3D characterization of bone strains in the rat tibia loading model

Bone strain is considered one of the factors inducing bone tissue response to loading. Nevertheless, where animal studies can provide detailed data on bone response, they only offer limited information on experimental bone strains. Including micro-CT-based finite element (micro FE) models in the analysis represents a potent methodology for quantifying strains in bone. Therefore, the main objective of this study was to develop and validate specimen-specific micro FE models for the assessment of bone strains in the rat tibia compression model. Eight rat limbs were subjected to axial compression loading; strain at the medio-proximal site of the tibiae was measured by means of strain gauges. Specimen-specific micro FE models were created and analyzed. Repeated measurements on each limb indicated that the effect of limb positioning was small (COV?= 6.45 ± 2.27 %). Instead, the difference in the measured strains between the animals was high (54.2%). The computational strains calculated at the strain gauge site highly correlated to the measured strains (R ²?=?0.95). Maximum peak strains calculated at exactly 25% of the tibia length for all specimens were equal to 435.11 ± 77.88 microstrains (COV?=?17.19%). In conclusion, we showed that strain gauge measurements are very sensitive to the exact strain gauge location on the bone; hence, the use of strain gauge data only is not recommended for studies that address at identifying reliable relationships between tissue response and local strains. Instead, specimen-specific micro FE models of rat tibiae provide accurate estimates of tissue-level strains.     

Filamin A stabilizes Fc gamma RI surface expression and prevents its lysosomal routing

Filamin A, or actin-binding protein 280, is a ubiquitously expressed cytosolic protein that interacts with intracellular domains of multiple receptors to control their subcellular distribution, and signaling capacity. In this study, we document interaction between FcgammaRI, a high-affinity IgG receptor, and filamin A by yeast two-hybrid techniques and coimmunoprecipitation. Both proteins colocalized at the plasma membrane in monocytes, but dissociated upon FcgammaRI triggering. The filamin-deficient cell line M2 and a filamin-reconstituted M2 subclone (A7), were used to further study FcgammaRI-filamin interactions. FcgammaRI transfection in A7 cells with filamin resulted in high plasma membrane expression levels. In filamin-deficient M2 cells and in filamin RNA-interference studies, FcgammaRI surface expression was consistently reduced. FcgammaRI localized to LAMP-1-positive vesicles in the absence of filamin as shown by confocal microscopy indicative for lysosomal localization. Mouse IgG2a capture experiments suggested a transient membrane expression of FcgammaRI before being transported to the lysosomes. These data support a pivotal role for filamin in FcgammaRI surface expression via retention of FcgammaRI from a default lysosomal pathway.     

Staphylococcal peptidoglycan initiates an inflammatory response and procoagulant activity in human vascular endothelial cells: a comparison with highly purified lipoteichoic acid and TSST-1

Staphylococcus aureus is one of the most significant pathogens in human sepsis and endocarditis. A hallmark of these endovascular S. aureus infections is that the coagulation system is triggered by a tissue factor (TF)-dependent pathway. This study demonstrates that highly purified S. aureus peptidoglycan, lipoteichoic acid (LTA) and TSST-1 increase TF mRNA and TF surface protein in human umbilical vein endothelial cells (ECs). Concomitantly, peptidoglycan- and LTA-activated ECs express significant TF-dependent procoagulant activity (TF PCA). In addition peptidoglycan, but not LTA or TSST-1, induced surface expression of the EC inflammation markers ICAM-1 and VCAM-1, which supported the adhesion of monocytes to these ECs. During the coculture of peptidoglycan-activated ECs and adherent monocytes, a marked additional increase of TF PCA was observed. Marginal increases in TF PCA were observed in cocultures of monocytes with LTA- or TSST-1-activated ECs. This study defines in particular staphylococcal peptidoglycan, previously known as a potent initiator of TF PCA in monocytes, as also being an activator of a coagulant response in human ECs that is further intensified by the presence of surface-bound monocytes.     

Significant association of DRD1 with nicotine dependence

Epidemiologic studies have strongly implicated genetics in smoking behavior. Genes in the dopaminergic system, which mediates the reinforcing and dependence-producing properties of nicotine, are plausible candidates for roles in nicotine dependence (ND). In this study, we examined five single-nucleotide polymorphisms (SNPs) within or near the dopamine D₁ receptor gene (DRD1) for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). The samples were obtained from 2,037 participants representing 200 European American (EA) and 402 African American (AA) families. Although we found significant associations of SNPs rs265973, rs686, and rs4532 in the AA sample; of rs4532 in the EA sample; and of rs265975, rs686, and rs4532 in the pooled sample with various ND measures, only the association of rs686 in the AA sample and of rs686 and rs4532 in the pooled sample remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotype C-T-A, formed by rs265973, rs265975, and rs686, was significantly associated with all three ND measures in both the AA and the pooled sample. Another haplotype, T-A-T, formed by rs265975, rs686, and rs4532, showed a significant association with FTND in the pooled sample. Furthermore, in a luciferase reporter assay, rs686, located in the 3′ untranslated region, caused differential luciferase activities, indicating that rs686 is a functional polymorphism affecting expression of DRD1.     

Modelling the stratum corneum lipid organisation with synthetic lipid mixtures: the importance of synthetic ceramide composition

Cholesterol (CHOL), free fatty acids (FFA) and nine classes of ceramides (CER1-CER9) form the main constituents of the intercellular lipid lamellae in stratum corneum (SC), which regulate the skin barrier function. Both the presence of a unique 13-nm lamellar phase, of which the formation depends on the presence of CER1, and its dense lateral packing are characteristic for the SC lipid organisation. The present study focuses on the lipid organisation in mixtures prepared with CHOL, FFA and a limited number of synthetic CER, namely CER1, CER3 and bovine brain CER type IV (∑CERIV). The main objective is to determine the optimal molar ratio of CER3 to ∑CERIV for the formation of the 13-nm lamellar phase. CER3 contains a uniform acyl chain length, whereas ∑CERIV contains fatty acids with varying chain lengths. Using small angle X-ray diffraction (SAXD), it is demonstrated that the CER3 to ∑CERIV ratio affects the formation of the 13-nm lamellar phase and that the optimal ratio depends on the presence of FFA. Furthermore, the formation of the 13-nm lamellar phase is not very sensitive to variations in the total CER level, which is similar to the in vivo situation.     

Influenza-Like-Illness and Clinically Diagnosed Flu: Disease Burden,Costs and Quality of Life for Patients Seeking Ambulatory Care or No Professional Care at All

This is one of the first studies to (1) describe the out-of-hospital burden of influenza-like-illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011–2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5–6 symptoms over a 6-day period; required 1.6 physician visits and 86–91% took medication. An average episode amounted to €51–€53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries.     

In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis,but Not of Primary Breast Tumors,to mTORC1 Inhibition

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Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8+ T Cell Cross-Priming

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