Taming the Chlorine Radical: Enforcing Steric Control over Chlorine-Radical-Mediated C-H Activation.

Chlorine radicals readily activate C-H bonds, but the high reactivity of these intermediates precludes their use in regioselective C-H functionalization reactions. We demonstrate that the secondary coordination sphere of a metal complex can confine photoeliminated chlorine radicals and afford steric control over their reactivity. Specifically, a series of iron(III) chloride pyridinediimine complexes exhibit activity for photochemical C(sp3)-H chlorination and bromination with selectivity for primary and secondary C-H bonds, overriding thermodynamic preference for weaker tertiary C-H bonds. Transient absorption spectroscopy reveals that Cl· remains confined through formation of a Cl·|arene complex with aromatic groups on the pyridinediimine ligand. Furthermore, photocrystallography confirms that this selectivity arises from the generation of Cl· within the steric environment defined by the iron secondary coordination sphere.

Management and Outcomes of Adults Diagnosed with Acute Pulmonary Embolism in Primary Care: Community-Based Retrospective Cohort Study.

BACKGROUND: The management and outcomes of patients diagnosed with acute pulmonary embolism in primary care have not been characterized. OBJECTIVE: To describe 30-day outcomes stratified by initial site-of-care decisions DESIGN: Multicenter retrospective cohort study PARTICIPANTS: Adults diagnosed with acute pulmonary embolism in primary care in a large, diverse community-based US health system (2013-2019) MAIN MEASURES: The primary outcome was a composite of 30-day serious adverse events (recurrent venous thromboembolism, major bleeding, and all-cause mortality). The secondary outcome was 7-day pulmonary embolism-related hospitalization, either initial or delayed. KEY RESULTS: Among 652 patient encounters (from 646 patients), median age was 64 years; 51.5% were male and 70.7% identified as non-Hispanic white. Overall, 134 cases (20.6%) were sent home from primary care and 518 cases (79.4%) were initially referred to the emergency department (ED) or hospital. Among the referred, 196 (37.8%) were discharged home from the ED without events. Eight patients (1.2%; 95% CI 0.5-2.4%) experienced a 30-day serious adverse event: 4 venous thromboemboli (0.6%), 1 major bleed (0.2%), and 3 deaths (0.5%). Seven of these patients were initially hospitalized, and 1 had been sent home from primary care. All 3 deaths occurred in patients with known metastatic cancer initially referred to the ED, hospitalized, then enrolled in hospice following discharge. Overall, 328 patients (50.3%) were hospitalized within 7 days: 322 at the time of the index diagnosis and 6 following initial outpatient management (4 clinic-only and 2 clinic-plus-ED patients). CONCLUSIONS: Patients diagnosed with acute pulmonary embolism in this primary care setting uncommonly experienced 30-day adverse events, regardless of initial site-of-care decisions. Over 20% were managed comprehensively by primary care. Delayed 7-day pulmonary embolism-related hospitalization was rare among the 51% treated as outpatients. Primary care management of acute pulmonary embolism appears to be safe and could have implications for cost-effectiveness and patient care experience.

Early Childhood Lutein and Zeaxanthin Intake Is Positively Associated with Early Childhood Receptive Vocabulary and Mid-Childhood Executive Function But No Other Cognitive or Behavioral Outcomes in Project Viva.

BACKGROUND: Lutein and zeaxanthin are carotenoids associated with better cognition in older adults. Recent evidence suggests that their dietary intake may also have cognitive implications in childhood. OBJECTIVE: The aim was to examine associations of early childhood lutein and zeaxanthin (L/Z) intake with cognition in early and mid-childhood. METHODS: Among 1378 children in Project Viva, a prospective cohort, mothers reported their child's dietary intake in early childhood (median: 3.2 y) using a food-frequency questionnaire. Child cognition and behavior were assessed at the same time point using the Peabody Picture Vocabulary Test (PPVT-III) and the Wide Range Assessment of Visual Motor Abilities (WRAVMA) and at mid-childhood (median: 7.7 y) using the Kaufman Brief Intelligence Test, the WRAVMA drawing subtest, the Wide Range Assessment of Memory and Learning, the Behavior Rating Inventory of Executive Function (BRIEF), and the Strengths and Difficulties Questionnaire. RESULTS: Children consumed a daily mean (SD) of 1.0 (0.4) mg L/Z in early childhood. Children in the third-quartile category of L/Z intake had a mean PPVT-III score 2.40 (95% CI: 0.27, 4.53) points higher than children in the lowest quartile category in early childhood, suggesting better receptive vocabulary. Children in the highest quartile category of L/Z intake had a parent-reported mean BRIEF Global Executive Composite score 1.65 (95% CI: -3.27, -0.03) points lower than children in the lowest quartile category in mid-childhood, indicating better executive function. We did not observe associations between L/Z intake and any of the other cognitive or behavioral outcomes assessed. CONCLUSIONS: The overall findings do not provide strong evidence of an association between child L/Z intake and cognition and behavior. However, the positive associations found between early childhood L/Z intake and early childhood receptive vocabulary and mid-childhood executive function, in addition to previous evidence of neurodevelopmental benefit of L/Z intake, suggest that this relation deserves further investigation.

Effects of daily almond consumption for six months on cognitive measures in healthy middle-aged to older adults: a randomized control trial.

BACKGROUND: Age-related cognitive decline is a major public health issue. Almonds are rich in nutrients that benefit cognitive function. OBJECTIVE: To investigate the impact of almonds on cognition in elderly adults. DESIGN: In a six-month, single-blinded, randomized-controlled trial, the effects of an almond intervention on cognition in healthy, middle-aged/older adults (50-75 years) was tested. Subjects were assigned to one of three groups: 1.5 oz/d almond (n = 19), 3 oz/d almond (n = 24), or 3.5 oz/d snack (control, matched for macronutrients in 3.0 oz almonds, (n = 17). Serum analyses for tocopherols, oxidative status and inflammation, and cognition were assessed at baseline (M0), three (M3), and six (M6) months. RESULTS: At M6, serum alpha-tocopherol concentrations increased by 8% from M0 (p < 0.05) in the 3 oz almond group but did not increase in the other groups. Serum markers of inflammation and oxidative stress were not significantly different throughout the study among the groups. There was no difference in change over time in cognitive tests among the groups. However, there was a significant improvement in visuospatial working memory (p = 0.023), visual memory and learning (p = 0.017), and spatial planning and working memory (p < 0.001) in subjects receiving 3 oz/d almonds at M6, while the snack group showed no improvement. CONCLUSIONS: Almonds did not significantly improve cognitive function in cognitively intact middle-aged/older adults over six months. However, a significant improvement at M6 in cognitive measures was observed with 3 oz/d almonds. While these results are encouraging, a study of longer duration in subjects at risk for age-related cognitive decline is warranted.Trial registration: ClinicalTrials.gov identifier: NCT03093896.

Capturing the Complete Reaction Profile of a C-H Bond Activation.

The activation of C-H bonds requires the generation of extremely reactive species, which hinders the study of this reaction and its key intermediates. To overcome this challenge, we synthesized an iron(III) chloride-pyridinediimine complex that generates a chlorine radical proximate to reactive C-H bonds upon irradiation with light. Transient spectroscopy confirms the formation of a Cl·|arene complex, which then activates C-H bonds on the PDI ligand to yield HCl and a carbon-centered radical as determined by photocrystallography. First-principles molecular dynamics-density functional theory calculations reveal the trajectory for the formation of a Cl·|arene intermediate. Together, these experimental and computational results show the complete reaction profile for the preferential activation of a C-H bond in the solid state.

Maternal Intake of Lutein and Zeaxanthin during Pregnancy Is Positively Associated with Offspring Verbal Intelligence and Behavior Regulation in Mid-Childhood in the Project Viva Cohort.

BACKGROUND: Lutein and zeaxanthin are carotenoids associated with better cognition at older age. To our knowledge, no previous study has evaluated their cognitive implications in the prenatal period, when the brain undergoes its most rapid development. OBJECTIVE: The objective of this study was to examine associations of maternal lutein and zeaxanthin (L/Z) intake during pregnancy with child cognition. DESIGN: Among 1580 mother-child pairs in Project Viva, a prospective cohort, we assessed maternal intake of L/Z during pregnancy using food frequency questionnaires and offspring cognition by the Visual Recognition Memory paradigm in infancy, the Peabody Picture Vocabulary Test and the Wide Range Assessment of Visual Motor Abilities (WRAVMA) in early childhood, and the Kaufman Brief Intelligence Test (KBIT-II), the WRAVMA drawing subtest, and the Wide Range Assessment of Memory and Learning in mid-childhood. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and Strengths and Difficulties Questionnaire. RESULTS: Mothers consumed a daily mean (SD) of 2.6 (2.0) mg L/Z in the first and second trimesters of pregnancy. Mean mid-childhood KBIT-II verbal scores were higher with greater maternal L/Z intake [difference of Q4-Q1 means for first trimester: 2.67 (95% CI: 0.13, 5.20) and for second trimester: 3.55 (95% CI: 0.81, 6.28)], indicating better verbal intelligence. Secondary analyses on cognitive subtests showed that mean mid-childhood BRIEF Behavioral Regulation Index scores were lower with greater maternal L/Z intake [difference of Q4-Q1 means for first trimester: -1.63 (95% CI: -3.22, -0.04) and for second trimester: -1.89 (95% CI: -3.58, -0.21)], indicating better behavior regulation ability. CONCLUSIONS: Higher maternal L/Z intake during pregnancy was associated with better offspring verbal intelligence and behavior regulation ability in mid-childhood, suggesting a potential benefit during prenatal development. We did not find a benefit of higher maternal L/Z intake on other child cognitive or behavioral outcomes. Project Viva is registered at clinicaltrials.gov as NCT02820402.

Short-Term Tea Consumption Is Not Associated with a Reduction in Blood Lipids or Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: A recent systematic review of epidemiological evidence suggests that higher amounts of tea intake are associated with lower risks of cardiovascular disease (CVD) incidence and mortality. OBJECTIVES: Our study objective was to assess mechanisms by which tea consumption may influence CVD risks. METHODS: A systematic review and meta-analysis was conducted to investigate the effects of green and/or black tea consumption (≥4 wk) on systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride (TG) in healthy populations and among at-risk adults (analyzed separately) with metabolic syndrome, prediabetes, and hypercholesterolemia. The Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the strength of evidence (SoE). RESULTS: A total of 14 unique RCTs which randomly assigned 798 participants to either green tea, black tea, or placebo controls were included in our analyses. Intervention durations ranged from 4 to 24 wk (mean: 7.4 wk). Individual studies were judged as moderate to high quality based on risk of bias assessments. SoE was low to moderate owing to low sample sizes and insufficient power for most included studies to observe changes in the measured CVD biomarkers. Meta-analyses showed no significant effects of tea consumption on SBP, DBP, total cholesterol, LDL cholesterol, HDL cholesterol, and TG in healthy and at-risk adults (i.e., adults with obesity, prediabetes, borderline hypercholesterolemia, and metabolic syndrome). CONCLUSIONS: Short-term (4-24 wk) tea consumption does not appear to significantly affect blood pressure or lipids in healthy or at-risk adults, although the evidence is limited by insufficient power to detect changes in these CVD biomarkers. High-quality RCTs with longer durations and sufficient sample sizes are needed to fully elucidate the effects of tea. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020134513.

Concentrations of Circulating Phylloquinone, but Not Cerebral Menaquinone-4, Are Positively Correlated with a Wide Range of Cognitive Measures: Exploratory Findings in Centenarians.

BACKGROUND: Vitamin K (VK) exists in the form of phylloquinone (PK) and menaquinones (MKs). Roles of VK on cognitive health in the elderly are emerging, but there is limited evidence on VK uptake and metabolism in human brain. OBJECTIVES: The primary objective of this study was to characterize VK distribution in brains of an elderly population with varied cognitive function. In addition, associations among circulating (a biomarker of VK intake) and cerebral VK concentrations and cognition were investigated. METHODS: Serum or plasma (n = 27) and brain samples from the frontal cortex (FC; n = 46) and the temporal cortex (TC; n = 33) were acquired from 48 decedents (aged 98-107 y; 25 demented and 23 nondemented) enrolled in the Georgia Centenarian Study. Both circulating and brain VK concentrations were measured using HPLC with fluorescence detection. Cognitive assessment was performed within 1 y prior to mortality. Partial correlations between serum/plasma or cerebral VK concentrations and cognitive function were performed, adjusting for covariates and separating by dementia and antithrombotic use. RESULTS: MK-4 was the predominant vitamer in both FC (mean ± SD = 4.92 ± 2.31 pmol/g, ≥89.15% ± 5.09% of total VK) and TC (4.60 ± 2.11 pmol/g, ≥89.71% ± 4.43% of total VK) regardless of cognitive status. Antithrombotic users had 34.0% and 53.9% lower MK-4 concentrations in FC (P < 0.05) and TC (P < 0.001), respectively. Circulating PK was not correlated with cerebral MK-4 or total VK concentrations. Circulating PK concentrations were significantly associated with a wide range of cognitive measures in nondemented centenarians (P < 0.05). In contrast, cerebral MK-4 concentrations were not associated with cognitive performance, either before or after exclusion of antithrombotic users. CONCLUSIONS: Circulating VK concentrations are not related to cerebral MK-4 concentrations in centenarians. Cerebral MK-4 concentrations are tightly regulated over a range of VK intakes and cognitive function. Circulating PK may reflect intake of VK-rich foods containing other dietary components beneficial to cognitive health. Further investigation of VK uptake and metabolism in the brain is warranted.

Daily almond consumption in cardiovascular disease prevention via LDL-C change in the U.S. population: a cost-effectiveness analysis.

BACKGROUND: Heart disease is the leading cause of death in the United States. The U.S. Food and Drug Administration approved the health claim that 1.5 oz (42.5 g) of nut intake may reduce the risk of cardiovascular disease. Previous studies have focused on the cost-effectiveness of other foods or dietary factors on primary cardiovascular disease prevention, yet not in almond consumption. This study aimed to examine the cost-effectiveness of almond consumption in cardiovascular disease primary prevention. PERSPECTIVE & SETTING: This study assessed the cost-effectiveness of consuming 42.5 g of almond from the U.S. healthcare sector perspective. METHODS: A decision model was developed for 42.5 g of almond per day versus no almond consumption and cardiovascular disease in the U.S. POPULATION: Parameters in the model were derived from the literature, which included the probabilities of increasing low-density lipoprotein cholesterol, developing acute myocardial infarction and stroke, treating acute myocardial infarction, dying from the disease and surgery, as well as the costs of the disease and procedures in the U.S. population, and the quality-adjusted life years. The cost of almonds was based on the current price in the U.S. market. Sensitivity analyses were conducted for different levels of willingness-to-pay, the probabilistic sensitivity analysis, ten-year risk prevention, different costs of procedures and almond prices, and patients with or without cardiovascular disease. RESULTS: The almond strategy had $363 lower cost and 0.02 higher quality-adjusted life years gain compared to the non-almond strategy in the base-case model. The annual net monetary benefit of almond consumption was $1421 higher per person than no almond consumption, when the willingness to pay threshold was set at $50,000 for annual health care expenditure. Almond was more cost-effective than non-almond in cardiovascular disease prevention in all the sensitivity analyses. CONCLUSION: Consuming 42.5 g of almonds per day is a cost-effective approach to prevent cardiovascular disease in the short term and potentially in the long term.

Unprecedented Five-Coordinate Iron(IV) Imides Generate Divergent Spin States Based on the Imide R-Groups.

Three five-coordinate iron(IV) imide complexes have been synthesized and characterized. These novel structures have disparate spin states on the iron as a function of the R-group attached to the imide, with alkyl groups leading to low-spin diamagnetic (S=0) complexes and an aryl group leading to an intermediate-spin (S=1) complex. The different spin states lead to significant differences in the bonding about the iron center as well as the spectroscopic properties of these complexes. Mössbauer spectroscopy confirmed that all three imide complexes are in the iron(IV) oxidation state. The combination of diamagnetism and 15 N labeling allowed for the first 15 N NMR resonance recorded on an iron imide. Multi-reference calculations corroborate the experimental structural findings and suggest how the bonding is distinctly different on the imide ligand between the two spin states.

Lutein Is Differentially Deposited across Brain Regions following Formula or Breast Feeding of Infant Rhesus Macaques.

Background: Lutein, a yellow xanthophyll, selectively accumulates in primate retina and brain. Lutein may play a critical role in neural and retinal development, but few studies have investigated the impact of dietary source on its bioaccumulation in infants. Objective: We explored the bioaccumulation of lutein in infant rhesus macaques following breastfeeding or formula-feeding. Methods: From birth to 6 mo of age, male and female rhesus macaques (Macaca mulatta) were either breastfed (BF) (n = 8), fed a formula supplemented with lutein, zeaxanthin, ß-carotene, and lycopene (237, 19.0, 74.2, and 338 nmol/kg, supplemented formula-fed; SF) (n = 8), or fed a formula with low amounts of these carotenoids (38.6, 2.3, 21.5, and 0 nmol/kg, unsupplemented formula-fed; UF) (n = 7). The concentrations of carotenoids in serum and tissues were analyzed by HPLC. Results: At 6 mo of age, the BF group exhibited significantly higher lutein concentrations in serum, all brain regions, macular and peripheral retina, adipose tissue, liver, and other tissues compared to both formula-fed groups (P < 0.001). Lutein concentrations were higher in the SF group than in the UF group in serum and all tissues, with the exception of macular retina. Lutein was differentially distributed across brain areas, with the highest concentrations in the occipital cortex, regardless of the diet. Zeaxanthin was present in all brain regions but only in the BF infants; it was present in both retinal regions in all groups but was significantly enhanced in BF infants compared to either formula group (P < 0.001). ß-Carotene accumulated across brain regions in all groups, but was not detected in retina. Although lycopene was found in many tissues of the SF group, it was not detected in the brain or retina. Conclusions: Although carotenoid supplementation of infant formula significantly increased serum and tissue lutein concentrations compared to unsupplemented formula, concentrations were still well below those in BF infants. Regardless of diet, occipital cortex showed selectively higher lutein deposition than other brain regions, suggesting lutein's role in visual processing in early life.

Dietary guidance for lutein: consideration for intake recommendations is scientifically supported.

Lutein, a yellow xanthophyll carotenoid found in egg yolks and many colorful fruits and vegetables, has gained public health interest for its putative role in visual performance and reducing the risk of age-related macular degeneration. The National Academies of Sciences, Engineering and Medicine's recommended Dietary Reference Intakes (DRIs) focus on preventing deficiency and toxicity, but there is a budding interest in establishing DRI-like guidelines for non-essential bioactives, like lutein, that promote optimal health and/or prevent chronic diseases. Lupton et al. developed a set of nine criteria to determine whether a bioactive is ready to be considered for DRI-like recommendations. These criteria include: (1) an accepted definition; (2) a reliable analysis method; (3) a food database with known amounts of the bioactive; (4) cohort studies; (5) clinical trials on metabolic processes; (6) clinical trials for dose-response and efficacy; (7) safety data; (8) systematic reviews and/or meta-analyses; (9) a plausible biological rationale. Based on a review of the literature supporting these criteria, lutein is ready to be considered for intake recommendations. Establishing dietary guidance for lutein would encourage the consumption of lutein-containing foods and raise public awareness about its potential health benefits.

The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is predominant in the human infant brain.

α-Tocopherol is the principal source of vitamin E, an essential nutrient that plays a crucial role in maintaining healthy brain function. Infant formula is routinely supplemented with synthetic α-tocopherol, a racaemic mixture of eight stereoisomers with less bioactivity than the natural stereoisomer RRR-α-tocopherol. α-Tocopherol stereoisomer profiles have not been previously reported in the human brain. In the present study, we analysed total α-tocopherol and α-tocopherol stereoisomers in the frontal cortex (FC), hippocampus (HPC) and visual cortex (VC) of infants (n 36) who died of sudden infant death syndrome or other conditions. RRR-α-tocopherol was the predominant stereoisomer in all brain regions (P<0·0001) and samples, despite a large intra-decedent range in total α-tocopherol (5-17 µg/g). Mean RRR-α-tocopherol concentrations in FC, HPC and VC were 10·5, 6·8 and 5·5 µg/g, respectively. In contrast, mean levels of the synthetic stereoisomers were RRS, 1-1·5; RSR, 0·8-1·0; RSS, 0·7-0·9; and Σ2S 0·2-0·3 µg/g. Samples from all but two decedents contained measurable levels of the synthetic stereoisomers, but the intra-decedent variation was large. The ratio of RRR:the sum of the synthetic 2R stereoisomers (RRS+RSR+RSS) averaged 2·5, 2·3 and 2·4 in FC, HPC and VC, respectively, and ranged from 1 to at least 4·7, indicating that infant brain discriminates against synthetic 2R stereoisomers in favour of RRR. These findings reveal that RRR-α-tocopherol is the predominant stereoisomer in infant brain. These data also indicate that the infant brain discriminates against the synthetic 2R stereoisomers, but is unable to do so completely. On the basis of these findings, investigation into the impact of α-tocopherol stereoisomers on neurodevelopment is warranted.

Macular pigment carotenoids in the retina and occipital cortex are related in humans.

OBJECTIVES: Lutein and zeaxanthin are dietary carotenoids that preferentially accumulate in the macular region of the retina. Together with meso-zeaxanthin, a conversion product of lutein in the macula, they form the macular pigment. Lutein is also the predominant carotenoid in human brain tissue and lutein status is associated with cognitive function in adults. The study objective was to evaluate the relationship between retinal and brain lutein and zeaxanthin in humans. METHODS: Donated brain tissue (occipital cortex and hippocampus) and matched retina were obtained from the National Disease Research Interchange, a national human tissue resource center which adheres to strict consent and confidentiality procedures. Decedents were men and women aged >50 years who either had normal cognitive function or Alzheimer's disease. Tissues were analyzed using standard lipid extractions followed by analysis on reverse-phase high performance liquid chromatography (HPLC) and normal-phase HPLC (for meso-zeaxanthin). RESULTS: Macular pigment carotenoids (lutein, meso-zeaxanthin, and zeaxanthin combined) in the retina were significantly related to the combined concentrations of lutein and zeaxanthin in the occipital cortex. When analyzed separately, only retinal lutein (plus meso-zeaxanthin), not zeaxanthin, was significantly related to lutein in the occipital cortex. No correlations were observed with lutein and zeaxanthin in the hippocampus. DISCUSSION: Total macular pigment density measured via non-invasive, psychophysical techniques can be used as a biomarker to ascertain brain lutein and zeaxanthin status in clinical studies.

"Stuttering" after minor head trauma.

Traumatic brain injury (TBI) is defined as impairment in brain function as a result of mechanical force. It is classified based on clinical findings using the Glasgow Coma Scale (GCS). Mild TBI is defined as GCS 14-15; moderate, 9-13; and severe, 3-8. Patients with the same TBI classification may have very different underlying pathology. In moderate to severe TBI, the primary pathology may include contusions, hemorrhage, diffuse axonal injury, direct cellular damage, "tearing and shearing of the tissues, loss of the blood-brain barrier, disruption of the neurochemical homeostasis and loss of the electrochemical function". Although the primary pathology associated with mild TBI may be milder versions of the same pathology associated with moderate and severe TBI, it is generally a metabolic injury. However, it is reported that 15% of patients with mild TBI and a GCS score of 14 or 15 will have an intracranial lesion; less than 1% of these require neurosurgical intervention. Although patients with mild TBI may have intracranial lesions, it is rare that the presenting and only physical examination finding is an isolated neurologic finding. Here we present a case of isolated head trauma with a single physical examination finding--expressive aphasia.

Targeted recruitment of adults with type 2 diabetes for a physical activity intervention.

Recruiting sufficient numbers of participants for physical activity trials for individuals with diabetes can be difficult because there are often many behavioral demands for participants, and inclusion and exclusion criteria can be extensive. This study examined the recruitment strategies used for a randomized, controlled trial designed to investigate the efficacy of an automated telephone intervention to promote physical activity in adults with type 2 diabetes in an urban Veterans Administration health care system. Traditional recruitment approaches of posting flyers and obtaining referrals from clinicians did not yield sufficient numbers of interested patients. Using the electronic medical record system to identify patients with uncontrolled diabetes allowed staff to send targeted mailings to participants, and 77% of participants were recruited using this method. The targeted mailing approach elicited a positive response rate of 12% (328 of 2,764 potential participants identified) and appeared to produce a more representative and appropriate sample than other recruitment methods used. Lessons learned in this study may be helpful to researchers in future trials who attempt to recruit participants with diabetes for physical activity protocols.

Bioavailability of AREDS1 micronutrients from softgel capsules and tablets: a pilot study.

PURPOSE: The benefits of antioxidant micronutrients in slowing progression to advanced stages of age-related macular degeneration (AMD) was supported by the 4/day tablet form investigated in the Age-related Eye Disease Study 1 (AREDS1) and the 2/day softgel form in the Age-related Eye Disease Study 2 (AREDS2). However, the choices of excipient, dosage form, and ingredient chemistry as well as the patient physiologies and pathologies can influence bioavailability and efficacy. The objective of the study was to explore the influence of dosage form on the bioavailability of the five primary AREDS1 and Tier-2 AREDS2 micronutrients: the metals zinc and copper, ß-carotene, and vitamins E and C. The intent was to establish by chemical analysis the relative bioavailabilities of these five micronutrients in plasma, or serum for the metals, as well as to identify any opportunities for improvements. METHODS: A total of 15 healthy men (5) and women (10) were recruited for a controlled, randomized, three-arm, crossover trial of the AREDS1 micronutrients. The study investigated responses in bioabsorption to a single dose of either four tablets or two softgels at the full dose level, or one softgel at the half-dose level. The bioavailability of each micronutrient was based on the pharmacokinetic profiles established through 15 samplings for each ingredient/dosage form in plasma/serum over the course of one week. RESULTS: Bioavailability was estimated using model-independent and model-dependent procedures. A statistical advantage of the dosage form was observed in only two cases from the exaggerated effects using the half-dose softgel and for the tablet dosage form for ß-carotene and vitamin E. An unanticipated complexity was suggested by the bimodal absorption of zinc. For these micronutrients, no disadvantage (though potential advantage) was inferred for the water-soluble components presented in a softgel formulation. Increased fractional absorption was observed for the smaller dose (one capsule versus two), but it was not sufficient to reach the level achieved by the full dose of either four tablets or two softgels. A model-dependent analysis permitted an estimation of the percentage of micronutrients absorbed, with zinc, the single most important ingredient, absorbed at about a 10% level. CONCLUSIONS: The results suggest modestly contradictory requirements in the dosage form for water-soluble and lipid-soluble ingredients, as based on a goal of improved bioavailability. Comparative consistency in bioavailability was observed across dosage forms, and most nutrients between AREDS1 and AREDS2 (full dose) formulations relative to the significant variations observed within this controlled population. The results emphasize the importance of defining the requisite bioavailability of each micronutrient and the influence of the dosage form that provides it. With the recognition of global and population-specific micronutrient deficiencies, notably in the elderly populations afflicted with AMD and their significant metabolic and health consequences, establishing efficient means of supplementation are of continuing epidemiologic interest.

Lutein and preterm infants with decreased concentrations of brain carotenoids.

OBJECTIVES: Lutein and zeaxanthin are dietary carotenoids that may influence visual and cognitive development. The objective of this study was to provide the first data on distribution of carotenoids in the infant brain and compare concentrations in preterm and term infants. METHODS: Voluntarily donated brain tissues from 30 infants who died during the first 1.5 years of life were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank. Tissues (hippocampus and prefrontal, frontal, auditory, and occipital cortices) were extracted using standard lipid extraction procedures and analyzed using reverse-phase high-pressure liquid chromatography. RESULTS: Lutein, zeaxanthin, cryptoxanthin, and ß-carotene were the major carotenoids found in the infant brain tissues. Lutein was the predominant carotenoid accounting for 59% of total carotenoids. Preterm infants (n = 8) had significantly lower concentrations of lutein, zeaxanthin, and cryptoxanthin in their brain compared with term infants (n = 22) despite similarity in postmenstrual age. Among formula-fed infants, preterm infants (n = 3) had lower concentrations of lutein and zeaxanthin compared with term infants (n = 5). Brain lutein concentrations were not different between breast milk-fed (n = 3) and formula-fed (n = 5) term decedents. In contrast, term decedents with measurable brain cryptoxanthin, a carotenoid that is inherently low in formula, had higher brain lutein, suggesting that the type of feeding is an important determinant of brain lutein concentrations. CONCLUSIONS: These data reveal preferential accumulation and maintenance of lutein in the infant brain despite underrepresentation in the typical infant diet. Further investigation on the impact of lutein on neural development in preterm infants is warranted.

Macular pigment optical density is related to cognitive function in older people.

BACKGROUND: the xanthophylls lutein (L) and zeaxanthin (Z) exist in relatively high concentration in multiple central nervous tissues (e.g. cortex and neural retina). L + Z in macula (i.e. macular pigment, MP) are thought to serve multiple functions, including protection and improvement of visual performance. Also, L + Z in the macula are related to L + Z in the cortex. OBJECTIVE: to determine whether macular pigment optical density (MPOD, L + Z in the macula) is related to cognitive function in older adults. METHODS: participants were older adults (n = 108, 77.6 ± 2.7 years) sampled from the age-related maculopathy ancillary study of the Health Aging and Body Composition Study (Memphis, TN, USA). Serum carotenoids were measured using high performance liquid chromatography. MPOD was assessed using heterochromatic flicker photometry. Eight cognitive tests designed to evaluate several cognitive domains including memory and processing speed were administered. Partial correlation coefficients were computed to determine whether cognitive measures were related to serum L + Z and MPOD. RESULTS: MPOD levels were significantly associated with better global cognition, verbal learning and fluency, recall, processing speed and perceptual speed, whereas serum L + Z was significantly related to only verbal fluency. CONCLUSION: MPOD is related to cognitive function in older people. Its role as a potential biomarker of cognitive function deserves further study.

Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates.

OBJECTIVES: Xanthophyll pigments lutein and zeaxanthin cross the blood-retina barrier to preferentially accumulate in the macular region of the neural retina. There they form macular pigment, protecting the retina from blue light damage and oxidative stress. Lutein and zeaxanthin also accumulate in brain tissue. The objective of the study was to evaluate the relationship between retinal and brain levels of these xanthophylls in non-human primates. METHODS: Study animals included rhesus monkeys reared on diets devoid of xanthophylls that were subsequently fed pure lutein or pure zeaxanthin (both at 3.9 µmol/kg per day, n = 6/group) and normal rhesus monkeys fed a stock diet (0.26 µmol/kg per day lutein and 0.24 µmol/kg per day zeaxanthin, n = 5). Retina (4 mm macular punch, 4-8 mm annulus, and periphery) and brain tissue (cerebellum, frontal cortex, occipital cortex, and pons) from the same animals were analyzed by reverse-phase high-performance liquid chromatography. RESULTS: Lutein in the macula and annulus was significantly related to lutein levels in the cerebellum, occipital cortex, and pons, both in bivariate analysis and after adjusting for age, sex and n-3 fatty acid status. In the frontal cortex the relationship was marginally significant. Macular zeaxanthin was significantly related to zeaxanthin in the cerebellum and frontal cortex, while the relationship was marginally significant in the occipital cortex and pons in a bivariate model. DISCUSSION: An integrated measure of total macular pigment optical density, which can be measured non-invasively, has the potential to be used as a biomarker to assess brain lutein and zeaxanthin status.