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1.  The Role of O-GlcNAc Signaling in the Pathogenesis of Diabetic Retinopathy 
Diabetic retinopathy is a leading cause of blindness worldwide. Despite laser and surgical treatments, anti-angiogenic and other therapies, and strict metabolic control, many patients progress to visual impairment and blindness. New insights are needed into the pathophysiology of diabetic retinopathy in order to develop new methods to improve the detection and treatment of disease and the prevention of blindness. Hyperglycemia and diabetes result in increased flux through the hexosamine biosynthetic pathway, which, in turn, results in increased post-translational modification of Ser/Thr residues of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). O-GlcNAcylation is involved in regulation of many nuclear and cytoplasmic proteins in a manner similar to protein phosphorylation. Altered O-GlcNAc signaling has been implicated in the pathogenesis of diabetes and may play an important role in the pathogenesis of diabetic retinopathy. The goal of this review is to summarize the biology of the hexosamine biosynthesis pathway and O-GlcNAc signaling, to present the current evidence for the role of OGlcNAc signaling in diabetes and diabetic retinopathy, and to discuss future directions for research on O-GlcNAc in the pathogenesis of diabetic retinopathy.
PMCID: PMC4037871  PMID: 24550151
diabetes; diabetic retinopathy; glucose toxicity; hexosamine biosynthesis pathway; O-GlcNAcylation
2.  Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease 
Neuroscience letters  2013;558:37-40.
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that is predominantly secreted by the choroid plexus of the brain and in the kidney. Klotho-deficient mice develop multiple aging phenotypes, including impaired cognition. Klotho concentrations have not been described in the CSF of humans. We measured klotho in the CSF of 20 older adults with Alzheimer's disease and in 20 older and 20 younger adults with normal cognition. In 10 adults, aged 38-87 years, CSF klotho measurements were made at baseline and every 6 hours up to 18-30 hours later. Mean (95% Confidence Interval [C.I.]) CSF klotho in men versus women were 899 (814, 983) and 716 (632, 801) pg/mL, respectively (P = 0.002). Mean (95% C.I.) CSF klotho in older adults with and without Alzheimer's disease were 664 (603, 725) and 776 (705, 828) pg/mL, respectively (P = 0.02), adjusting for sex. Mean (95% C.I.) klotho in older versus younger adults were 766 (658, 874) and 992 (884, 1100) pg/mL, respectively (P = 0.005), adjusting for sex. In the longitudinal study of CSF klotho, no significant circadian fluctuations were found in CSF klotho levels. This study suggests that CSF klotho concentrations are lower in females compared with males, in Alzheimer's disease, and in older versus younger adults.
PMCID: PMC4037850  PMID: 24211693
Aging; Alzheimer's Disease; Brain; Cerebrospinal Fluid; Klotho
3.  Relationship of maternal knowledge of anemia with maternal and child anemia and health-related behaviors targeted at anemia among families in Indonesia 
Maternal and child health journal  2012;16(9):1913-1925.
Our specific aim was to characterize maternal knowledge of anemia and its relationship to maternal and child anemia and to behaviors related to anemia reduction.
We examined the relationship between maternal knowledge of anemia and anemia in the mother and the youngest child, aged 6–59 mo, in 7,913 families from urban slums and 37,874 families from rural areas of Indonesia. Knowledge of anemia was defined based upon the mother’s ability to correctly name at least one symptom of anemia and at least one treatment or strategy for reducing anemia. Hemoglobin was measured in both the mother and the child.
In urban and rural areas, respectively, 35.8% and 36.9% of mothers had knowledge of anemia, 28.7% and 25.1% of mothers were anemic (hemoglobin <12 g/dL), and 62.3% and 54.0% of children were anemic (hemoglobin <11 g/dL). Maternal knowledge of anemia was associated with child anemia in urban and rural areas, respectively, (Odds Ratio [O.R.] 0.90, 95% Confidence Interval [C.I.] 0.79, 1.02, P = 0.10; O.R. 0.93, 95% C.I. 0.87, 0.98, P = 0.01) in multivariate logistic regression models adjusting for potential confounders. There was no significant association between maternal knowledge of anemia and maternal anemia. Maternal knowledge of anemia was significantly associated with iron supplementation during pregnancy and child consumption of fortified milk. There was no association of maternal knowledge of anemia with child deworming.
Maternal knowledge of anemia is associated with lower odds of anemia in children and with some health behaviors related to reducing anemia.
PMCID: PMC4101891  PMID: 22241619
anemia; children; knowledge; mothers; Indonesia
4.  Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults 
Journal of human hypertension  2012;27(6):397-399.
Fibroblast growth factor 21 (FGF21), a recently discovered endocrine factor, plays an important role in glucose and lipid metabolism and may contribute to the development of atherosclerosis and coronary heart disease. The present cross sectional study examined the relationship of FGF21 with hypertension in 744 community-dwelling adults who participated in the Baltimore Longitudinal Study of Aging.
PMCID: PMC4059993  PMID: 23190795
aging; fibroblast growth factor 21; hypertension
5.  Resveratrol levels and all-cause mortality in older community-dwelling adults 
JAMA internal medicine  2014;174(7):1077-1084.
Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anti-cancer effects in humans and is related to longevity in some lower organisms.
To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.
Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study (“Aging in the Chianti Region”), 1998-2009.
Two villages in the Chianti area, Tuscany region of Italy.
Population-based sample of 783 community-dwelling men and women, ≥65 y
24-h urinary resveratrol metabolites
Main outcomes and measures
Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α), and prevalent and incident cancer and cardiovascular disease
Mean (95% Confidence Interval) log total urinary resveratrol metabolite concentrations were 7.08 (6.69, 7.48) nmol/g creatinine. During nine years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4, 31.6, 33.5, and 37.4%, respectively (P = 0.67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% confidence interval 0.54, 1.17) when compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF-α, prevalent or incident cardiovascular disease or cancer. Conclusions: In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer, or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet do not have a substantial influence on health status and mortality risk.
PMCID: PMC4346286  PMID: 24819981
cancer; cardiovascular disease; inflammation; longevity; resveratrol; InCHIANTI
6.  Chronic CMV infection in older women: Longitudinal comparisons of CMV DNA in peripheral monocytes, anti-CMV IgG titers, serum IL-6 levels, and CMV pp65 (NLV)-specific CD8+ T-cell frequencies with twelve year follow-up 
Experimental gerontology  2014;0:84-89.
Chronic cytomegalovirus (CMV) infection may contribute significantly to T-cell immunosenescence, chronic inflammation, and adverse health outcomes in older adults. Recent studies suggest detectable CMV DNA in peripheral monocytes as a better indicator for this persistent viral infection than anti-CMV IgG serology. Here, we conducted longitudinal comparisons of anti-CMV IgG titers, CMV DNA in the peripheral monocytes, serum IL-6 levels, and CMV pp65 (NLV)-specific CD8+ T-cell frequencies in fifteen community-dwelling older women with twelve year follow-up. The results showed that anti-CMV IgG titers did not change over twelve years. Women with detectable CMV DNA had significantly higher IL-6 levels than those without, both at baseline (3.06+0.58 vs 1.19±0.37 pg/ml, respectively, p< .001) and at the follow-up (3.23±0.66 versus 0.98±0.37 pg/ml, respectively, p< .001). In addition, CMV pp65 (NLV)-specific CD8+ T cells were detected only in women who had CMV DNA with similar frequencies at both time points. These findings indicate that anti-CMV IgG serology is not sensitive to change nor useful for monitoring chronic CMV infection over time. They also provide a basis for further investigation into chronic CMV infection as defined by detectable CMV DNA in the peripheral monocytes and its impact on immunity and health in the elderly.
PMCID: PMC3989432  PMID: 24440388
chronic CMV infection; CMV DNA in monocytes; IL-6; CMV pp65 (NLV)-specific CD8+ T cells; longitudinal; aging
7.  Serum vitamin E concentrations among highly functioning hip fracture patients are higher than in nonfracture controls 
Malnutrition after hip fracture is common and associated with poor outcomes and protracted recovery. Low concentrations of vitamin E have been associated with incident decline in physical function among older adults and may, therefore, be particularly important to functionally compromised patients hip fracture patients. Serum concentrations of α-tocopherol and γ-tocopherol, the 2 major forms of vitamin E, were assessed in 148 female hip fracture patients 65 years or older from the Baltimore Hip Studies cohort 4 around the time of fracture (baseline) and at 2, 6, and 12 month postfracture follow-up visits (recovery). It was hypothesized that mean concentrations of both forms of vitamin E among these hip fracture patients would be lowest at the baseline visit and increase at each study visit during the year after fracture. Linear regression and generalized estimating equations were used to assess changes in vitamin E concentrations after adjustment for covariates and to determine predictors of vitamin E concentrations at baseline and throughout recovery. It was also hypothesized that vitamin E concentrations shortly after hip fracture would be lower than those in nonfracture controls after adjustment for covariates. To evaluate this hypothesis, linear regression was used to perform adjusted comparisons of baseline vitamin E concentrations among Baltimore Hip Studies cohort 4 participants to 1076 older women without history of hip fracture from the Women’s Health and Aging Study I, Invecchiare in Chianti Study, and the National Health and Nutrition Examination Surveys. Mean α-tocopherol was lowest at baseline, and time from fracture to blood draw was positively associated with baseline α-tocopherol (P = .005). Mean γ-tocopherol did not change appreciably throughout the year after fracture, although it fluctuated widely within individuals. Serum concentrations of α-tocopherol and γ-tocopherol were highest among the hip fracture population after adjustment (P < .0001). In general, highly cognitively and physically functioning hip fracture patients demonstrated higher vitamin E concentrations. Thus, the relatively high degree of function among this cohort of hip fracture patients may explain their higher-than-expected vitamin E concentrations.
PMCID: PMC4153436  PMID: 21481714
Vitamin E; Tocopherols; Antioxidants; Micronutrients; Hip fracture; Older women
8.  Serum Carboxymethyl-lysine, an Advanced Glycation End Product, and Age-Related Macular Degeneration: the Age Gene/Environment Susceptibility-Reykjavik Study 
JAMA ophthalmology  2014;132(4):464-470.
Advanced glycation end products have been implicated in the pathogenesis of age-related macular degeneration (AMD).
To investigate the relationship between serum carboxymethyl-lysine (CML), a major circulating advanced glycation end product, and AMD in older adults.
Cross-sectional study.
Population-based sample of older adults in the Age Gene/Environment Susceptibility-Reykjavik Study.
4907 adults, aged ≥66 years
Serum CML and risk factors for AMD.
Main Outcome Measures
Early or late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System.
Of the 4907 participants, 1025 (20.9%) had early AMD and 276 (5.6%) had late AMD. Mean (standard deviation [SD]) serum CML concentrations among adults with no AMD, early AMD, and late AMD (exudative AMD and pure geographic atrophy) were 3.0 (0.9), 3.1 (1.0), and 3.1 (0.9) μmol/L, respectively (P = 0.07). Log serum CML (per 1 log SD) was not associated with any AMD (early and late AMD) (Odds Ratio [O.R.] 0.97, 95% Confidence Interval [C.I.] 0.90, 1.04, P = 0.44) or with late AMD (O.R. = 0.94, 95% C.I. 0.82, 1.08, P = 0.36) in respective multivariable logistic regression models adjusting for age, sex, body mass index, smoking, and renal function.
Higher serum CML had no significant cross-sectional association with prevalent AMD in this large population-based cohort of older adults in Iceland.
PMCID: PMC4169215  PMID: 24481410
advanced glycation end products; age-related macular degeneration; aging; Iceland
9.  Proteomics and the Eye 
PMCID: PMC4346283  PMID: 24729286
10.  C-Reactive Protein (CRP), Interferon Gamma-Inducible Protein 10 (IP-10), and Lipopolysaccharide (LPS) Are Associated with Risk of Tuberculosis after Initiation of Antiretroviral Therapy in Resource-Limited Settings 
PLoS ONE  2015;10(2):e0117424.
The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain.
Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm).
We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis.
Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55–6.81) and IP-10 (aOR 1.89, 95% CI: 1.05–3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13–5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB.
Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.
PMCID: PMC4342263  PMID: 25719208
11.  Circulating selenium and carboxymethyl-lysine, an advanced glycation end product, are independent predictors of anemia in older community-dwelling adults 
To assess whether selenium and carboxymethyl-lysine (CML), two biomarkers of oxidative stress, are independent predictors of anemia in older, community-dwelling adults.
Plasma selenium, CML, folate, vitamin B12, testosterone, and markers of iron status and inflammation were measured at baseline in 1,036 adults, ≥65 years, in the InCHIANTI Study, a population-based cohort study of aging in Tuscany, Italy, and examined in relationship to prevalent anemia and incident anemia over 6 years of follow-up.
At enrollment, 11.6% of participants were anemic. Of 472 participants who were non-anemic at enrollment 72 (15.3%) developed anemia within 6 years of follow-up. At enrollment, plasma CML in the highest quartile (>425 ng/mL) and plasma selenium in the lowest quartile (<66.6 μg/L) predicted incident anemia (Hazards Ratio [H.R.] 1.67, 95% Confidence Interval [C.I.] 1.07–2.59, P = 0.02; H.R. 1.55, 95% C.I.1.01–2.38, P = 0.05, respectively) in a multivariate Cox proportional hazards model that adjusted for age, education, body mass index, cognition, inflammation, red cell distribution width, ferritin, vitamin B12, testosterone, and chronic diseases.
Elevated plasma carboxymethyl-lysine and low plasma selenium are long-term independent predictors of anemia among older community-dwelling adults. These findings support the idea that oxidative stress contributes to the development of anemia.
PMCID: PMC3377823  PMID: 22325035
advanced glycation end products; aging; anemia; carboxymethyl-lysine; oxidative stress; selenium
12.  Serum 25-Hydroxyvitamin D and Pulmonary Function in Older Disabled Community-Dwelling Women 
Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women.
We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women’s Health and Aging Study I.
Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV1 (p = .03), FVC (p = .18), and FEV1/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV1, FVC, or FEV1/FVC.
These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.
PMCID: PMC3732158  PMID: 22156439
Aging; Lung function; Parathyroid hormone; Vitamin D; Women
13.  A prospective study of common variants in the CX3CR1 gene and risk of macular degeneration: pooled analysis from five long-term studies 
JAMA ophthalmology  2014;132(1):84-95.
The CX3CR1 gene is implicated as a candidate gene for age-related macular degeneration (AMD) through several lines of evidence. There is uncertainty, however, as to whether common genetic variants in CX3CR1 alter risk of AMD, since prior studies have been inconsistent and mostly limited to evaluation of two non-synonymous variants, T280M (rs3732378) and V249I (rs3732379).
We aimed to determine if common variants in CX3CR1 predict future risk of AMD.
Prospective nested case-control study within five large study populations with long-term follow-up.
We measured genotypes for T280M, V249I and 13 other common single-nucleotide polymorphisms (SNPs) of the CX3CR1 gene among people who developed AMD (N=1110, including N=369 with neovascular AMD) and 2532 age- and sex-matched controls.
Main outcome measures
We determined the incidence rate ratios (RR) and 95% confidence intervals (CI) for incidence of AMD for each variant, and examined interactions with other AMD-associated variants and modifiable risk factors.
In additive genetic models, we identified non-significant associations with AMD for T280M (RR=0.87, P=0.074) and three other SNPs, rs2853707 (RR=0.88, P=0.069), rs12636547 (RR=0.85, P=0.098), and rs1877563 (RR=0.84, P=0.056), one of which, rs2853707, is positioned in the CX3CR1 promoter region and was associated with neovascular AMD (RR=0.75, P=0.028). We observed that a recessive model was a better fit to the data for some SNPs, with associations between rs11715522 and AMD (RR=1.27, P=0.034), and between rs2669845 (RR=3.10, P=0.035), rs2853707 (RR=0.48, P=0.050) and rs9868689 (RR=0.31, P=0.017) and neovascular AMD. Moreover, in exploratory analyses we identified a number of possible interactions including between V249I and rs2669845 and dietary intake of omega-3 fatty acids (P=0.004, and P=0.009, respectively) for AMD; between rs2669845 and obesity (P=0.031) for neovascular AMD; between T280M and complement component 3 (C3) R102G for AMD (P=0.027); between rs2669845 and Y402H in complement factor H (CFH) for AMD (P=0.037); and between rs2669845, rs2853707, and V249I and C3 R102G for neovascular AMD (P=0.008, 0.039 and 0.002, respectively).
This study failed to identify significant associations between common CX3CR1 variants and AMD after considering the number of SNPs analyzed and multiple comparisons. However, we observed evidence consistent with recessive modes of association, and that an effect of CX3CR1 variants may depend on other factors including dietary intake of omega-3 fatty acids, obesity, and genotypes at CFH Y402H and C3 R102G. If replicated in other populations, these findings would support a role for CX3CR1 in AMD, but also suggest that its role may involve mechanisms that are independent of the T280M/V249I variations.
PMCID: PMC4170669  PMID: 24287500
14.  Nutritional Amblyopia Combined with Night Blindness 
Case Reports in Ophthalmology  2012;3(3):389-391.
We report the case of an 18-year-old male who developed both nutritional amblyopia and night blindness. After nearly a lifetime of consuming a bizarre diet limited to French fries, pretzels, crackers, and carbonated sodas, he had a relatively sudden onset of night blindness and bilateral visual loss. The night blindness resolved after taking daily oral vitamin A supplements. Visual acuity gradually improved from light perception, both eyes, to 20/20 right eye and 20/25 left eye after multivitamin supplementation and vitamin B12 injections. The patient had bilateral optic atrophy and bilateral ring scotomas around a small area of fixation. The patient was unable to modify his diet despite professional advice and counseling.
PMCID: PMC3531945  PMID: 23275794
B complex vitamins; Nutritional amblyopia; Night blindness; Vitamin A
15.  Pre-Antiretroviral Therapy Serum Selenium Concentrations Predict WHO Stages 3, 4 or Death but not Virologic Failure Post-Antiretroviral Therapy 
Nutrients  2014;6(11):5061-5078.
A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28–99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86–95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30–9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium.
PMCID: PMC4245580  PMID: 25401501
HIV; selenium; antiretroviral therapy; nutrition; treatment failure; cohort studies
16.  Elevated Serum Carboxymethyl-Lysine, an Advanced Glycation End Product, Predicts Severe Walking Disability in Older Women: The Women's Health and Aging Study I 
Journal of Aging Research  2012;2012:586385.
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of sarcopenia. Our aim was to characterize the relationship between serum carboxymethyl-lysine (CML), a major circulating AGE, and incident severe walking disability (inability to walk or walking speed <0.4 m/sec) over 30 months of followup in 394 moderately to severely disabled women, ≥65 years, living in the community in Baltimore, Maryland (the Women's Health and Aging Study I). During followup, 154 (26.4%) women developed severe walking disability, and 23 women died. Women in the highest quartile of serum CML had increased risk of developing of severe walking disability in a multivariate Cox proportional hazards model, adjusting for age and other potential confounders. Women with elevated serum CML are at an increased risk of developing severe walking disability. AGEs are a potentially modifiable risk factor. Further work is needed to establish a causal relationship between AGEs and walking disability.
PMCID: PMC3437635  PMID: 22973514
17.  Relationship of the Presence of a Household Improved Latrine with Diarrhea and Under-Five Child Mortality in Indonesia 
We characterized the relationship of the presence of an improved latrine with diarrhea and under-five child mortality in Indonesia. The proportion of rural and urban families, respectively, without an improved latrine was 52.1% and 16.2%, with a child with a history of diarrhea in the last 7 days was 8.2% and 9.7%, and with a history of under-five child mortality was 11.1% and 8.5%. Among rural and urban families, respectively, lack of an improved latrine was associated with a child history of diarrhea in the last 7 days (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.18–1.29, P < 0.0001; OR = 1.20, 95% CI = 1.13–1.27, P < 0.0001) and under-five child mortality (OR = 1.29, 95% CI = 1.25–1.31, P < 0.0001; OR = 1.22, 95% CI = 1.12–1.32, P < 0.0001) in separate multivariable logistic regression models adjusting for covariates. The lack of a household improved latrine is associated with diarrhea and under-five child mortality in Indonesia.
PMCID: PMC3042822  PMID: 21363984
18.  Is hyperglycemia associated with frailty status in older women? 
To determine whether hyperglycemia is related to prevalent frailty status in older women.
Secondary data analysis of baseline data of a prospective cohort study.
Baltimore, Maryland.
Five hundred forty-three women aged 70 to 79.
Research used baseline data from 543 participants in the Women’s Health and Aging Studies I and II aged 70 to 79 who had all variables needed for analyses. The dependent variable was baseline frailty status (not frail, prefrail, frail), measured using an empirically derived model defining frailty according to weight loss, slow walking speed, weakness, exhaustion, and low activity (1–2 characteristics Present = prefrail, ≥3 = frail). Covariates included body mass index (BMI), interleukin-6 (IL-6), age, race, and several chronic diseases. Analyses included descriptive methods and multinomial logistic regression to adjust for key covariates.
A hemoglobin A1c (HbA1c) level of 6.5% or greater in older women was significantly associated with higher likelihood of prefrail and frail status (normal HbA1c <6.0% was reference). The association between HbA1C levels of 6.0% to 6.5% and frailty status was not different from that of normal HbA1c, but HbA1c levels of 6.5% to 6.9% had nearly twice the likelihood of frailty (odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.47–2.59) as normal HbA1c. A HbA1c level of 9.0% or greater was also strongly associated (OR = 2.57, 95% CI = 1.99,3.32). Significant associations were also seen between baseline prefrail and frail status and low (18.5–20.0 kg/m2) and high (.30.0 kg/m2) body mass index (BMI), interleukin-6, and all chronic diseases evaluated, but controlling for these covariates only minimally attenuated the independent association between HbA1c and frailty status.
Hyperglycemia is associated with greater prevalence of prefrail and frail status; BMI, inflammation, and comorbidities do not explain the association. Longitudinal research and study of alternative pathways are needed.
PMCID: PMC4120964  PMID: 19484839
hyperglycemia; frailty; older women
19.  The Human Eye Proteome Project: Perspectives on an emerging proteome 
Proteomics  2013;13(16):2500-2511.
There are an estimated 285 million people with visual impairment worldwide, of whom 39 million are blind. The pathogenesis of many eye diseases remains poorly understood. The human eye is currently an emerging proteome that may provide key insight into the biological pathways of disease. We review proteomic investigations of the human eye and present a catalogue of 4842 non-redundant proteins identified in human eye tissues and biofluids to date. We highlight the need to identify new biomarkers for eye diseases using proteomics. Recent advances in proteomics now allow the identification of hundreds to thousands of proteins in tissues and fluids, characterization of various post-translational modifications, and simultaneous quantification of multiple proteins. To facilitate proteomic studies of the eye, the Human Eye Proteome Project (HEPP) was organized in September 2012. The HEPP is one of the most recent components of the Biology/Disease-driven Human Proteome Project (B/D-HPP) whose overarching goal is to support the broad application of state-of-the-art measurements of proteins and proteomes by life scientists studying the molecular mechanisms of biological processes and human disease. The large repertoire of investigative proteomic tools has great potential to transform vision science and enhance understanding of physiology and disease processes that affect sight.
PMCID: PMC3978387  PMID: 23749747
Biomarker; Cornea; Eye; Proteomics; Retina; Vision
20.  Low Plasma Carotenoids and Skeletal Muscle Strength Decline over Six Years 
Higher intake of fruits and vegetables appears to protect against inflammation, poor physical performance, and disability, but their relationship with muscle strength is unclear. We examined the association between total plasma carotenoids, an indicator of fruit and vegetable intake, and changes in muscle strength over a 6-year follow-up in the participants aged 65 years and older in the InCHIANTI study, a population-based study in Tuscany, Italy.
Plasma carotenoids were measured at enrollment (1998–2000). Hip, knee and grip strength were measured at enrollment and 6 years later (2004–2006) in 628 of the 948 participants evaluated at baseline. Poor muscle strength was defined as the lowest sex-specific quartile of hip, knee and grip strength at enrollment. The main outcome was poor muscle strength at the six-year follow-up visit among those originally in the upper three quartiles of strength at enrollment.
Overall, 24.9% (110/441), 25.0% (111/444) and 24.9% (118/474) participants developed poor hip, knee and grip strength, respectively. After adjusting for potential confounders, participants in the lowest vs. the highest quartile of total plasma carotenoids at enrollment were at higher risk of developing poor hip (O.R. 2.25, 95% C.I. 1.13–4.48, P = 0.02), knee (O.R. 2.12, 95% C.I. 1.08–4.09, P = 0.03) and grip (O.R. 1.85, 95% C.I. 0.95–3.61, P = 0.07) muscle strength at the six-year follow-up visit.
These findings suggest that older community-dwelling adults with lower plasma carotenoids levels, a marker of poor fruit and vegetable intake, are at a higher risk of decline in skeletal muscle strength over time.
PMCID: PMC4101895  PMID: 18426961
carotenoids; InCHIANTI study; fruit; vegetable; sarcopenia
21.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
PMCID: PMC3652928  PMID: 23636237
22.  C-Reactive Protein and the Incidence of Macular Degeneration – Pooled Analysis of 5 Cohorts 
JAMA ophthalmology  2013;131(4):507-513.
To investigate the relationship between high-sensitivity C-reactive protein (hsCRP) and future risk of age-related macular degeneration (AMD) in US men and women.
We measured hsCRP in baseline blood samples from participants in five ongoing cohort studies. Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD, or 3 controls for each case of neovascular AMD). We used conditional logistic regression models to examine the relationship between hsCRP and AMD, and pooled findings using meta-analytic techniques.
After adjusting for cigarette smoking status, participants with high (> 3 mg/L) compared with low (< 1 mg/L) hsCRP levels, had cohort-specific odds ratios (OR) for incident AMD ranging from 0.94 (95% CI 0.58-1.51) in the Physicians’ Health Study to 2.59 (95% CI 0.58-11.67) in the Women’s Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q=5.61, p=0.23), we pooled findings across cohorts, and observed a significantly increased risk of incident AMD for high versus low hsCRP levels (OR=1.49, 95% CI 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR=1.84, 95% CI 1.14-2.98).
Overall these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms, and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.
PMCID: PMC3625501  PMID: 23392454
23.  Association of Plasma Selenium Concentrations with Total IGF-1 Among Older Community-Dwelling Adults: the InCHIANTI Study 
Background and Aims
Insulin-like growth factor (IGF-1) stimulates cell proliferation and inhibits cell apoptosis. Recent studies underline its importance as anabolic hormone and nutritional marker in older individuals. IGF-1 synthesis and bioactivity are modulated by nutritional factors including selenium intake. However, whether circulating IGF-1 levels are positively influenced by plasma selenium, one of the most important human antioxidants, is still unknown.
Selenium and total IGF-1 were measured in 951 men and women ≥65 years from the InCHIANTI study, Tuscany, Italy.
Means (SD) of plasma selenium and total IGF-1 were 0.95 (0.15) µmol/L and 113.4 (31.2) ng/mL, respectively. After adjustment for age and sex, selenium levels were positively associated with total IGF-1 (ß ± SE: 43.76±11.2, p=0.0001).After further adjustment for total energy and alcohol intake, serum alanine amino transferase (ALT), congestive heart failure, selenium remained significantly associated with IGF-1 (β ± SE: 36.7 ± 12.2, p=0.003). The association was still significant when IL-6 was introduced in the model (β ± SE: 40.1 ± 12.0, p=0.0008).
We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults.
PMCID: PMC3963695  PMID: 20416996
aging; total IGF-1; selenium
24.  Coverage of Vitamin A Capsule Programme in Bangladesh and Risk Factors Associated with Non-receipt of Vitamin A 
Vitamin A supplementation reduces child morbidity, mortality, and blindness. The coverage of the national vitamin A programme and risk factors for not receiving vitamin A were characterized using data from the Bangladesh Demographic and Health Survey 2004. Of 3,745 children aged 18–59 months, 3,237 (86.4%) received a vitamin A capsule each within the last six months. Children who missed vitamin A were more likely to be stunted (prevalence ratio [PR] 0.97, 95% confidence interval [CI] 0.95–1.00) and come from a family with a previous history of mortality of children aged less than five years (PR 0.95, 95% CI 0.91–0.99). Maternal education of ≥10 years (PR 1.09, 95% CI 1.04–1.13), 7–9 years (PR 1.08, 95% CI 1.04–1.12), and 1–6 years (PR 1.05, 95% CI 1.02–1.08) compared to no formal education was associated with the child not receiving vitamin A in a multivariate model, adjusting for potential confounders. Children missed by the vitamin A programme were more likely to come from families with lower maternal education. Special efforts are required to ensure that the coverage of the national vitamin A programme is increased further so that the most vulnerable children are also better protected against morbidity, mortality, and blindness.
PMCID: PMC2980876  PMID: 20411677
Blindness; Child; Morbidity; Mortality; Risk factors; Vitamin A; Vitamin A deficiency; Bangladesh
25.  Financial Strain Is Associated with Malnutrition Risk in Community-Dwelling Older Women 
This study examined the relationship between financial strain, or difficulty acquiring necessities, and malnutrition risk in a community dwelling sample of frail and nonfrail women aged 70–79 in the Women’s Health and Aging Study (n = 679). Malnutrition risk was measured with a modified version of the Mini-Nutritional Assessment Short Form (MNA-SF) and defined as a score <11, financial strain was measured by (1) sufficiency of money on a monthly basis and (2) adequacy of income for food, and income was measured by ordinal categories. Mean (SD) modified MNA-SF score was 12.2 (1.80), and 14.7% of women had malnutrition risk. Women who usually did not have enough money to make ends meet had more than four-fold increased odds of malnutrition risk (OR = 4.54; 95% CI: 2.26, 9.14) compared to their counterparts who had some money left over each month. This was only slightly attenuated after control for income and education, (OR = 4.08; 95% CI: 1.95, 8.52) remaining robust. These results show an association between financial strain and malnutrition risk, independent of income, in older women. Self-reported financial strain may be preferable to income as a screener for malnutrition risk in older adults in clinical and research settings.
PMCID: PMC3806140  PMID: 24163772

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