Holobiont nitrogen control and its potential for eutrophication resistance in an obligate photosymbiotic jellyfish.

BACKGROUND: Marine holobionts depend on microbial members for health and nutrient cycling. This is particularly evident in cnidarian-algae symbioses that facilitate energy and nutrient acquisition. However, this partnership is highly sensitive to environmental change-including eutrophication-that causes dysbiosis and contributes to global coral reef decline. Yet, some holobionts exhibit resistance to dysbiosis in eutrophic environments, including the obligate photosymbiotic scyphomedusa Cassiopea xamachana. METHODS: Our aim was to assess the mechanisms in C. xamachana that stabilize symbiotic relationships. We combined labelled bicarbonate (13C) and nitrate (15N) with metabarcoding approaches to evaluate nutrient cycling and microbial community composition in symbiotic and aposymbiotic medusae. RESULTS: C-fixation and cycling by algal Symbiodiniaceae was essential for C. xamachana as even at high heterotrophic feeding rates aposymbiotic medusae continuously lost weight. Heterotrophically acquired C and N were readily shared among host and algae. This was in sharp contrast to nitrate assimilation by Symbiodiniaceae, which appeared to be strongly restricted. Instead, the bacterial microbiome seemed to play a major role in the holobiont's DIN assimilation as uptake rates showed a significant positive relationship with phylogenetic diversity of medusa-associated bacteria. This is corroborated by inferred functional capacity that links the dominant bacterial taxa (~90 %) to nitrogen cycling. Observed bacterial community structure differed between apo- and symbiotic C. xamachana putatively highlighting enrichment of ammonium oxidizers and nitrite reducers and depletion of nitrogen-fixers in symbiotic medusae. CONCLUSION: Host, algal symbionts, and bacterial associates contribute to regulated nutrient assimilation and cycling in C. xamachana. We found that the bacterial microbiome of symbiotic medusae was seemingly structured to increase DIN removal and enforce algal N-limitation-a mechanism that would help to stabilize the host-algae relationship even under eutrophic conditions. Video abstract.

Infant feeding patterns in families with a diabetes history - observations from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study.

OBJECTIVE: To assess the association between diabetes family history and infant feeding patterns. DESIGN: Data on breast-feeding duration and age at first introduction of cow's milk and gluten-containing cereals were collected in 3-month intervals during the first 24 months of life. SETTING: Data from the multicentre TEDDY (The Environmental Determinants of Diabetes in the Young) study, including centres in the USA, Sweden, Finland and Germany. SUBJECTS: A total of 7026 children, including children with a mother with type 1 diabetes (T1D; n 292), gestational diabetes mellitus (GDM; n 404) or without diabetes but with a father and/or sibling with T1D (n 464) and children without diabetes family history (n 5866). RESULTS: While exclusive breast-feeding ended earlier and cow's milk was introduced earlier in offspring of mothers with T1D and GDM, offspring of non-diabetic mothers but a father and/or sibling with T1D were exclusively breast-fed longer and introduced to cow's milk later compared with infants without diabetes family history. The association between maternal diabetes and shorter exclusive breast-feeding duration was attenuated after adjusting for clinical variables (delivery mode, gestational age, Apgar score and birth weight). Country-specific analyses revealed differences in these associations, with Sweden showing the strongest and Finland showing no association between maternal diabetes and breast-feeding duration. CONCLUSIONS: Family history of diabetes is associated with infant feeding patterns; however, the associations clearly differ by country, indicating that cultural differences are important determinants of infant feeding behaviour. These findings need to be considered when developing strategies to improve feeding patterns in infants with a diabetes family history.

Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

AIMS: The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. METHODS: This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. RESULTS AND CONCLUSION: Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples.

Enrollment experiences in a pediatric longitudinal observational study: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

OBJECTIVE: Our objective was to identify characteristics of infants and their families who were enrolled, refused to enroll, or were excluded from The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHOD: 16,435 infants screened at birth and identified as at increased genetic risk for type 1 diabetes (T1DM) were placed into one of three categories: enrolled, excluded, or refused to enroll. Enrollment, exclusion and refusal rates were compared across countries and between infants from the general population (GP) and infants with a first degree T1DM relative (FDR). A multivariate logistic model was used to identify factors associated with TEDDY enrollment. RESULTS: TEDDY enrollment, exclusion, and refusal rates differed by country and by GP/FDR status but reasons for refusal to enroll were similar across countries and GP/FDR populations. Sweden had the highest enrollment rate, US had the highest exclusion rate, and Finland had the highest refusal rate. FDR infants were more likely to enroll than GP infants. Inability to re-contact the family was the most common reason for exclusion. Primary reasons for refusal to enroll included protocol factors (e.g. blood draws) or family factors (e.g., too busy). Study enrollment was associated with FDR status, European country of origin, older maternal age, a singleton birth, and having another child in TEDDY. CONCLUSIONS: Findings highlight the importance of country specific estimates for enrollment targets in longitudinal pediatric studies and suggest that enrollment estimates should be lowered when the study involves the general population, painful procedures, or makes multiple demands on families.

Phase I clinical and pharmacologic study of weekly cisplatin and irinotecan combined with amifostine for refractory solid tumors.

PURPOSE: This Phase I study was designed primarily to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of irinotecan and cisplatin with and without amifostine in children with refractory solid tumors. PATIENTS AND METHODS: Cisplatin, at a fixed dose of 30 mg/m(2), and escalating doses of irinotecan (starting dose, 40 mg/m(2)) were administered weekly for four consecutive weeks, every 6 weeks. After the MTD of irinotecan plus cisplatin was determined, additional cohorts of patients were enrolled with amifostine (825 mg/m(2)) support. Leukocyte DNA-platinum adducts and pharmacokinetics of cisplatin and WR-1065 (amifostine-active metabolite) were also determined. RESULTS: Twenty-four patients received 43 courses of therapy. The MTD for irinotecan administered in combination with cisplatin (30 mg/m(2)) was 50 mg/m(2). The DLTs of this combination were neutropenia and thrombocytopenia. With the addition of amifostine, at an irinotecan dose of 65 mg/m(2) and cisplatin dose of 30 mg/m(2), the DLT was hypocalcemia. Although no objective responses were observed, six patients received at least three courses of therapy. The amounts of platinum adducts (mean +/- SD) were 10 +/- 20 molecules/10(6) nucleotides. The maximum plasma concentrations (C(max)) for free cisplatin and WR-1065 were 4.5 +/- 1.6 micro M and approximately 89 +/- 10 micro M, respectively. The half-life (t(1/2)) for free plasma cisplatin was 25.4 +/- 5.4 min. The initial t(1/2) for plasma WR-1065 was approximately 7 min and terminal t(1/2) approximately 24 min. CONCLUSION: The combination of cisplatin and irinotecan administered weekly for 4 weeks in children with refractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >/=30% dose escalation for irinotecan, when administered in a combination regimen with cisplatin. However, effective antiemetics and calcium supplementation are necessary with the use of amifostine. Further escalation of irinotecan dosing, using these precautions for amifostine administration, may be possible.