Pneumococcal Polysaccharide Vaccine Ameliorates Murine Lupus

Current guidelines encourage administering pneumococcal vaccine Prevnar-13 to patients with lupus, but whether such vaccinations affect disease severity is unclear. To address this issue, we treated 3-month-old MRL-lpr mice, that spontaneously develop a lupus-like syndrome, with Prevnar-13 or vehicle control. After 3 months, we quantified circulating anti-Pneumococcal polysaccharide capsule (PPS) antibodies and signs of disease severity, including albuminuria, renal histology and skin severity score. We also compared immunophenotypes and function of T and B cells from treated and untreated animals. Prevnar-13 elicited the formation of anti-pneumococcal IgM and IgG. Prevnar-13 treated animals showed reduced albuminuria, renal histological lesions, and milder dermatitis compared to vehicle-treated controls. Mitigated disease severity was associated with reduced and increased T follicular helper cells (TFH) and T follicular regulatory cells (TFR), respectively, in Prevnar-treated animals. T cells from Prevnar-13 vaccinated mice showed differential cytokine production after aCD3/aCD28 stimulation, with significantly decreased IL-17 and IL-4, and increased IL-10 production compared to non-vaccinated mice. In conclusion, pneumococcal vaccination elicits anti-pneumococcal antibody response and ameliorates disease severity in MRL-lpr mice, which associates with fewer TFH and increased TFR. Together, the data support use of Prevnar vaccination in individuals with SLE

Dietary exposure to pesticide residues and associated health risks in infants and young children – Results of the French infant total diet study

A total diet study (TDS) was undertaken to estimate the chronic dietary exposure to pesticide residues and health risks for the French infants and young children below 3 years old. As a whole, 516 pesticides and metabolites were analysed in 309 food composite samples including 219 manufactured baby foods and 90 common foods, which cover 97% of infants and young children's diet. These composite samples were prepared using 5,484 food products purchased during all seasons from 2011 to 2012 and processed as consumed. Pesticide residues were detected in 67% of the samples and quantified in 27% of the baby food samples and in 60% of the common foods. Seventy-eight different pesticides were detected and 37 of these quantified at levels ranging from 0.02 to 594 µg/kg. The most frequently detected pesticides (greater than 5% samples) were (1) the fungicides 2-phenylphenol, azoxystrobin, boscalid, captan and its metabolite tetrahydrophthalimide, carbendazim, cyprodinil, difenoconazole, dodine, imazalil, metalaxyl, tebuconazole, thiabendazole, (2) the insecticides acetamiprid, pirimiphos-methyl and thiacloprid, (3) the herbicide metribuzin and (4) the synergist piperonyl butoxide. Dietary intakes were estimated for each of the 705 individuals studied and for 431 pesticides incl. 281 with a toxicological reference value (TRV). In the lower-bound scenario, which tends to underestimate the exposure, the TRV were never exceeded. In the upper-bound scenario that overestimates exposure, the estimated intakes exceeded the TRV for dieldrin and lindane (two persistent organic pollutants) and propylene thiourea, a metabolite of propineb. For these three substances, more sensitive analyses are needed to refine the assessment. For 17 other detected and/or prioritised pesticides, the risk could not be characterised due to the lack of a valid TRV, of certain food analyses or the absence of analytical standards for their metabolites. Keywords: Food safety, Infants and young children, Pesticide residues, Total diet study, Exposure assessment, Risk characterizatio

Chronic Dietary Exposure to a Low-Dose Mixture of Genistein and Vinclozolin Modifies the Reproductive Axis, Testis Transcriptome, and Fertility

Background: The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood.[br/] Objective: We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility.[br/] Methods: Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays.[br/] Results: The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the “neuroactive ligand-receptor interactions” family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production.[br/] Conclusions: Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose—albeit not environmental—of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility

Degradation dynamics and dissipation kinetics of an imidazole fungicide (Prochloraz) in aqueous medium of varying pH

Laboratory degradation studies were performed in water at pH 4.0, 7.0 and 9.2 using Prochloraz (450 EC) formulation at the concentration of 1.0 (T1) and 2.0 (T2) µg/mL. Water samples collected on 0 (2 h), 3, 7, 15, 30, 45, 60 and 90 days after treatments were processed for residue analysis of Prochloraz by HPLC-UV detector. In 60 days, dissipation was 89.1–90.5% at pH 4.0, 84.1–88.2% at pH 7.0, and 92.4–93.8% at pH 9.2 in both treatments. The results indicate that at pH 7.0 the degradation of Prochloraz was much slower as compared to other two. Between pH 4.0 and 9.2 the degradation of compound is little faster at pH 9.2. The half-life periods observed were 18.35 and 19.17 days at pH 4.0, 22.6 and 25.1 days at pH 7.0 and 15.8 and 16.6 days at pH 9.2 at T1 and T2 doses respectively

The Human Pancreas as a Source of Protolerogenic Extracellular Matrix Scaffold for a New-generation Bioartificial Endocrine Pancreas

OBJECTIVES: Our study aims at producing acellular extracellular matrix scaffolds from the human pancreas (hpaECMs) as a first critical step toward the production of a new-generation, fully human-derived bioartificial endocrine pancreas. In this bioartificial endocrine pancreas, the hardware will be represented by hpaECMs, whereas the software will consist in the cellular compartment generated from patient's own cells. BACKGROUND: Extracellular matrix (ECM)-based scaffolds obtained through the decellularization of native organs have become the favored platform in the field of complex organ bioengineering. However, the paradigm is now switching from the porcine to the human model. METHODS: To achieve our goal, human pancreata were decellularized with Triton-based solution and thoroughly characterized. Primary endpoints were complete cell and DNA clearance, preservation of ECM components, growth factors and stiffness, ability to induce angiogenesis, conservation of the framework of the innate vasculature, and immunogenicity. Secondary endpoint was hpaECMs’ ability to sustain growth and function of human islet and human primary pancreatic endothelial cells. RESULTS: Results show that hpaECMs can be successfully and consistently produced from human pancreata and maintain their innate molecular and spatial framework and stiffness, and vital growth factors. Importantly, hpaECMs inhibit human naïve CD4+ T-cell expansion in response to polyclonal stimuli by inducing their apoptosis and promoting their conversion into regulatory T cells. hpaECMs are cytocompatible and supportive of representative pancreatic cell types. DISCUSSION: We, therefore, conclude that hpaECMs has the potential to become an ideal platform for investigations aiming at the manufacturing of a regenerative medicine-inspired bioartificial endocrine pancreas

Rapid biolayer interferometry measurements of urinary CXCL9 to detect cellular infiltrates noninvasively after kidney transplantation

Introduction: measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. Methods: we developed a biolayer interferometry (BLI)−based assay to rapidly measure urinary CXCL9 in 200 pg/ml in subjects with ACR and ≤100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. Discussion: together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients

Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies

Introduction: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. Methods: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan–Meier estimator. Results: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R2 0.072; C3d: adjusted R2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q−) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q−) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30–1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d−); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d−) years; HR 0.38; 95% CI 0.15–0.97; p = 0.04]. Conclusion: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction

Survival in Southern European patients waitlisted for kidney transplant after graft failure: A competing risk analysis

Background Whether patients waitlisted for a second transplant after failure of a previous kidney graft have higher mortality than transplant-näive waitlisted patients is uncertain. Methods We assessed the relationship between a failed transplant and mortality in 3851 adult KT candidates, listed between 1984–2012, using a competing risk analysis in the total population and in a propensity score-matched cohort. Mortality was also modeled by inverse probability weighting (IPTW) competing risk regression. Results At waitlist entry 225 (5.8%) patients had experienced transplant failure. All-cause mortality was higher in the post-graft failure group (16% vs. 11%; P = 0.033). Most deaths occurred within three years after listing. Cardiovascular disease was the leading cause of death (25.3%), followed by infections (19.3%). Multivariate competing risk regression showed that prior transplant failure was associated with a 1.5-fold increased risk of mortality (95% confidence interval [CI], 1.01–2.2). After propensity score matching (1:5), the competing risk regression model revealed a subhazard ratio (SHR) of 1.6 (95% CI, 1.01–2.5). A similar mortality risk was observed after the IPTW analysis (SHR, 1.7; 95% CI, 1.1–2.6). Conclusions Previous transplant failure is associated with increased mortality among KT candidates after relisting. This information is important in daily clinical practice when assessing relisted patients for a retransplant.This study was supported in part by the Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional±FEDER, RETICS (REDINREN RD16/0009/0006, RD16/0009/0031

Growth Hormone Improves Growth Retardation Induced by Rapamycin without Blocking Its Antiproliferative and Antiangiogenic Effects on Rat Growth Plate

Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis