Validation of questionnaire algorithm based on repeated open application testing with the constituents of fragrance mix II:the EDEN Fragrance Study

Background: In a European study on contact allergy in the general population, it has been hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure and thereafter subsequent avoidance of scented products implied a diagnosis of allergic contact dermatitis. Objectives: The primary aim of this study was to validate this hypothesis/algorithm. The secondary aim was to investigate whether there was any association between the outcome of the recent repeated open application test (ROAT) and the patch test reactivity. Methods: One hundred nine subjects with and without contact allergy to fragrance mix II (FM II) were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT. Results: Twenty-four positive ROAT reactions were noted in total including 20 of those 32 with contact allergy to FM II. None of the volunteers reacted to the vehicle (P < 0.001). More individuals with a positive algorithm had positive ROATs when compared with those with a negative algorithm. However, the difference was not statistically significant (P = 0.12). The lower the patch test concentration eliciting a positive test reaction, the more likely was a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period. Conclusions: The algorithm used in this study was not validated but it was indicated in this ROAT setup. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period

Validation of a questionnaire algorithm based on repeated open application testing with the constituents of fragrance mix I

Background In a European study on contact allergy in the general population, it was hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure, and thereafter subsequent avoidance of scented products, implied a diagnosis of allergic contact dermatitis. Objectives The primary aim of this study was to validate this hypothesis and algorithm. The secondary aim was to investigate whether there was any association between the outcome of the repeated open application test (ROAT) and the patch test reactivity. Methods In total, 109 patients with and without contact allergy to fragrance mix (FM) I were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT. Results Positive ROAT reactions were noted in 26 of the 44 volunteers with contact allergy to FM I. None of the volunteers reacted to the vehicle (P <0 center dot 001). More individuals with a positive algorithm had positive ROATs than those with a negative algorithm. However, the difference was not statistically significant. The lower the patch test concentration eliciting a positive test reaction, the more likely a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period. Conclusions The algorithm used in this study was not substantiated in this ROAT set-up. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period. What's already known about this topic? To the best of our knowledge, a scientifically designed and conducted repeated open application test (ROAT) has never been performed before to validate a diagnosis of allergic contact dermatitis partly based on a questionnaire. What does this study add? This is the largest controlled, randomized and blinded ROAT performed to date. Higher patch test reactivity to fragrance mix I indicated a greater likelihood of a positive ROAT

Femoral Adipose Tissue May Accumulate the Fat That Has Been Recycled as VLDL and Nonesterified Fatty Acids

OBJECTIVE: Gluteo-femoral, in contrast to abdominal, fat accumulation appears protective against diabetes and cardiovascular disease. Our objective was to test the hypothesis that this reflects differences in the ability of the two depots to sequester fatty acids, with gluteo-femoral fat acting as a longer-term "sink." RESEARCH DESIGN AND METHODS: A total of 12 healthy volunteers were studied after an overnight fast and after ingestion of a mixed meal. Blood samples were taken from veins draining subcutaneous femoral and abdominal fat and compared with arterialized blood samples. Stable isotope-labeled fatty acids were used to trace specific lipid fractions. In 36 subjects, adipose tissue blood flow in the two depots was monitored with (133)Xe. RESULTS: Blood flow increased in response to the meal in both depots, and these responses were correlated (r(s) = 0.44, P &lt; 0.01). Nonesterified fatty acid (NEFA) release was suppressed after the meal in both depots; it was lower in femoral fat than in abdominal fat (P &lt; 0.01). Plasma triacylglycerol (TG) extraction by femoral fat was also lower than that by abdominal fat (P = 0.05). Isotopic tracers showed that the difference was in chylomicron-TG extraction. VLDL-TG extraction and direct NEFA uptake were similar in the two depots. CONCLUSIONS: Femoral fat shows lower metabolic fluxes than subcutaneous abdominal fat, but differs in its relative preference for extracting fatty acids directly from the plasma NEFA and VLDL-TG pools compared with chylomicron-TG

An Accuracy Assessment of Absolute Gravimetric Observations in Fennoscandia

We compare a suite of absolute gravimeters used to monitor the temporal changes of gravity at a number of sites in Fennoscandia. Direct comparisons are made from simultaneous observations at selected sites within and outside of the postglacial uplift region. We also compare results at sites visited by two instruments with some separation in time. We conclude from four years of data that gravity differences are obtained within an rms error of ± 3 Gal. The data reveal no systematic biases between the instruments, but occasional shifts from one year to another are noted. We consider that annual instrument comparisons are required to ensure data integrity in a regional observing program that extends over more than a decade

Final report of EURAMET.M.G-K3 regional comparison of absolute gravimeters

The regional key comparison of absolute gravimeters, EURAMET.M.G-K3 and the simultaneously organized additional comparison, was held in Germany at the Geodetic Observatory Wettzell of the German Federal Agency for Cartography and Geodesy in the spring of 2018.Here we present the list of the participants who actually performed measurements during the comparison, the data submitted by the operators as well as the results of the determination of the gravity as a function of height at the comparison sites. The measurement strategy is briefly discussed and the results of the data harmonization is documented. Finally, the results of the constrained least squares adjustment are presented including the degrees of equivalence of each gravimeter and the key comparison reference values.Main textTo reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).Export citation and abstract BibTeX RIS

Engineering Bispecificity into a Single Albumin-Binding Domain

Bispecific antibodies as well as non-immunoglobulin based bispecific affinity proteins are considered to have a very high potential in future biotherapeutic applications. In this study, we report on a novel approach for generation of extremely small bispecific proteins comprised of only a single structural domain. Binding to tumor necrosis factor-α (TNF-α) was engineered into an albumin-binding domain while still retaining the original affinity for albumin, resulting in a bispecific protein composed of merely 46 amino acids. By diversification of the non albumin-binding side of the three-helix bundle domain, followed by display of the resulting library on phage particles, bispecific single-domain proteins were isolated using selections with TNF-α as target. Moreover, based on the obtained sequences from the phage selection, a second-generation library was designed in order to further increase the affinity of the bispecific candidates. Staphylococcal surface display was employed for the affinity maturation, enabling efficient isolation of improved binders as well as multiparameter-based sortings with both TNF-α and albumin as targets in the same selection cycle. Isolated variants were sequenced and the binding to albumin and TNF-α was analyzed. This analysis revealed an affinity for TNF-α below 5 nM for the strongest binders. From the multiparameter sorting that simultaneously targeted TNF-α and albumin, several bispecific candidates were isolated with high affinity to both antigens, suggesting that cell display in combination with fluorescence activated cell sorting is a suitable technology for engineering of bispecificity. To our knowledge, the new binders represent the smallest engineered bispecific proteins reported so far. Possibilities and challenges as well as potential future applications of this novel strategy are discussed

Transcriptional Profiling of Chondrodysplasia Growth Plate Cartilage Reveals Adaptive ER-Stress Networks That Allow Survival but Disrupt Hypertrophy

Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology

Regional comparison of absolute gravimeters, EURAMET.M.G-K2 key comparison

In the framework of the regional EURAMET.M.G-K2 comparison of absolute gravimeters, 17 gravimeters were compared in November 2015. Four gravimeters were from different NMIs and DIs, they were used to link the regional comparison to the CCM.G.K2 by means of linking converter. Combined least-squares adjustments with weighted constraint was used to determine KCRV. Several pilot solutions are presented and compared with the official solution to demonstrate influences of different approaches (e.g. definition of weights and the constraint) on results of the adjustment. In case of the official solution, all the gravimeters are in equivalence with declared uncertainties. == Main text To reach the main text of this paper, click on Final Report [http://www.bipm.org/utils/common/pdf/final_reports/M/G-K2/EURAMET.M.G-K2.pdf] . Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/ [http://kcdb.bipm.org/] . The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA)