Eigenvalue asymptotics for weighted Laplace equations on rough Riemannian manifolds with boundary

Our topological setting is a smooth compact manifold of dimension two or higher with smooth boundary. Although this underlying topological structure is smooth, the Riemannian metric tensor is only assumed to be bounded and measurable. This is known as a rough Riemannian manifold. For a large class of boundary conditions we demonstrate a Weyl law for the asymptotics of the eigenvalues of the Laplacian associated to a rough metric. Moreover, we obtain eigenvalue asymptotics for weighted Laplace equations associated to a rough metric. Of particular novelty is that the weight function is not assumed to be of fixed sign, and thus the eigenvalues may be both positive and negative. Key ingredients in the proofs were demonstrated by Birman and Solomjak nearly fifty years ago in their seminal work on eigenvalue asymptotics. In addition to determining the eigenvalue asymptotics in the rough Riemannian manifold setting for weighted Laplace equations, we also wish to promote their achievements which may have further applications to modern problems

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants.</p

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan–Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p &lt; 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1–5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84–3.25) in deceased donation, and 2.22 (1.25–3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.</p

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level

Thymic stromal lymphopoietin as a novel mediator amplifying immunopathology in rheumatic disease

Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis

Comparison of five in vitro digestion models to study the bio-accessibilty of soil contanminants

Soil ingestion can be a major exposure route for humans to many immobile soil contaminants. Exposure to soil contaminants can be overestimated if oral bioavailability is not taken into account. Several in vitro digestion models simulating the human gastrointestinal tract have been developed to assess mobilization of contaminants from soil during digestion, i.e., bioaccessibility. Bioaccessibility is a crucial step in controlling the oral bioavailability for soil contaminants. To what extent in vitro determination of bioaccessibility is method dependent has, until now, not been studied. This paper describes a multi-laboratory comparison and evaluation of five in vitro digestion models. Their experimental design and the results of a round robin evaluation of three soils, each contaminated with arsenic, cadmium, and lead, are presented and discussed. A wide range of bioaccessibility values were found for the three soils: for As 6−95%, 1−19%, and 10−59%; for Cd 7−92%, 5−92%, and 6−99%; and for Pb 4−91%, 1−56%, and 3−90%. Bioaccessibility in many cases is less than 50%, indicating that a reduction of bioavailability can have implications for health risk assessment. Although the experimental designs of the different digestion systems are distinct, the main differences in test results of bioaccessibility can be explained on the basis of the applied gastric pH. High values are typically observed for a simple gastric method, which measures bioaccessibility in the gastric compartment at low pHs of 1.5. Other methods that also apply a low gastric pH, and include intestinal conditions, produce lower bioaccessibility values. The lowest bioaccessibility values are observed for a gastrointestinal method which employs a high gastric pH of 4.0

The additive inflammatory in vivo and in vitro effects of IL-7 and TSLP in arthritis underscore the therapeutic rationale for dual blockade

Introduction: The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. Methods: Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. Results: Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. Conclusion: TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA

Decreased expression of thymic stromal lymphopoietin in salivary glands of patients with primary Sjögren’s syndrome is associated with increased disease activity

Objectives: Thymic Stromal Lymphopoietin (TSLP) is a potent immunomodulatory cytokine involved in Th2- and Th17-mediated immune responses in different autoimmune diseases. TSLP expression in relation to disease activity was studied in salivary glands of primary Sjögren’s syndrome (pSS) patients as compared to non-SS sicca (nSS) controls. Methods: Tissue sections of minor salivary glands from pSS and nSS patients were stained with monoclonal antibodies against human TSLP, CD3, CD19 and cytokeratin high molecular weight (CK HMW) or stained for Alcian blue to detect mucus production. The number of TSLP-expressing cells was quantified and expression was correlated to local and systemic disease parameters. Results: The number of TSLP-expressing cells was significantly lower in pSS patients than in nSS controls and correlated with a range of disease markers. In pSS patients, TSLP was expressed outside of lymphocytic infiltrates at sections that also encompassed high numbers of intact acinar cells. This difference was independent of tissue destruction. Conclusions: Reduced TSLP expression in pSS patients is associated with increased local and systemic inflammatory markers. Loss of TSLP expression may contribute to Th1/Th17-associated immunopathology in pSS, in line with previous studies demonstrating that TSLP promotes a protective Th2 milieu at mucosal sites