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Single High-Dose Vitamin A Supplementation to Neonatal Piglets Results in a Transient Dose Response in Extrahepatic Organs and Sustained Increases in Liver Stores.

ABSTRACT: Background: Neonatal vitamin A (VA) supplementation is being evaluated as a public health policy for preventing infant mortality, but inconsistencies in mortality trials demand mechanistic work to determine biological plausibility.Objectives: We investigated the absorption, distribution, and storage of single large oral VA doses administered shortly after birth.Methods: Fifty pregnant sows (Sus scrofas domesticas) were fed a VA-free diet. Male and female newborn piglets (n = 313) were orally administered 0, 25,000, 50,000, or 200,000 IU VA in oil within 12 h of birth when mean ± SD weight was 1.56 ± 0.25 kg. Blood was drawn to determine absorption and storage 0.5-240 h after administration. Metabolic and postnatal dose-timing substudies were performed. Liver, lung, kidney, spleen, and adrenal VA concentrations were determined 7-240 h after administration.Results: Serum retinol and retinyl ester concentrations responded to treatment (P < 0.0001); however, differences between groups disappeared by 96 h. Liver VA concentrations responded to treatment (P < 0.0001), which persisted for 240 h. Liver VA for control piglets at 10 d (mean ± SD: 0.05 ± 0.02 ?mol/g) was ?0.1 ?mol/g (deficiency), whereas groups that received VA maintained concentrations >0.1 ?mol/g. Extrahepatic tissue VA concentrations displayed treatment effects (P ? 0.0077); groups that received treatments had higher VA concentrations than controls at early time points. Lung, kidney, and spleen VA did not differ between groups by 96 h, whereas adrenal glands did not differ by 240 h. Body weight was affected by treatment (P = 0.0002); VA-deficient piglets weighed 23-29% more than all treated groups 240 h after administration.Conclusions: A high dose of VA administered to newborn piglets was well absorbed, appeared in serum primarily as retinyl esters, and was taken up dose-dependently in all tissues studied; however, enhancement did not persist in sera, lungs, kidneys, spleens, or adrenal glands. Short-term impacts of retinoid signaling on weight gain remain to be elucidated, and longer follow-up studies are needed.

SUBMITTER: Gannon BM

PROVIDER: S-EPMC6584120 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Single High-Dose Vitamin A Supplementation to Neonatal Piglets Results in a Transient Dose Response in Extrahepatic Organs and Sustained Increases in Liver Stores.

Gannon Bryan M BM Davis Christopher R CR Nair Nivedita N Grahn Michael M Tanumihardjo Sherry A SA

The Journal of nutrition 20170405 5

Background: Neonatal vitamin A (VA) supplementation is being evaluated as a public health policy for preventing infant mortality, but inconsistencies in mortality trials demand mechanistic work to determine biological plausibility.Objectives: We investigated the absorption, distribution, and storage of single large oral VA doses administered shortly after birth.Methods: Fifty pregnant sows (Sus scrofas domesticas) were fed a VA-free diet. Male and female newborn pigle ...[more]

PMID: 28381532

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Project description:BackgroundVitamin A deficiency (VAD) impairs T-cell-mediated immunity. In regions where VAD is prevalent, vitamin A supplementation (VAS) reduces child mortality, perhaps by improving immune function.ObjectiveOur objective was to determine if neonatal VAS would improve thymic function in Bangladeshi infants, and to determine if such effects differed by sex or nutritional status (i.e., birth weight above/below the median).MethodsThree hundred and six infants were randomly assigned to 50,000 IU vitamin A (VA) or placebo (PL) within 48 h of birth. Primary outcomes were measured at multiple ages and included 1) thymic index (TI) at 1, 6, 10, and 15 wk; 2) T-cell receptor excision circles (TREC), an index of thymic output of naïve T cells; and 3) total/naïve T cells in peripheral blood at 6 wk, 15 wk, and 2 y. A mixed linear model for repeated measures was used to assess group differences at each age and identify interactions with sex and birth weight.ResultsVAS did not significantly (P = 0.21) affect TI overall (i.e., at all ages) but decreased TI by 7.8% (P = 0.029) at 6 wk: adjusted TI means for the PL and VA groups at 1, 6, 10, and 15 wk were 4.09 compared with 3.80 cm2, 7.78 compared with 7.18 cm2, 8.11 compared with 7.84 cm2, and 7.91 compared with 7.97 cm2, respectively. VAS did not significantly (P = 0.25) affect TREC overall but decreased TREC by 19% (P = 0.029) at 15 wk: adjusted TREC means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 13.6 compared with 16.1 copies/pg DNA, 19.4 compared with 15.7 copies/pg DNA, and 11.8 compared with 10.0 copies/pg DNA, respectively. VAS did not significantly affect overall total (P = 0.10) or naïve (P = 0.092) T cells: adjusted naïve T-cell means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 3259 compared with 3109 cells/µL, 3771 compared with 3487 cells/µL, and 1976 compared with 1898 cells/µL, respectively.ConclusionIn contrast to our hypothesis, VAS decreased thymic function early in infancy but health effects are presumably negligible owing to the transience and small magnitude of this effect. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.

Project description:BackgroundSustained inflation (SI) during chest compression (CC = CC+SI) has been recently shown as an alternative method during cardiopulmonary resuscitation in neonates. However, the optimal peak inflation pressure (PIP) of SI during CC+SI to improve ROSC and hemodynamic recovery is unknown.ObjectiveTo examine if different PIPs of SI during CC+SI will improve ROSC and hemodynamic recovery in severely asphyxiated piglets.MethodsTwenty-nine newborn piglets (1-3 days old) were anesthetized, intubated, instrumented and exposed to 30-min normocapnic hypoxia followed by asphyxia. Piglets were randomized into four groups: CC+SI with a PIP of 10 cmH2O (CC+SI_PIP_10, n = 8), a PIP of 20 cmH2O (CC+SI_PIP_20, n = 8), a PIP of 30 cmH2O (CC+SI_PIP_30, n = 8), and a sham-operated control group (n = 5). Heart rate, arterial blood pressure, carotid blood flow, cerebral oxygenation, and respiratory parameters were continuously recorded throughout the experiment.ResultsBaseline parameters were similar between all groups. There was no difference in asphyxiation (duration and degree) between intervention groups. PIP correlated positively with tidal volume (VT) and inversely with exhaled CO2 during cardiopulmonary resuscitation. Time to ROSC and rate of ROSC were similar between piglets resuscitated with CC+SI_PIP_10, CC+SI_PIP_20, and CC+SI_PIP_30 cmH2O: median (IQR) 75 (63-193) sec, 94 (78-210) sec, and 85 (70-90) sec; 5/8 (63%), 7/8 (88%), and 3/8 (38%) (p = 0.56 and p = 0.12, respectively). All piglets that achieved ROSC survived to four hours post-resuscitation. Piglets resuscitated with CC+SI_PIP_30 cmH2O exhibited increased concentrations of pro-inflammatory cytokines interleukin-1β and tumour necrosis factor-α in the frontoparietal cerebral cortex (both p<0.05 vs. sham-operated controls).ConclusionIn asphyxiated term newborn piglets resuscitated by CC+SI, the use of different PIPs resulted in similar time to ROSC, but PIP at 30 cmH2O showed a larger VT delivery, lower exhaled CO2 and increased tissue inflammatory markers in the brain.

Project description:Antibiotic exposure during neonatal development may result in transient or persistent alterations of key microbes that are vital for normal development of local and systemic immunity, potentially impairing immune competence later in life. To further elucidate the relationship between antibiotic exposure and immune development, newborn pigs were exposed to a therapeutic pediatric dose (30 mg/kg/day) of amoxicillin (AB) or placebo (PL) from post-natal day (PND) 0-14. Subsequently, immune cell phenotype, microbial composition, and immune response to an intraperitoneal (IP) challenge with Salmonella enterica serovar Typhimurium were evaluated. AB exposure caused significant changes in fecal microbial composition on PND 3 (P = 0.025). This stemmed from a 2-fold increase in Enterobacteriaceae with live cecal coliforms on PND 7 indicating at 10-fold increase (P = 0.036). Alterations in microbial composition were transient, and successional patterns were normalizing by PND 14 (P = 0.693). Differences in PBMC (peripheral blood mononuclear cell) immune cell subtypes were detected, with the percentage of CD3+CD4+ T cells among the broader T cell population (CD3+CD4+/CD3+) being significantly higher (P = 0.031) in AB pigs and the numbers of CD4+CD45RA+ (naïve) T cells per liter of blood were lower on PND 21 in AB pigs (P = 0.036). Meanwhile, PBMCs from AB pigs produced significantly more IFN? upon stimulation with a T-cell mitogen on PND 21 and 49 (P = 0.021). When AB pigs were challenged with heat-killed Salmonella (IP) on PND 49, IFN? gene expression in peripheral blood was upregulated compared to those treated with PL (P = 0.043). Additionally, AB pigs showed stronger activation among neutrophils infiltrating the peritoneal cavity after in vivo immune challenge, based on higher levels of NF-?B nuclear translocation (P = 0.001). Overall, our results indicate that early life treatment with a therapeutically relevant dose of a commonly prescribed antibiotic has a programming effect on the immune system. Despite antibiotics only causing a transient disruption in gut-associated microbial communities, implications were long-term, with antibiotic treated pigs mounting an upregulated response to an immune challenge. This research adds to the growing body of evidence indicating adverse immune outcomes of early life antibiotic exposures.

Dataset Information

Single High-Dose Vitamin A Supplementation to Neonatal Piglets Results in a Transient Dose Response in Extrahepatic Organs and Sustained Increases in Liver Stores.

Publications

Single High-Dose Vitamin A Supplementation to Neonatal Piglets Results in a Transient Dose Response in Extrahepatic Organs and Sustained Increases in Liver Stores.

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