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1.  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
2.  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
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.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
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.  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
14.  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
15.  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
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.  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
18.  Higher Serum Concentrations of Dietary Antioxidants are Associated with Lower Levels of Inflammatory Biomarkers during the Year after Hip Fracture 
Background & Aims
Chronic inflammation impairs recovery among the 1.6 million people who suffer from hip fracture annually. Vitamin E and the carotenoids are two classes of dietary antioxidants with profound anti-inflammatory effects, and the goal of this study was to assess whether higher post-fracture concentrations of these antioxidants were associated with lower levels of interleukin 6 (IL-6) and the soluble receptor for tumor necrosis factor-alpha (sTNF-αR1), two common markers of inflammation.
Serum concentrations of the dietary antioxidants and inflammatory markers were assessed at baseline and 2, 6, and 12 month follow-up visits among 148 hip fracture patients from The Baltimore Hip Studies. Generalized estimating equations modeled the relationship between baseline and time-varying antioxidant concentrations and inflammatory markers.
Higher post-fracture concentrations of vitamin E and the carotenoids were associated with lower levels of inflammatory markers. Associations were strongest at baseline, particularly between the α-tocopherol form of vitamin E and sTNF-αR1 (p=0.05) and total carotenoids and both sTNF-αR1(p=0.01) and IL-6 (p=0.05). Higher baseline and time-varying α-carotene and time-varying lutein concentrations were also associated with lower sTNF-αR1 at all post-fracture visits (p ≤ 0.05).
These findings suggest that a clinical trial increasing post-fracture intake of vitamin E and the carotenoids may be warranted.
PMCID: PMC3412071  PMID: 22365613
antioxidants; inflammation; vitamin E; carotenoids; micronutrients; hip fracture
19.  Patient Reported Differences in Dry Eye Disease between Men and Women: Impact, Management, and Patient Satisfaction 
PLoS ONE  2013;8(9):e76121.
Dry eye disease affects women twice as often as men, but there is little information on whether dry eye treatments, treatment satisfaction, or the impact of dry eye disease on patients’ lives and vision might differ by sex.
Questionnaire survey of 4000 participants in the Women’s Health Study and the Physicians’ Health Studies I and II with a prior report of a diagnosis of DED.
Among participants who re-confirmed a diagnosis of dry eye disease, we assessed symptoms, treatments, patient satisfaction and impact of dry eye disease, and analyzed differences between men and women using regression models.
The final study population consisted of 1,518 women (mean age 70.7 years) and 581 men (mean age 76.7 years), with a mean reported duration of dry eye disease of 10.5 years and 10.1 years, respectively. The frequency and severity of dry eye disease symptoms were higher among women (each P<0.0001), and women reported a greater impact on everyday activities (P<0.0001). Women were more likely to use artificial tears (P<0.0001) use them more often (P<0.0001), and to use Restasis® (P<0.0001), omega-3 fatty acids (P=0.0006), and have punctal occlusion (P=0.005). Women spent more money per month on dry eye treatments (P<0.0001), but reported greater dissatisfaction with treatment side effects (P=0.001), and the amount of time before treatments started working (P=0.03).
These data show that dry eye disease is generally experienced as being more severe among women, having a greater impact on their self-assessed well-being.
PMCID: PMC3786885  PMID: 24098772
20.  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
21.  Relationship of Low-Circulating “Anti-Aging” Klotho Hormone with Disability in Activities of Daily Living among Older Community-Dwelling Adults 
Rejuvenation Research  2012;15(3):295-301.
The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, ≥65 years, who participated in the “Invecchiare in Chianti” (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p=0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio=0.57, 95% confidence interval 0.35–0.93, p=0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women.
PMCID: PMC3388499  PMID: 22530731
23.  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
24.  Serum 25-Hydroxyvitamin D, Transitions between Frailty States, and Mortality among Older Adults: The Invecchiare in Chianti Study 
Frailty is a dynamic geriatric syndrome characterized by decreased reserve and increased vulnerability. Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in older adults are associated with many physiological changes that portend frailty and its consequences. We aimed to assess whether serum 25(OH)D concentrations relate to transitions between the states of robustness, prefrailty, and frailty, and to mortality.
Adults aged≥65 years (N=1,155) enrolled in Invecchiare in Chianti (InCHIANTI), a prospective cohort study in Tuscany, Italy.
Serum 25(OH)D concentrations measured at baseline and frailty state (robust, prefrail, frail) assessed at baseline and at three and six years post enrollment. Vital status was also determined at three and six years post enrollment.
The median (interquartile range) 25(OH)D concentration was 16.0 (10.4—25.6) ng/mL (multiply by 2.496 to convert to nmol/L). Prefrail participants with 25(OH)D<20 ng/mL were 8.9% (95% Confidence Interval [CI], 2.5—15.2%) more likely to die, 3.0% (95%CI, −5.6—14.6%) more likely to become frail, and 7.7% (95%CI, −3.5—18.7%) less likely to become robust than prefrail participants with 25(OH)D≥20 ng/mL. Among prefrail participants, each 5 ng/mL decrement of continuous 25(OH)D was associated with 1.46 times higher odds of dying (95%CI, 1.18—2.07) and 1.13 higher odds of incident frailty (95%CI, 0.90—1.39) versus recovery of robustness. Transitions from robustness or frailty were not associated with 25(OH)D.
Results provide evidence that prefrailty is an “at risk” state from which older adults with high 25(OH)D are more likely to recover than to decline. However, high 25(OH)D was not associated with recovery from frailty. Thus, 25(OH)D should be investigated as a potential therapy to treat prefrailty and prevent further decline.
PMCID: PMC3288698  PMID: 22283177
Frailty; Mortality; Vitamin D
25.  Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65495–503-specific CD8+ T cells in older adults 
Age  2011;33(4):607-614.
In immunocompetent individuals, cytomegalovirus (CMV) is thought to persist in a latent state in monocytes and myeloid progenitor cells, establishing a lifelong infection. In CMV-seropositive older adults, aging has been associated with both expansion of CMV pp65495–503-specific CD8+ T cell clones and shrinkage of the T cell repertoire that characterize T cell immunosenescence. In fact it has been suggested that chronic CMV infection is a driving force in age-related T cell immunosenescence. In older adults, chronic CMV infection is conventionally diagnosed by positive IgG serology which does not distinguish between past and persistent infections. To better define the relationship between chronic CMV infection and expansion of CMV pp65495–503-specific CD8+ T cells, we directly assessed CMV viral DNA in monocyte-enriched peripheral blood mononuclear cells in 16 HLA-A2-positive elderly volunteers (mean age = 83 years). While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65495–503 tetramer-positive CD8+ T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4). CMV IgM titers were negative for all 16 participants, suggesting that recent primary CMV infection was unlikely. These results demonstrate a strong association between the presence of CMV DNA in peripheral monocytes and the expansion of CD8+ T cells specific for the CMV immunodominant epitope pp65495–503. Although the sample size in this study is relatively small, these findings provide initial evidence suggesting the heterogeneity of CMV IgG-seropositive older adult population and CMV viral DNA detection in peripheral monocytes as an informative tool to better understand the relationship between chronic CMV infection and T cell immunosenescence.
PMCID: PMC3220402  PMID: 21274637
Monocytic CMV DNA; CMV pp65495–503-specific CD8+ T cells; CMV IgG serology; Older adults

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