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Nanocarriers based on amphiphilic block copolymers, with tailored temperature and pH responsiveness, were prepared. The hydrophilic blocks consist of temperature-sensitive [N-isopropylacryl...

International audience; Reports on the association of periodontal disease (PD) with systemic lupus erythematosus (SLE) have regularly been published. PD is a set of chronic inflammatory conditions linked to a dysbiotic microbial biofilm, which affects the periodontal tissues, resulting eventually in their destruction and contributing to systemic inflammation. SLE is a multi-system chronic inflammatory autoimmune disease that has a wide range of clinical presentations, touching multiple organ systems. Many epidemiological studies have investigated the two-way relationship between PD and SLE, though their results are heterogeneous. SLE and PD are multifactorial conditions and many biological-based hypotheses suggest common physiopathological pathways between the two diseases, including genetics, microbiology, immunity, and environmental common risk factors. By focusing on recent clinical and translational research, this review aimed to discuss and give an overview of the relationship of SLE with PD, as well as looking at the similarities in the immune-pathological aspects and the possible mechanisms connecting the development and progression of both diseases. more...

Background Childhood Systemic Lupus Erythematosus (cSLE) patients are younger at diagnosis and have a more severe disease course compared to adult onset SLE patients and develop significant complications related to disease and or immunosuppression. Moreover, female and minority populations experience higher rates of cSLE, with African American, Afro-Caribbean, and Hispanic populations being at greatest risk and having poor prognosis Methods The Pediatric Alliance for Lupus initiative addressed the dearth in education and resources in a multi-stage process. First, we conducted a need assessment identifying knowledge gaps among healthcare providers (HCPs), and resources needed to care for cSLE patients and their families. Second, we educated HCPs about the diagnosis and treatment of cSLE by Continuing Medical Education (CME) sessions/webinars (presented here). Third, HCPs participated in a Quality Improvement (QI) program on cSLE approved by the American Board of Pediatrics Maintenance of Certification Part 4. Finally, patients and caregivers were educated through the development of appropriate, culturally and linguistically sensitive cSLE resources. PAL disseminated materials among HCPs and the community to improve the awareness of the availability of these materials. Results According to results from the statewide needs assessment (representative of every county throughout NJ), HCPs face significant challenges in providing care to cSLE patients and their families, in part due to the multi-systemic nature of the autoimmune disease. Conclusion Based on this need, we developed educational sessions, with pre-post comparison data showing a significant increase in knowledge after HCP education. The 15 different materials developed as part of the endeavor is a major contribution to the cSLE community, HCPs and pediatric rheumatologists. Resources are available in multiple formats (PDF and web pages), and are accessible on the National Resource Center on Lupus, the latest web site of the Lupus Foundation of American that houses materials for SLE patients, their families, schools, HCPs, and the community at large. Improving cSLE knowledge will empower the children and adolescents and families by increasing their self-efficacy; and positively impact key health outcomes (transition readiness and HRQOL) that are not optimally addressed with current medical treatment alone. more...

The availability of safe and effective radiation countermeasures for the military and civilian population represents a significant unmet medical need. To expedite the development of countermeasures for life-threating situations, the United States Food and Drug Administration (US FDA) has implemented the “Animal Rule” which applies to the development and evaluation of drugs and biologics to reduce or prevent life-threatening conditions caused by exposure to lethal or permanently disabling agents where human efficacy trials are neither feasible nor ethical. In addition, the FDA has introduced several incentives (fast track, orphan drug status, and emergency use authorization [EUA]) to attract drug sponsors to develop such agents for human use. Repurposing is vital to make drugs available for life-threatening conditions. Drugs are commonly repurposed for new indications not originally envisioned. By repurposing a drug, it can be made available for human use much quicker, but this pathway also involves issues such as intellectual property rights as corporations are reluctant to expose their blockbuster pharmaceuticals to additional scientific scrutiny. Two radiomitigators for hematopoietic acute radiation syndrome (H-ARS) (Neupogen and Neulasta) have been approved by the FDA through repurposing. The EUA is a legal means for the FDA to approve new drugs or new indications for the previously approved drugs for use during a declared emergency and is a valid way to expedite drug development. Several promising agents with and without FDA investigational new drug (IND) status for ARS are under advanced development. In the next few years, we expect that the FDA will approve a few radioprotectors for H-ARS as well as gastrointestinal ARS via Animal Rule. more...

The possible detonation of a radiological dispersal device or improvised nuclear device in a metropolitan city, or the accidental exposures to a radiation source, nuclear accidents, or the all-to-often threats of radiological/nuclear terrorism have led to the urgent need to develop essential analytic tools to assess such radiation exposures, especially radiation doses to exposed individuals. This exposure-assessing work using biological samples, and discipline, is known as biodosimetry. As of late, this field has progressed significantly as it has made use of the advances within newer areas of biologic analytics, namely omics (genomics, proteomics, metabolomics, and transcriptomics), lymphocyte kinetics, optically stimulated luminescence, and electron paramagnetic resonance technology in addition to conventional cytogenetic techniques. The use of automated high throughput platforms and the planning for laboratory surge capacity during the time of need are the latest developments in the field of biomarkers for biodosimetry. Such biomarkers are also needed for radiation exposure/dose conversion estimates that are essential for the development and application of radiation countermeasures, from animals to humans and that are currently being developed following the US Food and Drug Administration Animal Rule. Here, we present and discuss the current status of various biomarkers for assessing radiation dose after radiation exposure. It is anticipated that with the advent of improved biomarkers and associated biomarker platforms for the acute radiation syndrome, exposed victims can be more efficiently triaged and appropriately treated than is currently allowable. The latest advances in the field, and identify the areas where improvement is needed are also listed and discussed. more...

Pressure injury prevention is required in all health care environments. Respiratory technology includes invasive and noninvasive positive pressure ventilation methods of support and life-saving equipment. Pressure injury can occur from tracheostomy tubes and their securement devices, or use of noninvasive positive pressure ventilation interfaces or the head gear. Methods instituted to decrease hospital-acquired pressure injury related to noninvasive positive pressure ventilation and tracheostomy securement devices are discussed. more...

Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69−40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF , or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12−0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01−0.57; P = .01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors. more...

Wheat landraces, wild relatives and other ‘exotic’ accessions are important sources of new favorable alleles. The use of those exotic alleles is facilitated by having access to information on the association of specific genomic regions with desirable traits. Here, we conducted a genome-wide association study (GWAS) using a wheat panel that includes landraces, synthetic hexaploids and other exotic wheat accessions to identify loci that contribute to increases in grain yield in southern Australia. The 568 accessions were grown in the field during the 2014 and 2015 seasons and measured for plant height, maturity, spike length, spike number, grain yield, plant biomass, HI and TGW. We used the 90K SNP array and two GWAS approaches (GAPIT and QTCAT) to identify loci associated with the different traits. We identified 17 loci with GAPIT and 25 with QTCAT. Ten of these loci were associated with known genes that are routinely employed in marker assisted selection such as Ppd-D1 for maturity and Rht-D1 for plant height and seven of those were detected with both methods. We identified one locus for yield per se in 2014 on chromosome 6B with QTCAT and three in 2015, on chromosomes 4B and 5A with GAPIT and 6B with QTCAT. The 6B loci corresponded to the same region in both years. The favorable haplotypes for yield at the 5A and 6B loci are widespread in Australian accessions with 112 out of 153 carrying the favorable haplotype at the 5A locus and 136 out of 146 carrying the favorable haplotype at the 6A locus, while the favorable haplotype at 4B is only present in 65 out of 149 Australian accessions. The low number of yield QTL in our study corroborate with other GWAS for yield in wheat, where most of the identified loci have very small effects. more...

Exposure to ionizing radiation induces a cascade of molecular events that ultimately impact endogenous metabolism. Qualitative and quantitative characterization of metabolomic profiles is a pragmatic approach to studying the risks of radiation exposure since it provides a phenotypic readout. Studies were conducted in irradiated nonhuman primates (NHP) to investigate metabolic changes in plasma and plasma-derived exosomes. Specifically, rhesus macaques (Macaca mulatta) were exposed to cobalt-60 gamma-radiation and plasma samples were collected prior to and after exposure to 5.8 Gy or 6.5 Gy radiation. Exosomes were isolated using ultracentrifugation and analyzed by untargeted profiling via ultra-performance liquid chromatography mass spectrometry (UPLC-MS) based metabolomic and lipidomic analyses, with the goal of identifying a molecular signature of irradiation. The enrichment of an exosomal fraction was confirmed using quantitative ELISA. Plasma profiling showed markers of dyslipidemia, inflammation and oxidative stress post-irradiation. Exosomal profiling, on the other hand, enabled detection and identification of low abundance metabolites that comprise exosomal cargo which would otherwise get obscured with plasma profiling. We discovered enrichment of different classes of metabolites including N-acyl-amino acids, Fatty Acid ester of Hydroxyl Fatty Acids (FAHFA&rsquo, s), glycolipids and triglycerides as compared to the plasma metabolome composition with implications in mediation of systemic response to radiation induced stress signaling. more...

Background As part of our statewide childhood injury prevention education efforts, Safe Kids New Jersey, led by Central Jersey Family Health Consortium launched the Home Safe Home pilot program in 2013 to reduce preventable home injuries among young children. Home Safe Home is a replicable, evidence based model that incorporates strategies to increase knowledge and awareness, thereby improving safety in a child’s home environment. Home Safe Home kits were provided at no cost to strengthen at-risk, low-income families by removing financial barriers to acquiring safety devices. The program provided the opportunity to work directly with home visitation programs and provide high risk families with key home safety education along with safety devices to help prevent needless injuries. Methods In total, 94 families participated in the home visitation based study. Intervention group families received education and home safety devices during the first home visit and follow-up during the second. Control group families received education at the first home visit and safety devices were distributed at the second visit upon need. Data collected included usage of safety devices, a home assessment, pre/post surveys, and home injury reduction. Results For those families receiving home safety education along with safety devices, there was 55% improvement of home safety, such that recommended usage of home safety devices, self-initiated safety interventions (tripping hazards, burn prevention, etc.), and safety precaution scores improved for both groups over time with the intervention group improving significantly more. In addition, the program provided leverage for enhancing capacity with increased funding and partnerships. In 2017, Home Safe Home was recognized by Safe Kids Worldwide for ‘Excellence in Home Safety in the U.S.’ Conclusions Provision of education and home safety devices through home visitation programs is an effective way to provide home safety education on unintentional injuries in the home. more...

Threats of nuclear terrorism coupled with potential unintentional ionizing radiation exposures have necessitated the need for large-scale response efforts of such events, including high-throughput biodosimetry for medical triage. Global metabolomics utilizing mass spectrometry (MS) platforms has proven an ideal tool for generating large compound databases with relative quantification and structural information in a short amount of time. Determining metabolite panels for biodosimetry requires experimentation to evaluate the many factors associated with compound concentrations in biofluids after radiation exposures, including temporal changes, pre-existing conditions, dietary intake, partial- vs. total-body irradiation (TBI), among others. Here, we utilize a nonhuman primate (NHP) model and identify metabolites perturbed in serum after 7.2 Gy TBI without supportive care [LD(70/60), hematologic (hematopoietic) acute radiation syndrome (HARS) level H3] at 24, 36, 48 and 96 h compared to preirradiation samples with an ultra-performance liquid chromatography quadrupole time-of-flight (UPLC-QTOF) MS platform. Additionally, we document changes in cytokine levels. Temporal changes observed in serum carnitine, acylcarnitines, amino acids, lipids, deaminated purines and increases in pro-inflammatory cytokines indicate clear metabolic dysfunction after radiation exposure. Multivariate data analysis shows distinct separation from preirradiation groups and receiver operator characteristic curve analysis indicates high specificity and sensitivity based on area under the curve at all time points after 7.2 Gy irradiation. Finally, a comparison to a 6.5 Gy (LD(50/60), HARS level H2) cohort after 24 h postirradiation revealed distinctly increased separations from the 7.2 Gy cohort based on multivariate data models and higher compound fold changes. These results highlight the utility of MS platforms to differentiate time and absorbed dose after a potential radiation exposure that may aid in assigning specific medical interventions and contribute as additional biodosimetry tools. more...

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004 more...

Background: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. Objective: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. Methods: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Results: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-mg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P= 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. Conclusions: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans. J Nutr doi: 10.3945/jn.114.202093. more...

The objective of this study is to examine the relationship of serum carboxymethyl-lysine (CML), an advanced glycation end product (AGE), with pulse pressure (PP), aortic pulse wave velocity (aPWV) and hypertension in older adults.AGEs are bioactive molecules that accumulate in tissues with ageing and can both cross-link collagen and induce inflammation in model systems. The relationship of AGEs with arterial stiffness and hypertension has not been well characterized in community-dwelling older adults.We measured serum CML and blood pressure in 3044 adults, aged 70-79 years, who participated in the Health, Aging and Body Composition Study, a population-based study of ageing in Pittsburgh, Pennsylvania and Memphis, Tennessee. aPWV was measured in 2468 participants.Participants in the highest tertile of serum CML had higher PP (highest tertile: beta = 2.85, SE = 0.82, P = 0.0005; middle tertile: beta = 0.60, SE = 0.80, P = 0.45), and higher aPWV (highest tertile: beta = 51.4, SE = 20.1, P = 0.01; middle tertile: beta = 3.2, SE = 19.8, P = 0.87) than those in the lowest tertile in multivariable linear regression models adjusting for age, sex, race, education, BMI, smoking, alcohol use, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes, cardiovascular disease and chronic kidney disease. Participants in the highest and middle tertiles of serum CML had higher odds of hypertension [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.06-1.60, P = 0.005; OR 1.27, 95% CI 1.05-1.53, P = 0.01, respectively] than those in the lowest tertile in a multivariable logistic regression model adjusting for the same covariates.Elevated serum CML was associated with arterial stiffness, as reflected by higher PP and aPWV, in older, community-dwelling adults. more...

High adiposity in midlife might increase risk for late-life brain pathology, including dementia. Using data from the prospective Age, Gene/Environment Susceptibility-Reykjavik Study of men and women (born 1907–1935), we studied the associations of overweight and obesity at midlife (mean age, 50 (standard deviation, 4.7) years) with 1.5-T brain magnetic resonance imaging measures of infarct-like brain lesions, cerebral microbleeds, total brain volume, and white matter lesions volume, as well as dementia, in late life (mean age, 76 (standard deviation, 5.2) years). We used linear and Poisson models to estimate associations in 3,864 persons after adjustment for sociodemographic, health, and lifestyle characteristics. In midlife, the prevalence of overweight was 39% and that of obesity was 8%. After a mean follow-up of 26.2 (standard deviation, 4.9) years, midlife overweight and obesity were not associated with infarct-like brain lesions (relative risk (RR) = 0.82, 95% confidence interval (CI): 0.61, 1.10), cerebral microbleeds (RR = 0.69, 95% CI: 0.37, 1.32), total brain volume (β = 0.05, 95% CI: −0.34, 0.45), white matter lesions volume (β = −0.10, 95% CI: −0.20, 0.01), or dementia (RR = 0.91, 95% CI: 0.49, 1.72) compared with normal weight. These findings do not support the hypothesis that high body mass index in midlife modulates the risk for dementia. more...

The American Society for Bioethics and Humanities promulgated standards for clinical ethics consultants and is currently developing a national Quality Attestation in Clinical Ethics Consultation to assist facilities in ensuring that those performing clinical ethics consultations meet minimum standards. As the field moves towards such professionalization, there is a need to provide access to qualified clinical ethicists at a broad range of medical facilities. Currently, however, there are insufficient numbers of trained clinical ethicists to staff all healthcare facilities, and many facilities lack the necessary resources to hire staff clinical ethicists. In this review, we describe several models for providing expert clinical ethics support to remote facilities that lack access to qualified clinical ethicists. Based on this analysis, we recommend telemedicine as the optimal model providing expert support to local ethics committee members tasked with providing clinical ethics consultation services. more...

Greater bone mineral density was observed after treating hypertension using angiotensin-converting enzyme inhibitor (ACEi). We report decreased rate of bone loss in hypertensive black men using ACEi for 9 years. There may be a gender- and race-specific effect of ACEi in the prevention of age-associated bone loss. There is evidence of bone mass preservation in patients receiving ACEis, commonly used to treat hypertension. However, limitations of previous studies include being cross-sectional or only including a short-term follow-up of patients using ACEi and including patients with diabetes, which affects bone metabolism. None of the previous studies described effects of ACEi stratified by race. The objective of this study was to investigate differences in changes in bone mineral density (BMD) in older adults who suffer from hypertension and had reported ACEi use during each study visit for at least 9 years during the study, stratified by gender and race. We used data from the Dynamics of Health, Aging and Body Composition (HABC) study, which enrolled 3075 community-dwelling older white and black individuals. We compared changes in femoral neck, total hip, and whole-body BMD after either no use of ACEi (n = 580) or long-term use (at least 9 years) of ACEi (n = 239) in HABC participants with hypertension and no known diagnosis of diabetes mellitus. Overall, BMD values significantly decreased for all subgroups over time. In the stratified multivariate analysis, long-term use of ACEi was associated with a reduced rate of decline for all three BMD measures among black men, but no significant effect was observed in the other subgroups. Our findings show a gender- and race-specific effect of ACEi in the prevention of age-associated bone loss that warrants further evaluation. more...

The current rate of yield gain in crops is insufficient to meet the predicted demands. Capturing the yield boost from heterosis is one of the few technologies that offers rapid gain. Hybrids are widely used for cereals, maize and rice, but it has been a challenge to develop a viable hybrid system for bread wheat due to the wheat genome complexity, which is both large and hexaploid. Wheat is our most widely grown crop providing 20% of the calories for humans. Here, we describe the identification of Ms1, a gene proposed for use in large-scale, low-cost production of male-sterile (ms) female lines necessary for hybrid wheat seed production. We show that Ms1 completely restores fertility to ms1d, and encodes a glycosylphosphatidylinositol-anchored lipid transfer protein, necessary for pollen exine development. This represents a key step towards developing a robust hybridization platform in wheat., Heterosis can rapidly boost yield in crop species but development of hybrid-breeding systems for bread wheat remains a challenge. Here, Tucker et al. describe the molecular identification of the wheat Ms1 gene and discuss its potential for large-scale hybrid seed production in wheat. more...

The threat of a radiological/nuclear event is a critical concern for all government agencies involved in national security and public health preparedness. Countermeasures that are safe, easily administered, and effective at diminishing or eliminating adverse health effects to individuals and the overall public health impact of radiation exposure are urgently needed. Radiation countermeasures included in this three-part series have been classified under various subheadings based specifically on their developmental stages for United States Food and Drug Administration (FDA) approval. We have included FDA-approved agents for acute radiation syndrome (ARS) in part I. This is part II in which we have reviewed FDA-approved agents for limited indications, internalized radionuclides, emesis, late effects, radiomitigators available in the strategic national stockpile (SNS), agents with FDA investigational new drug (IND) status, and those with NHP efficacy data without FDA IND. Agents discussed in part III are those agents that have been peer reviewed, published, and have demonstrated significant survival benefits in animal models of ARS. Agents investigated in in vitro models only or studied in animal models without peer-reviewed publications have not been included.The dearth of FDA-approved radiation countermeasures has prompted intensified research for a new generation of radiation countermeasures. A number of promising radiation countermeasures are currently moving forward with continued support and effort by both governmental agencies and by publicly and privately held pharmaceutical companies. There is a limited number of countermeasures which are progressing well following the Animal Rule and may get approved in the near future, thus serving to close the gap of this critically important, unmet radiobiomedical need. more...

JC virus (JCV) is a polyomavirus that infects approximately 75% of the population and encodes a T antigen (T-Ag) gene, which is oncogenic and inactivates the p53 and pRb/p107/p130 protein families. Previous work in our lab has identified the presence of T-Ag in colorectal neoplasms. While JCV remains in a latent state for the majority of those infected, we hypothesized that a disturbance in immunological control may permit JCV to reactivate, which may be involved in the development of colorectal neoplasia. Our aim was to determine the cell mediated immune response to JCV T-Ag, and determine if it is altered in patients with colorectal adenomatous polyps (AP) or cancers (CRC). Peripheral blood mononuclear cells (PBMCs) isolated from the blood of patients undergoing colonoscopy or colorectal surgery were stimulated by a peptide library covering the entire T-Ag protein of JCV. Cytokine production and T cell proliferation were evaluated following T-Ag stimulation using Luminex and flow cytometry assays. JCV T-Ag peptides stimulated secretion of IL-2, which induced T cell expansion in all three groups. However, stronger IL-10 and IL-13 production was seen in patients without colorectal neoplasms. IP-10 was produced at very high levels in all groups, but not significantly differently between groups. Most patients exhibited CD4(+) and CD8(+) T cells in response to stimulation by the T-Ag clusters. The combination of IL-2 and IP-10 secretion indicates the presence of T-Ag-specific Th1 cells in all patients, which is higher in patients without carcinoma. more...

Bone mineral density (BMD) and geometric bone measures are individually associated with prevalent osteoporotic fractures. Whether an aggregate of these measures would better associate with fractures has not been examined. We examined relationships between self-reported fractures and selected bone measures acquired by quantitative computerized tomography (QCT), a composite bone score, and QCT-acquired dual-energy X-ray absorptiometry-like total femur BMD in 2110 men and 2682 women in the Age, Gene/Environment Susceptibility-Reykjavik Study. The combined bone score was generated by summing gender-specific Z-scores for 4 QCT measures: vertebral trabecular BMD, femur neck cortical thickness, femur neck trabecular BMD, and femur neck minimal cross-sectional area. Except for the latter measure, lower scores for QCT measures, singly and combined, showed positive (p&nbsp more...

This article describes a study that explored factors which influenced undergraduate students’ perceptions of the racial climate at a predominantly white liberal arts university in the South. Mixed methods results suggest that race, aspects of the institutional climate, and frequent interracial dining experiences in the campus cafeteria differentially affected students’ campus racial climate perceptions. more...

Background: Aberrant activation of the canonical WNT signaling is a feature of colorectal cancer (CRC). Van-Gogh-like 2 (VANGL2) belongs to the non-canonical WNT pathway whose activation inhibits canonical WNT signaling. In this study, we investigated the role of VANGL2 and its epigenetic regulation in CRC. Methods: Van-Gogh-like 2 expression and promoter methylation after 5-aza-2'-deoxycytidine (5-aza) treatment were evaluated in CRC cells. DNA samples from 418 sporadic CRCs were tested for VANGL2 promoter methylation and microsatellite instability (MSI). Proliferation, colony formation and activation of the WNT pathway were tested in cells after VANGL2 overexpression. Results: Van-Gogh-like 2 mRNA was significantly higher in 5-aza-treated RKO, LOVO and SW48, whereas no differences were found in SW480. Van-Gogh-like 2 was fully methylated in RKO, SW48, HCT116, DLD1 and Caco2; partially methylated in LOVO, LS174T and SW837; and unmethylated in SW480, SW620 and HT29. Higher expression of VANGL2 mRNA was found in the unmethylated cell lines. In CRC specimens (8.93% MSI), methylated VANGL2 was associated with MSI, higher grade, proximal colon location and BRAF mutation. Van-Gogh-like 2 overexpression in SW480 significantly decreased proliferation, colony formation and beta-catenin levels. Conclusion: Van-Gogh-like 2 is frequently methylated in MSI-CRCs with BRAF mutation and may act as a tumour suppressor gene, counteracting WNT/beta-catenin signaling. more...

Aims The C677T variant in the methylenetetrahydrofolate reductase ( MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase ( MTR; EC 2.1.1.13) and methionine synthase reductase ( MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache ( n = 367), migraine without aura ( n = 85), migraine with aura ( n = 167), and no headache ( n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population. more...

Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)–associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity. more...

We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES–Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). We examined if lifelong physical activity is important for maintaining bone strength in the elderly. The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES–Reykjavik Study. Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly. more...

We studied the effect of birth size on glucose and insulin metabolism among old non-diabetic individuals. We also explored the combined effect of birth size and midlife body mass index (BMI) on type 2 diabetes in old age. Our study comprised 1,682 Icelanders whose birth records included anthropometrical data. The same individuals had participated in the prospective population-based Reykjavik Study, where BMI was assessed at a mean age of 47 years, and in the AGES-Reykjavik Study during 2002 to 2006, where fasting glucose, insulin and HbA₁c were measured and homeostasis model assessment for the degree of insulin resistance (HOMA-IR) calculated at a mean age of 75.5 years. Type 2 diabetes was determined as having a history of diabetes, using glucose-modifying medication or fasting glucose of >7.0 mmol/l. Of the participants, 249 had prevalent type 2 diabetes in old age. Lower birth weight and body length were associated with higher fasting glucose, insulin, HOMA-IR and HbA₁c among old non-diabetic individuals. Higher birth weight and ponderal index at birth decreased the risk for type 2 diabetes in old age, odds ratio (OR), 0.61 [95 % confidence interval (CI), 0.48–0.79] and 0.96 (95 % CI, 0.92–1.00), respectively. Compared with those with high birth weight and low BMI in midlife, the odds of diabetes was almost five-fold for individuals with low birth weight and high BMI (OR, 4.93; 95 % CI, 2.14–11.37). Excessive weight gain in adulthood might be particularly detrimental to the health of old individuals with low birth weight. peerReviewed more...

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p more...

Previous studies have reported associations of polymorphisms in the IGF1 gene with phenotypes of body composition (BC). The purpose of this study was to identify phenotypes of BC and physical function that were associated with the IGF1 promoter polymorphism (rs35767, −C1245T). Subjects from the Health, Aging, and Body Composition Study, white males and females (n = 925/836) and black males and females (533/705) aged 70–79 years were genotyped for the polymorphism. Phenotypes of muscle size and function, bone mineral density, and BC were analyzed for associations with this polymorphism. To validate and compare these findings, a cohort of young (mean age = 24.6, SD = 5.9) white men and women (n = 173/296) with similar phenotypic measurements were genotyped. An association with BC was identified in elderly females when significant covariates (physical activity, age, smoking status, body mass index) were included. White women with C/C genotype had 3% more trunk fat and 2% more total fat than those with C/T (P more...

Retinal focal arteriolar signs (e.g., focal arteriolar narrowing and arteriovenous [AV] nicking) and retinopathy lesions (e.g., retinal hemorrhages and microaneurysms) are common retinal vascular lesions among older adults. Among people age 65 years and older, the prevalence was 9.6% for focal arteriolar narrowing, 7.7% for AV nicking, and 8.3% for retinopathy lesions.1 Similarly, older adults frequently have evidence of diffuse cerebral microvascular disease indicated by white matter hyperintensities (WMHs)2,3 and focal vascular disease evidenced by brain infarcts on magnetic resonance images (MRI).4,5 Two large population-based studies suggest that individuals with retinal microvascular lesions are more likely to perform poorly on cognitive tests,6–8 and to have an increased risk of dementia.7,8 Silent brain infarcts and more severe WMHs also increase the risk of cognitive decline and dementia.9–11 The vasculature in the brain and retina share similar features in anatomy, physiology, and metabolic activity.12,13 Therefore, it is of interest to characterize the relation of brain and retinal vascular lesions, and to investigate the predictability of ocular microvascular changes for brain vascular lesions. Studies of middle-aged people suggest that retinal focal arteriolar narrowing and AV nicking, and retinal hemorrhages and microaneurysms in particular, are associated with brain infarcts as well as more severe WMHs.14,15 However, findings from two population-based studies of older people are inconsistent with those from studies of middle-aged adults; the Rotterdam Scan Study found no association of focal arteriolar narrowing with the severity of WMHs and lacunar infarcts,16 and in the Cardiovascular Health Study only AV nicking, but neither focal arteriolar narrowing nor retinopathy, was associated with cerebral white matter changes and small brain infarcts.17 Here, we investigate whether retinal microvascular lesions are correlated with cerebral WMHs and infarcts in an elderly population. We extend previous research by examining (1) whether an increasing load of cerebrovascular lesions is associated with the burden of retinal microvascular disease, and (2) whether there are particular locations of cerebrovascular lesions that are more highly correlated with retinal microvascular changes. more...

OBJECTIVE—Diabetes increases the risk for microvascular disease. The retina and the brain both have intricate microvascular systems that are developmentally similar. We sought to examine whether microvascular lesions in the retina and in the brain are associated and whether this association differs among people with and without diabetes. RESEARCH DESIGN AND METHODS—The analysis included 4,218 participants of the Icelandic population-based Age, Gene/Environment Susceptibility-Reykjavik Study who were born in 1907–1935 and who were previously followed as a part of the Reykjavik Study. Retinal focal arteriolar narrowing, arteriovenous (AV) nicking, and microaneurysms/hemorrhages were evaluated on digital retinal images of both eyes. Cerebral microbleeds (CMBs) were evaluated from magnetic resonance images. Data were analyzed with logistic and multinomial logistic regression models controlling for demographics, major cardiovascular risk factors, cerebral infarcts, and white matter lesions. RESULTS—Evidence of brain microbleeds was found in 485 (11.5%) people, including 192 with multiple (≥2) microbleeds. Subjects with signs of retinal microvascular lesions were at a significantly increased likelihood for having multiple CMBs. People with diabetes in combination with the presence of either retinal AV nicking (odds ratio [OR] 2.47 [95% CI 1.42–4.31]) or retinal microaneurysms/hemorrhages (2.28 [1.24–4.18]) were significantly more likely to have multiple CMBs. CONCLUSIONS—Retinal microvascular abnormalities and brain microbleeds may occur together in older adults. People with both diabetes and signs of retinal microvascular lesions (AV nicking and microaneurysms/hemorrhages) are more likely to have multiple microbleeds in the brain. Microvascular disease in diabetes extends to the brain. more...

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped acrossor= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications. more...

Background Associations of atherosclerosis risk factors with unrecognized myocardial infarction ( UMI ) are unclear. We investigated associations of midlife risk factors with UMI and recognized MI ( RMI ) detected 31 years later by cardiac magnetic resonance. Methods and Results The Reykjavik Study (1967–1991) collected serial risk factors in subjects, mean ( SD ) age 48 (7) years. In ICELAND ‐ MI (2004–2007), 936 survivors (76 (5) years) were evaluated by cardiac magnetic resonance. Analysis included logistic regression and random effects modeling. Comparisons are relative to subjects without MI . At baseline midlife evaluation, a modified Framingham risk score was significantly higher in RMI and in UMI versus no MI (7.4 (6.3)%; 7.1 (6.2)% versus 5.4 (5.8)%, P RMI and UMI were more frequent in men (65%, 64% versus 43%; P UMI (138 (17) mm Hg versus 133 (17) mm Hg; P P BP was significantly higher in RMI (88 (10) mm Hg versus 84 (10) mm Hg; P RMI (6.7 (1.1) mmol/L versus 6.2 (1.1) mmol/L; P =0.0005; and 1.4 (0.7) mmol/L versus 1.1 (0.7) mmol/L; P UMI ( P =0.08). Serial midlife systolic BP was significantly higher in UMI versus no MI (β [ SE ] = 2.69 [1.28] mm Hg, P =0.04). Serial systolic and diastolic BP were significantly higher in RMI versus no MI (4.12 [1.60] mm Hg, P =0.01 and 2.05 [0.91] mm Hg, P =0.03) as were cholesterol (0.43 [0.11] mmol/L, P =0.0001) and triglycerides (0.3 [0.06] mmol/L, P Conclusions Midlife vascular risk factors are associated with UMI and RMI detected by cardiac magnetic resonance 31 years later. Systolic blood pressure was the most significant modifiable risk factor associated with later UMI . more...

To better understand the potential impact of hearing impairment (HI) and hearing aid use on emotional vitality and mental health in older adults.We investigated the cross-sectional association of HI with emotional vitality in 1,903 adults aged 76-85 years in the Health ABC study adjusted for demographic and cardiovascular risk factors. Hearing was defined by the speech frequency pure tone average (no impairment25 dB, mild impairment 25-40 dB, and moderate or greater impairment40 dB). Emotional vitality was defined as having a high sense of personal mastery, happiness, low depressive symptomatology, and low anxiety.Compared with individuals with no HI, participants with moderate or greater HI had a 23% lower odds of emotional vitality (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.59-0.99). Hearing aid use was not associated with better emotional vitality (OR = 0.98; 95% CI: 0.81-1.20).HI is associated with lower odds of emotional vitality in older adults. Further studies are needed to examine the longitudinal impact of HI on mental health and well-being. more...

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests. more...

OBJECTIVES: To test the hypothesis that increased long-term mortality after hospitalization for community-acquired pneumonia (CAP) is independent of comorbid conditions. DESIGN: Prospective observational cohort study in metropolitan areas. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Three thousand seventy-five subjects aged 70 to 79 over 5.2 years. MEASUREMENTS: Unadjusted and adjusted mortality from an initial hospitalization for CAP were compared with mortality from different causes of hospitalization, including cancer, fracture, congestive heart failure (CHF), cerebrovascular accident (CVA), and other causes. Demographics, smoking, nutritional markers, functional status, inflammatory markers, and chronic health conditions were adjusted for. RESULTS: Of the 106 subjects hospitalized for CAP, 22 (20.8%) and 38 (35.8%) died at 1 and 5 years. Subjects hospitalized with CAP had higher mortality than nonhospitalized subjects (adjusted odds ratio (OR)=7.8, 95% confidence interval (CI)=4.2–14.4). One- and 5-year mortality after CAP hospitalization were higher than mortality from other causes requiring hospitalization and remained unchanged in multivariable analysis (adjusted OR=3.5, 95% CI=1.5–8.1; adjusted OR=5.6, 95% CI=2.8–11.2, respectively). One- and 5-year mortality after hospitalization for CAP were similar to or higher than mortality after an initial hospitalization for CHF, CVA, or fracture. Rehospitalization was common in subjects hospitalized for CAP and may explain greater long-term mortality. CONCLUSION: In this high-functioning cohort of older persons, an initial hospitalization for CAP was associated with greater long-term mortality, independent of prehospitalization comorbid conditions. Hospitalization for CAP has as serious a prognosis as hospitalization for CHF, stroke, or major fracture. more...

In older adults with aortic stenosis, we evaluated whether accelerometer-measured physical activity provides distinct clinical information apart from self-reported surveys or performance-based function tests. We employed wrist-mounted accelerometry in 52 subjects with severe aortic stenosis prior to transcatheter aortic valve replacement (TAVR). Daily daytime activity was estimated using the maximum 10 h of daily accelerometer-measured activity (M10) reported in activity counts. Subjects completed baseline surveys (New York Heart Association (NYHA), Short Form 12 (SF12), Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQol-5D (EQ-5D), Revised Life Orientation Test (LOT-R), Life Space, Detailed Activity Form) and performance-based function tests (Short Physical Performance Battery, 6-min walk test distance, grip strength) to estimate functional status. Simple and multiple linear regression models were used to evaluate the relationship between accelerometer-measured activity and survey data and performance-based function tests. Among all baseline surveys and performance-based function tests, the only statistically significant univariable relationships identified were weak, negative associations between M10 and SF-12 Mental Composite Score (R2=0.1970, P=0.04) and between M10 and grip strength (R2=0.1568, P=0.004). Neither multiple linear regression of overall survey data (R2=0.6159, P=0.23) nor performance-based function tests (R2=0.1743, P=0.10) correlated with M10. Self-reported surveys and performance-based function tests are not meaningfully correlated with daytime accelerometer-measured activity. The results of our study suggest that accelerometer-measured physical activity provides distinct clinical information apart from self-reported surveys or performance-based function tests. more...

BACKGROUND There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. METHODS A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52±7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (±4) years later. RESULTS After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005). CONCLUSION Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life. more...

Purpose: Although cyclooxygenase (COX)-2 inhibitors could represent the most effective chemopreventive tool against colorectal cancer (CRC), their use in clinical practice is hampered by cardiovascular side effects. Consumption of ω-3-polyunsaturated fatty acids (ω-3-PUFAs) is associated with a reduced risk of CRC. Therefore, in this study, we assessed the efficacy of a novel 99% pure preparation of ω-3-PUFA eicosapentaenoic acid as free fatty acids (EPA-FFA) on polyps in ApcMin/+ mice. Experimental design: ApcMin/+ and corresponding wild-type mice were fed control diet (Ctrl) or diets containing either EPA-FFA 2.5% or 5%, for 12 weeks while monitoring food intake and body weight. Results: We found that both EPA-FFA diets protected from the cachexia observed among ApcMin/+ animals fed Ctrl diet (P < 0.0054), without toxic effect, in conjunction with a significant decrease in lipid peroxidation in the treated arms. Moreover, both EPA-FFA diets dramatically suppressed polyp number (by 71.5% and 78.6%, respectively; P < 0.0001) and load (by 82.5% and 93.4%, respectively; P < 0.0001) in both small intestine and colon. In addition, polyps less than 1 mm in size were predominantly found in the EPA-FFA 5% arm whereas those 1 to 3 mm in size were more frequent in the Ctrl arm (P < 0.0001). Interestingly, in the EPA-FFA groups, mucosal arachidonic acid was replaced by EPA (P < 0.0001), leading to a significant reduction in COX-2 expression and β-catenin nuclear translocation. Moreover, in the EPA-FFA arms, we found a significant decrease in proliferation throughout the intestine together with an increase in apoptosis. Conclusions: Our data make 99% pure EPA-FFA an excellent candidate for CRC chemoprevention. Clin Cancer Res; 16(23); 5703–11. ©2010 AACR. more...

BACKGROUND Studies of older persons show consumption of light-to-moderate amounts of alcohol is positively associated with cognitive function and, separately, is negatively associated with total brain volume (TBV). This is paradoxical as generally, cognitive function is positively associated with TBV. We examined the relationships of TBV, global cognitive function (GCF), and alcohol consumption in a population-based cohort of 3,363 men and women (b. 1907-1935) participating in the Age Gene/Environment Susceptibility-Reykjavik Study (2002-2006) and who were free of dementia or mild cognitive impairment METHODS Drinking status (never, former, and current) and current amount of alcohol consumed were assessed by questionnaire. GCF is a composite score derived from a battery of cognitive tests. TBV, standardized to head size, is estimated quantitatively from brain magnetic resonance imaging. RESULTS Among women and not men, adjusting for demographic and cardiovascular risk factors, current drinkers had significantly higher GCF scores than abstainers and former drinkers (p < .0001); and GCF was associated with amount consumed. TBV was not associated with drinking status or amount consumed in men or women. GCF and TBV did significantly differ in their associations across alcohol categories (p interaction < .001). Within categories of alcohol intake, GCF and TBV were positively associated. CONCLUSIONS The difference in associations of alcohol intake to brain structure and function suggests there may be unmeasured factors that contribute to maintaining better GCF relative to TBV. However, at higher levels of reasonable alcohol consumption, there may be factors leading to reduced brain volume. more...