolated from all inoculated plants. Control plants did not exhibit any disease symptoms, and crown tissue was symptomless. The test was repeated and the results were similar. While M. phaseolina has been periodically associated with strawberry in California (3), to my knowledge, this is the first report of charcoal rot disease on commercial strawberry in California. Charcoal rot of strawberry has been reported in Egypt, France, India, Israel, and the United States (Florida and Illinois) (2,4). Similar to previous reports (2,4), many of the affected California fields were not preplant fumigated with methyl bromide + chloropicrin fumigants, and it is possible that under these changing production practices this pathogen may increase in importance in California. References: (1) P. Holliday and E. Punithalingam. No. 275 in: Descriptions of Pathogenic Fungi and Bacteria. CMI, Kew, Surrey, UK, 1970. (2) J. Mertely et al. Plant Dis.89:434, 2005. (3) S. Wilhelm. Plant Dis. Rep. 41:941, 1957. (4) A. Zveibil and S. Freeman. Plant Dis. 89:1014, 2005.
Objective An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real ...world. Methods This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. Results Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. Conclusions Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit–risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.
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