Supplementation with RRR- or all-rac-α-Tocopherol Differentially Affects the α-Tocopherol Stereoisomer Profile in the Milk and Plasma of Lactating Women.

Background: The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is known to be more bioactive than synthetic α-tocopherol (all-rac-α-tocopherol). However, the influence of this difference on the α-tocopherol stereoisomer profile of human milk is not understood.Objective: We investigated whether supplemental RRR-α-tocopherol or all-rac-α-tocopherol differentially affected the distribution of α-tocopherol stereoisomers in milk and plasma from lactating women.Methods: Eighty-nine lactating women aged 19-40 y and with a body mass index (in kg/m2) ≤30 were randomly assigned at 4-6 wk postpartum to receive a daily supplement containing 45.5 mg all-rac-α-tocopherol acetate (ARAC), 22.8 mg all-rac-α-tocopherol acetate + 20.1 mg RRR-α-tocopherol (MIX), or 40.2 mg RRR-α-tocopherol (RRR). Milk and plasma were analyzed for α-tocopherol structural isomers and α-tocopherol stereoisomers at baseline and after 6 wk supplementation with the use of chiral HPLC.Results: There were no significant treatment group or time-dependent changes in milk or plasma α, γ, or δ-tocopherol. RRR-α-tocopherol was the most abundant stereoisomer in both milk and plasma in each group. Supplementation changed both milk and plasma percentage RRR-α-tocopherol (RRR > MIX > ARAC) (P < 0.05) and percentage non-RRR-α-tocopherol (ARAC > MIX > RRR) (P < 0.05). In the RRR group, percentage RRR-α-tocopherol increased in milk (mean ± SEM: 78% ± 2.3% compared with 82% ± 1.7%) (P < 0.05) and plasma (mean ± SEM: 77% ± 1.8% compared with 87% ± 1%) (P < 0.05). In contrast, the percentage RRR-α-tocopherol decreased in the MIX and ARAC groups (MIX, P < 0.05; ARAC, P < 0.0001), and percentage non-RRR-α-tocopherol stereoisomers increased (MIX, P < 0.05; ARAC, P < 0.0001) commensurate with an accumulation of 2S-α-tocopherol stereoisomers (P < 0.05) in both milk and plasma. Milk and plasma RRR-α-tocopherol was positively correlated at baseline (r = 0.67; P < 0.0001) and 6 wk (r = 0.80; P < 0.0001).Conclusion: The α-tocopherol supplementation strategy differentially affected the α-tocopherol milk and plasma stereoisomer profile in lactating women. RRR-α-tocopherol increased milk and plasma percentage RRR-α-tocopherol, whereas all-rac-α-tocopherol acetate reduced these percentages. Because RRR-α-tocopherol is the most bioactive stereoisomer, investigating the impact of supplement-driven changes in the milk α-tocopherol stereoisomer profile on the α-tocopherol status of breastfed infants is warranted.

Lutein supplementation increases breast milk and plasma lutein concentrations in lactating women and infant plasma concentrations but does not affect other carotenoids.

Lutein is a carotenoid that varies in breast milk depending on maternal intake. Data are lacking with regard to the effect of dietary lutein supplementation on breast milk lutein concentration during lactation and subsequent plasma lutein concentration in breast-fed infants. This study was conducted to determine the impact of lutein supplementation in the breast milk and plasma of lactating women and in the plasma of breast-fed infants 2-3 mo postpartum. Lutein is the dominant carotenoid in the infant brain and the major carotenoid found in the retina of the eye. Eighty-nine lactating women 4-6 wk postpartum were randomly assigned to be administered either 0 mg/d of lutein (placebo), 6 mg/d of lutein (low-dose), or 12 mg/d of lutein (high-dose). The supplements were consumed for 6 wk while mothers followed their usual diets. Breast milk carotenoids were measured weekly by HPLC, and maternal plasma carotenoid concentrations were measured at the beginning and end of the study. Infant plasma carotenoid concentrations were assessed at the end of the study. No significant differences were found between dietary lutein + zeaxanthin intake and carotenoid concentrations in breast milk and plasma or body mass index at baseline. Total lutein + zeaxanthin concentrations were greater in the low- and high-dose-supplemented groups than in the placebo group in breast milk (140% and 250%, respectively; P < 0.0001), maternal plasma (170% and 250%, respectively; P < 0.0001), and infant plasma (180% and 330%, respectively; P < 0.05). Lutein supplementation did not affect other carotenoids in lactating women or their infants. Lactating women are highly responsive to lutein supplementation, which affects plasma lutein concentrations in the infant. This trial was registered at clinicaltrials.gov as NCT01747668.

Clinical epidemiology of COVID-19 among hospitalized children in rural western Kenya.

The epidemiology of pediatric COVID-19 in sub-Saharan Africa and the role of fecal-oral transmission in SARS-CoV-2 are poorly understood. Among children and adolescents in Kenya, we identify correlates of COVID-19 infection, document the clinical outcomes of infection, and evaluate the prevalence and viability of SARS-CoV-2 in stool. We recruited a prospective cohort of hospitalized children aged two months to 15 years in western Kenya between March 1 and June 30 2021. Children with SARS-CoV-2 were followed monthly for 180-days after hospital discharge. Bivariable logistic regression analysis was used to identify the clinical and sociodemographics correlates of SARS-CoV-2 infection. We also calculated the prevalence of SARS-CoV-2 detection in stool of confirmed cases. Of 355 systematically tested children, 55 (15.5%) were positive and were included in the cohort. The commonest clinical features among COVID-19 cases were fever (42/55, 76%), cough (19/55, 35%), nausea and vomiting (19/55, 35%), and lethargy (19/55, 35%). There were no statistically significant difference in baseline sociodemographic and clinical characteristics between SARS-CoV-2 positive and negative participants. Among positive participants, 8/55 (14.5%, 95%CI: 5.3%-23.9%) died; seven during the inpatient period. Forty-nine children with COVID-19 had stool samples or rectal swabs available at baseline, 9 (17%) had PCR-positive stool or rectal swabs, but none had SARS-CoV-2 detected by culture. Syndromic identification of COVID-19 is particularly challenging among children as the presenting symptoms and signs mirror other common pediatric diseases. Mortality among children hospitalized with COVID-19 was high in this cohort but was comparable to mortality seen with other common illnesses in this setting. Among this small set of children with COVID-19 we detected SARS-CoV-2 DNA, but were not able to culture viable SARs-CoV-2 virus, in stool. This suggests that fecal transmission may not be a substantial risk in children recently diagnosed and hospitalized with COVID-19 infection.

Potential for Front of Pack Labeling Exposure to Impact US Dietary Choices: A Population-Based Cross-Sectional Study Using NHANES 2017-2018.

In recent years, front-of-pack nutrition labeling (FOPL) schemes have proliferated, but the components of the diet subject to FOPL have not been described. This study quantified the proportion and elements of the diet that would be subject to FOPL in the US. The 2017-2018 National Health and Nutrition Examination Survey (n = 7121; age ≥2 year) 24-h dietary recalls were used to identify foods/beverages subject to FOPL. The proportion of dietary energy and additional dietary constituents subject to FOPL was estimated. Overall, 57% of dietary energy would be subject to FOPL. Individuals consuming more away-from-home meals had lower exposure to FOPL. Adults with a healthy-weight and those consuming a more healthful diet had more exposure to FOPL. Protein, sodium, potassium, whole fruit, vegetables, and unprocessed meats were less subject to FOPL as compared to total sugars, added sugars, calcium, fruit juice, milk, yogurt, nuts/seeds and whole grains. Because less than 60% of the diet would be impacted by FOPL, implementation of such a policy may have limited reach for the US diet and demonstrates some inconsistencies with current dietary guidance regarding the under- and over-representation of key food groups and nutrients.

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization.

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con-A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con-A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.

Behavioral recovery from acute hypoxia is reliant on leptin.

Individuals affected by hypoxia experience a variety of immune-associated sickness symptoms including malaise, fatigue, lethargy and loss of interest in the physical and social environment. Recently, we demonstrated that the interleukin (IL)-1beta arm of the neuroimmune system was critical to the sickness symptoms caused by hypoxia, and that IL-1 receptor antagonist (IL-1RA), IL-1beta's endogenous inhibitor, was critical to promoting sickness recovery. Here, we report that leptin is key to recovery from hypoxia because it dramatically augmented IL-1RA production in mice. We found that hypoxia increased leptin in white adipose tissue (WAT) which in turn, caused a marked rise in serum IL-1RA. Interestingly, in-vitro, leptin was a more potent inducer of IL-RA, in macrophages, than hypoxia. In leptin receptor defective (db/db) and leptin deficient (ob/ob) mice, sickness recovery from hypoxia was delayed 3-fold. Importantly, in ob/ob mice, leptin administration completely reversed this delayed recovery and induced a marked increase in serum IL-1RA. Finally, leptin administration to normal mice reduced hypoxia recovery time by 1/3 and dramatically increased WAT and serum IL-1RA. Leptin did not alter recovery from hypoxia in IL-1RA knock out mice. These results show that by enhancing IL-1RA production leptin promoted sickness recovery from hypoxia.

Acute hypoxia, diabetes, and neuroimmune dysregulation: converging mechanisms in the brain.

Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity.

A Slow-Digesting, Low-Glycemic Load Nutritional Beverage Improves Glucose Tolerance in Obese Pregnant Women Without Gestational Diabetes.

BACKGROUND: Obesity is a risk factor for gestational diabetes (gestational diabetes). Low-glycemic index diets attenuate hyperglycemia. We designed a study to determine whether a slow-digesting, low-glycemic load (SD-LGL) beverage improves glucose tolerance in obese pregnant women without GDM. METHODS: This was a 3-arm comparison study comparing the effects of an SD-LGL nutritional beverage (glycemic load [GL] 730), an isocaloric control beverage (GL 1124), and habitual diet on glycemia in obese pregnant women. Sixteen women (mean body mass index 37 kg/m2) were recruited at 24-28 weeks to receive either the SD-LGL or eucaloric control beverage. This was consumed with breakfast and as a midafternoon snack over 2 days with a controlled diet. Following a 2-day washout period of habitual diet, women completed 2 days on the alternative beverage with controlled diet. A 10-h fast preceded each intervention phase. Twenty-four hour glucose was measured using continuous glucose monitoring. RESULTS: Consumption of the lower GL beverage was associated with improved measures of glycemia, compared with the control beverage and habitual diet at different time periods. Glucose estimates for control versus SD-LDL at 24 h (0.23 mmol/L [0.16 to 0.31], P < 0.001), daytime (0.26 mmol/L [0.18 to 0.34], P < 0.001), and nighttime (0.05 mmol/L [-0.01 to 0.11], P = 0.09). Postprandial glucose was lower after breakfast but not after dinner, compared with the control beverage (0.09 mmol/L [0.01 to 0.18], P = 0.03). CONCLUSION: A slow-digesting, low-glycemic nutritional beverage may facilitate improved glucose control in obese pregnant women. To address potential benefit for clinical outcomes, a randomized controlled trial is warranted.

Assessment of the Nutrition Care Process in US Hospitals Using a Web-Based Tool Demonstrates the Need for Quality Improvement in Malnutrition Diagnosis and Discharge Care.

Background: Malnutrition in hospitalized patients is a pervasive problem in the United States. To our knowledge, although malnutrition has been acknowledged as a concern for >40 y, it has not yet been well addressed with a systematic, process improvement approach. Objectives: We aimed to characterize the current nutrition care process in US hospitals to establish a baseline for improvements. We also aimed to demonstrate the application of a web-based quality improvement tool as a simple approach to address malnutrition in hospitalized patients. Methods: We established a web-based tool to measure and assess nutrition care practices from hospital electronic medical records. Individual institutions self-selected to participate and were assigned a unique identifier to input data. Aggregated patient data from registered institutions were assessed. Data from all institutions were combined and are presented as the totals for each variable. Results: Of 243 registered users, 97 provided data and 150 reports were included in the analysis, resulting in a total of 107,106 patients. Almost all patients (89.98%) were screened for malnutrition risk within 24 h of admission, and ∼30% were at risk for malnutrition. Of those at risk, ∼65% received a registered dietitian nutritionist consultation or an order for an oral nutrition supplement. The rate of malnutrition diagnosis for those at risk was ∼14%, and <10% of patients received a recommendation or prescription for an oral nutrition supplement at discharge. Conclusions: Malnutrition remains an issue for hospitalized patients, particularly the gap between those screened as at risk and those diagnosed with malnutrition. Moreover, discharge recommendations for patients who are screened as at risk for malnutrition are also lacking. These data demonstrate that a web-based quality improvement tool could be used to capture the nutrition care practice at an institution level to provide directed approaches for addressing hospital malnutrition and improving care of patients at risk for malnutrition.

Generation of leptin receptor bone marrow chimeras: recovery from irradiation, immune cellularity, cytokine expression, and metabolic parameters.

Leptin regulates appetite and metabolism but also immunity and inflammation. Although functional leptin receptors (LepR) are expressed on hematopoietic cells, the role of these receptors in regulating immune function in vivo remains controversial. To clarify this issue, we performed bone marrow (BM) transplantation between obese db/db mice, lacking LepR, and wild-type (WT) mice. Results indicate that expression of LepR on BM-derived cells directly, though partially, regulates spleen and thymus cellularity, although the environment of db mice contributes to maintaining reduced cellularity of these organs. Selective expression of LepR on BM-derived cells also modulates leptin and adiponectin levels, with induction of a more favorable adipokine environment in the WT→db/db group. However, LepR signaling in BM-derived cells is not involved in regulation of body weight (BW) and composition, glycemia, hepatosteatosis or adipose tissue inflammation, although it modulates expression of interleukin (IL)-1ß in the brain. Finally, data indicate that db mice have an increased susceptibility to irradiation compared to WT mice in terms of BW loss and recovery of leukocyte counts in peripheral blood. Therefore, interpretation of results obtained using BM chimeras between WT and db mice should take into account the difference in radiation sensitivity between the two types of animals.

Accelerated recovery from acute hypoxia in obese mice is due to obesity-associated up-regulation of interleukin-1 receptor antagonist.

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 +/- 77 pg/mg protein in HFD mice as compared with 15 +/- 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.

Type 2 diabetes impairs insulin receptor substrate-2-mediated phosphatidylinositol 3-kinase activity in primary macrophages to induce a state of cytokine resistance to IL-4 in association with overexpression of suppressor of cytokine signaling-3.

Chronic elevation of proinflammatory markers in type 2 diabetes (T2D) is well defined, but the role of anti-inflammatory cytokines in T2D is less clear. In this study, we report that normal IL-4-dependent elaboration of IL-1 receptor antagonist (IL-1RA) requires IRS-2-mediated PI3K activity in primary macrophages. We also show that macrophages isolated from obese/diabetic db/db mice have impaired IRS-2-mediated PI3K activity and constitutively overexpress suppressor of cytokine signaling (SOCS)-3, which impairs an important IL-4 anti-inflammatory function. Peritoneal proinflammatory cytokine levels were examined in diabese (db/db) mice, and IL-6 was found to be nearly 7-fold higher than in nondiabese (db/+) control mice. Resident peritoneal macrophages were isolated from db/db mice and were found to constitutively overexpress IL-6 and were unable to elaborate IL-1RA in response to IL-4-like db/+ mouse macrophages. Inhibition of PI3K with wortmannin or blockage of IRS-2/PI3K complex formation with a cell permeable IRS-2-derived tyrosine phosphopeptide inhibited IL-4-dependent IL-1RA production in db/+ macrophages. Examination of IL-4 signaling in db/db macrophages revealed that IL-4-dependent IRS-2/PI3K complex formation and IRS-2 tyrosine phosphorylation was reduced compared with db/+ macrophages. SOCS-3/IL-4 receptor complexes, however, were increased in db/db mouse macrophages compared with db/+ mice macrophages as was db/db mouse macrophage SOCS-3 expression. These results indicate that in the db/db mouse model of T2D, macrophage expression of SOCS-3 is increased, and impaired IL-4-dependent IRS-2/PI3K formation induces a state of IL-4 resistance that disrupts IL-4-dependent production of IL-1RA.

Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK.

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-alpha production by resident peritoneal macrophages (PerMphi) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-alpha in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMphi. Ex vivo stimulation of PerMphi with LPS produced a similar 3-fold increase in TNF-alpha production in db/db PerMphi when compared with db/+ PerMphi. PerMphi isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-alpha in response to LPS than PerMphi incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMphi from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-alpha production in PerMphi from db/db mice. Taken together, these data indicate that augmented TNF-alpha production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.