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1.  B.A.I.L.A. - A Latin dance randomized controlled trial for older Spanish-speaking Latinos: Rationale, design, and methods 
Contemporary clinical trials  2014;38(2):397-408.
Physical activity (PA) has documented health benefits, but older Latinos are less likely to engage in leisure time PA than older non-Latino whites. Dance holds promise as a culturally appropriate form of PA that challenges individuals physically and cognitively. This paper describes a randomized controlled trial that will test the efficacy of BAILAMOS©, a 4-month Latin dance program followed by a 4-month maintenance program, for improving lifestyle PA and health outcomes. Older adults (n = 332), aged 55+, Latino/Hispanic, Spanish speaking, with low PA levels, and at risk for disability will be randomized to one of two programs, a dance program or health education control group. BAILAMOS© is a 4-month program that meets two times per week for one hour per session. Dance sessions focus on instruction, including four styles of dance, and couples dancing. Bi-monthly “Fiestas de Baile” (dance parties) are also included, in which participants dance and practice what they have learned.. Monthly 1-hour discussion sessions utilize a Social Cognitive framework and focus on knowledge, social support, and self-efficacy to increase lifestyle PA. The health education control group will meet one time per week for two hours per session. Primary outcomes including PA changes and secondary outcomes including self-efficacy, physical function, cognitive function, and disability will be assessed at baseline, 4, and 8 months. It is hypothesized that PA, self-efficacy, physical function, cognitive function, and functional limitations and disability scores will be significantly better in the BAILAMOS© group at 4 and 8 months compared to the control group.
doi:10.1016/j.cct.2014.06.012
PMCID: PMC4123962  PMID: 24969395
Physical activity; Latin Dance; Latino; Aging; Older adults
2.  High performance wash-free magnetic bioassays through microfluidically enhanced particle specificity 
Scientific Reports  2015;5:11693.
Magnetic biosensors have emerged as a sensitive and versatile platform for high performance medical diagnostics. These magnetic biosensors require well-tailored magnetic particles as detection probes, which need to give rise to a large and specific biological signal while showing very low nonspecific binding. This is especially important in wash-free bioassay protocols, which do not require removal of particles before measurement, often a necessity in point of care diagnostics. Here we show that magnetic interactions between magnetic particles and magnetized sensors dramatically impact particle transport and magnetic adhesion to the sensor surfaces. We investigate the dynamics of magnetic particles’ biomolecular binding and magnetic adhesion to the sensor surface using microfluidic experiments. We elucidate how flow forces can inhibit magnetic adhesion, greatly diminishing or even eliminating nonspecific signals in wash-free magnetic bioassays, and enhancing signal to noise ratios by several orders of magnitude. Our method is useful for selecting and optimizing magnetic particles for a wide range of magnetic sensor platforms.
doi:10.1038/srep11693
PMCID: PMC4485157  PMID: 26123868
3.  Is Model Fitting Necessary for Model-Based fMRI? 
PLoS Computational Biology  2015;11(6):e1004237.
Model-based analysis of fMRI data is an important tool for investigating the computational role of different brain regions. With this method, theoretical models of behavior can be leveraged to find the brain structures underlying variables from specific algorithms, such as prediction errors in reinforcement learning. One potential weakness with this approach is that models often have free parameters and thus the results of the analysis may depend on how these free parameters are set. In this work we asked whether this hypothetical weakness is a problem in practice. We first developed general closed-form expressions for the relationship between results of fMRI analyses using different regressors, e.g., one corresponding to the true process underlying the measured data and one a model-derived approximation of the true generative regressor. Then, as a specific test case, we examined the sensitivity of model-based fMRI to the learning rate parameter in reinforcement learning, both in theory and in two previously-published datasets. We found that even gross errors in the learning rate lead to only minute changes in the neural results. Our findings thus suggest that precise model fitting is not always necessary for model-based fMRI. They also highlight the difficulty in using fMRI data for arbitrating between different models or model parameters. While these specific results pertain only to the effect of learning rate in simple reinforcement learning models, we provide a template for testing for effects of different parameters in other models.
Author Summary
In recent years, model-based fMRI has emerged as a powerful technique in psychology and neuroscience. With this method, computational models of behavior can be leveraged to identify where, whether and how different algorithms are implemented in the brain. Yet this approach seems to have an Achilles heel in that the models frequently have free parameters, and errors in setting these parameters could lead to errors in interpretation of the data. Here we asked whether this potential weakness, in theory, is an actual weakness in practice. In particular, we tested whether errors in estimating participants’ learning rate in a trial-and-error reinforcement learning setting would have adverse effects on identifying the neural substrates of the learning process. Amazingly, it turns out that even gross errors in the learning rate lead to only minute changes in the neural results. The good news is that precise identification of free parameters is not always necessary; the corollary bad news is that it may be harder to identify the precise computational roles of different brain areas than we had previously appreciated. Based on our analytical results, we offer suggestions for designing experiments that maximize or minimize sensitivity to model parameters, as needed.
doi:10.1371/journal.pcbi.1004237
PMCID: PMC4472514  PMID: 26086934
4.  Prognostic factors for clinical failure of exacerbations in elderly outpatients with moderate-to-severe COPD 
Background
Acute exacerbations represent a significant burden for patients with moderate-to-severe chronic obstructive pulmonary disease. Each exacerbation episode is frequently associated with a lengthy recovery and impaired quality of life. Prognostic factors for outpatients that may predict poor outcome after treatment with antibiotics recommended in the guidelines, are not fully understood. We aimed to identify pretherapy factors predictive of clinical failure in elderly (≥60 years old) outpatients with acute Anthonisen type 1 exacerbations.
Trial registration
NCT00656747.
Methods
Based on the moxifloxacin in AECOPDs (acute exacerbations of chronic obstructive pulmonary disease) trial (MAESTRAL) database, this study evaluated pretherapy demographic, clinical, sputum bacteriological factors using multivariate logistic regression analysis, with internal validation by bootstrap replicates, to investigate their possible association with clinical failure at end of therapy (EOT) and 8 weeks posttherapy.
Results
The analyses found that the independent factors predicting clinical failure at EOT were more frequent exacerbations, increased respiratory rate and lower body temperature at exacerbation, treatment with long-acting anticholinergic drugs, and in vitro bacterial resistance to study drug. The independent factors predicting poor outcome at 8 weeks posttherapy included wheezing at preexacerbation, mild or moderate (vs extreme) sleep disturbances, lower body temperature at exacerbation, forced expiratory volume in 1 second <30%, lower body mass index, concomitant systemic corticosteroids for the current exacerbation, maintenance long-acting β2-agonist and long-acting anticholinergic treatments, and positive sputum culture at EOT.
Conclusion
Several bacteriological, historical, treatment-related factors were identified as predictors of early (EOT) and later (8 weeks posttherapy) clinical failure in this older outpatient population with moderate-to-severe chronic obstructive pulmonary disease. These patients should be closely monitored and sputum cultures considered before and after treatment.
doi:10.2147/COPD.S80926
PMCID: PMC4459615  PMID: 26082623
AECOPD; clinical failure; prognostic factor; long-term outcome; poor outcome
5.  Biomechanical Properties of the Skin in Cutis Laxa 
doi:10.1038/jid.2014.224
PMCID: PMC4199921  PMID: 24844858
extracellular matrix; elastic tissue; human genetics; inborn genetic diseases; diagnostic techniques and procedures
6.  Cognitive Aging and Rate of Hospitalization in an Urban Population of Older People 
Background.
The association of age-related cognitive change with hospitalization is not well understood.
Methods.
At 3-year intervals for a mean of 8.7 years, 2,273 older residents of a geographically defined urban community underwent cognitive testing from which a global measure was derived. Hospitalization data were obtained from Part A Medicare beneficiary records. The association of level of cognitive function and rate of cognitive decline in each 3-year interval with subsequent rate of hospitalization was assessed using mixed-effects count regression models.
Results.
There were 9,091 hospitalizations involving 1,810 of the 2,273 individuals in the cohort (79.6%). Rate of hospitalization increased by 9.7% (95% confidence interval [CI]: 7.2, 12.3) with each additional study year; by 32.7% (95% CI: 26.8, 38.0) for each 1 point lower on the global cognitive measure at the beginning of an observation interval; and by 24.3% (95% CI: 16.6, 32.6) for each 1-point decrease in the global cognitive measure during the previous observation period. These associations persisted after adjustment for comorbidities and exclusion of those with a Mini-Mental State Examination score less than 26.
Conclusion.
Individual differences in trajectories of cognitive aging are associated with subsequent risk of hospitalization.
doi:10.1093/gerona/glt145
PMCID: PMC3968825  PMID: 24115773
Cognitive aging; Epidemiology; Hospital related; Public health.
7.  Natural History of Anal Human Papillomavirus Infection in Heterosexual Women and Risks Associated With Persistence 
Anal human papillomavirus (HPV) 16 infections were more likely to persist than other high-risk HPV types, and sexual behaviors were strongly associated with its persistence. As HPV-16 is responsible for 90% of anal cancers, prevention should include education around sexual practices.
Background. Anal cancer is more common in women than in men, yet little is known about the natural history of human papillomavirus (HPV) in women. The objective was to examine the natural history of anal HPV in heterosexual women.
Methods. Young women participating in an HPV cohort study were seen at 4-month intervals for cervical and anal HPV testing. Time to clearance was estimated using the Kaplan-Meier approach; risks for persistence were assessed using Cox regression models.
Results. Seventy-five women (mean age, 23.5 ± 4.1 years) who tested positive for anal HPV were followed for a mean of 84.5 ± 44.9 months. By 3 years, 82.5% of anal non-16 high-risk (HR) HPV, 82.6% of low-risk (LR) HPV, and 76.2% of HPV-16 infections had cleared. By 3 years, only 36.4% of women had become negative for all HPV types. In the multivariable model, concurrent cervical HPV-16 (P < .001), weekly alcohol use (P = .015), anal touching during sex (P = .045), recent anal sex (P = .04), and no condom use during anal sex (P = .04) were associated with HPV-16 persistence. Greater number of new sex partners (P = .024) and condom use during vaginal sex (P = .003) were associated with clearance. Similar associations were found for clearance in all HR-HPV infections. Only concomitant cervical HPV was associated with non-16 HR-HPV persistence.
Conclusions. The majority of anal HPV infections cleared within 3 years. HPV-16 infections were slower to clear than other HR-HPV infections, consistent with its role in anal cancer. Specific sexual behaviors were associated with persistence, suggesting that education and behavioral interventions may decrease persistence.
doi:10.1093/cid/cit947
PMCID: PMC3935503  PMID: 24368624
anal; human papillomavirus infection; persistence; women
8.  Harm Avoidance and Cerebral Infarction 
Neuropsychology  2013;28(2):305-311.
Objective
Harm avoidance, a trait indicative of behavioral inhibition, is associated with disability and dementia in old age, but the basis of these associations is uncertain. We test the hypothesis that higher level of harm avoidance is associated with increased likelihood of cerebral infarction.
Methods
Older persons without dementia completed a standard measure of harm avoidance. During a mean of 3.5 years of follow-up, 257 (of 1,082) individuals died of whom 206 (80%) underwent brain autopsy. Number of chronic cerebral infarcts (microscopic plus gross; expressed as 0,1, or >1) was assessed on neuropathologic examination, completed in 192 individuals at the time of analyses.
Results
On postmortem examination, chronic cerebral infarcts were found in 89 (42 with 1, 47 with >1). Higher harm avoidance was associated with higher likelihood of infarcts (odds ratio = 1.083, 95% confidence interval 1.040–1.128). A moderately high level of the trait (score=17, 75th percentile) was associated with a 2.4-fold increase in the likelihood of infarction compared to a moderately low level of the trait (score = 6, 25th percentile). These associations persisted in models that controlled for other cardiovascular risk factors.
Conclusion
Higher level of the harm avoidance trait may be a risk factor for cerebral infarction.
doi:10.1037/neu0000022
PMCID: PMC4061767  PMID: 24364391
harm avoidance; clinical-pathologic study; microinfarcts; cerebral lacunes
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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)

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