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1.  Gene Behavior Interaction of Depressive Symptoms and the Apolipoprotein E ε4 Allele on Cognitive Decline 
Psychosomatic medicine  2014;76(2):101-108.
Objective
Depressive symptoms and the APOE ε4 allele are independent risk factors for cognitive decline. However, it is not clear whether the presence of both depressive symptoms and the APOE ε4 allele increases cognitive decline.
Methods
A prospective study of a population-based sample of 4,150 (70% African American and 63% women) participants, aged 65 years and older, who were interviewed at 3-year intervals. Depressive symptoms were measured using the 10-item version of the Center for Epidemiologic Studies Depression scale, with each item coded as presence or absence of a symptom. The APOE genotype was ascertained by DNA samples collected during follow-up. Cognitive function was assessed at the initial and follow-up interviews (average follow-up of 9.2 years), using a standardized global cognitive score.
Results
There were 1405 (34%) participants with one or more copies of the APOE ε4 allele. In participants with no depressive symptoms, cognitive function decreased by 0.0412-unit per year among those with no copies and 0.0704-unit per year among those with one or more copies of the APOE ε4 allele. For each additional symptom of depression, cognitive decline increased by 0.0021-unit per year among those with no copies and 0.0051-unit per year among those with one or more copies of the APOE ε4 allele. The three-way interaction of depressive symptoms, APOE ε4 allele, and time was significant (p=0.021).
Conclusions
The association of depressive symptoms on cognitive decline was increased among participants with one or more copies of the APOE ε4 allele compared to those without the allele.
doi:10.1097/PSY.0000000000000029
PMCID: PMC4142223  PMID: 24434953
APOE Gene; Depressive Symptoms; Cognitive Decline; Gene Behavior Interaction
2.  Radiographic evaluation of the ankle syndesmosis 
Canadian Journal of Surgery  2015;58(1):58-62.
Background
Radiographic measurements to document ankle anatomy have been suggested in recent literature to be inadequate. Focus has been put on stress views and computed tomography; however, there are also issues with these modalities. An orthogonal view that could be used both statically and dynamically could help determine syndesmotic stability. The purpose of this study was to determine a parameter on a normal lateral ankle radiograph that will increase the reliability of standard radiography in diagnosing syndesmotic integrity.
Methods
Three orthopedic surgeons reviewed 80 lateral ankle radiographs. Thirty of those radiographs were reviewed on a second occasion. Rotation of the radiographs was determined by evaluating the overlap of the talar dome. Four radiographic parameters were measured 1 cm above the tibial plafond: fibular width, tibial width, and anterior and posterior tibiofibular intervals.
Results
Seventy-two radiographs were determined by consensus to be adequate. Means and ratios were documented to determine the relationship of the fibula to the tibia. Interrater reliability ranged from moderate to near-perfect, and the intrarater reliability was documented for each ratio. The anterior tibiofibular ratio was shown to be strong to near-perfect. It demonstrates that 40% of the tibia should be seen anterior to the fibula at 1cm above the tibial plafond.
Conclusion
The anterior tibiofibular ratio provides an orthogonal measure for the syndesmosis that, in conjunction with those parameters previously documented, could clinically and economically improve the diagnosis of syndesmotic disruptions.
doi:10.1503/cjs.004214
PMCID: PMC4309766  PMID: 25621912
3.  Wafer-scale synthesis of monodisperse synthetic magnetic multilayer nanorods 
Nano letters  2013;14(1):333-338.
A double exposure technique has been used to fabricate nanoimprint stamps for making monodisperse nanorods with controllable lengths. The nanorod length is defined by a normal photolithography projection process whereas the nanorod width is defined by an edge-lithography process using a soft polydimethylsiloxane (PDMS) contact mask. Taking advantage of edge-lithography, the nanorod width can be less than the diffraction limit of the exposure light. Using these nanorod stamps, synthetic magnetic multilayer (SMM) nanorods have been fabricated using nanoimprint lithography, resulting in a length variation of ~3%. Nanorod magnetic properties have been characterized in both longitudinal and in-plane transverse directions of the nanorods. A theoretical model has been established to explain the magnetic responses and has revealed that both shape anisotropy and interlayer interactions are important in determining the properties of SMM nanorods.
doi:10.1021/nl404089t
PMCID: PMC3931460  PMID: 24329003
Nanorod; magnetic; synthesis; nanoimprint lithography; nano-patterning
4.  Total Daily Activity Declines More Rapidly With Increasing Age in Older Adults 
Longitudinal studies of objectively measured physical activity are lacking in older adults. We tested whether objective measures of total daily activity decline more rapidly in older adults. This prospective, observational cohort study included 519 community-dwelling older persons from across metropolitan Chicago participating in the Rush Memory and Aging Project. Repeated total daily activity measures (leisure and non-leisure physical activity) were derived from actigraphic recordings for up to 10 days. Generalized estimating equation models which controlled for demographics measures were employed. At baseline, age was inversely related with the level of total daily activity (Estimate, −0.014, S.E., 0.002, p<0.001). During up to 6 years of follow-up, total daily activity declined by about 0.070 × 105 activity counts/day/yr (Estimate −0.065, S.E. 0.005, p<0.001). Total daily activity declined 3% more rapidly for each additional year of age at baseline (Estimate −0.002, S.E. 0.001, p=0.027). Thus, total daily activity declined almost twice as fast in an individual 91 years old at baseline versus an individual 71 years old. A higher level of education was associated with a slower rate of decline (Estimate 0.004, S.E. 0.002, p<0.018). The associations of age and education with the rate of declining total daily activity were unchanged when controlling for baseline level of motor and cognitive function, other late-life activities and chronic health conditions. These data suggest that total daily activity in very old adults declines more rapidly with increasing age. Thus, physical inactivity is likely to become a larger problem in our aging population.
doi:10.1016/j.archger.2013.08.001
PMCID: PMC3889486  PMID: 24007938
Aging; Actigraphy; Physical Activity; Total Daily Activity
5.  Perceived Stress and Change in Cognitive Function Among Adults Aged 65 and Older 
Psychosomatic medicine  2013;76(1):80-85.
Objective
Exposure to acute and chronic stress can affect learning and memory but most evidence comes from animal studies or clinical observations. Almost no population-based studies have investigated the relation of stress to cognition or changes in cognition over time. We examined whether higher levels of perceived stress were associated with accelerated decline in cognitive function in older blacks and whites from a community-based population sample.
Methods
Participants included 6,207 black and white adults (65.7% black, 63.3% women) from the Chicago Health and Aging project. Two to five in-home assessments were completed over an average of 6.8 years of follow up, and included sociodemographics, health behaviors, psychosocial measures, cognitive function tests, and health history. Perceived stress was measured by a 6-item scale, and a composite measure of four tests of cognition was used to determine cognitive function at each assessment.
Results
Mixed effects regression models showed that increasing levels of perceived stress were related to lower initial cognitive scores (B=-0.0379, SE=0.0025, p<.001) and a faster rate of cognitive decline (stress × time interaction: B=-0.0015, SE=0.0004, p<.001). Results were similar after adjusting for demographic variables, smoking, systolic blood pressure, body mass index, chronic medical conditions, and psychosocial factors and did not vary by race, sex, age or education.
Conclusion
Increasing levels of stress are independently associated with accelerated declines in cognitive function in black and white adults aged 65 and above.
doi:10.1097/PSY.0000000000000016
PMCID: PMC4185366  PMID: 24367123
aging; cognitive function; longitudinal; risk factors; stress
6.  APOE ε4, Alzheimer’s disease pathology, cerebrovascular disease, and cognitive change over the years prior to death 
Psychology and aging  2013;28(4):10.1037/a0031642.
Background
Much remains to be learned about the effect of the APOE ε4 allele on the trajectory of cognitive aging including the onset of terminal decline and rates of decline before and after, particularly in the presence of Alzheimer’s disease (AD) brain pathology.
Objective
To examine the association of APOE ε4 allele with the late-life cognitive trajectory and test the hypothesis that association of ε4 with cognitive decline is explained by AD neuropathology.
Methods
Participants (N=581) came from two longitudinal clinical-pathologic studies of aging and dementia, the Religious Orders Study and the Memory and Aging Project, which involve uniform annual cognitive assessments and brain autopsy. Longitudinal measures of cognition were derived from detailed annual neuropsychological testing. Participants with 1 or more copies of ε4 allele (ε2/4 excluded) were considered ε4 carriers. Global AD pathology was summarized based on counts of neuritic plaques, diffuse plaques and neurofibrillary tangles. Separate measures of amyloid load and tangle density were assessed using immunohistochemistry. A uniform examination was conducted to document chronic cerebral infarctions. Lewy bodies were identified using alpha-synuclein immunostained sections of substantia nigra, limbic, and neocortical regions. Random change point models were applied to examine the association of ε4 allele with onset of terminal decline as well as pre-terminal and terminal slopes.
Results
On average, the onset of terminal decline occurred around 3 years before death and the rate of terminal decline was 8-fold faster than the pre-terminal decline. The presence of ε4 allele was associated with an earlier onset of terminal decline and faster rates of decline before and after the onset. After adjusting for global AD pathology, the ε4 allele was no longer associated with onset of terminal decline or pre-terminal slope, and the association with terminal slope became marginal. Similarly, ε4 allele was not associated with trajectory of cognitive aging after replacing global AD pathology with the more molecularly-specific measures of amyloid and tau tangles. The result was essentially unchanged after controlling for other common age-related brain pathologies.
Conclusion
The APOE ε4 allele is an important determinant of the change in late-life cognition, including terminal decline. The association is primarily working through AD pathology.
doi:10.1037/a0031642
PMCID: PMC3766432  PMID: 23647000
7.  Brainstem Aminergic Nuclei and Late Life Depressive Symptoms 
JAMA psychiatry (Chicago, Ill.)  2013;70(12):10.1001/jamapsychiatry.2013.2224.
Context
The neurobiologic basis of late life depressive symptoms is not well understood.
Objective
To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late life depressive symptoms.
Design
Longitudinal clinical-pathologic cohort study.
Setting
Residences of participants in the Chicago metropolitan area.
Participants
A total of 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean of 5.7 years (SD = 2.8), died, and underwent a neuropathologic examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus coeruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area.
Main Outcome Measure
Number of depressive symptoms on the Center for Epidemiological Studies Depression scale averaged across annual evaluations (mean = 1.61, SD = 1.48, range: 0–6, skewness = 0.94).
Results
Brainstem Lewy bodies were associated with depressive symptoms and the association was attenuated in those on antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine-hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with higher level of depressive symptoms (estimate = −0.014, SE = 0.003, p<0.001, increase in adjusted R2 = 16.3%). The association was not modified by medications or cognitive impairment. Neither tyrosine-hydroxlyase-immunoreactive neurons in the locus coeruleus nor tryptophan-hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms.
Conclusions
The results suggest that the mesolimbic dopamine system, especially the ventral tegemental area, plays an important role in late life depressive symptoms.
doi:10.1001/jamapsychiatry.2013.2224
PMCID: PMC3856195  PMID: 24132763
8.  TDP-43 Pathology, Cognitive Decline, and Dementia in Old Age 
JAMA neurology  2013;70(11):10.1001/jamaneurol.2013.3961.
Importance
Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood.
Objective
To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late life cognitive decline.
Design
Longitudinal clinical-pathologic cohort study.
Setting
More than 40 Catholic groups across the United States.
Participants
A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified.
Main Outcome Measure
Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death.
Results
TDP-43 pathology ranging from sparse to severe was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. TDP-43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment.
Conclusion
The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.
doi:10.1001/jamaneurol.2013.3961
PMCID: PMC3830649  PMID: 24080705
9.  A neonatal oral Mycobacterium tuberculosis-SIV prime / intramuscular MVA-SIV boost combination vaccine induces both SIV and Mtb-specific immune responses in infant macaques 
Trials in vaccinology  2013;2:53-63.
Mother-to-child-transmission of HIV by breast-feeding remains a major obstacle in the eradication of HIV infection. Compared to adults, HIV-infected infants have more rapid disease and show higher susceptibility to co-infections like tuberculosis (TB). Although the Bacille Calmette-Guérin vaccine can be administered at birth to protect against TB, BCG can disseminate in HIV-infected infants and increase mortality. Thus, a pediatric combination vaccine to stop both HIV and TB infection in infants is urgently needed.
Towards the goal of developing a pediatric combination HIV-TB vaccine to prevent both oral HIV acquisition by breast-feeding and TB infection, we tested and optimized an immunization regimen using a novel live attenuated Mycobacterium tuberculosis vaccine engineered to express simian immunodeficiency (SIV) antigens followed by heterologous MVA-SIV boosting in the infant macaque model. A single oral dose of the attenuated Mtb-SIV vaccine strain mc26435 during the first week of life was sufficient to induce persistent TB-specific immune responses. SIV-specific immunity was induced at low but comparable magnitudes after oral or intradermal priming, and was enhanced following MVA-SIV boosts. T cell responses were most pronounced in intestinal tissues and oral lymph nodes. Importantly, in addition to plasma SIV-specific IgG and IgA antibodies, infant macaques developed mucosal SIV-specific IgA in saliva and intestinal IgA and IgG. While future SIV and Mtb challenge studies will be needed to determine the protective efficacy of the Mtb-SIV / MVA-SIV vaccine, infants at high risk for oral HIV acquisition by breast-feeding and TB infection could profoundly benefit from an effective combination vaccine.
doi:10.1016/j.trivac.2013.09.005
PMCID: PMC3894789  PMID: 24454591
10.  FLI1 Expression is Correlated with Breast Cancer Cellular Growth, Migration, and Invasion and Altered Gene Expression 
Neoplasia (New York, N.Y.)  2014;16(10):801-813.
ETS factors have been shown to be dysregulated in breast cancer. ETS factors control the expression of genes involved in many biological processes, such as cellular proliferation, differentiation, and apoptosis. FLI1 is an ETS protein aberrantly expressed in retrovirus-induced hematological tumors, but limited attention has been directed towards elucidating the role of FLI1 in epithelial-derived cancers. Using data mining, we show that loss of FLI1 expression is associated with shorter survival and more aggressive phenotypes of breast cancer. Gain and loss of function cellular studies indicate the inhibitory effect of FLI1 expression on cellular growth, migration, and invasion. Using Fli1 mutant mice and both a transgenic murine breast cancer model and an orthotopic injection of syngeneic tumor cells indicates that reduced Fli1 contributes to accelerated tumor growth. Global expression analysis and RNA-Seq data from an invasive human breast cancer cell line with over expression of either FLI1 and another ETS gene, PDEF, shows changes in several cellular pathways associated with cancer, such as the cytokine-cytokine receptor interaction and PI3K-Akt signaling pathways. This study demonstrates a novel role for FLI1 in epithelial cells. In addition, these results reveal that FLI1 down-regulation in breast cancer may promote tumor progression.
doi:10.1016/j.neo.2014.08.007
PMCID: PMC4212256  PMID: 25379017
Ad-FLI1, Ad-GFP-FLI1; EMT, Epithelial-mesenchymal transition; ER, Estrogen receptor; FLI1, Friend leukemia virus integration 1; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; GEO, Gene Expression Omnibus; GOBO, Gene expression-based Outcome for Breast cancer Online; IDC, Invasive ductal carcinoma; IHC, Immunohistochemistry; ILC, Invasive lobular carcinoma; N, Normal Breast Tissue; PDEF, Prostate-derived ETS factor; PyVT, FVB/N-Tg(MMTV-PyVT)634Mul/J; Rb, Retinoblastoma; T, Tumor; uPA, Urokinase plasminogen activator
11.  Phenotyping structural abnormalities in mouse embryos using high-resolution episcopic microscopy 
Disease Models & Mechanisms  2014;7(10):1143-1152.
The arrival of simple and reliable methods for 3D imaging of mouse embryos has opened the possibility of analysing normal and abnormal development in a far more systematic and comprehensive manner than has hitherto been possible. This will not only help to extend our understanding of normal tissue and organ development but, by applying the same approach to embryos from genetically modified mouse lines, such imaging studies could also transform our knowledge of gene function in embryogenesis and the aetiology of developmental disorders. The International Mouse Phenotyping Consortium is coordinating efforts to phenotype single gene knockouts covering the entire mouse genome, including characterising developmental defects for those knockout lines that prove to be embryonic lethal. Here, we present a pilot study of 34 such lines, utilising high-resolution episcopic microscopy (HREM) for comprehensive 2D and 3D imaging of homozygous null embryos and their wild-type littermates. We present a simple phenotyping protocol that has been developed to take advantage of the high-resolution images obtained by HREM and that can be used to score tissue and organ abnormalities in a reliable manner. Using this approach with embryos at embryonic day 14.5, we show the wide range of structural abnormalities that are likely to be detected in such studies and the variability in phenotypes between sibling homozygous null embryos.
doi:10.1242/dmm.016337
PMCID: PMC4174525  PMID: 25256713
Phenotype screen; HREM; Imaging; 3D; Episcopic
12.  Matrix-insensitive protein assays push the limits of biosensors in medicine 
Nature medicine  2009;15(11):1327-1332.
Advances in biosensor technologies for in vitro diagnostics have the potential to transform the practice of medicine. Despite considerable work in the biosensor field, there is still no general sensing platform that can be ubiquitously applied to detect the constellation of biomolecules in diverse clinical samples (for example, serum, urine, cell lysates or saliva) with high sensitivity and large linear dynamic range. A major limitation confounding other technologies is signal distortion that occurs in various matrices due to heterogeneity in ionic strength, pH, temperature and autofluorescence. Here we present a magnetic nanosensor technology that is matrix insensitive yet still capable of rapid, multiplex protein detection with resolution down to attomolar concentrations and extensive linear dynamic range. The matrix insensitivity of our platform to various media demonstrates that our magnetic nanosensor technology can be directly applied to a variety of settings such as molecular biology, clinical diagnostics and biodefense.
doi:10.1038/nm.2032
PMCID: PMC4165514  PMID: 19820717
13.  KAT6A, a Chromatin Modifier from the 8p11-p12 Amplicon is a Candidate Oncogene in Luminal Breast Cancer 
Neoplasia (New York, N.Y.)  2014;16(8):644-655.
The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.
doi:10.1016/j.neo.2014.07.007
PMCID: PMC4234874  PMID: 25220592
14.  Much of late life cognitive decline is not due to common neurodegenerative pathologies 
Annals of neurology  2013;74(3):10.1002/ana.23964.
Objective
The pathologic indices of Alzheimer's disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.
Methods
856 deceased participants from two longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer's pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (i.e., non-linear decline).
Results
Cognition declined a mean of about 0.11 unit per year (estimate=−0.109, SE=0.004, p<0.001) with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE=0.112, p<0.001). In separate analyses, global Alzheimer's pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2% and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline and the majority remained unexplained. Further, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for a less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.
Interpretation
The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.
doi:10.1002/ana.23964
PMCID: PMC3845973  PMID: 23798485
15.  Cognitive decline impairs financial and health literacy among community-based older persons without dementia 
Psychology and aging  2013;28(3):614-624.
Literacy is an important determinant of health and well-being across the lifespan but is critical in aging, when many influential health and financial decisions are made. Prior studies suggest that older persons exhibit lower literacy than younger persons, particularly in the domains of financial and health literacy, but the reasons why remain unknown. The objectives of this study were to: a) examine pathways linking diverse resources (i.e., education, word knowledge, cognitive function, and decision making style) to health and financial literacy among older persons and determine the extent to which the relation of age with literacy represents a direct effect versus an indirect effect due to decrements in specific cognitive functions (i.e., executive functions and episodic memory), and b) test the hypothesis that declines in executive function and episodic memory are associated with lower literacy among older persons without dementia. 645 community-based older persons without dementia underwent detailed assessments of diverse resources, including education, word knowledge, cognitive function (i.e., executive function, episodic memory) and decision making style (i.e., risk aversion), and completed a measure of literacy that included items similar to those assessed in the Health and Retirement Study, such as numeracy, financial concepts such as compound inflation and knowledge of stocks and bonds, and important health concepts such as understanding of drug risk and Medicare Part D. Path analysis revealed a strong effect of age on literacy, with about half of the effect of age on literacy due to decrements in executive functions and episodic memory. In addition, executive function had an indirect effect on literacy via decision making style (i.e., risk aversion), and education and word knowledge had independent effects on literacy. Finally, among (n=447) persons with repeated cognitive assessments available for up to 14 years, regression analysis supported the association of multiple resources with literacy; moreover, more rapid declines in executive function and episodic memory over an average of 6.4 years prior to the literacy assessment predicted lower literacy scores (p’s<0.02), but rate of decline in word knowledge did not. These findings suggest that diverse individual resources contribute to financial and health literacy and lower literacy in old age is partially due to declines in executive function and episodic memory.
doi:10.1037/a0033103
PMCID: PMC3778113  PMID: 23957225
16.  Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips† 
Lab on a chip  2014;14(1):78-88.
Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of “liquid biopsies” from cancer patients.
doi:10.1039/c3lc50580d
PMCID: PMC4144998  PMID: 23969419
17.  Evidence of mycobacterial disease in COPD patients with lung volume reduction surgery; the importance of histological assessment of specimens: a cohort study 
BMC Pulmonary Medicine  2014;14:124.
Background
Patients with COPD are at risk of non-tuberculous mycobacterial infection (NTM). This study examined the histology of lung tissue from COPD patients following lung volume reduction with particular focus on evidence of mycobacterial infection.
Methods
Retrospective histological study of 142 consecutive lung volume reduction surgical specimens (126 separate patients) at Royal Brompton Hospital between 2000 – 2013, with prospectively collected preoperative data on exacerbation rate, lung function and body mass index.
Results
92% of patients had at least one other histological diagnosis in addition to emphysema. 10% of specimens had histological evidence of mycobacterial infection, one with co-existent aspergilloma. Mycobacteria were only identified in those patients with granulomas that were necrotising. These patients had higher exacerbation rates, lower TLCO and FEV1.
Conclusion
A proportion of severe COPD patients will have evidence of mycobacterial infection despite lack of clinical and radiological suspicion. This may have implications for long-term management of these patients.
doi:10.1186/1471-2466-14-124
PMCID: PMC4125594  PMID: 25086862
COPD; Mycobacterium; Non tuberculous mycobacterium (NTM); Lung volume reduction surgery (LVRS)
18.  Life-span cognitive activity, neuropathologic burden, and cognitive aging 
Neurology  2013;81(4):314-321.
Objective:
To test the hypothesis that cognitive activity across the life span is related to late-life cognitive decline not linked to common neuropathologic disorders.
Methods:
On enrollment, older participants in a longitudinal clinical-pathologic cohort study rated late-life (i.e., current) and early-life participation in cognitively stimulating activities. After a mean of 5.8 years of annual cognitive function testing, 294 individuals had died and undergone neuropathologic examination. Chronic gross infarcts, chronic microscopic infarcts, and neocortical Lewy bodies were identified, and measures of β-amyloid burden and tau-positive tangle density in multiple brain regions were derived.
Results:
In a mixed-effects model adjusted for age at death, sex, education, gross and microscopic infarction, neocortical Lewy bodies, amyloid burden, and tangle density, more frequent late-life cognitive activity (estimate = 0.028, standard error [SE] = 0.008, p < 0.001) and early-life cognitive activity (estimate = 0.034, SE = 0.013, p = 0.008) were each associated with slower cognitive decline. The 2 measures together accounted for 14% of the residual variability in cognitive decline not related to neuropathologic burden. The early-life–activity association was attributable to cognitive activity in childhood (estimate = 0.027, SE = 0.012, p = 0.026) and middle age (estimate = 0.029, SE = 0.013, p = 0.025) but not young adulthood (estimate = −0.020, SE = 0.014, p = 0.163).
Conclusions:
More frequent cognitive activity across the life span has an association with slower late-life cognitive decline that is independent of common neuropathologic conditions, consistent with the cognitive reserve hypothesis.
doi:10.1212/WNL.0b013e31829c5e8a
PMCID: PMC3772831  PMID: 23825173
19.  Resistance to Infection, Early and Persistent Suppression of Simian Immunodeficiency Virus SIVmac251 Viremia, and Significant Reduction of Tissue Viral Burden after Mucosal Vaccination in Female Rhesus Macaques 
Journal of Virology  2014;88(1):212-224.
The efficacy of oral, intestinal, nasal, and vaginal vaccinations with DNA simian immunodeficiency virus (SIV)/interleukin-2 (IL-2)/IL-15, SIV Gag/Pol/Env recombinant modified vaccinia virus Ankara (rMVA), and AT-2 SIVmac239 inactivated particles was compared in rhesus macaques after low-dose vaginal challenge with SIVmac251. Intestinal immunization provided better protection from infection, as a significantly greater median number of challenges was necessary in this group than in the others. Oral and nasal vaccinations provided the most significant control of disease progression. Fifty percent of the orally and nasally vaccinated animals suppressed viremia to undetectable levels, while this occurred to a significantly lower degree in intestinally and vaginally vaccinated animals and in controls. Viremia remained undetectable after CD8+ T-cell depletion in seven vaccinated animals that had suppressed viremia after infection, and tissue analysis for SIV DNA and RNA was negative, a result consistent with a significant reduction of viral activity. Regardless of the route of vaccination, mucosal vaccinations prevented loss of CD4+ central memory and CD4+/α4β7+ T-cell populations and reduced immune activation to different degrees. None of the orally vaccinated animals and only one of the nasally vaccinated animals developed AIDS after 72 to 84 weeks of infection, when the trial was closed. The levels of anti-SIV gamma interferon-positive, CD4+, and CD8+ T cells at the time of first challenge inversely correlated with viremia and directly correlated with protection from infection and longer survival.
doi:10.1128/JVI.02523-13
PMCID: PMC3911749  PMID: 24155376
20.  Single-Step Selection of Bivalent Aptamers Validated by Comparison with SELEX Using High-Throughput Sequencing 
PLoS ONE  2014;9(6):e100572.
The identification of nucleic acid aptamers would be advanced if they could be obtained after fewer rounds of selection and amplification. In this paper the identification of bivalent aptamers for thrombin by SELEX and single-step selection are compared using next generation sequencing and motif finding informatics. Results show that similar aptamers are identified by both methods. This is significant because it shows that next generation sequencing and motif finding informatics have the potential to simplify the selection of aptamers by avoiding multiple rounds of enzymatic transcription and amplification.
doi:10.1371/journal.pone.0100572
PMCID: PMC4070925  PMID: 24963654
21.  Resilient Brain Aging: Characterization of Discordance between Alzheimer’s Disease Pathology and Cognition 
Current Alzheimer research  2013;10(8):844-851.
Background
Although it is now evident that normal cognition can occur despite significant AD pathology, few studies have attempted to characterize this discordance, or examine factors that may contribute to resilient brain aging in the setting of AD pathology.
Methods
More than 2,000 older persons underwent annual evaluation as part of participation in the Religious Orders Study or Rush Memory Aging Project. A total of 966 subjects who had brain autopsy and comprehensive cognitive testing proximate to death were analyzed. Resilience was quantified as a continuous measure using linear regression modeling, where global cognition was entered as a dependent variable and global pathology was an independent variable. Studentized residuals generated from the model represented the discordance between cognition and pathology, and served as measure of resilience. The relation of resilience index to known risk factors for AD and related variables was examined.
Results
Multivariate regression models that adjusted for demographic variables revealed significant associations for early life socioeconomic status, reading ability, APOE-ε4 status, and past cognitive activity. A stepwise regression model retained reading level (estimate = 0.10, SE = 0.02; p < 0.0001) and past cognitive activity (estimate = 0.27, SE = 0.09; p = 0.002), suggesting the potential mediating role of these variables for resilience.
Conclusions
The construct of resilient brain aging can provide a framework for quantifying the discordance between cognition and pathology, and help identify factors that may mediate this relationship.
PMCID: PMC4060425  PMID: 23919768
Cognitive activity; Neuropathology; Reading level; Reserve; Resilience
22.  Gut Microbiota in HIV Infection: Implication for Disease Progression and Management 
Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression.
doi:10.1155/2014/803185
PMCID: PMC4082943  PMID: 25024700
23.  The Influence of Cognitive Decline on Well Being in Old Age 
Psychology and aging  2013;28(2):304-313.
The study addressed the hypothesis that late life cognitive decline leads to loss of well being. Participants are older persons from the Rush Memory and Aging Project. Beginning in 2001, they underwent annual clinical evaluations that included detailed cognitive performance testing and a 10-item self report measure of purpose in life, an aspect of well being. Initial analyses involved 1,049 individuals who were without dementia at baseline and followed a mean of 5.0 years. The intercepts and slopes of global cognition and purpose were positively correlated and level of cognition at a given evaluation predicted level of purpose at the subsequent evaluation, consistent with the study hypothesis. Purpose also predicted subsequent cognition. These findings persisted in analyses that excluded mild cognitive impairment or controlled for time varying levels of depressive symptoms or disability. To see if cognitive decline’s correlation with purpose differed from its correlation with other aspects of well being, we conducted additional analyses on a subgroup of 560 persons without dementia who completed a multidimensional measure of well being once between 2008 and 2011. More rapid cognitive decline in the period preceding well being assessment (mean = 5.5 years, standard deviation = 2.8) was associated with lower level of nearly all aspects of well being (5 of 6 measures), but the extent of the association varied across well being dimensions and was stronger for purpose than for self acceptance and autonomy. The results support the hypothesis that cognitive aging leads to diminished well being, particularly aspects such as purpose in life that involve behavioral regulation.
doi:10.1037/a0031196
PMCID: PMC3692607  PMID: 23421323
well being; purpose in life; cognitive decline; longitudinal study
24.  Association of brain pathology with the progression of frailty in older adults 
Neurology  2013;80(22):2055-2061.
Objective:
We tested the hypothesis that brain pathology is associated with the rate of progression of physical frailty in older adults.
Methods:
A total of 791 older adults participating in the Religious Orders Study and Memory and Aging Project had annual clinical evaluations from which a previously established composite measure of physical frailty was derived and brain autopsy after death. A uniform neuropathologic examination included the assessment of macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, Alzheimer disease and Lewy body pathology, and nigral neuronal loss.
Results:
Mean follow-up before death was 6.4 years and age at death was 88.5 years. More than 95% of cases had evidence of one or more brain pathologies. In a linear mixed-effect model controlling for age, sex, and education, frailty increased at approximately 0.12 unit/year (estimate 0.117, SE 0.035, p < 0.001). The rate of progression of frailty was accelerated with increasing age (estimate 0.002, SE 0.001, p = 0.012). In separate models, the presence of macroinfarcts, Alzheimer disease and Lewy body pathology, and nigral neuronal loss was associated with a more rapid progression of frailty (all p values ≤0.010). When these 4 brain pathologies were considered together in a single model, Alzheimer disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of progression of frailty and accounted for more than 8% of the variance unexplained by demographic variables alone.
Conclusion:
The accumulation of common brain pathologies contributes to progressive physical frailty in old age.
doi:10.1212/WNL.0b013e318294b462
PMCID: PMC3716398  PMID: 23635961
25.  Rapid Characterization of Magnetic Moment of Cells for Magnetic Separation 
IEEE transactions on magnetics  2013;49(7):3434-3437.
NCI-H1650 lung cancer cell lines labeled with magnetic nanoparticles via the Epithelial Cell Adhesion Molecule (EpCAM) antigen were previously shown to be captured at high efficiencies by a microfabricated magnetic sifter. If fine control and optimization of the magnetic separation process is to be achieved, it is vital to be able to characterize the labeled cells’ magnetic moment rapidly. We have thus adapted a rapid prototyping method to obtain the saturation magnetic moment of these cells. This method utilizes a cross-correlation algorithm to analyze the cells’ motion in a simple fluidic channel to obtain their magnetophoretic velocity, and is effective even when the magnetic moments of cells are small. This rapid characterization is proven useful in optimizing our microfabricated magnetic sifter procedures for magnetic cell capture.
doi:10.1109/TMAG.2013.2245310
PMCID: PMC3996843  PMID: 24771946
Cell separation; magnetic devices; magnetic microspheres; magnetic nanoparticles; magnetic separation

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